Decoding Patient Heterogeneity Influencing Radiation-Induced Brain Necrosis.

PURPOSE: In radiotherapy (RT) for brain tumors, patient heterogeneity masks treatment effects, complicating the prediction and mitigation of radiation-induced brain necrosis. Therefore, understanding this heterogeneity is essential for improving outcome assessments and reducing toxicity. EXPERIMENTAL DESIGN: We developed a clinically practical pipeline to clarify the relationship between dosimetric features and outcomes by identifying key variables. We processed data from a cohort of 130 patients treated with proton therapy for brain and head and neck tumors, utilizing an expert-augmented Bayesian network to understand variable interdependencies and assess structural dependencies. Critical evaluation involved a 3-level grading system for each network connection and a Markov blanket analysis to identify variables directly impacting necrosis risk. Statistical assessments included log-likelihood ratio (LLR), integrated discrimination index (IDI), net reclassification index (NRI), and receiver operating characteristic (ROC). RESULTS: The analysis highlighted tumor location and proximity to critical structures like white matter and ventricles as major determinants of necrosis risk. The majority of network connections were clinically supported, with quantitative measures confirming the significance of these variables in patient stratification (LLR=12.17, p=0.016; IDI=0.15; NRI=0.74). The ROC curve area was 0.66, emphasizing the discriminative value of non-dosimetric variables. CONCLUSIONS: Key patient variables critical to understanding brain necrosis post-RT were identified, aiding the study of dosimetric impacts and providing treatment confounders and moderators. This pipeline aims to enhance outcome assessments by revealing at-risk patients, offering a versatile tool for broader applications in RT to improve treatment personalization in different disease sites.

Lithium inelastic cross-sections and their impact on micro and nano dosimetry of boron neutron capture.

Objective.To present a new set of lithium-ion cross-sections for (i) ionization and excitation processes down to 700 eV, and (ii) charge-exchange processes down to 1 keV u-1. To evaluate the impact of the use of these cross-sections on micro a nano dosimetric quantities in the context of boron neutron capture (BNC) applications/techniques.Approach.The Classical Trajectory Monte Carlo method was used to calculate Li ion charge-exchange cross sections in the energy range of 1 keV u-1to 10 MeV u-1. Partial Li ion charge states ionization and excitation cross-sections were calculated using a detailed charge screening factor. The cross-sections were implemented in Geant4-DNA v10.07 and simulations and verified using TOPAS-nBio by calculating stopping power and continuous slowing down approximation (CSDA) range against data from ICRU and SRIM. Further microdosimetric and nanodosimetric calculations were performed to quantify differences against other simulation approaches for low energy Li ions. These calculations were: lineal energy spectra (yf(y) andyd(y)), frequency mean lineal energyyF-, dose mean lineal energyyD-and ionization cluster size distribution analysis. Microdosimetric calculations were compared against a previous MC study that neglected charge-exchange and excitation processes. Nanodosimetric results were compared against pure ionization scaled cross-sections calculations.Main results.Calculated stopping power differences between ICRU and Geant4-DNA decreased from 33.78% to 6.9%. The CSDA range difference decreased from 621% to 34% when compared against SRIM calculations. Geant4-DNA/TOPAS calculated dose mean lineal energy differed by 128% from the previous Monte Carlo. Ionization cluster size frequency distributions for Li ions differed by 76%-344.11% for 21 keV and 2 MeV respectively. With a decrease in theN1within 9% at 10 keV and agreeing after the 100 keV. With the new set of cross-sections being able to better simulate low energy behaviors of Li ions.Significance.This work shows an increase in detail gained from the use of a more complete set of low energy cross-sections which include charge exchange processes. Significant differences to previous simulation results were found at the microdosimetric and nanodosimetric scales that suggest that Li ions cause less ionizations per path length traveled but with more energy deposits. Microdosimetry results suggest that the BNC's contribution to cellular death may be mainly due to alpha particle production when boron-based drugs are distributed in the cellular membrane and beyond and by Li when it is at the cell cytoplasm regions.

Monte Carlo dosimetric analyses on the use of90Y-IsoPet intratumoral therapy in canine subjects.

Objective.To investigate different dosimetric aspects of90Y-IsoPet™ intratumoral therapy in canine soft tissue sarcomas, model the spatial spread of the gel post-injection, evaluate absorbed dose to clinical target volumes, and assess dose distributions and treatment efficacy.Approach.Six canine cases treated with90Y-IsoPet™ for soft tissue sarcoma at the Veterinary Health Center, University of Missouri are analyzed in this retrospective study. The dogs received intratumoral IsoPet™ injections, following a grid pattern to achieve a near-uniform dose distribution in the clinical target volume. Two dosimetry methods were performed retrospectively using the Monte Carlo toolkit OpenTOPAS: imaging-based dosimetry obtained from post-injection PET/CT scans, and stylized phantom-based dosimetry modeled from the planned injection points to the gross tumor volume. For the latter, a Gaussian parameter with variable sigma was introduced to reflect the spatial spread of IsoPet™. The two methods were compared using dose-volume histograms (DVHs) and dose homogeneity, allowing an approximation of the closest sigma for the spatial spread of the gel post-injection. In addition, we compared Monte Carlo-based dosimetry with voxel S-value (VSV)-based dosimetry to investigate the dosimetric differences.Main results.Imaging-based dosimetry showed differences between Monte Carlo and VSV calculations in tumor high-density areas with higher self-absorption. Stylized phantom-based dosimetry indicated a more homogeneous target dose with increasing sigma. The sigma approximation of the90Y-IsoPet™ post-injection gel spread resulted in a median sigma of approximately 0.44 mm across all cases to reproduce the dose heterogeneity observed in Monte Carlo calculations.Significance.The results indicate that dose modeling based on planned injection points can serve as a first-order approximation for the delivered dose in90Y-IsoPet™ therapy for canine soft tissue sarcomas. The dosimetry evaluation highlights the non-uniformity of absorbed doses despite the gel spread, emphasizing the importance of considering tumor dose heterogeneity in treatment evaluation. Our findings suggest that using Monte Carlo for dose calculation seems more suitable for this type of tumor where high-density areas might play an important role in dosimetry.

A framework for in-field and out-of-field patient specific secondary cancer risk estimates from treatment plans using the TOPAS Monte Carlo system.

Objective. To allow the estimation of secondary cancer risks from radiation therapy treatment plans in a comprehensive and user-friendly Monte Carlo (MC) framework.Method. Patient planning computed tomography scans were extended superior-inferior using the International Commission on Radiological Protection's Publication 145 computational mesh phantoms and skeletal matching. Dose distributions were calculated with the TOPAS MC system using novel mesh capabilities and the digital imaging and communications in medicine radiotherapy extension interface. Finally, in-field and out-of-field cancer risk was calculated using both sarcoma and carcinoma risk models with two alternative parameter sets.Result. The TOPAS MC framework was extended to facilitate epidemiological studies on radiation-induced cancer risk. The framework is efficient and allows automated analysis of large datasets. Out-of-field organ dose was small compared to in-field dose, but the risk estimates indicate a non-negligible contribution to the total radiation induced cancer risk.Significance. This work equips the TOPAS MC system with anatomical extension, mesh geometry, and cancer risk model capabilities that make state-of-the-art out-of-field dose calculation and risk estimation accessible to a large pool of users. Furthermore, these capabilities will facilitate further refinement of risk models and sensitivity analysis of patient specific treatment options.

Dose Rate Effects from the 1950s through to the Era of FLASH.

Numerous dose rate effects have been described over the past 6-7 decades in the radiation biology and radiation oncology literature depending on the dose rate range being discussed. This review focuses on the impact and understanding of altering dose rates in the context of radiation therapy, but does not discuss dose rate effects as relevant to radiation protection. The review starts with a short historic review of early studies on dose rate effects, considers mechanisms thought to underlie dose rate dependencies, then discusses some current issues in clinical findings with altered dose rates, the importance of dose rate in brachytherapy, and the current timely topic of the use of very high dose rates, so-called FLASH radiotherapy. The discussion includes dose rate effects in vitro in cultured cells, in in vivo experimental systems and in the clinic, including both tumors and normal tissues. Gaps in understanding dose rate effects are identified, as are opportunities for improving clinical use of dose rate modulation.

Extended Pharmacokinetics Improve Site-Specific Prodrug Activation Using Radiation.

Radiotherapy is commonly used to treat cancer, and localized energy deposited by radiotherapy has the potential to chemically uncage prodrugs; however, it has been challenging to demonstrate prodrug activation that is both sustained in vivo and truly localized to tumors without affecting off-target tissues. To address this, we developed a series of novel phenyl-azide-caged, radiation-activated chemotherapy drug-conjugates alongside a computational framework for understanding corresponding pharmacokinetic and pharmacodynamic (PK/PD) behaviors. We especially focused on an albumin-bound prodrug of monomethyl auristatin E (MMAE) and found it blocked tumor growth in mice, delivered a 130-fold greater amount of activated drug to irradiated tumor versus unirradiated tissue, was 7.5-fold more efficient than a non albumin-bound prodrug, and showed no appreciable toxicity compared to free or cathepsin-activatable drugs. These data guided computational modeling of drug action, which indicated that extended pharmacokinetics can improve localized and cumulative drug activation, especially for payloads with low vascular permeability and diffusivity and particularly in patients receiving daily treatments of conventional radiotherapy for weeks. This work thus offers a quantitative PK/PD framework and proof-of-principle experimental demonstration of how extending prodrug circulation can improve its localized activity in vivo.

Sustained and Localized Drug Depot Release Using Radiation-Activated Scintillating Nanoparticles.

Clinical treatment of cancer commonly incorporates X-ray radiation therapy (XRT), and developing spatially precise radiation-activatable drug delivery strategies may improve XRT efficacy while limiting off-target toxicities associated with systemically administered drugs. Nevertheless, achieving this has been challenging thus far because strategies typically rely on radical species with short lifespans, and the inherent nature of hypoxic and acidic tumor microenvironments may encourage spatially heterogeneous effects. It is hypothesized that the challenge could be bypassed by using scintillating nanoparticles that emit light upon X-ray absorption, locally forming therapeutic drug depots in tumor tissues. Thus a nanoparticle platform (Scintillating nanoparticle Drug Depot; SciDD) that enables the local release of cytotoxic payloads only after activation by XRT is developed, thereby limiting off-target toxicity. As a proof-of-principle, SciDD is used to deliver a microtubule-destabilizing payload MMAE (monomethyl auristatin E). With as little as a 2 Gy local irradiation to tumors, MMAE payloads are released effectively to kill tumor cells. XRT-mediated drug release is demonstrated in multiple mouse cancer models and showed efficacy over XRT alone (p < 0.0001). This work shows that SciDD can act as a local drug depot with spatiotemporally controlled release of cancer therapeutics.

Voxel-wise dose rate calculation in clinical pencil beam scanning proton therapy.

OBJECTIVE: Clinical outcomes after proton therapy have shown some variability that is not fully understood. Different approaches have been suggested to explain the biological outcome, but none has yet provided a comprehensive and satisfactory rationale for observed toxicities. The relatively recent transition from passive scattering (PS) to pencil beam scanning (PBS) treatments has significantly increased the voxel-wise dose rate in proton therapy. In addition, the dose rate distribution is no longer uniform along the cross section of the target but rather highly heterogeneous, following the spot placement. We suggest investigating dose rate as potential contributor to a more complex proton RBE model. Approach. Due to the time structure of the PBS beam delivery the instantaneous dose rate is highly variable voxel by voxel. Several possible parameters to represent voxel-wise dose rate for a given clinical PBS treatment plan are detailed. These quantities were implemented in the scripting environment of our treatment planning system, and computations experimentally verified. Sample applications to treated patient plans are shown. Main Results. Computed dose rates we experimentally confirmed. Dose rate maps vary depending on which method is used to represent them. Mainly, the underlying time and dose intervals chosen determine the topography of the resultant distributions. The maximum dose rates experienced by any target voxel in a given PBS treatment plan in our system range from ~100 to ~450 Gy(RBE)/min, a factor of 10 - 100 increase compared to PS. These dose rate distributions are very heterogeneous, with distinct hot spots. Significance. Voxel-wise dose rates for current clinical PBS treatment plans vary greatly from clinically established practice with PS. The exploration of different dose rate measures to evaluate potential correlations with observed clinical outcomes is suggested, potentially adding a missing component in the understanding of proton RBE.

Modeling the impact of tissue oxygen profiles and oxygen depletion parameter uncertainties on biological response and therapeutic benefit of FLASH.

BACKGROUND: Ultra-high dose rate (FLASH) radiation has been reported to efficiently suppress tumor growth while sparing normal tissue; however, the mechanism of the differential tissue sparing effect is still not known. Oxygen has long been known to profoundly impact radiobiological responses, and radiolytic oxygen depletion has been considered to be a possible cause or contributor to the FLASH phenomenon. PURPOSE: This work investigates the impact of tissue pO2 profiles, oxygen depletion per unit dose (g), and the oxygen concentration yielding half-maximum radiosensitization (the average of its maximum value and one) (k) in tumor and normal tissue. METHODS: We developed a model that considers the dependent relationship between oxygen depletion and change of radiosensitivity by FLASH irradiation. The model assumed that FLASH irradiation depletes intracellular oxygen more rapidly than it diffuses into the cell from the extracellular environment. Cell survival was calculated based on the linear quadratic-linear model and the radiosensitivity related parameters were adjusted in 1 Gy increments of the administered dose. The model reproduced published experimental data that were obtained with different cell lines and oxygen concentrations, and was used to analyze the impact of parameter uncertainties on the radiobiological responses. This study expands the oxygen depletion analysis of FLASH to normal human tissue and tumor based on clinically determined aggregate and individual patient pO2 profiles. RESULTS: The results show that the pO2 profile is the most essential factor that affects biological response and analyses based on the median pO2 rather than the full pO2 profile can be unreliable and misleading. Additionally, the presence of a small fraction of cells on the threshold of radiobiologic hypoxia substantially alters biological response due to FLASH oxygen depletion. We found that an increment in the k value is generally more protective of tumor than normal tissue due to a higher frequency of lower pO2 values in tumors. Variation in the g value affects the dose at which oxygen depletion impacts response, but does not alter the dose-dependent response trends, if the g value is identical in both tumor and normal tissue. CONCLUSIONS: The therapeutic efficacy of FLASH oxygen depletion is likely patient and tissue-dependent. For breast cancer, FLASH is beneficial in a minority of cases; however, in a subset of well oxygenated tumors, a therapeutic gain may be realized due to induced normal tissue hypoxia.

Effects of Differing Underlying Assumptions in In Silico Models on Predictions of DNA Damage and Repair.

The induction and repair of DNA double-strand breaks (DSBs) are critical factors in the treatment of cancer by radiotherapy. To investigate the relationship between incident radiation and cell death through DSB induction many in silico models have been developed. These models produce and use custom formats of data, specific to the investigative aims of the researchers, and often focus on particular pairings of damage and repair models. In this work we use a standard format for reporting DNA damage to evaluate combinations of different, independently developed, models. We demonstrate the capacity of such inter-comparison to determine the sensitivity of models to both known and implicit assumptions. Specifically, we report on the impact of differences in assumptions regarding patterns of DNA damage induction on predicted initial DSB yield, and the subsequent effects this has on derived DNA repair models. The observed differences highlight the importance of considering initial DNA damage on the scale of nanometres rather than micrometres. We show that the differences in DNA damage models result in subsequent repair models assuming significantly different rates of random DSB end diffusion to compensate. This in turn leads to disagreement on the mechanisms responsible for different biological endpoints, particularly when different damage and repair models are combined, demonstrating the importance of inter-model comparisons to explore underlying model assumptions.

Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [177Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [177Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [177Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [177Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [177Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [177Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [177Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.

The complexity of DNA damage by radiation follows a Gamma distribution: insights from the Microdosimetric Gamma Model.

Introduction: DNA damage is the main predictor of response to radiation therapy for cancer. Its Q8 quantification and characterization are paramount for treatment optimization, particularly in advanced modalities such as proton and alpha-targeted therapy. Methods: We present a novel approach called the Microdosimetric Gamma Model (MGM) to address this important issue. The MGM uses the theory of microdosimetry, specifically the mean energy imparted to small sites, as a predictor of DNA damage properties. MGM provides the number of DNA damage sites and their complexity, which were determined using Monte Carlo simulations with the TOPAS-nBio toolkit for monoenergetic protons and alpha particles. Complexity was used together with a illustrative and simplistic repair model to depict the differences between high and low LET radiations. Results: DNA damage complexity distributions were were found to follow a Gamma distribution for all monoenergetic particles studied. The MGM functions allowed to predict number of DNA damage sites and their complexity for particles not simulated with microdosimetric measurements (yF) in the range of those studied. Discussion: Compared to current methods, MGM allows for the characterization of DNA damage induced by beams composed of multi-energy components distributed over any time configuration and spatial distribution. The output can be plugged into ad hoc repair models that can predict cell killing, protein recruitment at repair sites, chromosome aberrations, and other biological effects, as opposed to current models solely focusing on cell survival. These features are particularly important in targeted alpha-therapy, for which biological effects remain largely uncertain. The MGM provides a flexible framework to study the energy, time, and spatial aspects of ionizing radiation and offers an excellent tool for studying and optimizing the biological effects of these radiotherapy modalities.

An integrated Monte Carlo track-structure simulation framework for modeling inter and intra-track effects on homogenous chemistry.

Objective. The TOPAS-nBio Monte Carlo track structure simulation code, a wrapper of Geant4-DNA, was extended for its use in pulsed and longtime homogeneous chemistry simulations using the Gillespie algorithm.Approach. Three different tests were used to assess the reliability of the implementation and its ability to accurately reproduce published experimental results: (1) a simple model with a known analytical solution, (2) the temporal evolution of chemical yields during the homogeneous chemistry stage, and (3) radiolysis simulations conducted in pure water with dissolved oxygen at concentrations ranging from 10µM to 1 mM with [H2O2] yields calculated for 100 MeV protons at conventional and FLASH dose rates of 0.286 Gy s-1and 500 Gy s-1, respectively. Simulated chemical yield results were compared closely with data calculated using the Kinetiscope software which also employs the Gillespie algorithm.Main results. Validation results in the third test agreed with experimental data of similar dose rates and oxygen concentrations within one standard deviation, with a maximum of 1% difference for both conventional and FLASH dose rates. In conclusion, the new implementation of TOPAS-nBio for the homogeneous long time chemistry simulation was capable of recreating the chemical evolution of the reactive intermediates that follow water radiolysis.Significance. Thus, TOPAS-nBio provides a reliable all-in-one chemistry simulation of the physical, physico-chemical, non-homogeneous, and homogeneous chemistry and could be of use for the study of FLASH dose rate effects on radiation chemistry.

Absence of Tissue-Sparing Effects in Partial Proton FLASH Irradiation in Murine Intestine.

Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as well as the hypothesis that lymphocyte depletion is a cause of the FLASH effect. A 16 × 12 mm2 elliptical field with a dose rate of ~120 Gy/s was provided by a 228 MeV proton pencil beam. Partial abdominal irradiation was delivered to C57BL/6j and immunodeficient Rag1-/-/C57 mice. Proliferating crypt cells were counted at 2 days post exposure, and the thickness of the muscularis externa was measured at 280 days following irradiation. FLASH irradiation did not reduce the morbidity or mortality of conventional irradiation in either strain of mice; in fact, a tendency for worse survival in FLASH-irradiated mice was observed. There were no significant differences in lymphocyte numbers between FLASH and conventional-dose-rate mice. A similar number of proliferating crypt cells and a similar thickness of the muscularis externa following FLASH and conventional dose rate irradiation were observed. Partial abdominal FLASH proton irradiation at 120 Gy/s did not spare normal intestinal tissue, and no difference in lymphocyte depletion was observed. This study suggests that the effect of FLASH irradiation may depend on multiple factors, and in some cases dose rates of over 100 Gy/s do not induce a FLASH effect and can even result in worse outcomes.

Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps.

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.

TOPAS-imaging: extensions to the TOPAS simulation toolkit for medical imaging systems.

Objective. The TOol for PArticle Simulation (TOPAS) is a Geant4-based Monte Carlo software application that has been used for both research and clinical studies in medical physics. So far, most users of TOPAS have focused on radiotherapy-related studies, such as modeling radiation therapy delivery systems or patient dose calculation. Here, we present the first set of TOPAS extensions to make it easier for TOPAS users to model medical imaging systems.Approach. We used the extension system of TOPAS to implement pre-built, user-configurable geometry components such as detectors (e.g. flat-panel and multi-planar detectors) for various imaging modalities and pre-built, user-configurable scorers for medical imaging systems (e.g. digitizer chain).Main results. We developed a flexible set of extensions that can be adapted to solve research questions for a variety of imaging modalities. We then utilized these extensions to model specific examples of cone-beam CT (CBCT), positron emission tomography (PET), and prompt gamma (PG) systems. The first of these new geometry components, the FlatImager, was used to model example CBCT and PG systems. Detected signals were accumulated in each detector pixel to obtain the intensity of x-rays penetrating objects or prompt gammas from proton-nuclear interaction. The second of these new geometry components, the RingImager, was used to model an example PET system. Positron-electron annihilation signals were recorded in crystals of the RingImager and coincidences were detected. The simulated data were processed using corresponding post-processing algorithms for each modality and obtained results in good agreement with the expected true signals or experimental measurement.Significance. The newly developed extension is a first step to making it easier for TOPAS users to build and simulate medical imaging systems. Together with existing TOPAS tools, this extension can help integrate medical imaging systems with radiotherapy simulations for image-guided radiotherapy.

Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations.

PURPOSE: Radiation-induced lymphopenia has gained attention recently as the result of its correlation with survival in a range of indications, particularly when combining radiation therapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters. METHODS AND MATERIALS: We assembled a cohort of 17 patients with hepatocellular carcinoma treated with proton RT alone in 15 fractions (fx) using conventional dose rates (beam-on time [BOT], 120 seconds) for whom weekly absolute lymphocyte counts (ALCs) during RT and follow-up were available. We used HEDOS, a time-dependent, whole-body, blood flow computational framework, in combination with explicit liver blood flow modeling, to calculate the dose volume histograms for circulating lymphocytes for changing BOTs (1 second-300 seconds) and fractionations (5 fx, 15 fx). From this, we used the linear cell survival model and an exponential model to determine patient-specific lymphocyte radiation sensitivity, α, and recovery, σ, respectively. RESULTS: The in vivo-derived patient-specific α had a median of 0.65 Gy-1 (range, 0.30-1.38). Decreasing BOT to 1 second led to an increased average end-of-treatment ALC of 27.5%, increasing to 60.3% when combined with the 5-fx regimen. Decreasing to 5 fx at the conventional dose rate led to an increase of 17.0% on average. The benefit of both increasing dose rate and reducing the number of fractions was patient specificࣧpatients with highly sensitive lymphocytes benefited most from decreasing BOT, whereas patients with slow lymphocyte recovery benefited most from the shorter fractionation regimen. CONCLUSIONS: We observed that increasing dose rate at the same fractionation reduced ALC depletion more significantly than reducing the number of fractions. High-dose-rates led to an increased sparing of lymphocytes when shortening the fractionation regimen, particularly for patients with radiosensitive lymphocytes at elevated risk.

Proton FLASH effects on mouse skin at different oxygen tensions.

Objective. Irradiation at FLASH dose rates (>40 Gy s-1) has received great attention due to its reported normal tissue sparing effect. The FLASH effect was originally observed in electron irradiations but has since been shown to also occur with both photon and proton beams. Several mechanisms have been proposed to explain the tissue sparing at high dose rates, including effects involving oxygen, such as depletion of oxygen within the irradiated cells. In this study, we investigated the protective role of FLASH proton irradiation on the skin when varying the oxygen concentration.Approach. Our double scattering proton system provided a 1.2 × 1.6 cm2elliptical field at a dose rate of ∼130 Gy s-1. The conventional dose rate was ∼0.4 Gy s-1. The legs of the FVB/N mice were marked with two tattooed dots and fixed in a holder for exposure. To alter the skin oxygen concentration, the mice were breathing pure oxygen or had their legs tied to restrict blood flow. The distance between the two dots was measured to analyze skin contraction over time.Main results. FLASH irradiation mitigated skin contraction by 15% compared to conventional dose rate irradiation. The epidermis thickness and collagen deposition at 75 d following 25 to 30 Gy exposure suggested a long-term protective function in the skin from FLASH irradiation. Providing the mice with oxygen or reducing the skin oxygen concentration removed the dose-rate-dependent difference in response.Significance. FLASH proton irradiation decreased skin contraction, epidermis thickness and collagen deposition compared to standard dose rate irradiations. The observed oxygen-dependence of the FLASH effect is consistent with, but not conclusive of, fast oxygen depletion during the exposure.

Prediction of DNA rejoining kinetics and cell survival after proton irradiation for V79 cells using Geant4-DNA.

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.