Dynamic oxygen assessment techniques enable determination of anesthesia's impact on tissue.

Tissue oxygenation is well understood to impact radiosensitivity, with reports demonstrating a significant effect of breathing condition and anesthesia type on tissue oxygenation levels and radiobiological response. However, the temporal kinetics of intracellular and extracellular oxygenation have never been quantified, on the timescale that may affect radiotherapy studies. C57BL/6 mice were anesthetized using isoflurane at various percentages or ketamine/xylazine (ket/xyl: 100/10 mg/kg) (N = 48). Skin pO2 was measured using Oxyphor PdG4 and tracked after anesthetization began. Oxyphor data was validated with relative measurements of intracellular oxygen via protoporphyrin IX (PpIX) delayed fluorescence (DF) imaging. Ex vivo localization of both PdG4 Oxyphor and PpIX were quantified. Under all isoflurane anesthesia conditions, leg skin pO2 levels significantly increased from 12-15 mmHg at the start of anesthesia induction (4-6 minutes) to 24-27 mmHg after 10 minutes (p < 0.05). Ketamine/xylazine anesthesia led to skin pO2 maintained at 15-16 mmHg throughout the 10-minute study period (p < 0.01). An increase of pO2 in mice breathing isoflurane was demonstrated with Oxyphor and PpIX DF, indicating similar intracellular and extracellular oxygenation. These findings demonstrate the importance of routine anesthesia administration, where consistency in the timing between induction and irradiation may be crucial to minimizing variability in radiation response.

Commissioning an ultra-high-dose-rate electron linac with end-to-end tests.

Objective. The FLASH effect can potentially be used to improve the therapeutic ratio of radiotherapy (RT) through delivery of Ultra-high-dose-rate (UHDR) irradiation. Research is actively being conducted to translate UHDR-RT and for this purpose the Mobetron is capable of producing electron beams at both UHDR and conventional dose rates for FLASH research and translation. This work presents commissioning of an UHDR Mobetron with end-to-end tests developed for preclinical research.Approach. UHDR electron beams were commissioned with an efficient approach utilizing a 3D-printed water tank and film to fully characterize beam characteristics and dependences on field size, pulse width (PW) and pulse repetition frequency (PRF). This commissioning data was used to implement a beam model using the GAMOS Monte Carlo toolkit for the preclinical research. Then, the workflow for preclinical FLASH irradiation was validated with end-to-end tests delivered to a 3D-printed mouse phantom with internal inhomogeneities.Main results.PDDs, profiles and output factors acquired with radiochromic films were precisely measured, with a PRF that showed little effect on the UHDR beam energy and spatial characteristics. Increasing PW reduced theDmaxand R50by 2.08 mmµs-1and 1.28 mmµs-1respectively. An end-to-end test of the preclinical research workflow showed that both profiles in head-foot and lateral directions were in good agreement with the MC calculations for the heterogeneous 3D printed mouse phantom with Gamma index above 93% for 2 mm/2% criteria, and 99% for 3 mm/3%.Significance. The UHDR Mobetron is a versatile tool for FLASH preclinical research and this comprehensive beam model and workflow was validated to meet the requirements for conducting translational FLASH research.

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.

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.

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.

High-energy open-fracture model with initial experience of fluorescence-guided bone perfusion assessment.

High-energy orthopedic injuries cause severe damage to soft tissues and are prone to infection and healing complications, making them a challenge to manage. Further research is facilitated by a clinically relevant animal model with commensurate fracture severity and soft-tissue damage, allowing evaluation of novel treatment options and techniques. Here we report a reproducible, robust, and clinically relevant animal model of high-energy trauma with extensive soft-tissue damage, based on compressed air-driven membrane rupture as the blast wave source. As proof-of-principle showing the reproducibility of the injury, we evaluate changes in tissue and bone perfusion for a range of different tibia fracture severities, using dynamic contrast-enhanced fluorescence imaging and microcomputed tomography. We demonstrate that fluorescence tracer temporal profiles for skin, femoral vein, fractured bone, and paw reflect the increasing impact of more powerful blasts causing a range of Gustilo grade I-III injuries. The maximum fluorescence intensity of distal tibial bone following 0.1 mg/kg intravenous indocyanine green injection decreased by 35% (p < 0.01), 75% (p < 0.001), and 87% (p < 0.001), following grade I, II, and III injuries, respectively, compared to uninjured bone. Other kinetic parameters of bone and soft tissue perfusion extracted from series of fluorescence images for each animal also showed an association with severity of trauma. In addition, the time-intensity profile of fluorescence showed marked differences in wash-in and wash-out patterns for different injury severities and anatomical locations. This reliable and realistic high-energy trauma model opens new research avenues to better understand infection and treatment strategies. Level of evidence: Level III; Case-control.

White matter hyperintensities and their associations with suicidality in psychiatrically hospitalized children and adolescents.

OBJECTIVE: Increasingly, researchers and clinicians are recognizing that there may be biological markers associated with increased risk of suicide. The objective of this study was to compare white matter hyperintensities in psychiatrically hospitalized children and youth with and without a history of suicide attempt while controlling for other variables. METHOD: White matter hyperintensities of 153 child and adolescent psychiatry inpatients were rated on T2-weighted magnetic resonance imaging scans using a modified Coffey scale. DSM-IV diagnosis, history of suicide attempt, and control variables such as gender, age, comorbid medical illnesses, developmental disorder, substance abuse, severity of mental illness, head injury, and possible cerebral hypoxia were obtained from discharge medical records. RESULTS: Within the unipolar depression group (n = 48), white matter hyperintensities were significantly associated with a higher prevalence of past suicide attempts (Fisher exact test, p =.03). Logistic regression analysis confirmed this relationship, indicating that none of the control variables confounded our results and suggesting a specificity of 0.94. CONCLUSIONS: This is the first report of an increased prevalence of white matter hyperintensities in children and youth with unipolar depression and a history of suicide attempt. Replication and expansion of our preliminary findings could be of great clinical interest.

Subanalysis of the location of white matter hyperintensities and their association with suicidality in children and youth.

Our previous research with psychiatrically hospitalized children and youth indicates that white matter hyperintensities (WMH) on T2-weighted MRI images are associated with a history of suicide attempt. This subanalysis of the specific locations of the WMH suggests that youth with deep WMH in the parietal lobe but not in the frontal lobe have a significantly higher prevalence of reported past suicide attempt.