Search

Simulation of water radiolysis and the subsequent chemistry provides important information on the effect of ionizing radiation on biological material. The Geant4 Monte Carlo toolkit has added chemical processes via the Geant4-DNA project. The TOPAS tool simplifies the modeling of complex radiotherapy applications with Geant4 without requiring advanced computational skills, extending the pool of users. Thus, a new extension to TOPAS, TOPAS-nBio, is under development to facilitate the configuration of track-structure simulations as well as water radiolysis simulations with Geant4-DNA for radiobiological studies. In this work, radiolysis simulations were implemented in TOPAS-nBio. Users may now easily add chemical species and their reactions, and set parameters including branching ratios, dissociation schemes, diffusion coefficients, and reaction rates. In addition, parameters for the chemical stage were re-evaluated and updated from those used by default in Geant4-DNA to improve the accuracy of chemical yields. Simulation results of time-dependent and LET-dependent primary yields Gx (chemical species per 100 eV deposited) produced at neutral pH and 25 °C by short track-segments of charged particles were compared to published measurements. The LET range was 0.05–230 keV µm−1. The calculated Gx values for electrons satisfied the material balance equation within 0.3%, similar for protons albeit with long calculation time. A smaller geometry was used to speed up proton and alpha simulations, with an acceptable difference in the balance equation of 1.3%. Available experimental data of time-dependent G-values for agreed with simulated results within 7%  ±  8% over the entire time range; for over the full time range within 3%  ±  4%; for H2O2 from 49%  ±  7% at earliest stages and 3%  ±  12% at saturation. For the LET-dependent Gx, the mean ratios to the experimental data were 1.11  ±  0.98, 1.21  ±  1.11, 1.05  ±  0.52, 1.23  ±  0.59 and 1.49  ±  0.63 (1 standard deviation) for , , H2, H2O2 and , respectively. In conclusion, radiolysis and subsequent chemistry with Geant4-DNA has been successfully incorporated in TOPAS-nBio. Results are in reasonable agreement with published measured and simulated data. [ABSTRACT FROM AUTHOR]

Whilst Monte Carlo (MC) simulations of proton energy deposition have been well-validated at the macroscopic level, their microscopic validation remains lacking. Equally, no gold-standard yet exists for experimental metrology of individual proton tracks. In this work we compare the distributions of stochastic proton interactions simulated using the TOPAS-nBio MC platform against confocal microscope data for Al2O3:C,Mg fluorescent nuclear track detectors (FNTDs). We irradiated mm3 FNTD chips inside a water phantom, positioned at seven positions along a pristine proton Bragg peak with a range in water of 12 cm. MC simulations were implemented in two stages: (1) using TOPAS to model the beam properties within a water phantom and (2) using TOPAS-nBio with Geant4-DNA physics to score particle interactions through a water surrogate of Al2O3:C,Mg. The measured median track integrated brightness (IB) was observed to be strongly correlated to both (i) voxelized track-averaged linear energy transfer (LET) and (ii) frequency mean microdosimetric lineal energy, , both simulated in pure water. Histograms of FNTD track IB were compared against TOPAS-nBio histograms of the number of terminal electrons per proton, scored in water with mass-density scaled to mimic Al2O3:C,Mg. Trends between exposure depths observed in TOPAS-nBio simulations were experimentally replicated in the study of FNTD track IB. Our results represent an important first step towards the experimental validation of MC simulations on the sub-cellular scale and suggest that FNTDs can enable experimental study of the microdosimetric properties of individual proton tracks. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (GNPs) have shown potential as dose enhancers for radiation therapy. Since damage to the genome affects the viability of a cell, it is generally assumed that GNPs have to localise within the cell nucleus. In practice, however, GNPs tend to localise in the cytoplasm yet still appear to have a dose enhancing effect on the cell. Whether this effect can be attributed to stress-induced biological mechanisms or to physical damage to extra-nuclear cellular targets is still unclear. There is however growing evidence to suggest that the cellular response to radiation can also be influenced by indirect processes induced when the nucleus is not directly targeted by radiation. The mitochondrion in particular may be an effective extra-nuclear radiation target given its many important functional roles in the cell. To more accurately predict the physical effect of radiation within different cell organelles, we measured the full chemical composition of a whole human lymphocytic JURKAT cell as well as two separate organelles; the cell nucleus and the mitochondrion. The experimental measurements found that all three biological materials had similar ionisation energies  ∼70 eV, substantially lower than that of liquid water  ∼78 eV. Monte Carlo simulations for 10–50 keV incident photons showed higher energy deposition and ionisation numbers in the cell and organelle materials compared to liquid water. Adding a 1% mass fraction of gold to each material increased the energy deposition by a factor of  ∼1.8 when averaged over all incident photon energies. Simulations of a realistic compartmentalised cell show that the presence of gold in the cytosol increases the energy deposition in the mitochondrial volume more than within the nuclear volume. We find this is due to sub-micron delocalisation of energy by photoelectrons, making the mitochondria a potentially viable indirect radiation target for GNPs that localise to the cytosol. [ABSTRACT FROM AUTHOR]

Computational models of tumor growth are valuable for simulating the dynamics of cancer progression and treatment responses. In particular, agent-based models (ABMs) tracking individual agents and their interactions are useful for their flexibility and ability to model complex behaviors. However, ABMs have often been confined to small domains or, when scaled up, have neglected crucial aspects like vasculature. Additionally, the integration into tumor ABMs of precise radiation dose calculations using gold-standard Monte Carlo (MC) methods, crucial in contemporary radiotherapy, has been lacking. Here, we introduce AMBER, an Agent-based fraMework for radioBiological Effects in Radiotherapy that computationally models tumor growth and radiation responses. AMBER is based on a voxelized geometry, enabling realistic simulations at relevant pre-clinical scales by tracking temporally discrete states stepwise. Its hybrid approach, combining traditional ABM techniques with continuous spatiotemporal fields of key microenvironmental factors such as oxygen and vascular endothelial growth factor, facilitates the generation of realistic tortuous vascular trees. Moreover, AMBER is integrated with TOPAS, an MC-based particle transport algorithm that simulates heterogeneous radiation doses. The impact of radiation on tumor dynamics considers the microenvironmental factors that alter radiosensitivity, such as oxygen availability, providing a full coupling between the biological and physical aspects. Our results show that simulations with AMBER yield accurate tumor evolution and radiation treatment outcomes, consistent with established volumetric growth laws and radiobiological understanding. Thus, AMBER emerges as a promising tool for replicating essential features of tumor growth and radiation response, offering a modular design for future expansions to incorporate specific biological traits., (© 2024. The Author(s), under exclusive licence to the Society for Mathematical Biology.)

Objective. To present and validate a method to simulate from first principles the effect of oxygen on radiation-induced double-strand breaks (DSBs) using the Monte Carlo Track-structure code TOPAS-nBio. Approach. Two chemical models based on the oxygen fixation hypothesis (OFH) were developed in TOPAS-nBio by considering an oxygen adduct state of DNA and creating a competition kinetic mechanism between oxygen and the radioprotective molecule WR-1065. We named these models 'simple' and 'detailed' due to the way they handle the hydrogen abstraction pathways. We used the simple model to obtain additional information for the •OH-DNA hydrogen abstraction pathway probability for the detailed model. These models were calibrated and compared with published experimental data of linear and supercoiling fractions obtained with R6K plasmids, suspended in dioxane as a hydroxyl scavenger, and irradiated with 137 Cs gamma-rays. The reaction rates for WR-1065 and O 2 with DNA were taken from experimental works. Single-Strand Breaks (SSBs) and DSBs as a function of the dose for a range of oxygen concentrations [O 2 ] (0.021%-21%) were obtained. Finally, the hypoxia reduction factor (HRF) was obtained from DSBs. Main Results. Validation results followed the trend of the experimental within 12% for the supercoiled and linear plasmid fractions for both models. The HRF agreed with measurements obtained with 137 Cs and 200-280 kVp x-ray within experimental uncertainties. However, the HRF at an oxygen concentration of 2.1% overestimated experimental results by a factor of 1.7 ± 0.1. Increasing the concentration of WR-1065 from 1 mM to 10-100 mM resulted in a HRF difference of 0.01, within the 8% statistical uncertainty between TOPAS-nBio and experimental data. This highlights the possibility of using these chemical models to recreate experimental HRF results. Significance. Results support the OFH as a leading cause of oxygen radio-sensitization effects given a competition between oxygen and chemical DNA repair molecules like WR-1065., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

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 three-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, integrated discrimination index, net reclassification index, and receiver operating characteristic (ROC)., Results: The analysis highlighted tumor location and proximity to critical structures such as 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 (log-likelihood ratio = 12.17; P = 0.016; integrated discrimination index = 0.15; net reclassification index = 0.74). The ROC curve area was 0.66, emphasizing the discriminative value of nondosimetric 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., (©2024 American Association for Cancer Research.)

Radionuclides used for imaging and therapy can show high molecular specificity in the body with appropriate targeting ligands. We hypothesized that local energy delivered by molecularly targeted radionuclides could chemically activate prodrugs at disease sites while avoiding activation in off-target sites of toxicity. As proof-of-principle, we tested whether this strategy of " RA dionuclide i nduced D rug E ngagement for R elease" ( RAiDER ) could locally deliver combined radiation and chemotherapy to maximize tumor cytotoxicity while minimizing exposure to activated chemotherapy in off-target sites., Methods: We screened the ability of radionuclides to chemically activate a model radiation-activated prodrug consisting of the microtubule destabilizing monomethyl auristatin E caged by a radiation-responsive phenyl azide ("caged-MMAE") and interpreted experimental results using the radiobiology computational simulation suite TOPAS-nBio. RAiDER was evaluated in syngeneic mouse models of cancer using fibroblast activation protein inhibitor (FAPI) agents 99m Tc-FAPI-34 and 177 Lu-FAPI-04, the prostate-specific membrane antigen (PSMA) agent 177 Lu-PSMA-617, combined with caged-MMAE or caged-exatecan. Biodistribution in mice, combined with clinical dosimetry, estimated the relationship between radiopharmaceutical uptake in patients and anticipated concentrations of activated prodrug using RAiDER., Results: RAiDER efficiency varied by 250-fold across radionuclides ( 99m Tc> 177 Lu> 64 Cu> 68 Ga> 223 Ra> 18 F), yielding up to 1.22µM prodrug activation per Gy of exposure from 99m Tc. Computational simulations implicated low-energy electron-mediated free radical formation as driving prodrug activation. Clinically relevant radionuclide concentrations chemically activated caged-MMAE restored its ability to destabilize microtubules and increased its cytotoxicity by up to 600-fold compared to non-irradiated prodrug. Mice treated with 99m Tc-FAPI-34 and caged-MMAE accumulated up to 3000× greater concentrations of activated MMAE in tumors compared to other tissues. RAiDER with 99m Tc-FAPI-34 or 177 Lu-FAPI-04 delayed tumor growth, while monotherapies did not ( P <0.03). Clinically-guided dosimetry suggests sufficient radiation doses can be delivered to activate therapeutically meaningful levels of prodrug., Conclusion: This proof-of-concept study shows that RAiDER is compatible with multiple radionuclides commonly used in nuclear medicine and has the potential to improve the efficacy of radiopharmaceutical therapies to treat cancer safely. RAiDER thus shows promise as an effective strategy to treat disseminated malignancies and broadens the capability of radiopharmaceuticals to trigger diverse biological and therapeutic responses.

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., (© 2024 Institute of Physics and Engineering in Medicine.)

Objective. To investigate different dosimetric aspects of 90 Y-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 with 90 Y-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 the 90 Y-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 in 90 Y-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., (© 2024 Institute of Physics and Engineering in Medicine.)

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., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

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 -1 to 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 ) and yd ( 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 the N 1 within 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., (© 2024 Institute of Physics and Engineering in Medicine.)

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 ., Competing Interests: The authors declare the following competing financial interest(s): M.A.M. has received unrelated support from Genentech/Roche and Pfizer and research funding from Ionis Pharmaceuticals. R.W. has consulted for Boston Scientific, ModeRNA, Earli, and Accure Health, none of whom contributed to or were involved in this research. Patents are pending and/or awarded with the authors and Massachusetts General Hospital., (© 2024 The Authors. Published by American Chemical Society.)

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., (© 2024 Wiley‐VCH GmbH.)

Objective . We provide optimal particle split numbers for speeding up TOPAS Monte Carlo simulations of linear accelerator (linac) treatment heads while maintaining accuracy. In addition, we provide a new TOPAS physics module for simulating photoneutron production and transport. Approach. TOPAS simulation of a Siemens Oncor linac was used to determine the optimal number of splits for directional bremsstrahlung splitting as a function of the field size for 6 MV and 18 MV x-ray beams. The linac simulation was validated against published data of lateral dose profiles and percentage depth-dose curves (PDD) for the largest square field (40 cm side). In separate simulations, neutron particle split and the custom TOPAS physics module was used to generate and transport photoneutrons, called 'TsPhotoNeutron'. Verification of accuracy was performed by comparing simulations with published measurements of: (1) neutron yields as a function of beam energy for thick targets of Al, Cu, Ta, W, Pb and concrete; and (2) photoneutron energy spectrum at 40 cm laterally from the isocenter of the Oncor linac from an 18 MV beam with closed jaws and MLC. Main results. The optimal number of splits obtained for directional bremsstrahlung splitting enhanced the computational efficiency by two orders of magnitude. The efficiency decreased with increasing beam energy and field size. Calculated lateral profiles in the central region agreed within 1 mm/2% from measured data, PDD curves within 1 mm/1%. For the TOPAS physics module, at a split number of 146, the efficiency of computing photoneutron yields was enhanced by a factor of 27.6, whereas it improved the accuracy over existing Geant4 physics modules. Significance. This work provides simulation parameters and a new TOPAS physics module to improve the efficiency and accuracy of TOPAS simulations that involve photonuclear processes occurring in high- Z materials found in linac components, patient devices, and treatment rooms, as well as to explore new therapeutic modalities such as very-high energy electron therapy., (© 2024 Institute of Physics and Engineering in Medicine.)

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 relative biological effectiveness (RBE)., (© 2024 Institute of Physics and Engineering in Medicine.)

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 pO 2 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 pO 2 profiles., Results: The results show that the pO 2 profile is the most essential factor that affects biological response and analyses based on the median pO 2 rather than the full pO 2 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 pO 2 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., (© 2023 American Association of Physicists in Medicine.)

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., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

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 [ 177 Lu]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 [ 177 Lu]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 [ 177 Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [ 177 Lu]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 [ 177 Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [ 177 Lu]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 [ 177 Lu]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 177 Lu 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., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objective: MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and  has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370., Methods: This was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated., Results: MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.)., Conclusion: The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8., (© 2023. The Author(s).)

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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective . To commission a proton, double-scattering FLASH beamline by maximizing efficiency and field size, enabling higher-linear energy transfer FLASH radiotherapy to cells and small animals using a spread-out Bragg peak (SOBP) treatment configuration. We further aim to provide a configuration guide for the design of future FLASH proton double-scattering (DS) beamlines. Approach . Beam spot size and spread were measured with film and implemented into TOol for PArticle Simulation (TOPAS). Monte Carlo simulations were optimized to verify the ideal positioning, dimensions, and material of scattering foils, secondary scatterers, ridge filters, range compensators, and apertures. A ridge filter with three discrete heights was used to create a spread-out Bragg peak (SOBP) and was experimentally verified using our in-house experimental FLASH beamline. The increase in dose rate was compared to nominal shoot-through techniques. Results . The configuration and scatterer distance producing the largest field size of acceptable flatness, without drastically compromising dose rate was determined to be an elliptical field of 2 cm × 1.5 cm (25% larger than a previous configuration). SOBP testing yielded three distinct but connected spikes in dose with flatness under 5%. Reducing the thickness of the (first) scattering foil by a factor of two was found to increase efficiency by 50%. The new settings increased the field size, provided a Bragg peak treatment option, and increased the maximum available dose rate by 85%, as compared to the previous, shoot through method. Significance . Beam line updates established FLASH dose rates of over 135 Gy s -1 (potentially higher) at our double-scattering beamline, increased the efficiency and field size, and enabled SOBP treatments by incorporating an optimized ridge filter. Based on our simulations we provide parametric suggestions when commissioning a new proton DS beamline. This enhanced FLASH beamline for SOBP irradiations with higher dose rates and larger field sizes will enable a wider variety of experimentation in future studies., (© 2023 Institute of Physics and Engineering in Medicine.)