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Background: Phenomenological relative biological effectiveness (RBE) models for proton therapy, based on the dose-averaged linear energy transfer (LET), have been developed to address the apparent RBE increase towards the end of the proton range. The results of these phenomenological models substantially differ due to varying empirical assumptions and fitting functions. In contrast, more theory-based approaches are used in carbon ion radiotherapy, such as the microdosimetric kinetic model (MKM). However, implementing microdosimetry-based models in LET-based proton therapy treatment planning systems poses challenges., Purpose: This work presents a LET-based version of the MKM that is practical for clinical use in proton radiotherapy., Methods: At first, we derived an approximation of the Mayo Clinic Florida (MCF) MKM for relatively-sparsely ionizing radiation such as protons. The mathematical formalism of the proposed model is equivalent to the original MKM, but it maintains some key features of the MCF MKM, such as the determination of model parameters from measurable cell characteristics. Subsequently, we carried out Monte Carlo calculations with PHITS in different simulated scenarios to establish a heuristic correlation between microdosimetric quantities and the dose averaged LET of protons., Results: A simple allometric function was found able to describe the relationship between the dose-averaged LET of protons and the dose-mean lineal energy, which includes the contributions of secondary particles. The LET-based MKM was used to model the in vitro clonogenic survival RBE of five human and rodent cell lines (A549, AG01522, CHO, T98G, and U87) exposed to pristine and spread-out Bragg peak (SOBP) proton beams. The results of the LET-based MKM agree well with the biological data in a comparable or better way with respect to the other models included in the study. A sensitivity analysis on the model results was also performed., Conclusions: The LET-based MKM integrates the predictive theoretical framework of the MCF MKM with a straightforward mathematical description of the RBE based on the dose-averaged LET, a physical quantity readily available in modern treatment planning systems for proton therapy., (© 2024 American Association of Physicists in Medicine.)

The repair of DNA double-strand breaks is a crucial yet delicate process which is affected by a multitude of factors. In this study, our goal is to analyse the influence of the linear energy transfer (LET) on the DNA repair kinetics. By utilizing the database of repair of DNA and aggregating the results of 84 experiments, we conduct various model fits to evaluate and compare different hypothesis regarding the effect of LET on the rejoining of DNA ends. Despite the considerable research efforts dedicated to this topic over the past decades, our findings underscore the complexity of the relationship between LET and DNA repair kinetics. This study leverages big data analysis to capture overall trends that single experimental studies might miss, providing a valuable model for understanding how radiation quality impacts DNA damage and subsequent biological effects. Our results highlight the gaps in our current understanding, emphasizing the pressing need for further investigation into this phenomenon., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective. This work investigates the use of passive luminescence detectors to determine different types of averaged linear energy transfer (LET-) for the energies relevant to proton therapy. The experimental results are compared to reference values obtained from Monte Carlo simulations. Approach. Optically stimulated luminescence detectors (OSLDs), fluorescent nuclear track detectors (FNTDs), and two different groups of thermoluminescence detectors (TLDs) were irradiated at four different radiation qualities. For each irradiation, the fluence- (LET-f) and dose-averaged LET (LET-d) were determined. For both quantities, two sub-types of averages were calculated, either considering the contributions from primary and secondary protons or from all protons and heavier, charged particles. Both simulated and experimental data were used in combination with a phenomenological model to estimate the relative biological effectiveness (RBE). Main results. All types ofLET-could be assessed with the luminescence detectors. The experimental determination ofLET-fis in agreement with reference data obtained from simulations across all measurement techniques and types of averaging. On the other hand,LET-dcan present challenges as a radiation quality metric to describe the detector response in mixed particle fields. However, excluding secondaries heavier than protons from theLET-dcalculation, as their contribution to the luminescence is suppressed by ionization quenching, leads to equal accuracy betweenLET-fandLET-d. Assessment of RBE through the experimentally determinedLET-dvalues agrees with independently acquired reference values, indicating that the investigated detectors can determineLET-with sufficient accuracy for proton therapy. Significance. OSLDs, TLDs, and FNTDs can be used to determineLET-and RBE in proton therapy. With the capability to determine dose through ionization quenching corrections derived fromLET-, OSLDs and TLDs can simultaneously ascertain dose,LET-, and RBE. This makes passive detectors appealing for measurements in phantoms to facilitate validation of clinical treatment plans or experiments related to proton therapy., (Creative Commons Attribution license.)

Objective . To develop a new model (Mayo Clinic Florida microdosimetric kinetic model, MCF MKM) capable of accurately describing the in vitro clonogenic survival at low and high linear energy transfer (LET) using single-event microdosimetric spectra in a single target. Methodology . The MCF MKM is based on the 'post-processing average' implementation of the non-Poisson microdosimetric kinetic model and includes a novel expression to compute the particle-specific quadratic-dependence of the cell survival with respect to dose ( β of the linear-quadratic model). A new methodology to a priori calculate the mean radius of the MCF MKM subnuclear domains is also introduced. Lineal energy spectra were simulated with the Particle and Heavy Ion Transport code System (PHITS) for 1 H, 4 He, 12 C, 20 Ne, 40 Ar, 56 Fe, and 132 Xe ions and used in combination with the MCF MKM to calculate the ion-specific LET-dependence of the relative biological effectiveness (RBE) for Chinese hamster lung fibroblasts (V79 cell line) and human salivary gland tumor cells (HSG cell line). The results were compared with in vitro data from the Particle Irradiation Data Ensemble (PIDE) and in silico results of different models. The possibility of performing experiment-specific predictions to explain the scatter in the in vitro RBE data was also investigated. Finally, a sensitivity analysis on the model parameters is also included. Main results . The RBE values predicted with the MCF MKM were found to be in good agreement with the in vitro data for all tested conditions. Though all MCF MKM model parameters were determined a priori , the accuracy of the MCF MKM was found to be comparable or superior to that of other models. The model parameters determined a priori were in good agreement with the ones obtained by fitting all available in vitro data. Significance . The MCF MKM will be considered for implementation in cancer radiotherapy treatment planning with accelerated ions., (© 2022 Institute of Physics and Engineering in Medicine.)

Objective . To investigate similarities and differences in the formalism, processing, and the results of relative biological effectiveness (RBE) calculations with a biological weighting function (BWF), the microdosimetric kinetic model (MKM) and subsequent modifications (non-Poisson MKM, modified MKM). This includes: (a) the extension of the V79-RBE 10% BWF to model the RBE for other clonogenic survival levels; (b) a novel implementation of MKMs as weighting functions; (c) a benchmark against Chinese Hamster lung fibroblast (V79) in vitro data; (d) a study on the effect of pre- or post- processing the average biophysical quantities used for the RBE calculations; (e) a possible modification of the modified MKM parameters to improve the model accuracy at high linear energy transfer (LET). Methodology . Lineal energy spectra were simulated for two spherical targets (diameter = 0.464 or 1.0 μ m) using PHITS for 1 H, 4 He, 12 C, 20 Ne, 40 Ar, 56 Fe and 132 Xe ions. The results of the in silico calculations were compared with published in vitro data. Main results . All models appear to underestimate the RBE α of hydrogen ions. All MKMs generally overestimate the RBE 50% , RBE 10% and RBE 1% for ions with an LET greater than ∼200 keV μ m -1 . This overestimation is greater for small surviving fractions and is likely due to the assumption of a radiation-independent quadratic term of clonogenic survival ( ß ). The overall RBE trends seem to be best described by the novel 'post-processing average' implementation of the non-Poisson MKM. In case of calculations with the non-Poisson MKM, pre- or post- processing the average biophysical quantities affects the computed RBE values significantly. Significance . This study presents a systematic analysis of the formalism and results of widely used microdosimetric models of clonogenic survival for ions relevant for cancer particle therapy and space radiation protection. Points for improvements were highlighted and will contribute to the development of upgraded biophysical models., (© 2022 Institute of Physics and Engineering in Medicine.)

728 simulated microdosimetric lineal energy spectra (26 different ions between 1 H and 238 U, 28 energy points from 1 to 1000 MeV/n) were used in combination with a recently-developed biological weighting function (Parisi et al 2020 Phys. Med. Biol. 1361-6560) and 571 published in vitro clonogenic survival curves in order to: (1) assess prediction intervals for the in silico results by deriving an empirical indication of the experimental uncertainty from the dispersion in the in vitro hamster lung fibroblast (V79) data used for the development of the biophysical model; (2) explore the possibility of modeling the relative biological effectiveness (RBE) of the 10% clonogenic survival of asynchronized normoxic repair-competent mammalian cell lines other than the one used for the development of the model (V79); (3) investigate the predictive power of the model through a comparison between in silico results and in vitro data for 10 ions not used for the development of the model. At first, different strategies for the assessment of the in silico prediction intervals were compared. The possible sources of uncertainty responsible for the dispersion in the in vitro data were also shortly reviewed. Secondly, also because of the relevant scatter in the in vitro data, no statistically-relevant differences were found between the RBE 10 of the investigated different asynchronized normoxic repair-competent mammalian cell lines. The only exception (Chinese Hamster peritoneal fibroblasts, B14FAF28), is likely due to the limited dataset (all in vitro ion data were extracted from a single publication), systematic differences in the linear energy transfer calculations for the employed very-heavy ions, and the use of reference photon survival curves extracted from a different publication. Finally, the in silico predictions for the 10 ions not used for the model development were in good agreement with the corresponding in vitro data., (© 2021 Institute of Physics and Engineering in Medicine.)

A new methodology for assessing linear energy transfer (LET) and relative biological effectiveness (RBE) in proton therapy beams using thermoluminescent detectors is presented. The method is based on the different LET response of two different lithium fluoride thermoluminescent detectors (LiF:Mg,Ti and LiF:Mg,Cu,P) for measuring charged particles. The relative efficiency of the two detector types was predicted using the recently developed Microdosimetric d(z) Model in combination with the Monte Carlo code PHITS. Afterwards, the calculated ratio of the expected response of the two detector types was correlated with the fluence- and dose- mean values of the unrestricted proton LET. Using the obtained proton dose mean LET as input, the RBE was assessed using a phenomenological biophysical model of cell survival. The aforementioned methodology was benchmarked by exposing the detectors at different depths within the spread out Bragg peak (SOBP) of a clinical proton beam at iThemba LABS. The assessed LET values were found to be in good agreement with the results of radiation transport computer simulations performed using the Monte Carlo code GEANT4. Furthermore, the estimated RBE values were compared with the RBE values experimentally determined by performing colony survival measurements with Chinese Hamster Ovary (CHO) cells during the same experimental run. A very good agreement was found between the results of the proposed methodology and the results of the in vitro study.

An improved biological weighting function (IBWF) is proposed to phenomenologically relate microdosimetric lineal energy probability density distributions with the relative biological effectiveness (RBE) for the in vitro clonogenic cell survival (surviving fraction = 10%) of the most commonly used mammalian cell line, i.e. the Chinese hamster lung fibroblasts (V79). The IBWF, intended as a simple and robust tool for a fast RBE assessment to compare different exposure conditions in particle therapy beams, was determined through an iterative global-fitting process aimed to minimize the average relative deviation between RBE calculations and literature in vitro data in case of exposure to various types of ions from 1H to 238U. By using a single particle- and energy- independent function, it was possible to establish an univocal correlation between lineal energy and clonogenic cell survival for particles spanning over an unrestricted linear energy transfer range of almost five orders of magnitude (0.2 keV µm−1 to 15 000 keV µm−1 in liquid water). The average deviation between IBWF-derived RBE values and the published in vitro data was ∼14%. The IBWF results were also compared with corresponding calculations (in vitro RBE10 for the V79 cell line) performed using the modified microdosimetric kinetic model (modified MKM). Furthermore, RBE values computed with the reference biological weighting function (BWF) for the in vivo early intestine tolerance in mice were included for comparison and to further explore potential correlations between the BWF results and the in vitro RBE as reported in previous studies. The results suggest that the modified MKM possess limitations in reproducing the experimental in vitro RBE10 for the V79 cell line in case of ions heavier than 20Ne. Furthermore, due to the different modelled endpoint, marked deviations were found between the RBE values assessed using the reference BWF and the IBWF for ions heavier than 2H. Finally, the IBWF was unchangingly applied to calculate RBE values by processing lineal energy density distributions experimentally measured with eight different microdosimeters in 19 1H and 12C beams at ten different facilities (eight clinical and two research ones). Despite the differences between the detectors, irradiation facilities, beam profiles (pristine or spread out Bragg peak), maximum beam energy, beam delivery (passive or active scanning), energy degradation system (water, PMMA, polyamide or low-density polyethylene), the obtained IBWF-based RBE trends were found to be in good agreement with the corresponding ones in case of computer-simulated microdosimetric spectra (average relative deviation equal to 0.8% and 5.7% for 1H and 12C ions respectively). [ABSTRACT FROM AUTHOR]

Abstract Due to their common use for dose measurements in space and hadron therapy facilities, it is of fundamental importance to know the efficiency of luminescent detectors for measuring a wide range of particles and energies. However, due to experimental limitations it is often not possible to irradiate the detectors with very high energies, less common isotopes or exotic particles. Furthermore, the efficiency determination at low energies is biased with associated large uncertainties in range, linear energy transfer and dose. This paper presents the recently developed Microdosimetric d(z) Model able to assess the relative efficiency of thermoluminescent detectors for measuring different radiation qualities by relating the simulated dose probability distribution of the specific energy in nanometric targets with an experimentally determined response function. The model was tested in case of LiF:Mg, Ti (MTS) and LiF:Mg,Cu,P (MCP) thermoluminescent detectors exposed to charged particles from 1H to 132Xe in the energy range 3–1000 MeV/u. A comparison with experimentally determined efficiency results showed a very good agreement in case of calculations performed in a simulated target size of 40 nm. This validated model can be used to assess detector efficiency to exotic particles, unavailable radiation qualities and energies at ground level accelerators or complex mixed fields. The assumptions behind the model, its methodology and results are discussed in detail. Furthermore, a systematic investigation on the effect of simulation parameters on the calculated efficiency values is included in the manuscript. Highlights • A model based on microdosimetry was developed for predicting TLD efficiency. • LiF:Mg, Ti and LiF:Mg,Cu,P efficiency was determined for particles from 1H to 132Xe. • The determined efficiencies depend on the site size of the calculations. • For a site size of 40 nm, very good agreement with experimental data was found. [ABSTRACT FROM AUTHOR]

Thermoluminescent detectors (TLDs) are solid state detectors commonly used for dose monitoring and dose mapping in many earth and space applications. Among all the crystals available, the ones based on lithium fluoride (LiF) are the most widely spread and studied around the world. In the last years the use of these TLDs in complex heavy charged particles (HCPs) fields, as in spacecraft or in radiotherapy beams, has grown rapidly leading to the necessity of an accurate characterization of the detectors’ response in these radiation environments. In this work, 6 LiF:Mg,Ti, 7 LiF:Mg,Ti, 6 LiF:Mg,Cu,P and 7 LiF:Mg,Cu,P detectors were exposed to different radiation qualities in order to investigate the dependence of their relative luminescence efficiency on the linear energy transfer (LET) of the incident particles. The measured efficiencies were in good agreement with literature. In relation to this issue, different dose assessment methods, i.e. peak height, signal integration over different regions of interest (ROIs) and glow curve deconvolution, were compared and their influence on the measured relative luminescence efficiency values was assessed. For both LiF:Mg,Ti and LiF:Mg,Cu,P detectors, no relevant differences were found in the relative luminescence efficiency evaluated by means of main peak height, main peak ROI and main peak deconvolution. On the other hand, if the integration of the signal is extended to the high temperature zone (248–310 °C) of LiF:Mg,Ti or the low temperature zone (125–185 °C) of LiF:Mg,Cu,P, significant deviations were found. [ABSTRACT FROM AUTHOR]

This review explores current experimental methods for determining the radiation quality in ion beams. In this context, radiation quality is commonly evaluated using the averaged linear energy transfer (LET), a metric employed to assess the response of both biological and physical systems. Dose and averaged LET can be experimentally determined with passive detectors through various techniques that have seen recent improvements. Another metric related to the LET is the mean lineal energy, which is measurable using microdosimetric detectors. This review focuses on the available possibilities for evaluating the radiation quality using three microdosimeters (mini-TEPC, Silicon Telescope, and SOI Microplus), three passive luminescence detectors (based on optical, thermo-, and radiophoto-luminescence), three track-based detectors (track-etched detector, Timepix, fluorescent nuclear track detector), and a chemical detector based on alanine. A comparison of detector properties is provided along with an overview of the underlying mechanisms enabling LET assessment or measurements of the mean lineal energy with each detector type. Finally, this review summarizes the current possibilities of LET determination with respect to the needs for quality assurance in particle therapy. Areas for future research and development are suggested. • Review of experimental radiation quality assessment via LET or yD. • Understand operating principles of passive and active LET detectors. • Tables summarize detector properties for LET or yD assessment. • Gain recommendations for LET-QA in particle therapy. [ABSTRACT FROM AUTHOR]