FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response.

In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFß1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues. SIGNIFICANCE: These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.

The effects of flumazenil on ventilatory and recovery characteristics in horses following midazolam-ketamine induction and isoflurane anaesthesia.

BACKGROUND: Flumazenil antagonises the actions of benzodiazepines. There has been no prior research specifically investigating this anaesthetic reversal agent for horses. OBJECTIVES: To determine the effects of flumazenil administration in horses on (a) ventilatory parameters after midazolam-ketamine induction and maintenance with isoflurane in oxygen and on (b) the characteristics of recovery from general anaesthesia. STUDY DESIGN: Blinded, randomised, crossover experiment. METHODS: Six horses were randomly assigned to receive high-dose flumazenil (Fhigh , 20 µg/kg), low-dose flumazenil (Flow , 10 µg/kg) and saline (control). Cardioventilatory parameters were monitored. After 90 minutes of isoflurane anaesthesia, a bolus of Fhigh , Flow or saline was administered i.v. The horses were recovered using head and tail rope assistance. The times to first movement, to achievement of sternal recumbency, to the first attempt to stand and the total recovery time were determined. The recovery quality was evaluated using a 115-point recovery scoring system. The cardioventilatory parameters and recovery times were analysed using mixed-effects regression analyses. Intraclass correlation (ICC) analysis was used to evaluate the recovery scores. A Mann-Whitney U test assessed the relationship between recovery score and flumazenil administration. RESULTS: A significant difference with flumazenil administration was found for SpO2 , mean arterial pressure, I:E ratio, minute volume of ventilation (MV) and peak inspiratory pressure. There was a significant difference with flumazenil administration for the time to sternal recumbency, the time to the first attempt to rise and the total recovery time. There was no significant difference in total recovery score with flumazenil administration. MAIN LIMITATIONS: Plasma levels of midazolam and flumazenil were not obtained. CONCLUSIONS: Flumazenil has a dose-dependent effect on MV and recovery time, which may make it useful in cases for which a prolonged anaesthetic recovery is undesirable.

Changes in Arterial Blood Pressure and Oxygen Tension as a Result of Hoisting in Isoflurane Anesthetized Healthy Adult Horses.

Background: In anesthetized adult horses, changes in recumbency can influence the cardiovascular system but how arterial blood pressures and oxygen tension change in isoflurane anesthetized animals as a direct result of hoisting has not been investigated. Objective: To evaluate effects of hoisting on hemodynamic function and pulmonary gas exchange in isoflurane-anesthetized horses. Study Design: Prospective, experimental study. Methods: Six adult horses were anesthetized three times using isoflurane in pure oxygen (inspired fraction 0.9-1.0), and allowed breathing spontaneously in lateral recumbency. After 45 min horses were hoisted using a single hoist-hobble system for 5 min and returned into left lateral recumbency. Heart rate (HR), respiratory rate (RR), and systolic (SAP), diastolic (DAP), and mean arterial blood pressures (MAP) were measured every minute starting from 5 min before to 5 min after hoisting. Arterial blood gas samples were collected before, during, and after hoisting. Results: Significant changes in hemodynamic parameters and PaO2 but not PaCO2 were found between baseline recordings and measurements obtained during and early after hoisting. The MAP decreased within the 1st min of hoisting from a mean of 74 ± 17 mmHg at baseline to 57 ± 20 mmHg (p < 0.05). Thereafter, it rapidly recovered to baseline before continuing to rise to higher than baseline values and then remaining elevated for 5 min after horses were returned into lateral recumbency. Simultaneously, the HR increased by 6-9 beats per min during the initial 3 min of hoisting before returning close to baseline values (p < 0.05). The PaO2 decreased significantly from a mean of 324.9 ±137.0 mmHg at baseline to a mean of 141.3 ± 104.2 mmHg during hoisting (p < 0.001) without recovering any more to baseline values. Clinical significance: Hoisting an adult horse during or at the end of isoflurane anesthesia carries the risk of a precipitous, though short-lived (1-2 min), drop in arterial blood pressures and a persistent decrease in arterial oxygenation. While in systemically healthy animals the observed functional impairments were not life-threatening, they may be more severe in systemically compromised horses.Therefore, arterial blood pressures and oxygenation must be carefully monitored when hoisting sick equine patients during or at the end of inhalant anesthesia.

Pharmacokinetics and pharmacodynamics of midazolam following intravenous and intramuscular administration to sheep.

OBJECTIVE To determine the pharmacokinetic and pharmacodynamic effects of midazolam following IV and IM administration in sheep. ANIMALS 8 healthy adult rams. PROCEDURES Sheep were administered midazolam (0.5 mg/kg) by the IV route and then by the IM route 7 days later in a crossover study. Physiologic and behavioral variables were assessed and blood samples collected for determination of plasma midazolam and 1-hydroxymidazolam (primary midazolam metabolite) concentrations immediately before (baseline) and at predetermined times for 1,440 minutes after midazolam administration. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Following IV administration, midazolam was rapidly and extensively distributed and rapidly eliminated; mean ± SD apparent volume of distribution, elimination half-life, clearance, and area under the concentration-time curve were 838 ± 330 mL/kg, 0.79 ± 0.44 hours, 1,272 ± 310 mL/h/kg, and 423 ± 143 h·ng/mL, respectively. Following IM administration, midazolam was rapidly absorbed and bioavailability was high; mean ± SD maximum plasma concentration, time to maximum plasma concentration, area under the concentration-time curve, and bioavailability were 820 ± 268 ng/mL, 0.46 ± 0.26 hours, 1,396 ± 463 h·ng/mL, and 352 ± 148%, respectively. Respiratory rate was transiently decreased from baseline for 15 minutes after IV administration. Times to peak sedation and ataxia after IV administration were less than those after IM administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated midazolam was a suitable short-duration sedative for sheep, and IM administration may be a viable alternative when IV administration is not possible.