Response to Re: Estimating and reducing dose received by cardiac devices for patients undergoing radiotherapy.

In reply to Dimitris N. Mihailidis regarding our manuscript entitled "Estimating and reducing dose received by cardiac devices for patients undergoing radiotherapy".

Technical Note: Out-of-field dose measurement at near surface with plastic scintillator detector.

Out-of-field dose depends on multiple factors, making peripheral dosimetry com-plex. Only a few dosimeters have the required features for measuring peripheral dose. Plastic scintillator dosimeters (PSDs) offer numerous dosimetric advantages as required for out-of-field dosimetry. The purpose of this study is to determine the potential of using PSD as a surface peripheral dosimeter. Measurements were performed with a parallel-plate ion chamber, a small volume ion chamber, and with a PSD. Lateral-dose measurements (LDM) at 0.5 cm depth and depth-dose curve (PDD) were made and compared to the dose calculation provided by a treatment planning system (TPS). This study shows that a PSD can measure a dose as low as 0.51 ± 0.17 cGy for photon beam and 0.58 ± 0.20 cGy for electron beam with a difference of 0.2 and 0.1 cGy compared to a parallel-plate ion chamber. This study demonstrates the potential of using PSD as an out-of-field dosimeter since measure-ments with PSD avoid averaging over a too-large depth, at 1 mm diameter, and can make precise measurement at very low dose. Also, electronic equilibrium is easier to reach with PSD due to its small sensitive volume and its water equivalence.

Smart imaging of acute lung injury: exploration of myeloperoxidase activity using in vivo endoscopic confocal fluorescence microscopy.

The pathophysiology of acute lung injury (ALI) is well characterized, but its real-time assessment at bedside remains a challenge. When patients do not improve after 1 wk despite supportive therapies, physicians have to consider open lung biopsy (OLB) to identify the process(es) at play. Sustained inflammation and inadequate repair are often observed in this context. OLB is neither easy to perform in a critical setting nor exempt from complications. Herein, we explore intravital endoscopic confocal fluorescence microscopy (ECFM) of the lung in vivo combined with the use of fluorescent smart probe(s) activated by myeloperoxidase (MPO). MPO is a granular enzyme expressed by polymorphonuclear neutrophils (PMNs) and alveolar macrophages (AMs), catalyzing the synthesis of hypoclorous acid, a by-product of hydrogen peroxide. Activation of these probes was first validated in vitro in relevant cells (i.e., AMs and PMNs) and on MPO-non-expressing cells (as negative controls) and then tested in vivo using three rat models of ALI and real-time intravital imaging with ECFM. Semiquantitative image analyses revealed that in vivo probe-related cellular/background fluorescence was associated with corresponding enhanced lung enzymatic activity and was partly prevented by specific MPO inhibition. Additional ex vivo phenotyping was performed, confirming that fluorescent cells were neutrophil elastase(+) (PMNs) or CD68(+) (AMs). This work is a first step toward "virtual biopsy" of ALI without OLB.

Estimating and reducing dose received by cardiac devices for patients undergoing radiotherapy.

The objectives of this project are to quantify the dose reduction effect provided by a lead shield for patients with cardiac implantable electronic devices (CIED) during a clinically realistic radiation treatment on phantom and to provide a simple model of dose estimation to predict dose received by CIED in a wide range of situations. The shield used in this project is composed of a lead sheet wrapped in thermoplastic. Dose measurements were made with a plastic scintillation detector (PSD). The phantom was treated with ten different plans. Three of these cases were treated with intensity-modulated radiation therapy (IMRT) and the others received standard 3D conformal radiation therapy (3D CRT). Lateral dose measurement for photon fields was made to establish a dose prediction model. On average, the use of the lead shield reduced the dose to CIEDs by 19% ± 13%. Dose reduction was most important for breast cases, with a mean reduction of 31% ± 15%. In three cases, the total dose reduction was more than 25 cGy over the complete treatment. For the three IMRT cases, the mean dose reduction was 11% ± 9%. On average, the difference between the TPS prediction and the measurement was 71%, while it was only 14% for the dose prediction model. It was demonstrated that a lead shield can be efficiently used for reducing doses to CIED with a wide range of clinical plans. In patients treated with IMRT modality treatment, the shielding should be used only for those with more than two anterior fields over seven fields. In the case of 3D CRT patients, the shielding should be used for those with a dose on the CIED higher than 50 cGy and with a reduction of dose higher than 10 cGy. The dose prediction model developed in this study can be an easy way to have a better estimation of the out-of-field dose than the TPS.

Metrology for advanced radiotherapy using particle beams with ultra-high dose rates.

Dosimetry of ultra-high dose-rate (UHDR) beams is one of the critical components which is required for safe implementation of FLASH radiotherapy into clinical practice. In the past years several national and international programmes have emerged with the aim to address some of the needs that are required for translation of this modality to clinics. These involve the establishment of dosimetry standards as well as the validation of protocols and dosimetry procedures. This review provides an overview of recent developments in the field of dosimetry for FLASH radiotherapy, with particular focus on primary and secondary standard instruments, and provides a brief outlook on the future work which is required to enable clinical implementation of FLASH radiotherapy.

The PTB water calorimeter for determining the absolute absorbed dose to water in ultra-high pulse dose rate electron beams.

Objective. The purpose of this investigation is to establish the water calorimeter as the primary standard in PTB's ultra-high pulse dose rate (UHPDR) 20 MeV reference electron beams.Approach. The calorimetric measurements were performed at the PTB research linac facility using the UHPDR reference electron beam setups that enable a dose per pulse between about 0.1 Gy and 6 Gy. The beam is monitored by an in-flange integrating current transformer. The correction factors required to determine the absorbed dose to water were evaluated using thermal and Monte Carlo simulations. Measurements were performed with different total doses delivered per pulse by modifying the instantaneous dose rate within a pulse and by changing the pulse length. The obtained temperature-time traces were compared to the simulated ones to validate the thermal simulations. In addition, absorbed-dose-to-water measurements obtained using the secondary standard alanine dosimeter system were compared to measurements performed with the primary standard.Main results. The simulated and measured temperature-time traces were shown to be consistent, within combined uncertainties, with one another. Measurements with alanine dosimeters proved to be consistent withink= 1 of the total combined uncertainty with the absorbed dose to water determined using the primary standard.Significance. The total relative standard uncertainty of absorbed dose to water determined using the PTB water calorimeter primary standard in UHPDR electron beams was estimated to be less than 0.5%, and the combined correction factors were found to deviate from 1 by less than 1% for both PTB UHPDR 20 MeV reference electron beams. The water calorimeter is therefore considered to be an established primary standard for the higher energy UHPDR reference electron beams.

Thermal neutron detection and track recognition method in reference and out-of-field radiotherapy FLASH electron fields using Timepix3 detectors.

Objective.This work presents a method for enhanced detection, imaging, and measurement of the thermal neutron flux.Approach. Measurements were performed in a water tank, while the detector is positioned out-of-field of a 20 MeV ultra-high pulse dose rate electron beam. A semiconductor pixel detector Timepix3 with a silicon sensor partially covered by a6LiF neutron converter was used to measure the flux, spatial, and time characteristics of the neutron field. To provide absolute measurements of thermal neutron flux, the detection efficiency calibration of the detectors was performed in a reference thermal neutron field. Neutron signals are recognized and discriminated against other particles such as gamma rays and x-rays. This is achieved by the resolving power of the pixel detector using machine learning algorithms and high-resolution pattern recognition analysis of the high-energy tracks created by thermal neutron interactions in the converter.Main results. The resulting thermal neutrons equivalent dose was obtained using conversion factor (2.13(10) pSv·cm2) from thermal neutron fluence to thermal neutron equivalent dose obtained by Monte Carlo simulations. The calibrated detectors were used to characterize scattered radiation created by electron beams. The results at 12.0 cm depth in the beam axis inside of the water for a delivered dose per pulse of 1.85 Gy (pulse length of 2.4µs) at the reference depth, showed a contribution of flux of 4.07(8) × 103particles·cm-2·s-1and equivalent dose of 1.73(3) nSv per pulse, which is lower by ∼9 orders of magnitude than the delivered dose.Significance. The presented methodology for in-water measurements and identification of characteristic thermal neutrons tracks serves for the selective quantification of equivalent dose made by thermal neutrons in out-of-field particle therapy.

Charge collection efficiency of commercially available parallel-plate ionisation chambers in ultra-high dose-per-pulse electron beams.

Objective. This investigation aims to experimentally determine the charge collection efficiency (CCE) of six commercially available parallel-plate ionisation chamber (PPIC) models in ultra-high dose-per-pulse (UHDPP) electron beams.Approach. The CCE of 22 PPICs has been measured in UHDPP electron beams at the National Metrology Institution of Germany (PTB). The CCE was determined for a dose per pulse (DPP) range between 0.1 and 6.4 Gy (pulse duration of 2.5µs). The results obtained with the different PPICs were compared to evaluate the reproducibility, intra- and inter-model variation, and the performance of a CCE empirical model.Main results. The intra-model variation was, on average, 4.0%, which is more than three times the total combined relative standard uncertainty and was found to be greater at higher DPP (up to 20%). The inter-model variation for the PPIC with 2 mm electrode spacing, which was found to be, on average, 10%, was also significant compared to the relative uncertainty and the intra-model variation. The observed CCE variation could not be explained only by the expected deviation of the electrode spacing from the nominal value within the manufacturing tolerance. It should also be noted that a substantial polarity effect, between 0.914(5) and 1.201(3), was observed, and significant intra- and inter-model variation was observed on this effect.Significance. For research and pre-clinical study, the commercially available PPIC with a well-known CCE (directly measured for the specific chamber) and with a small electrode spacing could be used for relative and absolute dosimetry with a lower-limit uncertainty of 1.6% (k= 1) in the best case. However, to use a PPIC as a secondary standard in UHDPP electron beams for clinical purposes would require new model development to reduce the ion recombination, the polarity effect, and the total standard uncertainty on the dose measurement.

Characterization of the PTB ultra-high pulse dose rate reference electron beam.

Purpose. This investigation aims to present the characterisation and optimisation of an ultra-high pulse dose rate (UHPDR) electron beam at the PTB facility in Germany. A Monte Carlo beam model has been developed for dosimetry study for future investigation in FLASH radiotherapy and will be presented.Material and methods. The 20 MeV electron beams generated by the research linear accelerator has been characterised both in-beamline with profile monitors and magnet spectrometer, and in-water with a diamond detector prototype. The Monte Carlo model has been used to investigate six different setups to enable different dose per pulse (DPP) ranges and beam sizes in water. The properties of the electron radiation field in water have also been characterised in terms of beam size, quality specifierR50and flatness. The beam stability has also been studied.Results. The difference between the Monte-Carlo simulated and measuredR50was smaller than 0.5 mm. The simulated beam sizes agreed with the measured ones within 2 mm. Two suitable setups have been identified for delivering reference UHPDR electron beams. The first one is characterised by a SSD of 70 cm, while in the second one an SSD of 90 cm is used in combination with a 2 mm aluminium scattering plates. The two set-ups are quick and simple to install and enable an expected overall DPP range from 0.13 Gy up to 6.7 Gy per pulse.Conclusion. The electron beams generated by the PTB research accelerator have shown to be stable throughout the four-months length of this investigation. The Monte Carlo models have shown to be in good agreement for beam size and depth dose and within 1% for the beam flatness. The diamond detector prototype has shown to be a promising tool to be used for relative measurements in UHPDR electron beams.

Absorbed-dose-to-water measurement using alanine in ultra-high-pulse-dose-rate electron beams.

Objective. The aim of the presented study is to evaluate the dose response of the PTB's secondary standard system, which is based on alanine and electron spin resonance (ESR) spectroscopy measurement, in ultra-high-pulse-dose-rate (UHPDR) electron beams.Approach. The alanine dosimeter system was evaluated in the PTB's UHPDR electron beams (20 MeV) in a range of 0.15-6.2 Gy per pulse. The relationship between the obtained absorbed dose to water per pulse and the in-beamline charge measurement of the electron pulses acquired using an integrating current transformer (ICT) was evaluated. Monte Carlo simulations were used to determine the beam quality conversion and correction factors required to perform alanine dosimetry.Main results. The beam quality conversion factor from the reference quality60Co to 20 MeV obtained by Monte Carlo simulation, 1.010(1), was found to be within the standard uncertainty of the consensus value, 1.014(5). The dose-to-water relative standard uncertainty was determined to be 0.68% in PTB's UHPDR electron beams.Significance. In this investigation, the dose-response of the PTB's alanine dosimeter system was evaluated in a range of dose per pulse between 0.15 Gy and 6.2 Gy and no evidence of dose-response dependency of the PTB's secondary standard system based on alanine was observed. The alanine/ESR system was shown to be a precise dosimetry system for evaluating absorbed dose to water in UHPDR electron beams.

Calorimeter measurements of absolute dose in aluminum, a surrogate of bone, to validate dose-to-medium in Acuros XB.

Objective. While the accuracy of dose calculations in water with Acuros XB is well established, experimental validation of dose in bone is limited. Acuros XB reports both dose-to-medium and dose-to-water, and these values differ in bone, but there are no reports of measurements of validation in bone. This work compares Acuros XB calculations to measurements of absolute dose in aluminum (medium similar to bone). The validity of using selected relative dosimeters in aluminum is also investigated.Approach. A calorimeter with an aluminum core embedded in an aluminum phantom was selected as bone surrogate for the measurement of absolute dose. Matching the medium of the core to the medium of the phantom allowed eliminating the calculation of the conversion between media. The dose was measured at the fixed depth of 3.3 cm in aluminum (∼9 g·cm-2) with 6X, 10X, 6FFF and 10FFF photon beams from a TrueBeam Varian linac. In addition, experimental cross-calibration between water and aluminum was performed for an IBA CC13 ionization chamber, a PTW microDiamond and EBT3 Gafchromic film.Main results. Calculations with Acuros XB dose-to-medium in aluminum differed from the calorimetry data by -2.8% to -3.5%, depending on the beam. Use of dose-to-water would have resulted in about 39% discrepancy. The cross calibration coefficient between water and aluminum yielded values of about 0.87 for the CC13 chamber, 0.91 for the microDiamond, and 0.88 for the film, and independent of the beam within about ±1%.Significance. It was demonstrated the value of the dose-to-medium in aluminum (surrogate of bone) computed with Acuros XB is close to the value of the absolute dose measured with a calorimeter, and there is a significant discrepancy when dose-to-water is used instead. The use of an ionization chamber, a microDiamond and Gafchromic film in aluminum required a considerable correction from calibration in water.

Numerical modeling of air-vented parallel plate ionization chambers for ultra-high dose rate applications.

PURPOSE: Air-vented ionization chambers have been the secondary standard for radiation dosimetry since the origins of radiation metrology. However, the feasibility of their use in ultra-high dose rate pulsed beams has been a matter of discussion, as large losses are caused by ion recombinations and no suitable theoretical model is available for their correction. The theories developed by Boag and his contemporaries since the 1950s, which have provided the standard ion recombination correction factor in clinical dosimetry, do not provide an accurate description when used under the limit conditions of ultra-high dose rates (UHDRs). Moreover, the high-ion recombination effects of ionization chambers under extreme dose-rate applications are an obstacle to the development of adequate dosimetry standards. METHODS: In this article, the charge carrier transport equations within a parallel plate ionization chamber (PPIC) have been solved numerically with a double aim. First, this numerical model provides a more accurate tool that can be used to evaluate ion recombination correction for established PPICs in pulsed ultra-high dose rate regimes. Second, studying the chamber behavior in detail allow as to explore the limits of new chamber designs in order to improve their performance under UHDRs. The model presented here has been tested by measuring the instantaneous current of one unit of a Roos chamber (i.e., the time-resolved current during and after the irradiation pulse under UHDR conditions) and comparing these results with the absolute value of the simulated current. RESULTS: The experimental data show consistent agreement with the results obtained using the numerical model. The experimental instantaneous current reveals effects such as the variation of the free electron fraction with the dose per pulse that are supported by the numerical model but cannot be explained in the framework of Boag's theory. CONCLUSIONS: Numerical solutions of the charge carrier released and transport in ionization chambers are able to estimate the effects observed when PPICs are irradiated with ultra-high dose rate beams and to provide new insight into processes related to recombination losses at UHDRs. These models can be reliably extended to include regions where current analytical solutions are not valid. An agreement of better than 5 % between the experimental and simulated effective free electron fraction is found. We were able to reproduce the instantaneous current from a Roos chamber. The discrepancies observed between the experimental data and the numerical simulations can be attributed to the uncertainty about the transport parameters involved in the calculation.

The probe-format graphite calorimeter, Aerrow, for absolute dosimetry in ultrahigh pulse dose rate electron beams.

PURPOSE: The purpose of this investigation is to evaluate the use of a probe-format graphite calorimeter, Aerrow, as an absolute and relative dosimeter of high-energy pulse dose rate (UHPDR) electron beams for in-water reference and depth-dose-type measurements, respectively. METHODS: In this paper, the calorimeter system is used to investigate the potential influence of dose per pulses delivered up to 5.6 Gy, the number of pulses delivered per measurement, and its potential for relative measurement (depth-dose curve measurement). The calorimeter system is directly compared against an Advanced Markus ion chamber. The finite element method was used to calculate heat transfer corrections along the percentage depth dose of a 20-MeV electron beam. Monte Carlo-calculated dose conversion factors necessary to calculate absorbed dose-to-water at a point from the measured dose-to-graphite are also presented. RESULTS: The comparison of Aerrow against a fully calibrated Advanced Markus chamber, corrected for the saturation effect, has shown consistent results in terms of dose-to-water determination. The measured reference depth is within 0.5 mm from the expected value from Monte Carlo simulation. The relative standard uncertainty estimated for Aerrow was 1.06%, which is larger compared to alanine dosimetry (McEwen et al. https://doi.org/10.1088/0026-1394/52/2/272) but has the advantage of being a real-time detector. CONCLUSION: In this investigation, it was demonstrated that the Aerrow probe-type graphite calorimeter can be used for relative and absolute dosimetries in water in an UHPDR electron beam. To the author's knowledge, this is the first reported use of an absorbed dose calorimeter for an in-water percentage depth-dose curve measurement. The use of the Aerrow in quasi-adiabatic mode has greatly simplified the signal readout, compared to isothermal mode, as the resistance was directly measured with a high-stability digital multimeter.

Thermoplastic wrapped lead sheet to reduce cardiac device cumulative dose.

The objective of this project is to evaluate the percentage dose reduction in cardiac implantable electronic devices (CIEDs) using a thermoplastic wrapped lead sheet. The dose to CIED is evaluated in various situations with and without a lead shield. The efficiency of this type of shielding is supported by measurements made with a commercial plastic scintillation detector (PSD). Percentage depth dose (PDD) curve and lateral dose measurements (LDMs) were made with and without shielding for photon and electron beams. Photon LDMs were made at a depth of 0.5 cm. PSD measurements were compared with dose calculation from the treatment planning system (TPS). The benefit of shielding is greater at 23 MV than at 6 MV, with an average reduction of 71% and 59% of dose, respectively, for out-of-field distance range between 3 and 15 cm. Measurement of posterior beams shows there is no significant increase in skin dose due to backscatter from the lead sheet even when the field intercepts it. Large deviations between TPS calculation and measurements have been observed. The use of lead shielding with an anterior field is advised and provides an easy way to decrease the cumulative dose to CIEDs. Interception of shielding by an electron beam would increase significantly the cumulative dose to CIED for high energies or decrease the quality of the treatment. For a posterior out-of-field, shielding does not have a significant impact on CIED dose.

Determination of Wair in high-energy electron beams using graphite detectors.

PURPOSE: ICRU Report 90 on Key Data for Ionizing-Radiation Dosimetry: Measurement Standards and Applications (2014) has reaffirmed the recommended value of the mean energy required to create an ion pair in air, Wair , to be 33.97(12) eV. The report also indicates that this "constant" of radiation dosimetry is energy independent above 10 keV, since there is no theoretical or experimental evidence to the contrary. The goal of this investigation is to obtain additional experimental determinations of Wair in high energy beams and thus to verify the suggested energy independence. METHODS: Wair can be evaluated by combining ionometric and calorimetric measurements with a calculated ratio of the absorbed dose in the ion chamber air cavity and that of the calorimeter absorbing element. In this investigation, a graphite parallel plate chamber and a graphite calorimeter were used and the dose ratio was calculated using the EGSnrc Monte Carlo code. Measurements were made in electron beams from the NRC Vickers linear accelerator at two incident energies, 20 and 35 MeV. A range of average energies at the measurement point were obtained by inserting graphite plates in the primary beam. RESULTS: The average value of Wair obtained in this investigation is 33.85(18) eV which is consistent with the recommended value of 33.97(12) eV where the number in brackets represents the combined standard uncertainty of the value, referring to the corresponding last digits. The individual values of Wair do not show any statistically significant energy dependence. CONCLUSION: The overall combined uncertainty of 0.5% meets the original target of the investigation. A larger-scale investigation, involving more individual energy points and a wider range of electron energies is required to go further and, for example, comment on the Wair energy dependency question raised by Tessier et al. [Med. Phys. 2018;45:370-381].