LET-based approximation of the microdosimetric kinetic model for proton radiotherapy.

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.

Adaptive intensity modulated proton therapy using 4D robust planning: a proof-of-concept for the application of dose mimicking approach.

OBJECTIVE: A 4D robust optimisation (4DRO) is usually employed when the tumour respiratory motion needs to be addressed. However, it is computationally demanding, and an automated method is preferable for adaptive planning to avoid manual trial-and-error. This study proposes a 4DRO technique based on dose mimicking for automated adaptive planning. Approach: Initial plans for 4DRO intensity modulated proton therapy were created on an average CT for four patients with clinical target volume (CTV) in the lung, oesophagus, or pancreas, respectively. These plans were robustly optimised using three phases of 4DCT and accounting for setup and density uncertainties. Weekly 4DCTs were used for adaptive replanning, using a constant relative biological effectiveness (cRBE) of 1.1. Two methods were used: (1) template-based adaptive (TA) planning and (2) dose-mimicking-based adaptive (MA) planning. The plans were evaluated using variable RBE (vRBE) weighted doses and biologically consistent dose accumulation (BCDA). Main results: MA and TA plans had comparable CTV coverage except for one patient where the MA plan had a higher D98 and lower D2 but with an increased D2 in few organs at risk (OARs). CTV D98 deviations in non-adaptive plans from the initial plans were up to -7.2 percentage points (p.p.) in individual cases and -1.8 p.p. when using BCDA. For the OARs, MA plans showed a reduced mean dose and D2 compared to the TA plan, with few exceptions. The vRBE-weighted accumulated doses had a mean dose and D2 difference of up to 0.3 Gy and 0.5 Gy, respectively, in the OARs with respect to cRBE-weighted dose. Significance: MA plans indicate better performance in target coverage and OAR dose sparing compared to the TA plans in 4DRO adaptive planning. Moreover, MA method is capable of handling both forms of anatomical variation, namely, changes in density and relative shifts in the position of OARs.

Quiescence-Origin Senescence: A New Paradigm in Cellular Aging.

Cellular senescence, traditionally viewed as a consequence of proliferating and growing cells overwhelmed by extensive stresses and damage, has long been recognized as a critical cellular aging mechanism. Recent research, however, has revealed a novel pathway termed "quiescence-origin senescence", where cells directly transition into senescence from the quiescent state, bypassing cell proliferation and growth. This opinion paper presents a framework conceptualizing a continuum between quiescence and senescence with quiescence deepening as a precursor to senescence entry. We explore the triggers and controllers of this process and discuss its biological implications. Given that the majority of cells in the human body are dormant rather than proliferative, understanding quiescence-origin senescence has significant implications for tissue homeostasis, aging, cancer, and various disease processes. The new paradigm in exploring this previously overlooked senescent cell population may reshape our intervention strategies for age-related diseases and tissue regeneration.

Comparing the biological effectiveness of low energy 100 kV and high energy 5 MeV X-rays against Oriental fruit fly (Diptera: Tephritidae).

Radioisotope irradiators (using cesium-137 or cobalt-60) are used as sources of ionizing radiation to control quarantine or phytosanitary insect pests in internationally traded fresh commodities and to sterilize insects used in sterile insect release programs. There are institutional initiatives to replace isotopic irradiators (producing γ-rays) with lower-energy X-ray machines due to concerns about radiological terrorism and increasingly stringent regulations on the movement of radioisotopes. Questions remain about whether the biological effects of low-energy X-rays are comparable to those of γ-rays since differences in energy levels and dose rates of X-rays may have different efficacies. We compared adult emergence, flight ability, and adult survival in the Oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritdae), after irradiation of third instar larvae with 100 kV or 5 MeV (5,000 kV) X-rays at 20 and 40 Gy in replicated studies. At 20 Gy, the adult emergence rate was significantly lower after irradiation with 100 kV compared to 5 MeV X-rays, suggesting higher efficacy at the lower energy level. In a follow-up study using 100 kV X-rays, applying 20 Gy using a slow dose rate (0.24 Gy min-1) resulted in significantly higher adult emergence than did a fast dose rate (3.3 Gy min-1), suggesting lower efficacy. Although our study suggests higher efficacy of low energy 100 kV X-rays, there is uncertainty in measuring the dose from an X-ray tube operating at 100 kV using an ionization chamber; we discuss how this uncertainty may change the interpretation of the results. Using a 100 kV X-ray irradiator to develop a phytosanitary treatment may underestimate the dose required for insect control using commercial high-energy γ-ray or X-ray systems.

RBE-based dose planning, and calculation of TCP and NTCP with gold nanoparticles for intermediate photon energy in pancreatic cancer.

Objective.This study simulated the potential of gold nanoparticles (GNPs) to improve the effectiveness of radiation therapy in pancreatic cancer cases. The purpose of this study was to assess the impact of GNPs on tumor control probability (TCP) and normal tissue complication probability (NTCP) in pancreatic cancer cases undergoing radiation therapy. The work aimed to compare treatment plans generated with a novel 2.5 MV beam using GNPs to conventional 6 MV plans and evaluate the dose-volume histogram (DVH), TCP, and NTCP.Approach.Treatment planning for five pancreatic computed tomography (CT) images was performed using the open-source MATLAB-based treatment planning program matRad. MATLAB codes were developed to calculate the relative biological effectiveness (RBE) of GNPs and apply the corresponding dose and RBE values to each voxel. TCP and NTCP were calculated based on the applied RBE values.Main results.Adding GNPs to the 2.5 MV treatment plan resulted in a significant increase in TCP, from around 59% to 93.5%, indicating that the inclusion of GNPs improved the effectiveness of the radiation treatment. The range in NTCP without GNPs was relatively larger compared to that with GNPs.Significance.The results indicated that the addition of GNPs to a 2.5 MV plan can increase TCP while maintaining a relatively low NTCP value (<1%). The use of GNPs may also reduce NTCP values by decreasing the dose to normal tissues while maintaining the same prescribed dose to the tumor. Hence, the addition of GNPs can improve the balance between TCP and NTCP.

Quantifying the Dosimetric Impact of Proton Range Uncertainties on RBE-Weighted Dose Distributions in Intensity-Modulated Proton Therapy for Bilateral Head and Neck Cancer.

BACKGROUND: In current clinical practice, intensity-modulated proton therapy (IMPT) head and neck cancer (HNC) plans are generated using a constant relative biological effectiveness (cRBE) of 1.1. The primary goal of this study was to explore the dosimetric impact of proton range uncertainties on RBE-weighted dose (RWD) distributions using a variable RBE (vRBE) model in the context of bilateral HNC IMPT plans. METHODS: The current study included the computed tomography (CT) datasets of ten bilateral HNC patients who had undergone photon therapy. Each patient's plan was generated using three IMPT beams to deliver doses to the CTV_High and CTV_Low for doses of 70 Gy(RBE) and 54 Gy(RBE), respectively, in 35 fractions through a simultaneous integrated boost (SIB) technique. Each nominal plan calculated with a cRBE of 1.1 was subjected to the range uncertainties of ±3%. The McNamara vRBE model was used for RWD calculations. For each patient, the differences in dosimetric metrices between the RWD and nominal dose distributions were compared. RESULTS: The constrictor muscles, oral cavity, parotids, larynx, thyroid, and esophagus showed average differences in mean dose (Dmean) values up to 6.91 Gy(RBE), indicating the impact of proton range uncertainties on RWD distributions. Similarly, the brachial plexus, brain, brainstem, spinal cord, and mandible showed varying degrees of the average differences in maximum dose (Dmax) values (2.78-10.75 Gy(RBE)). The Dmean and Dmax to the CTV from RWD distributions were within ±2% of the dosimetric results in nominal plans. CONCLUSION: The consistent trend of higher mean and maximum doses to the OARs with the McNamara vRBE model compared to cRBE model highlighted the need for consideration of proton range uncertainties while evaluating OAR doses in bilateral HNC IMPT plans.

Modelling of RBE differences in selected points within similar spread-out Bragg-peaks (SOBP) placed at superficial and deep water phantom locations in passively scattered beams but not in scanned pencil beams: A hypothesis.

PURPOSE: To model relative biological effectiveness (RBE) differences found in two studies which used spread-out Bragg-peaks (SOBP) placed at (a) superficial depth and (b) at the maximum range depth. For pencil beam scanning (PBS), RBE at similar points within the SOBP did not change between the two extreme SOBP placement depths; in passively scattered beams (PSB), high RBE values (typically 1.2-1.3) were found within superficially- placed SOBP but reduced to lower values (1-1.07) at similar points within the extreme-depth positioned SOBP. The dose, LET (linear energy transfer) distributions along each SOBP were closely comparable regardless of placement depth, but significant changes in dose rate occurred with depth in the PSB beam. METHODS: The equations used allow α and ß changes with falling dose rate (the converse to FLASH studies) in PSB, resulting in reduced α/ß ratios, compatible with a reduction in micro-volumetric energy transfer (the product of Fluence and LET), with commensurate reductions in RBE. The experimental depth-distances, positions within SOBP, observed dose-rates and radiosensitivity ratios were used to estimate the changes in RBE. RESULTS: RBE values within a 5 % tolerance limit of the experimental results for PSB were found at the deepest SOBP placement. No RBE changes were predicted for PBS beams, as in the published results. CONCLUSIONS: Enhanced proton therapy toxicity might occur with PBS when compared with PSB for deeply positioned SOBP due to the maintenance of higher RBE. Scanned pencil beam users need to be vigilant about RBE and further research is indicated.

Novel radiation quality metrics accounting for proton energy spectra for RBE proton models.

BACKGROUND: For proton therapy, a relative biological effectiveness (RBE) of 1.1 is widely applied clinically. However, due to abundant evidence of variable RBE in vitro, and as suggested in studies of patient outcomes, RBE might increase by the end of the proton tracks, as described by several proposed variable RBE models. Typically, the dose averaged linear energy transfer ( LET d $\text{LET}_d$ ) has been used as a radiation quality metric (RQM) for these models. However, the optimal choice of RQM has not been fully explored. PURPOSE: This study aims to propose novel RQMs that effectively weight protons of different energies, and assess their predictive power for variable RBE in proton therapy. The overall objective is to identify an RQM that better describes the contribution of individual particles to the RBE of proton beams. METHODS: High-throughput experimental set-ups of in vitro cell survival studies for proton RBE determination are simulated utilizing the SHIELD-HIT12A Monte Carlo particle transport code. For every data point, the proton energy spectra are simulated, allowing the calculation of novel RQMs by applying different power levels to the spectra of LET or effective Q $Q$ ( Q eff $Q_\mathrm{eff}$ ) values. A phenomenological linear-quadratic-based RBE model is then applied to the in vitro data, using various RQMs as input variables, and the model performance is evaluated by root-mean-square-error (RMSE) for the logarithm of cell surviving fractions of each data point. RESULTS: Increasing the power level, that is, putting an even higher weight on higher LET particles when constructing the RQM is generally associated with an increased model performance, with dose averaged LET 3 $\text{LET}^3$ (i.e., dose averaged cubed LET, cLET d $\mathrm{cLET}_d$ ) resulting in a RMSE value 0.31, compared to 0.45 for a model based on (linearly weighted) LET d $\text{LET}_d$ , with similar trends also observed for track averaged and Q eff $Q_\mathrm{eff}$ -based RQMs. CONCLUSIONS: The results indicate that improved proton variable RBE models can be constructed assuming a non-linear RBE(LET) relationship for individual protons. If similar trends hold also for an in vitro-environment, variable RBE effects are likely better described by cLET d $\mathrm{cLET}_d$ or tracked averaged cubed LET ( cLET t $\mathrm{cLET}_t$ ), or corresponding Q eff $Q_\mathrm{eff}$ -based RQM, rather than linearly weighted LET d $\text{LET}_d$ or LET t $\text{LET}_t$ which is conventionally applied today.

Evaluation of relative biological effectiveness for diseases of the circulatory system based on microdosimetry.

In the next decade, the International Commission on Radiological Protection (ICRP) will issue the next set of general recommendations, for which evaluation of relative biological effectiveness (RBE) for various types of tissue reactions would be needed. ICRP has recently classified diseases of the circulatory system (DCS) as a tissue reaction, but has not recommended RBE for DCS. We therefore evaluated the mean and uncertainty of RBE for DCS by applying a microdosimetric kinetic model specialized for RBE estimation of tissue reactions. For this purpose, we analyzed several RBE data for DCS determined by past animal experiments and evaluated the radius of the subnuclear domain best fit to each experiment as a single free parameter included in the model. Our analysis suggested that RBE for DCS tends to be lower than that for skin reactions, and their difference was borderline significant due to large variances of the evaluated parameters. We also found that RBE for DCS following mono-energetic neutron irradiation of the human body is much lower than that for skin reactions, particularly at the thermal energy and around 1 MeV. This tendency is considered attributable not only to the intrinsic difference of neutron RBE between skin reactions and DCS but also to the difference in the contributions of secondary γ-rays to the total absorbed doses between their target organs. These findings will help determine RBE by ICRP for preventing tissue reactions.

A perspective on tumor radiation resistance following high-LET radiation treatment.

High-linear energy transfer (LET) radiation is a promising alternative to conventional low-LET radiation for therapeutic gain against cancer owing to its ability to induce complex and clustered DNA lesions. However, the development of radiation resistance poses a significant barrier. The potential molecular mechanisms that could confer resistance development are translesion synthesis (TLS), replication gap suppression (RGS) mechanisms, autophagy, epithelial-mesenchymal transition (EMT) activation, release of exosomes, and epigenetic changes. This article will discuss various types of complex clustered DNA damage, their repair mechanisms, mutagenic potential, and the development of radiation resistance strategies. Furthermore, it highlights the importance of careful consideration and patient selection when employing high-LET radiotherapy in clinical settings.

Relative biological effectiveness of oxygen ion beams in the rat spinal cord: Dependence on linear energy transfer and dose and comparison with model predictions.

Background and purpose: Ion beams exhibit an increased relative biological effectiveness (RBE) with respect to photons. This study determined the RBE of oxygen ion beams as a function of linear energy transfer (LET) and dose in the rat spinal cord. Materials and methods: The spinal cord of rats was irradiated at four different positions of a 6 cm spread-out Bragg-peak (LET: 26, 66, 98 and 141 keV/µm) using increasing levels of single and split oxygen ion doses. Dose-response curves were established for the endpoint paresis grade II and based on ED50 (dose at 50 % effect probability), the RBE was determined and compared to model predictions. Results: When LET increased from 26 to 98 keV/µm, ED50 decreased from 17.2 ± 0.3 Gy to 13.5 ± 0.4 Gy for single and from 21.7 ± 0.4 Gy to 15.5 ± 0.5 Gy for split doses, however, at 141 keV/µm, ED50 rose again to 15.8 ± 0.4 Gy and 17.2 ± 0.4 Gy, respectively. As a result, the RBE increased from 1.43 ± 0.05 to 1.82 ± 0.08 (single dose) and from 1.58 ± 0.04 to 2.21 ± 0.08 (split dose), respectively, before declining again to 1.56 ± 0.06 for single and 1.99 ± 0.06 for split doses at the highest LET. Deviations from RBE-predictions were model-dependent. Conclusion: This study established first RBE data for the late reacting central nervous system after single and split doses of oxygen ions. The data was used to validate the RBE-dependence on LET and dose of three RBE-models. This study extends the existing data base for protons, helium and carbon ions and provides important information for future patient treatments with oxygen ions.

Evaluation of Helium Ion Radiotherapy in Combination with Gemcitabine in Pancreatic Cancer In Vitro.

BACKGROUND: Pancreatic cancer is one of the most aggressive and lethal cancers. New treatment strategies are highly warranted. Particle radiotherapy could offer a way to overcome the radioresistant nature of pancreatic cancer because of its biological and physical characteristics. Within particles, helium ions represent an attractive therapy option to achieve the highest possible conformity while at the same time protecting the surrounding normal tissue. The aim of this study was to evaluate the cytotoxic efficacy of helium ion irradiation in pancreatic cancer in vitro. METHODS: Human pancreatic cancer cell lines AsPC-1, BxPC-3 and Panc-1 were irradiated with photons and helium ions at various doses and treated with gemcitabine. Photon irradiation was performed with a biological cabin X-ray irradiator, and helium ion irradiation was performed with a spread-out Bragg peak using the raster scanning technique at the Heidelberg Ion Beam Therapy Center (HIT). The cytotoxic effect on pancreatic cancer cells was measured with clonogenic survival. The survival curves were compared to the predicted curves that were calculated via the modified microdosimetric kinetic model (mMKM). RESULTS: The experimental relative biological effectiveness (RBE) of helium ion irradiation ranged from 1.0 to 1.7. The predicted survival curves obtained via mMKM calculations matched the experimental survival curves. Mainly additive cytotoxic effects were observed for the cell lines AsPC-1, BxPC-3 and Panc-1. CONCLUSION: Our results demonstrate the cytotoxic efficacy of helium ion radiotherapy in pancreatic cancer in vitro as well as the capability of mMKM calculation and its value for biological plan optimization in helium ion therapy for pancreatic cancer. A combined treatment of helium irradiation and chemotherapy with gemcitabine leads to mainly additive cytotoxic effects in pancreatic cancer cell lines. The data generated in this study may serve as the radiobiological basis for future experimental and clinical works using helium ion radiotherapy in pancreatic cancer treatment.

A method to predict space radiation biological effectiveness for non-cancer effects following intense Solar Particle Events.

In addition to the continuous exposure to cosmic rays, astronauts in space are occasionally exposed to Solar Particle Events (SPE), which involve less energetic particles but can deliver much higher doses. The latter can exceed several Gy in a few hours for the most intense SPEs, for which non-stochastic effects are thus a major concern. To identify adequate shielding conditions that would allow respecting the dose limits established by the various space agencies, the absorbed dose in the considered organ/tissue must be multiplied by the corresponding Relative Biological Effectiveness (RBE), which is a complex quantity depending on several factors including particle type and energy, considered biological effect, level of effect (and thus absorbed dose), etc. While in several studies only the particle-type dependence of RBE is taken into account, in this work we developed and applied a new approach where, thanks to an interface between the FLUKA Monte Carlo transport code and the BIANCA biophysical model, the RBE dependence on particle energy and absorbed dose was also considered. Furthermore, we included in the considered SPE spectra primary particles heavier than protons, which in many studies are neglected. This approach was then applied to the October 2003 SPE (the most intense SPE of solar cycle 23, also known as "Halloween event") and the January 2005 event, which was characterized by a lower fluence but a harder spectrum, i.e., with higher-energy particles. The calculation outcomes were then discussed and compared with the current dose limits established for skin and blood forming organs in case of 30-days missions. This work showed that the BIANCA model, if interfaced to a radiation transport code, can be used to calculate the RBE values associated to Solar Particle Events. More generally, this work emphasizes the importance of taking into account the RBE dependence on particle energy and dose when calculating equivalent doses.

The sensitivity of radiobiological models in carbon ion radiotherapy (CIRT) and its consequences on the clinical treatment plan: Differences between LEM and MKM models.

PURPOSE: Carbon ion radiotherapy (CIRT) relies on relative biological effectiveness (RBE)-weighted dose calculations. Japanese clinics predominantly use the microdosimetric kinetic model (MKM), while European centers utilize the local effect model (LEM). Despite both models estimating RBE-distributions in tissue, their physical and mathematical assumptions differ, leading to significant disparities in RBE-weighted doses. Several European clinics adopted Japanese treatment schedules, necessitating adjustments in dose prescriptions and organ at risk (OAR) constraints. In the context of these two clinically used standards for RBE-weighted dose estimation, the objective of this study was to highlight specific scenarios for which the translations between models diverge, as shortcomings between them can influence clinical decisions. METHODS: Our aim was to discuss planning strategies minimizing those discrepancies, ultimately striving for more accurate and robust treatments. Evaluations were conducted in a virtual water phantom and patient CT-geometry, optimizing LEM RBE-weighted dose first and recomputing MKM thereafter. Dose-averaged linear energy transfer (LETd) distributions were also assessed. RESULTS: Results demonstrate how various parameters influence LEM/MKM translation. Similar LEM-dose distributions lead to markedly different MKM-dose distributions and variations in LETd. Generally, a homogeneous LEM RBE-weighted dose aligns with lower MKM values in most of the target volume. Nevertheless, paradoxical MKM hotspots may emerge (at the end of the range), potentially influencing clinical outcomes. Therefore, translation between models requires great caution. CONCLUSIONS: Understanding the relationship between these two clinical standards enables combining European and Japanese based experiences. The implementation of optimal planning strategies ensures the safety and acceptability of the clinical plan for both models and therefore enhances plan robustness from the RBE-weighted dose and LETd distribution point of view. This study emphasizes the importance of optimal planning strategies and the need for comprehensive CIRT plan quality assessment tools. In situations where simultaneous LEM and MKM computation capabilities are lacking, it can provide guidance in plan design, ultimately contributing to enhanced CIRT outcomes.

An updated variable RBE model for proton therapy.

Objective.While a constant relative biological effectiveness (RBE) of 1.1 forms the basis for clinical proton therapy, variable RBE models are increasingly being used in plan evaluation. However, there is substantial variation across RBE models, and several newin vitrodatasets have not yet been included in the existing models. In this study, an updatedin vitroproton RBE database was collected and used to examine current RBE model assumptions, and to propose an up-to-date RBE model as a tool for evaluating RBE effects in clinical settings.Approach.A proton database (471 data points) was collected from the literature, almost twice the size of the previously largest model database. Each data point included linear-quadratic model parameters and linear energy transfer (LET). Statistical analyses were performed to test the validity of commonly applied assumptions of phenomenological RBE models, and new model functions were proposed forRBEmaxandRBEmin(RBE at the lower and upper dose limits). Previously published models were refitted to the database and compared to the new model in terms of model performance and RBE estimates.Main results.The statistical analysis indicated that the intercept of theRBEmaxfunction should be a free fitting parameter and RBE estimates were clearly higher for models with free intercept.RBEminincreased with increasing LET, while a dependency ofRBEminon the reference radiation fractionation sensitivity (α/ßx) did not significantly improve model performance. Evaluating the models, the new model gave overall lowest RMSE and highest R2 score. RBE estimates in the distal part of a spread-out-Bragg-peak in water (α/ßx= 2.1 Gy) were 1.24-1.51 for original models, 1.25-1.49 for refits and 1.42 for the new model.Significance.An updated RBE model based on the currently largest database among published phenomenological models was proposed. Overall, the new model showed better performance compared to refitted published RBE models.

Optimizing linear energy transfer distribution in intensity-modulated proton therapy using the alternating direction method of multipliers.

Purpose: This study develop a novel linear energy transfer (LET) optimization method for intensity-modulated proton therapy (IMPT) with minimum monitor unit (MMU) constraint using the alternating direction method of multipliers (ADMM). Material and methods: The novel LET optimization method (ADMM-LET) was proposed with (1) the dose objective and the LET objective as the optimization objective and (2) the non-convex MMU threshold as a constraint condition. ADMM was used to solve the optimization problem. In the ADMM-LET framework, the optimization process entails iteratively solving the dose sub-problem and the LET sub-problem, simultaneously ensuring compliance with the MMU constraint. Three representative cases, including brain, liver, and prostate cancer, were utilized to evaluate the performance of the proposed method. The dose and LET distributions from ADMM-LET were compared to those obtained using the published iterative convex relaxation (ICR-LET) method. Results: The results demonstrate the superiority of ADMM-LET over ICR-LET in terms of LET distribution while achieving a comparable dose distribution. More specifically, for the brain case, the maximum LET (unit: keV/µm) at the optic nerve decreased from 5.45 (ICR-LET) to 1.97 (ADMM-LET). For the liver case, the mean LET (unit: keV/µm) at the clinical target volume increased from 4.98 (ICR-LET) to 5.50 (ADMM-LET). For the prostate case, the mean LET (unit: keV/µm) at the rectum decreased from 2.65 (ICR-LET) to 2.14 (ADMM-LET). Conclusion: This study establishes ADMM-LET as a new approach for LET optimization with the MMU constraint in IMPT, offering potential improvements in treatment outcomes and biological effects.

Variation of the relative biological effectiveness in the penumbra of ion therapy beams estimated using different microdosimetric approaches.

Background and Purpose: The effort to translate clinical findings across institutions employing different relative biological effectiveness (RBE) models of ion radiotherapy has rapidly grown in recent years. Nevertheless, even for a chosen RBE model, different implementations exist. These approaches might consider or disregard the dose-dependence of the RBE and the radial variation of the radiation quality around the beam axis. This study investigated the theoretical impact of disregarding these effects during the RBE calculations. Materials and Methods: Microdosimetric simulations were carried out using the Monte Carlo code PHITS along the spread out Bragg peaks of 1H, 4He, 12C, 16O, and 20Ne ions in a water phantom. The RBE was computed using different implementations of the Mayo Clinic Florida microdosimetric kinetic model (MCF MKM) and the modified MKM, considering or not the radial variation of the radiation quality in the penumbra of the ion beams and the dose-dependence of the RBE. Results: For an OAR located 5 mm laterally from the target volume, disregarding the radial variation of the radiation quality or the dose-dependence of the RBE could result in an overestimation of the RBE-weighted dose up to a factor of âˆ¼ 3.5 or âˆ¼ 1.7, respectively. Conclusions: The RBE-weighted dose to OARs close to the tumor volume was substantially impacted by the approach employed for the RBE calculations, even when using the same RBE model and cell line. Therefore, care should be taken in considering these differences while translating clinical findings between institutions with dissimilar approaches.

Application of Antioxidant Poly-Lactic Acid/Polyhydroxybutyrate (PLA/PHB) Films with Rice Bran Extract for the Preservation of Fresh Pork Meat.

Poly-lactic acid/polyhydroxybutyrate (PLA/PHB) bio-based films suppose an environmentally friendly alternative to petroleum-derived packaging. In addition, rice bran extracts (RBEs) are an interesting source of bioactive compounds. In the present study, active films were formulated with 0.3% (w/v) or 0.5% (w/v) RBE (low-RBE and high-RBE) and compared to PLA/PHB films with no RBE. The migrations of active compounds as well as the antimicrobial and the antioxidant activities were analyzed in the three film formulations. The effects of active PLA/PHB films on fresh pork meat were evaluated by measuring the instrumental color, lipid and protein oxidations, and microbiological status of meat refrigerated for 1, 5, or 9 days. The developed films presented antioxidant activity in vitro, but they did not have an antimicrobial effect against bacterial development (E. coli nor L. innocua). The PLA/PHB film with no extract prevented changes in the instrumental color of meat during storage. However, the antioxidant effect of the PLA/PHB films on fresh pork was negligible, and the inclusion of high doses of extract favored microbial development in the pork during storage. Despite the lack of activity of active PLA/PHB films on meat, their use could be a sustainable alternative to the petroleum-based films.

Potential Therapeutic Improvements in Prostate Cancer Treatment Using Pencil Beam Scanning Proton Therapy with LETd Optimization and Disease-Specific RBE Models.

PURPOSE: To demonstrate the feasibility of improving prostate cancer patient outcomes with PBS proton LETd optimization. METHODS: SFO, IPT-SIB, and LET-optimized plans were created for 12 patients, and generalized-tissue and disease-specific LET-dependent RBE models were applied. The mean LETd in several structures was determined and used to calculate mean RBEs. LETd- and dose-volume histograms (LVHs/DVHs) are shown. TODRs were defined based on clinical dose goals and compared between plans. The impact of robust perturbations on LETd, TODRs, and DVH spread was evaluated. RESULTS: LETd optimization achieved statistically significant increased target volume LETd of ~4 keV/µm compared to SFO and IPT-SIB LETd of ~2 keV/µm while mitigating OAR LETd increases. A disease-specific RBE model predicted target volume RBEs > 1.5 for LET-optimized plans, up to 18% higher than for SFO plans. LET-optimized target LVHs/DVHs showed a large increase not present in OARs. All RBE models showed a statistically significant increase in TODRs from SFO to IPT-SIB to LET-optimized plans. RBE = 1.1 does not accurately represent TODRs when using LETd optimization. Robust evaluations demonstrated a trade-off between increased mean target LETd and decreased DVH spread. CONCLUSION: The demonstration of improved TODRs provided via LETd optimization shows potential for improved patient outcomes.

Equivalent uniform RBE-weighted dose in eye plaque brachytherapy.

BACKGROUND: Brachytherapy for ocular melanoma is based on the application of eye plaques with different spatial dose nonuniformity, time-dependent dose rates and relative biological effectiveness (RBE). PURPOSE: We propose a parameter called the equivalent uniform RBE-weighted dose (EUDRBE) that can be used for quantitative characterization of integrated cell survival in radiotherapy modalities with the variable RBE, dose nonuniformity and dose rate. The EUDRBE is applied to brachytherapy with 125I eye plaques designed by the Collaborative Ocular Melanoma Study (COMS). METHODS: The EUDRBE is defined as the uniform dose distribution with RBE = 1 that causes equal cell survival for a given nonuniform dose distribution with the variable RBE > 1. The EUDRBE can be used for comparison of cell survival for nonuniform dose distributions with different RBE, because they are compared to the reference dose with RBE = 1. The EUDRBE is applied to brachytherapy with 125I COMS eye plaques that are characterized by a steep dose gradient in tumor base-apex direction, protracted irradiation during time intervals of 3-8 days, and variable dose-rate dependent RBE with a maximum of about 1.4. The simulations are based on dose of 85 Gy prescribed to the farthest intraocular extent of the tumor (tumor apex). To compute the EUDRBE in eye plaque brachytherapy and correct for protracted irradiation, the distributions of physical dose have been converted to non-uniform distributions of biologically effective dose (BED) to include the biological effects of sublethal cellular repair, Our radiobiological analysis considers the combined effects of different time-dependent dose rates, spatial dose non-uniformity, dose fractionation and different RBE and can be used to derive optimized dose regimens brachytherapy. RESULTS: Our simulations show that the EUDRBE increases with the prescription depths and the maximum increase may achieve 6% for the tumor height of 12 mm. This effect stems from a steep dose gradient within the tumor that increases with the prescription depth. The simulations also show that the EUDRBE increase may achieve 12% with increasing the dose rate when implant duration decreases. The combined effect of dose nonuniformity and dose rate may change the EUDRBE up to 18% for the same dose prescription of 85 Gy to tumor apex. The absolute dose range of 48-61 Gy (RBE) for the EUDRBE computed using 4 or 5 fractions is comparable to the dose prescriptions used in stereotactic body radiation therapy (SBRT) with megavoltage X-rays (RBE = 1) for different cancers. The tumor control probabilities in SBRT and eye plaque brachytherapy are very similar at the level of 80% or higher that support the hypothesis that the selected approximations for the EUDRBE are valid. CONCLUSIONS: The computed range of the EUDRBE in 125I COMS eye plaque brachytherapy suggests that the selected models and hypotheses are acceptable. The EUDRBE can be useful for analysis of treatment outcomes and comparison of different dose regimens in eye plaque brachytherapy.