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Purpose: Treatment planning for CyberKnife (CK) (Accuray, USA) can be performed with Precision (Accuray, USA) or RayStation (RS) (RaySearch Laboratories, Sweden) treatment planning systems (TPS). RaySearch recently released a new version of the CK module in RS 12A. The objective of the study was to compare plan quality between RS 12A and Precision., Methods: Fifty nine plans were optimized with both TPS and compared; 39 were for brain metastases and 20 were for vertebral metastases. To avoid bias in plan comparison, Precision plans were recomputed in RS with the dose algorithm and beam model of RS, and then compared to RS plans. The comparison was divided into 3 parts in order to reflect the potential of RS and the differences with Precision, in terms of technical aspects of delivery efficiency and dose distribution. We compared the dose to the target and to the organs at risk (OAR), the conformity index (CI), the gradient, as well as the number of monitor units (MU), and the number of beams and nodes. Finally, a global plan quality index (PQI) was calculated., Results: RS plans showed an equivalent target coverage for brain metastases but worse for vertebrae. OAR sparing was improved in RS but with a lower CI compared to Precision. Using an appropriate planning methodology in RS, plans with comparable quality to Precision could be obtained, but at the cost of a longer optimization time. The PQI obtained with RS was better than Precision, except for some brain cases., Conclusion: RS is an adequate alternative for CK planning as it is possible to obtain plan quality comparable to Precision. However, the optimization time is longer compared to Precision and more attention must be paid to the choice of the initial conditions in terms of the number of beams and nodes., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Purpose: We describe a multicenter cross validation of ultra-high dose rate (UHDR) (>= 40 Gy/s) irradiation in order to bring a dosimetric consensus in absorbed dose to water. UHDR refers to dose rates over 100-1000 times those of conventional clinical beams. UHDR irradiations have been a topic of intense investigation as they have been reported to induce the FLASH effect in which normal tissues exhibit reduced toxicity relative to conventional dose rates. The need to establish optimal beam parameters capable of achieving the in vivo FLASH effect has become paramount. It is therefore necessary to validate and replicate dosimetry across multiple sites conducting UHDR studies with distinct beam configurations and experimental set-ups., Materials and Methods: Using a custom cuboid phantom with a cylindrical cavity (5 mm diameter by 10.4 mm length) designed to contain three type of dosimeters (thermoluminescent dosimeters (TLDs), alanine pellets, and Gafchromic films), irradiations were conducted at expected doses of 7.5 to 16 Gy delivered at UHDR or conventional dose rates using various electron beams at the Radiation Oncology Departments of the CHUV in Lausanne, Switzerland and Stanford University, CA., Results: Data obtained between replicate experiments for all dosimeters were in excellent agreement (±3%). In general, films and TLDs were in closer agreement with each other, while alanine provided the closest match between the expected and measured dose, with certain caveats related to absolute reference dose., Conclusion: In conclusion, successful cross-validation of different electron beams operating under different energies and configurations lays the foundation for establishing dosimetric consensus for UHDR irradiation studies, and, if widely implemented, decrease uncertainty between different sites investigating the mechanistic basis of the FLASH effect., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

A patient with a cutaneous lymphoma was treated on the same day for 2 distinct tumors using a 15 Gy single electron dose given in a dose rate of 0.08 Gy/second versus 166 Gy/second. Comparing the two treatments, there was no difference for acute reactions, late effects at 2 years and tumor control., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: RaySearch (AB, Stockholm) has released a module for CyberKnife (CK) planning within its RayStation (RS) treatment planning system (TPS)., Purpose: To create and validate beam models of fixed, Iris, and multileaf collimators (MLC) of the CK M6 for Monte Carlo (MC) and collapsed cone (CC) algorithms in the RS TPS., Methods: Measurements needed for the creation of the beam models were performed in a water tank with a stereotactic PTW 60018 diode. Both CC and MC models were optimized in RS by minimizing the differences between the measured and computed profiles and percentage depth doses. The models were then validated by comparing dose from the plans created in RS with both single and multiple beams in different phantom conditions with the corresponding measured dose. Irregular field shapes and off-axis beams were also tested for the MLC. Validation measurements were performed using an A1SL ionization chamber, EBT3 Gafchromic films, and a PTW 1000 SRS detector. Finally, patient-specific QAs with gamma criteria of 3%/1 mm were performed for each model., Results: The models were created in a straightforward manner with efficient tools available in RS. The differences between computed and measured doses were within ±1% for most of the configurations tested and reached a maximum of 3.2% for measurements at a depth of 19.5-cm. With respect to all collimators and algorithms, the maximum averaged dose difference was 0.8% when considering absolute dose measurements on the central axis. The patient-specific QAs led to a mean result of 98% of points fulfilling gamma criteria., Conclusions: We created both CC and MC models for fixed, Iris, and MLC collimators in RS. The dose differences for all collimators and algorithms were within ±1%, except for depths larger than 9 cm. This allowed us to validate both models for clinical use., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: To commission and evaluate the Monte Carlo (MC) dose calculation algorithm for the CyberKnife equipped with a multileaf collimator (MLC)., Methods: We created a MC model for the MLC using an integrated module of the CyberKnife treatment planning software (TPS). Two parameters could be optimized: the maximum energy and the source full width at half-maximum (FWHM). The optimization was performed by minimizing the differences between the measured and the MC calculated tissue phantom ratios and profiles. MLC plans were calculated in the TPS with the MC algorithm and irradiated on different phantoms. The dose was measured using an A1SL ionization chamber and EBT3 Gafchromic films, and then compared to the TPS dose to obtain dose differences (ΔD). Finally, patient-specific quality assurances (QA) were performed with global gamma index criteria of 3%/1 mm., Results: The maximum energy and source FWHM showing the best agreement with measurements were 6.4 MeV and 1.8 mm. The output factors calculated with these parameters gave an agreement within ±1% with measurements. The ΔD showed that MC model systematically underestimated the dose with an average of -1.5% over all configurations tested. For depths deeper than 12 cm, the ΔD increased, up to -3.0% (maximum at 15.5 cm depth)., Conclusions: The MC model for MLC of CyberKnife is clinically acceptable but underestimates the delivered dose by an average of -1.5%. Therefore, we recommend using the MC algorithm with the MLC only in heterogeneous regions and for shallow-seated tumors., (© 2021 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves relatively large irradiation volumes with high cytotoxic doses., Experimental Design: Therefore, we aimed at simultaneously investigating the antitumor efficacy and neuroprotective benefits of FLASH-RT 1-month after exposure, using a well-characterized murine orthotopic glioblastoma model. As fractionated regimens of radiotherapy are the standard of care for glioblastoma treatment, we incorporated dose fractionation to simultaneously validate the neuroprotective effects and optimized tumor treatments with FLASH-RT., Results: The capability of FLASH-RT to minimize the induction of radiation-induced brain toxicities has been attributed to the reduction of reactive oxygen species, casting some concern that this might translate to a possible loss of antitumor efficacy. Our study shows that FLASH and CONV-RT are isoefficient in delaying glioblastoma growth for all tested regimens. Furthermore, only FLASH-RT was found to significantly spare radiation-induced cognitive deficits in learning and memory in tumor-bearing animals after the delivery of large neurotoxic single dose or hypofractionated regimens., Conclusions: The present results show that FLASH-RT delivered with hypofractionated regimens is able to spare the normal brain from radiation-induced toxicities without compromising tumor cure. This exciting capability provides an initial framework for future clinical applications of FLASH-RT. See related commentary by Huang and Mendonca, p. 662 ., (©2020 American Association for Cancer Research.)

FLASH radiation therapy (FLASH-RT) reference dosimetry to obtain traceability, repeatability and stability of irradiations cannot be performed with conventional dosimetric methods, such as monitor chambers or ionization chambers. Until now, only passive dosimeters have provided the necessary dosimetric data. Alanine dosimetry is accurate; however, to be used for FLASH-RT in biological experiments and for clinical transfer to humans, the reading time needs to be reduced, while preserving a maximum deviation to the reference of ±2%. Optimization of alanine dosimetry was based on the acquisition of electron paramagnetic resonance (EPR) spectra with a Bruker spectrometer. Reading parameters such as the conversion time, the number of scans, the time constant, the microwave power and the modulation amplitude of the magnetic field were optimized as a trade-off between the signal-to-noise ratio (SNR) and the reading time of one measurement using the reference 10.1 Gy alanine pellet. After optimizing the parameters, we compared the doses measured with alanine pellets up to 100 Gy with the reference doses, and then determined the number of measurements necessary to get a difference lower than ±2%. A low-dose alanine pellet of 4.9 Gy was also measured to evaluate the quality of the optimization for doses lower than 10 Gy. The optimization of the Bruker default parameters made it possible to reduce the reading time for one measurement from 5.6 to 2.6 min. That reduction was not at the cost of the SNR because it was kept comparable to the default parameters. Three measurements were enough to obtain a maximum dose deviation to the reference of 1.8% for the range of 10-100 Gy. The total reading time for the three measurements was 7.8 min (3 × 2.6 min). For lower doses such as 4.9 Gy, three measurements led to a deviation greater than 5%. By increasing the number of measurements to five, the average difference to the reference dose was reduced to less than 5% with a total reading time increased to 13.0 min. For doses between 10 Gy and 100 Gy, the optimized acquisition parameters made it possible to keep the average differences between the reference and the measured doses below ±2%, for a reading time of 7.8 min. This enabled an accurate and fast dose determination for biological preparations as part of FLASH-beam irradiations., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Purpose: Preclinical studies using a new treatment modality called FLASH Radiotherapy (FLASH-RT) need a two-phase procedure to ensure minimal uncertainties in the delivered dose. The first phase requires a new investigation of the reference dosimetry lying outside the conventional metrology framework from national metrology institutes but necessary to obtain traceability, repeatability, and stability of irradiations. The second consists of performing special quality assurance procedure prior to irradiation., Materials and Methods: The Oriatron eRT6 (PMB-Alcen, France) is an experimental high dose-per-pulse linear accelerator, delivering a 6 MeV pulsed electron beam with mean dose-rates, ranging from a few Gy/min up to thousands of Gy/s. Absolute dosimetry is investigated with alanine, thermo-luminescent dosimeters (TLD) and radiochromic films as well as an ionization chamber for relative stability. The beam characteristic and dosimetry are prepared for three different setups., Results: A cross-check between alanine, films and TLD revealed a dose agreement within 3% for dose-rates between 0.078 Gy/s and 1050 Gy/s, showing that these dosimeters are suitable for absolute dosimetry for FLASH-RT. In absence of appropriate setup dependent corrections, active dosimetry can reveal dose deviations up to 15% of the prescribed dose. These differences reduce to less than 3% when our dosimetric procedure is applied., Conclusion: We developed procedures to accurately irradiate biological models. Our method is based on validated absolute dosimeters and extends their use to routine FLASH irradiations. We reached an agreement of 3% between the delivered and prescribed dose and developed the requirements needed for workflows of preclinical and clinical studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Endothelin-1 (ET-1) is an important modulator of vasomotor tone that is thought to participate in the etiology of cardiovascular disease by virtue of its ability to amplify the contractile responses of vascular smooth muscle cells to the effects of other vasoactive agents. Despite this fact, few studies have quantitated the expected contribution of ET-1 to the enhanced contractile responses elicited in the presence of another spasmogen. As a first step in this direction, ET-1 and phenylephrine (PE) were used to evaluate the effects of co-activation of the ETA/B or alpha-1 adrenergic receptors, respectively, on contractile responses in isolated rings of rabbit aorta, mesenteric and femoral artery, or strips of corporal tissue. Cumulative steady-state concentration-response curves (CRCs) were constructed to PE alone before the construction of a CRC to ET-1 alone, or a mixture of PE and ET-1 using a previously described drug concentration paradigm. Computer fits of the logistic equation to CRC data revealed that in all vascular tissues examined, the partial substitution of PE with ET-1 was associated with a significant vessel-dependent approximately 3- to 30-fold leftward shift in the CRC (P < .01, Student's t test for paired samples), as judged by a significant increase in the pEC50 (negative logarithm of the concentration of drug that elicits one-half of the calculated maximal effect), in the absence of any detectable effect on the calculated maximal contractile response (Emax) or the slope factor (rho). A theoretical CRC constructed using the Pöch and Holzmann method for equiactive substitution demonstrated that the responses to mixtures of PE and ET-1 were often the result of simple additivity of agonist effects in these preparations, and thus, were "expected" based on detailed knowledge of the individual effects of these two agonists. Regardless of the precision of the Poch and Holzmann CRC in predicting the effects of this drug mixture in these vascular tissues, comparison of the "expected" contractile response with the "observed" response represents an important first step toward establishing a more uniform nomenclature for describing the physiological/pathophysiological effects of mixtures of drugs on diverse vasculature.

After injury, the peripheral nervous system (PNS) is capable of full regeneration and recovery of function. Many molecular events that are the hallmarks of the regenerating PNS are recapitulations of developmental processes. The expression of one such molecule, the POU transcription factor suppressed cAMP-inducible POU protein (SCIP), is required for the establishment of normal nerves and is reexpressed during regeneration. Here we describe markedly accelerated regeneration and hypertrophy of both myelin and axons in transgenic mice that express an amino-terminal deletion of the SCIP molecule. This mutant SCIP molecule retains the POU-specific and POU homeodomain moieties, which allow for both DNA binding and some protein-protein interaction. We demonstrate that the transgene indirectly effects dramatic axonal changes. This is the first demonstration of a genetically controlled acceleration of neural regeneration.

Kinetic studies were conducted on the contractile response elicited by phenylephrine (PE) and 5-hydroxytryptamine (5-HT) activation of the alpha 1-adrenergic- and 5-HT2 receptor subtypes, respectively, in aortic rings isolated from streptozotocin (STZ)-diabetic and age-matched control rats. The maximal PE- and 5-HT-induced contractile responses were separated into distinct phasic and tonic components, and the tonic portion of the response was assessed by evaluation of the calculated maximal rate constant for onset of contraction (kobsmax; min-1). Statistical analysis revealed that the mean kobsmax values for PE alone (10 microM), 5-HT alone (10 microM) and mixtures of PE and 5-HT (10 microM each) were significantly greater in diabetic animals than in age-matched control animals. These increases in kobsmax resulted in significant diabetes-related increases in the rate and relative magnitude of response generation during the initial minutes of contraction. Such observations emphasize the importance of kinetic studies, and given the central role played by the aorta in cardiovascular homeostasis, suggest that altered aortic contractility may play a role in some aspects of diabetic vascular disease. Moreover, if these kinetic alterations reflect a more generalized feature of diabetic vasculature (e.g., resistance vessels), then it is conceivable that such changes may further exacerbate diabetic vasculopathy.