Accurate dose mapping is essential for the performance qualification of electron beam sterilization of medical devices to ensure compliance with specified sterility assurance levels while avoiding material degradation. This study employs Monte Carlo models to compare alanine pellet and Ris & oslash; B3 film dosimeters with respect to their ability to measure surface dose as defined by a 1 mu m water layer present on the surface, and resolve dose gradients in 10 MeV electron beams. The findings show that while alanine pellets remain suitable for dose mapping when placed on surfaces with uniform irradiation and small dose gradients, thin film dosimeters are required for accurate surface dose mapping in complex geometries or where strong localized dose gradients are present, highlighting the need for application specific dosimeter selection.

Time-resolved luminescence measurements provide a powerful means of investigating luminescence processes across timescales, ranging from picoseconds to seconds. These measurements are typically enabled by pulsed stimulation, where light pulses of fixed durations are applied to a sample. Luminescence can then be recorded both during and after the pulsed light stimulation, allowing discrimination between stimulation and emission, as well as isolation of luminescence components with different lifetimes.Quartz and feldspar minerals are the two natural minerals most commonly used in luminescence studies. Time-resolved luminescence of feldspars has been investigated since the early 1990s, while quartz time-resolved signals has come into focus since around 2000. Over the past three decades, the extensive research into time-resolved and pulsed luminescence properties of these two minerals has provided insights into the lifetime of recombination and relaxation processes of various emissions in these minerals. These differences in the luminescence decay of quartz and feldspar offers a practical solution for discriminating their luminescence.This review is aimed at researchers specialising in the field of luminescence dating, who embark on their first pulsed and time-resolved luminescence journeys. It provides practical information on measurement techniques for conducting time-resolved luminescence measurements and presents an overview of research findings, accumulated over the past 3.5 decades highlighting both the fundamental processes revealed and the applications enabled by these methods.

BACKGROUND AND PURPOSE: Dose-response modification of FLASH has previously been established for acute skin toxicity in protons. This study used a similar experimental setup to quantify the dose-response modification of electron FLASH irradiation for acute skin- and late fibrotic toxicity in mice. The setup similarity enabled quantitative comparison of the acute skin response for electrons to protons. METHOD: Female unanaesthetised C3D2F1 mice were restrained with the right hindleg fixated and submerged in a water bath for horizontal electron irradiation at 16 MeV. Mice were randomised in groups of varying single doses (19.4-57.6 Gy) and irradiated with either 0.162 Gy/s conventional (CONV) or 233 Gy/s FLASH dose rate using 8-10 mice per group. Acute skin toxicity was assessed daily from the 8th to the 28th day post-irradiation. The same mice were kept for a fibrotic assay of leg extension assessment done biweekly until 52 weeks post-irradiation. The dose-modifying factor (DMF) of FLASH was quantified from dose-response curves. RESULTS AND DISCUSSION: Electron FLASH irradiated mice showed a considerable skin-sparing effect with a DMF of 1.45-1.54 and a smaller fibrotic-sparing effect with a DMF of 1.15. The development of acute skin toxicity was similar between CONV and FLASH groups with biological equivalent doses based on the DMF. The acute response of the electron irradiations was similar to previous reports on protons. CONCLUSION: Despite apparent differences, e.g. average and instantaneous dose rates, the acute skin toxicity of electron beams and previously published proton beams were remarkably similar regarding both biological response and quantified acute skin DMFs.

ObjectiveA favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model.Material/MethodsRadiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment.ResultsComparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4).ConclusionFull dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

PurposePreclinical studies have shown a preferential normal tissue sparing effect of FLASH radiotherapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biological effect of varying dose rates, time structure, and of introducing pauses in the dose delivery.Materials and MethodsThe right hind limbs of non-anaesthetized mice were irradiated in the entrance plateau of a PBS proton beam with 39.3 Gy. Experiment 1 with varying field dose rates (0.7- 80 Gy/s) without repainting, Experiment 2 with varying field dose rates (0.37- 80 Gy/s) with repainting, and Experiment 3 where the dose was split into 2, 3, 4 or 6 identical deliveries with 2 minutes pauses. In total 320 mice were included with 6-25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation.ResultsThe Dose rate50, dose rate to induce response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into two deliveries reduced the FLASH effect, and for three or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity.ConclusionsThe dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where two or more FLASH fields overlap within the same treatment session.

BACKGROUND AND PURPOSE:In proton therapy, a relative biological effectiveness (RBE) of 1.1 is used toreach an isoeffective biological response between photon and proton doses. However, the RBE varies with biological endpoints and linear energy transfer (LET), two key parameters in radiotherapy. Few in vivo studies have investigated the increasing RBE with increasing LET. This study aims to test the hypothesis that the RBE varies between endpoints and has a distal edge effect in vivo. MATERIALS AND METHODS:Unanesthetized micewere restrainedin jigs where their right hind legs were irradiated with a single dose of protons at the center (LET, all = 5.3 keV/μm) and distal edge (LET, all = 7.6 keV/μm) of a spread-out Bragg peak (SOBP). 6 MV photons were used as reference. The acute damage and skin toxicity were scored daily until day 30, and the late damage was evaluated using a joint contracture assay for one year after treatment. RESULTS:An acute damage RBE of 1.06 ± 0.02(1.02-1.10) and late damage RBE of 1.16 ± 0.08(1.00-1.32) were found, displaying an enhanced RBE for late damage in the center SOBP. The distal edge RBE for acute and late damage was 1.15 ± 0.02(1.10-1.19) and 1.26 ± 0.09(1.07-1.43), showing a similar center-to-distal edge RBE enhancement of 8 % and 9 % for acute and late damage. CONCLUSION:The findings demonstrate an increased RBE for late damage than acute damage and the distal edge effect is evident with increased RBE at the distal end of the proton SOBP in vivo.

Fiber coupled luminescence detectors based on organic plastic scintillators or inorganic materials such as Al2O3:C are suitable for dosimetry in strong magnetic fields as found in MR-linacs. The main finding of this work was that field-output factor measurements at the maximum dose point are less variable than if measured at the central beam axis (CAX). In contrast to plastic scintillators, Al2O3:C was found to have a yield of radioluminescence per dose that (within uncertainty) is independent of the magnetic field strength.

Current international protocols such as the IAEA/AAPM TRS-483 for small field dosimetry do not include recommendations for measurements in strong magnetic fields as found in MR-Linacs (i.e. megavoltage x-ray radiotherapy units with built-in magnetic resonance imaging). A EURAMET research project was therefore launched to support the traceability of such measurements and to contribute to the metrological basis for future recommendations. Given the high degree of water equivalence and the small size of fiber-coupled plastic scintillators, one objective of the project was to study the suitability of this detector type for dosimetry in MR-Linacs and to demonstrate their use in a clinical environment. This manuscript reports results of that work. A protocol for measuring field output factors with plastic scintillation detectors was developed. The protocol is based on calibration of the scintillators directly in a water phantom positioned in the MR-Linac rather than in a water-equivalent solid phantom as has been a common technique for conventional linacs. A detailed uncertainty budget was established involving all known sources of uncertainty including the systematic influence of light attenuation through the fiber when measuring in different field sizes. The protocol was used to measure field output factors at five MR-Linac’s (four Viewray MRIdian’s and one Elekta Unity). The protocol showed a high level of robustness leading to a less than 0.3 % deviation between field output factors calculated based on calibration data obtained before or after the field-output factor measurements. The correction for light attenuation was less than 0.4 % for all fields measured but showed a systematic offset, with larger corrections needed for small field sizes.This robustness of the protocol was further demonstrated by the closeness of agreement (agreement within uncertainty) for field-output factor measurements with two different scintillators (BCF-12 and BCF-60) for square fields (size: 0.83 cm x 0.83 cm or larger) in four nominally identical Viewray MRIdian's. To test the accuracy of the scintillator measurements, the system was used for characterization of a PTW 60019 micro diamond detector in a Viewray MRIdian. Scintillator based correction factors for output factor measurements with the micro diamond detector were found to be in agreement with independent Monte-Carlo computations. The study therefore supports that plastic scintillation detectors are an excellent option for measuring field output factors in MR-Linacs.

Infrared Stimulated Luminescence (IRSL) techniques are being increasingly used for dating sedimentary feldspars in the middle to late Quaternary. By employing several subsequent stimulations at increasing temperatures, a series of post-IR IRSL (pIRIR) signals with different characteristics (stability and bleachability) can be obtained for an individual sample. It has been experimentally demonstrated that higher-temperature pIRIR signals are more stable, but they tend to exhibit larger residual doses up to few tens of Gy, potentially causing severe age overestimation in young samples. In this study we conducted comprehensive bleaching experiments of IRSL and pIRIR signals using a loess sample from China, and demonstrated that non-bleachable components in the IR (and possibly pIRIR) signals do exist. The level of such non-bleachable signal shows clearly positive correlation with preheat/stimulation temperature, which further supports the notion that lower temperature pIRIR are advantageous to date young samples and sediments especially from difficult-to-bleach environments. These results display a potential in constrain the pre-burial light exposure history of sediment utilizing multiple feldspar post-IR IRSL (pIRIR) signals. For the studied loess sample, we infer that prior to its last burial, the sample has received an equivalent of >264 h exposure to the SOL2 simulator (more than 2,000 h of natural daylight).

BackgroundThe purpose of this study was to investigate acute normal tissue responses in the head and neck region following proton- or X-irradiation of a murine model.Materials and methodsFemale C57BL/6J mice were irradiated with protons (25 or 60 MeV) or X-rays (100 kV). The radiation field covered the oral cavity and the major salivary glands. For protons, two different treatment plans were used, either with the Bragg Peak in the middle of the mouse (BP) or outside the mouse (transmission mode; TM). Delivered physical doses were 41, 45, and 65 Gy given in 6, 7, and 10 fractions for BP, TM, and X-rays, respectively. Alanine dosimetry was used to assess delivered doses. Oral mucositis and dermatitis were scored using CTC v.2.0-based tables. Saliva was collected at baseline, right after end of irradiation, and at day 35.ResultsThe measured dose distribution for protons (TM) and X-rays was very similar. Oral mucositis appeared earlier, had a higher score and was found in a higher percentage of mice after proton irradiation compared to X-irradiation. Dermatitis, on the other hand, had a similar appearance after protons and X-rays. Compared to controls, saliva production was lower right after termination of proton- and X-irradiation. The BP group demonstrated saliva recovery compared to the TM and X-ray group at day 35.ConclusionWith lower delivered doses, proton irradiation resulted in similar skin reactions and increased oral mucositis compared to X-irradiation. This indicates that the relative biological effectiveness of protons for acute tissue responses in the mouse head and neck is greater than the clinical standard of 1.1. Thus, there is a need for further investigations of the biological effect of protons in normal tissues.

The combination of magnetic resonance (MR) imaging and linear accelerators (linacs) into MR-Linacs enables continuous MR imaging and advanced gated treatments of patients. Previously, a dose-rate transient (∼8% reduced dose rate during the initial 0.5 s of each beam) was identified for a Viewray MRIdian MR-Linac (Klavsenet al2022Radiation Measurement106759). Here, the dose-rate transient is studied in more detail at four linacs of the same type at different hospitals. The implications of dose-rate transients were examined for gated treatments. The dose-rate transients were investigated using dose-per pulse measurements with organic plastic scintillators in three experiments: (i) A gated treatment with the scintillator placed in a moving target in a dynamic phantom, (ii) a gated treatment with the same dynamic conditions but with the scintillator placed in a stationary target, and (iii) measurements in a water-equivalent material to examine beam quality deviations at a dose-per-pulse basis. Gated treatments (i) compared with non-gated treatments with a static target in the same setup showed a broadening of accumulated dose profiles due to motion (dose smearing). The linac with the largest dose-rate transient had a reduced accumulated dose of up to (3.1 ± 0.65) % in the center of the PTV due to the combined dose smearing and dose-rate transient effect. Dose-rate transients were found to vary between different machines. Two MR-Linacs showed initial dose-rate transients that could not be identified from conventional linearity tests. The source of the transients includes an initial change in photon fluence rate and an initial change in x-ray beam quality. For gated treatments, this caused a reduction of more than 1% dose delivered at the central part of the beam for the studied, cyclic-motion treatment plan. Quality assurance of this effect should be considered when gated treatment with the Viewray MRIdian is implemented clinically.

Time-resolved luminescence measurements can be used to explore luminescence processes in minerals and the defects involved. It has also been applied to feldspars and knowledge has been gained regarding potential crystal defects associated with luminescence productions in these minerals, but also regarding processes governing electron-hole recombination leading to luminescence emission. Here we present time-resolved infrared stimulated luminescence (IRSL) signals measured for a range of mineralogically well characterised single crystal alkali feldspars. We explore time-resolved luminescence for the blue (~410 nm) and the yellow-green emission (~550 nm) in response to different irradiation doses and by comparing different IRSL signals. Firstly, we explore whether the lifetimes measured represent excited state or recombination lifetimes. Secondly, we investigate sample-dependent changes in blue and yellow-green time-resolved signals and link those to physical properties of the samples.Our results show that the timescales on which the blue and the yellow-green emission occur differ significantly, with the blue signal on the µs-scale, and the yellow-green emission on the ms-scale. We do not observe any dependence of the time-resolved signal on signal integration, dose given or IRSL signal measured. However, inter-sample variability is shown for both emissions. In the blue we only observe small differences in decay time scale between single-phase feldspars and perthites, however larger differences are measured between samples that were artificially disordered compared to ordered feldspars. Longer lifetimes observed for disordered feldspars are suggested to be linked to either changes in the recombination centre or to increased band-tail states transport due to an increase in the width or density of the sub-conduction band-tail states. The data indicates the potential of using time-resolved IRSL of the blue emission to get an indication of the state of order of a feldspar. For the yellow-green emission slow signal decays are observed for single-phase feldspars, likely indicating a spin-forbidden transition. Interestingly, similar lifetimes were observed for K- and Na-feldspar end members.

Determination of beam quality correction factors is crucial for performing accurate alanine pellet dosimetry in non-reference fields. For some complex irradiation geometries, interpolation from literature data is more convenient than an experimental approach to establish these factors. Here we investigate the validity of extracting quality correction factors from literature data based on information on beam qualifiers such as half-value layer (HVL) or effective energy ${E}_{\text{eff}}$. A combination of Monte Carlo calculated dose ratios and a microdosimetric assessment of the relative efficiency allows for numerical evaluation of quality correction factors for a wide array of X-ray qualities. The computational analysis demonstrates that the average energy of the X-ray beam is optimal for characterizing the relative response. Special care should be taken when using the common X-ray beam qualifiers HVL or ${E}_{\text{eff}}$ to determine quality correction factors from literature data.

YKL-40 (also named chitinase 3 like-1 protein [CHI3L1]) is a secreted chitinase-like protein which is upregulated in cancers and suggested to have pro-tumorigenic activity. YKL-40 lacks enzymatic function, but it can bind carbohydrates such as chitin. Chitooligosaccharides (COS) derived from deacetylation and hydrolysis of chitin might be used for the blockade of YKL-40 function. Here, public single-cell RNA sequencing datasets were used to elucidate the cellular source of YKL-40 gene expression in human tumors. Fibroblasts and myeloid cells were the primary sources of YKL-40. Screening of YKL-40 gene expression in syngeneic mouse cancer models showed the highest expression in the Lewis lung carcinoma (LL2) model. LL2 was used to investigate COS monotherapy and combinations with immune checkpoint inhibitors (anti-PD-L1 and anti-CTLA-4) (ICIs) and radiotherapy (8 Gy × 3) (RT). COS tended to reduce plasma YKL-40 levels, but it did not affect tumor growth. LL2 showed minimal responses to ICIs, or to RT alone. Interestingly, ICIs combined with COS led to delayed tumor growth. RT also enhanced the efficacy of ICIs; however, the addition of COS did not further delay the tumor growth. COS may exert their anti-tumorigenic effects through the inhibition of YKL-40, but additional functions of COS should be investigated.

PURPOSE:Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model. METHODS AND MATERIALS:Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33-0.63 Gy/s field dose rate, 244 MeV) or FLASH (71-89 Gy/s field dose rate, 250 MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40-60 Gy (8-14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90 days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25 days post irradiation, and radiation induced fibrosis (RIF) within 24 weeks post irradiation. RESULTS:TCD50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0-51.4) Gy for CONV and 51.3 (48.6-54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD50 (dose for 50% of mice displaying moist desquamation) of <40.1 Gy for CONV and 52.3 (50.0-54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD50 (dose for 50% of mice displaying fibrosis) of 48.6 (43.2-50.8) Gy for CONV and 55.6 (52.5-60.1) Gy for FLASH (dose modifying factor of 1.14). CONCLUSIONS:FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis.