Anesthetic Oxygen Use and Sex Are Critical Factors in the FLASH Sparing Effect.

Purpose: Ultra High Dose-Rate (UHDR) radiation has been reported to spare normal tissue, compared with Conventional Dose-Rate (CDR) radiation. However, important work remains to be done to improve the reproducibility of the FLASH effect. A better understanding of the biologic factors that modulate the FLASH effect may shed light on the mechanism of FLASH sparing. Here, we evaluated whether sex and/or the use of 100% oxygen as a carrier gas during irradiation contribute to the variability of the FLASH effect. Methods and Materials: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary postradiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female), skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: Neither supplemental oxygen nor sex affected time to ulceration in CDR irradiated mice. In the UHDR group, skin damage occured earlier in male and female mice that received 100% oxygen compared room air and female mice ulcerated sooner than male mice. However, there was no significant difference in time to ulceration between male and female UHDR mice that received room air. Oxygen measurements showed that tissue oxygenation was significantly higher when using 100% oxygen as the anesthesia carrier gas than when using room air, and female mice showed higher levels of tissue oxygenation than male mice under 100% oxygen. Conclusions: The skin FLASH sparing effect is significantly reduced when using oxygen during anesthesia rather than room air. FLASH sparing was also reduced in female mice compared to male mice. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

Electron beam response corrections for an ultra-high-dose-rate capable diode dosimeter.

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

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.

Rapid Switching of a C-Series Linear Accelerator Between Conventional and Ultrahigh-Dose-Rate Research Mode With Beamline Modifications and Output Stabilization.

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

First Monte Carlo beam model for ultra-high dose rate radiotherapy with a compact electron LINAC.

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

Biomarkers for predicting atrial fibrillation: An explorative sub-analysis of the randomised SCREEN-AF trial.

BACKGROUND: Atrial fibrillation (AF) is a common treatable risk factor for stroke. Screening for paroxysmal AF in general practice is difficult, but biomarkers might help improve screening strategies. OBJECTIVES: We investigated six blood biomarkers for predicting paroxysmal AF in general practice. METHODS: This was a pre-specified sub-study of the SCREEN-AF RCT done in Germany. Between 12/2017-03/2019, we enrolled ambulatory individuals aged 75 years or older with a history of hypertension but without known AF. Participants in the intervention group received active AF screening with a wearable patch, continuous ECG monitoring for 2x2 weeks and usual care in the control group. The primary endpoint was ECG-confirmed AF within six months after randomisation. High-sensitive Troponin I (hsTnI), brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), N-terminal pro atrial natriuretic peptide (NT-ANP), mid-regional pro atrial natriuretic peptide (MR-pro ANP) and C-reactive protein (CRP) plasma levels were investigated at randomisation for predicting AF within six months after randomisation. RESULTS: Blood samples were available for 291 of 301 (96.7%) participants, including 8 with AF (3%). Five biomarkers showed higher median results in AF-patients: BNP 78 vs. 41 ng/L (p = 0.012), NT-pro BNP 273 vs. 186 ng/L (p = 0.029), NT-proANP 4.4 vs. 3.5 nmol/L (p = 0.027), MR-pro ANP 164 vs. 125 pmol/L (p = 0.016) and hsTnI 7.4 vs. 3.9 ng/L (p = 0.012). CRP levels were not different between groups (2.8 vs 1.9 mg/L, p = 0.1706). CONCLUSION: Natriuretic peptide levels and hsTnI are higher in patients with AF than without and may help select patients for AF screening, but larger trials are needed.

BNP, NT-pro BNP, NT-ANP and MR-pro ANP and hsTnI levels are higher in patients with AF than without AFWith a sensitivity at 100%, BNP had the highest specificity of 60% (BNP level 50.1ng/L), followed by NT-pro BNP with a specificity of 53% (179ng/l).

Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial.

Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 µV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Imaging and characterization of optical emission fromex vivotissue during conventional and UHDR PBS proton therapy.

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

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Anesthetic oxygen use and sex are critical factors in the FLASH sparing effect.

Introduction: Ultra-high dose-rate (UHDR) radiation has been reported to spare normal tissue compared to conventional dose-rate (CDR) radiation. However, reproducibility of the FLASH effect remains challenging due to varying dose ranges, radiation beam structure, and in-vivo endpoints. A better understanding of these inconsistencies may shed light on the mechanism of FLASH sparing. Here, we evaluate whether sex and/or use of 100% oxygen as carrier gas during irradiation contribute to the variability of the FLASH effect. Methods: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary post-radiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female) skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: In the UHDR group, time to ulceration was significantly shorter in mice that received 100% oxygen compared to room air, and amongst them female mice ulcerated sooner compared to males. However, no significant difference was observed between male and female UHDR mice that received room air. Oxygen measurements showed significantly higher tissue oxygenation using 100% oxygen as the anesthesia carrier gas compared to room air, and female mice showed higher levels of tissue oxygenation compared to males under 100% oxygen. Conclusion: The FLASH sparing effect is significantly reduced using oxygen during anesthesia compared to room air. The FLASH sparing was significantly lower in female mice compared to males. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

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.

Mean dose rate in ultra-high dose rate electron irradiation is a significant predictor for O2consumption and H2O2yield.

Objective. The objective of this study was to investigate the impact of mean and instantaneous dose rates on the production of reactive oxygen species (ROS) during ultra-high dose rate (UHDR) radiotherapy. The study aimed to determine whether either dose rate type plays a role in driving the FLASH effect, a phenomenon where UHDR radiotherapy reduces damage to normal tissues while maintaining tumor control.Approach. Assays of hydrogen peroxide (H2O2) production and oxygen consumption (ΔpO2) were conducted using UHDR electron irradiation. Aqueous solutions of 4% albumin were utilized as the experimental medium. The study compared the effects of varying mean dose rates and instantaneous dose rates on ROS yields. Instantaneous dose rate was varied by changing the source-to-surface distance (SSD), resulting in instantaneous dose rates ranging from 102to 106Gy s-1. Mean dose rate was manipulated by altering the pulse frequency of the linear accelerator (linac) and by changing the SSD, ranging from 0.14 to 1500 Gy s-1.Main results. The study found that both ΔH2O2and ΔpO2decreased as the mean dose rate increased. Multivariate analysis indicated that instantaneous dose rates also contributed to this effect. The variation in ΔpO2was dependent on the initial oxygen concentration in the solution. Based on the analysis of dose rate variation, the study estimated that 7.51 moles of H2O2were produced for every mole of O2consumed.Significance. The results highlight the significance of mean dose rate as a predictor of ROS production during UHDR radiotherapy. As the mean dose rate increased, there was a decrease in oxygen consumption and in H2O2production. These findings have implications for understanding the FLASH effect and its potential optimization. The study sheds light on the role of dose rate parameters and their impact on radiochemical outcomes, contributing to the advancement of UHDR radiotherapy techniques.

Characterization of a diode dosimeter for UHDR FLASH radiotherapy.

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

Education case report: CAMPEP Medical Physics PhD education program within Engineering.

Medical physics doctoral programs have large variations in organization, administration and financing. Blending a medical physics stream into an engineering graduate program has advantages of pre-existing financial and educational infrastructures. A case study of the accredited program at Dartmouth was carried out, analyzing operational, financial, educational and outcome features. The support structures provided by each institutional partner were outlined, including engineering school, graduate school, and radiation oncology. The initiatives undertaken by founding faculty were reviewed, along with allocated resources, financial model, and peripheral entrepreneurship activities, each with quantitative outcome metrics. Currently 14 PhD students are enrolled, supported by 22 faculty across both engineering and clinical departments. The total peer-reviewed publications are ≈75/year, while the conventional medical physics fraction of this is about 14/year. Following program formation, a significant rise was seen in jointly published papers between engineering and medical physics faculty, up from 5.6 to 13.3 papers/year, with students publishing an average of 11.3/person with 5.7/person as first author. Student support was predominantly via federal grants, with a stable $5.5million/year, using about $610K/year supporting student stipends and tuition. First year funding, recruiting and staff support were via engineering school. Faculty teaching effort was supported by agreement with each home department, and student services were provided by engineering and graduate schools. Student outcomes were exceptional, with high numbers of presentations, awards, and residency placements at research universities. The lack of financial and student support in medical physics can be mitigated by this hybrid design of blending medical physics doctoral students into an engineering graduate program, providing complementary strengths. Future growth in medical physics programs might consider following this pathway, strengthening research collaborations for clinical physics and engineering faculty, as long as there is vested commitment to teach by the faculty and department leadership.

Ninety-Day Stroke or Transient Ischemic Attack Recurrence in Patients Prescribed Anticoagulation in the Emergency Department With Atrial Fibrillation and a New Transient Ischemic Attack or Minor Stroke.

Background For patients with atrial fibrillation seen in the emergency department (ED) following a transient ischemic attack (TIA) or minor stroke, the impact of initiating oral anticoagulation immediately rather than deferring the decision to outpatient follow-up is unknown. Methods and Results We conducted a planned secondary data analysis of a prospective cohort of 11 507 adults in 13 Canadian EDs between 2006 and 2018. Patients were eligible if they were aged 18 years or older, with a final diagnosis of TIA or minor stroke with previously documented or newly diagnosed atrial fibrillation. The primary outcome was subsequent stroke, recurrent TIA, or all-cause mortality within 90 days of the index TIA diagnosis. Secondary outcomes included stroke, recurrent TIA, or death and rates of major bleeding. Of 11 507 subjects with TIA/minor stroke, atrial fibrillation was identified in 11.2% (1286, mean age, 77.3 [SD 11.1] years, 52.4% male). Over half (699; 54.4%) were already taking anticoagulation, 89 (6.9%) were newly prescribed anticoagulation in the ED. By 90 days, 4.0% of the atrial fibrillation cohort had experienced a subsequent stroke, 6.5% subsequent TIA, and 2.6% died. Results of a multivariable logistic regression indicate no association between prescribed anticoagulation in the ED and these 90-day outcomes (composite odds ratio, 1.37 [95% CI, 0.74-2.52]). Major bleeding was found in 5 patients, none of whom were in the ED-initiated anticoagulation group. Conclusions Initiating oral anticoagulation in the ED following new TIA was not associated with lower recurrence rates of neurovascular events or all-cause mortality in patients with atrial fibrillation.

Prolonged cardiac monitoring for stroke prevention: A systematic review and meta-analysis of randomized-controlled clinical trials.

Introduction: Prolonged cardiac monitoring (PCM) substantially improves the detection of subclinical atrial fibrillation (AF) among patients with history of ischemic stroke (IS), leading to prompt initiation of anticoagulants. However, whether PCM may lead to IS prevention remains equivocal. Patients and methods: In this systematic review and meta-analysis, randomized-controlled clinical trials (RCTs) reporting IS rates among patients with known cardiovascular risk factors, including but not limited to history of IS, who received PCM for more than 7 days versus more conservative cardiac rhythm monitoring methods were pooled. Results: Seven RCTs were included comprising a total of 9048 patients with at least one known cardiovascular risk factor that underwent cardiac rhythm monitoring. PCM was associated with reduction of IS occurrence compared to conventional monitoring (Risk Ratio: 0.76; 95% CI: 0.59-0.96; I 2 = 0%). This association was also significant in the subgroup of RCTs investigating implantable cardiac monitoring (Risk Ratio: 0.75; 95% CI: 0.58-0.97; I 2 = 0%). However, when RCTs assessing PCM in both primary and secondary prevention settings were excluded or when RCTs investigating PCM with a duration of 7 days or less were included, the association between PCM and reduction of IS did not retain its statistical significance. Regarding the secondary outcomes, PCM was related to higher likelihood for AF detection and anticoagulant initiation. No association was documented between PCM and IS/transient ischemic attack occurrence, all-cause mortality, intracranial hemorrhage, or major bleeding. Conclusion: PCM may represent an effective stroke prevention strategy in selected patients. Additional RCTs are warranted to validate the robustness of the reported associations.

Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps.

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.

Color-resolved Cherenkov imaging allows for differential signal detection in blood and melanin content.

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

Prospective Validation of Computed Tomography to Identify Patients at High Risk for Stroke After Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Computed tomography (CT) findings of acute and chronic ischemia are associated with subsequent stroke risk in patients with transient ischemic attack. We sought to validate these associations in a large prospective cohort of patients with transient ischemic attack or minor stroke. METHODS: This prospective cohort study enrolled emergency department patients from 13 hospitals with transient ischemic attack who had CT imaging. Primary outcome was stroke within 90 days. Secondary outcomes were stroke within 2 or 7 days. CT findings were abstracted from radiology reports and classified for the presence of acute ischemia, chronic ischemia, or microangiopathy. Multivariable logistic regression was used to test associations with primary and secondary end points. RESULTS: From 8670 prospectively enrolled patients between May 2010 and May 2017, 8382 had a CT within 24 hours. From this total population, 4547 (54%) patients had evidence of acute ischemia, chronic ischemia, or microangiopathy on CT, of whom 175 had a subsequent stroke within 90 days (3.8% subsequent stroke rate; adjusted odds ratio [aOR], 2.33 [95% CI, 1.62-3.36]). This was in comparison to those with CT imaging without ischemia. Findings associated with an increased risk of stroke at 90 days were isolated acute ischemia (6.0%; aOR, 2.42 [95% CI, 1.03-5.66]), acute ischemia with microangiopathy (10.7%; aOR, 3.34 [95% CI, 1.57-7.14]), chronic ischemia with microangiopathy (5.2%; aOR, 1.83 [95% CI, 1.34-2.50]), and acute ischemia with chronic ischemia and microangiopathy (10.9%; aOR, 3.49 [95% CI, 1.54-7.91]). Acute ischemia with chronic ischemia and microangiopathy were most strongly associated with subsequent stroke within 2 days (aOR, 4.36 [95% CI, 1.31-14.54]) and 7 days (aOR, 4.50 [95% CI, 1.73-11.69]). CONCLUSIONS: In patients with transient ischemic attack or minor stroke, CT evidence of acute ischemia with chronic ischemia or microangiopathy significantly increases the risk of subsequent stroke within 90 days of index visit. The combination of all 3 findings results in the greatest early risk.