Manuel Bardies

Implementation of new physics models for low energy electrons in liquid water in Geant4-DNA

A new alternative set of elastic and inelastic cross sections has been added to the very low energy extension of the Geant4 Monte Carlo simulation toolkit, Geant4-DNA, for the simulation of electron interactions in liquid water. These cross sections have been obtained from the CPA100 Monte Carlo track structure code, which has been a reference in the microdosimetry community for many years. They are compared to the default Geant4-DNA cross sections and show better agreement with published data. In order to verify the correct implementation of the CPA100 cross section models in Geant4-DNA, simulations of the number of interactions and ranges were performed using Geant4-DNA with this new set of models, and the results were compared with corresponding results from the original CPA100 code. Good agreement is observed between the implementations, with relative differences lower than 1% regardless of the incident electron energy. Useful quantities related to the deposited energy at the scale of the cell or the organ of interest for internal dosimetry, like dose point kernels, are also calculated using these new physics models. They are compared with results obtained using the well-known Penelope Monte Carlo code.

Model-based versus specific dosimetry in diagnostic context: Comparison of three dosimetric approaches

PURPOSE The dosimetric assessment of novel radiotracers represents a legal requirement in most countries. While the techniques for the computation of internal absorbed dose in a therapeutic context have made huge progresses in recent years, in a diagnostic scenario the absorbed dose is usually extracted from model-based lookup tables, most often derived from International Commission on Radiological Protection (ICRP) or Medical Internal Radiation Dose (MIRD) Committee models. The level of approximation introduced by these models may impact the resulting dosimetry. The aim of this work is to establish whether a more refined approach to dosimetry can be implemented in nuclear medicine diagnostics, by analyzing a specific case. METHODS The authors calculated absorbed doses to various organs in six healthy volunteers administered with flutemetamol ((18)F) injection. Each patient underwent from 8 to 10 whole body 3D PET/CT scans. This dataset was analyzed using a Monte Carlo (MC) application developed in-house using the toolkit gate that is capable to take into account patient-specific anatomy and radiotracer distribution at the voxel level. They compared the absorbed doses obtained with GATE to those calculated with two commercially available software: OLINDA/EXM and STRATOS implementing a dose voxel kernel convolution approach. RESULTS Absorbed doses calculated with gate were higher than those calculated with OLINDA. The average ratio between gate absorbed doses and OLINDAs was 1.38 ± 0.34 σ (from 0.93 to 2.23). The discrepancy was particularly high for the thyroid, with an average GATE/OLINDA ratio of 1.97 ± 0.83 σ for the six patients. Differences between STRATOS and GATE were found to be higher. The average ratio between GATE and STRATOS absorbed doses was 2.51 ± 1.21 σ (from 1.09 to 6.06). CONCLUSIONS This study demonstrates how the choice of the absorbed dose calculation algorithm may introduce a bias when gamma radiations are of importance, as is the case in nuclear medicine diagnostics.

PSMA-Targeted Radionuclide Therapy and salivary gland toxicity: why does it matter?

1Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France; 2AixMarseille University, APHM, IFSTTAR, LBA, Hôpital de la Conception, Chirurgie Maxillo-Faciale, Marseille, France; 3Inserm, UMR1037, CRCT, Toulouse, France; 4Université Toulouse III–Paul Sabatier, UMR1037, CRCT, Toulouse, France; 5Inserm, UMR1068, CRCM, Aix-Marseille University, Marseille, France; 6Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; 7Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany; and 8Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany

Internal dosimetry with the Monte Carlo code GATE: validation using the ICRP/ICRU female reference computational model

The purpose of this work was to validate GATE-based clinical scale absorbed dose calculations in nuclear medicine dosimetry. GATE (version 6.2) and MCNPX (version 2.7.a) were used to derive dosimetric parameters (absorbed fractions, specific absorbed fractions and S-values) for the reference female computational model proposed by the International Commission on Radiological Protection in ICRP report 110. Monoenergetic photons and electrons (from 50 keV to 2 MeV) and four isotopes currently used in nuclear medicine (fluorine-18, lutetium-177, iodine-131 and yttrium-90) were investigated. Absorbed fractions, specific absorbed fractions and S-values were generated with GATE and MCNPX for 12 regions of interest in the ICRP 110 female computational model, thereby leading to 144 source/target pair configurations. Relative differences between GATE and MCNPX obtained in specific configurations (self-irradiation or cross-irradiation) are presented. Relative differences in absorbed fractions, specific absorbed fractions or S-values are below 10%, and in most cases less than 5%. Dosimetric results generated with GATE for the 12 volumes of interest are available as supplemental data. GATE can be safely used for radiopharmaceutical dosimetry at the clinical scale. This makes GATE a viable option for Monte Carlo modelling of both imaging and absorbed dose in nuclear medicine.

Optimization of GATE simulations for whole-body planar scintigraphic acquisitions using the XCAT male phantom with 177Lu-DOTATATE biokinetics in a Siemens Symbia T2

Simulations of planar whole body acquisitions in therapeutic procedures are often extensively time-consuming and therefore rarely used. However, optimising tools and variance reduction techniques can be employed to overcome this problem. In this paper, a variety of features available in GATE are explored and their capabilities to reduce simulation time are evaluated. For this purpose, the male XCAT phantom was used as a virtual patient with 177Lu-DOTATATE pharmacokinetic for whole body planar acquisition simulations in a Siemens Symbia T2 model. Activity distribution was divided into 8 compartments that were simulated separately. GATE optimization techniques included reducing the amount of time spent in both voxel and detector tracking. Some acceleration techniques led to a decrease of CPU-time by a factor of 167, while image statistics were kept constant. In that context, the simulation of therapeutic procedure imaging would still require 46days on a single CPU, but this could be reduced to hours on a dedicated cluster.

Realistic multi-cellular dosimetry for 177Lu-labelled antibodies: model and application

Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General-purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin®, a novel 177Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of 177Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions.

Nonlinearity in MCF7 Cell Survival Following Exposure to Modulated 6 MV Radiation Fields: Focus on the Dose Gradient Zone

The study of cell survival following exposure to nonuniform radiation fields is taking on particular interest because of the increasing evidence of a nonlinear relationship at low doses. We conducted in vitro experiments using the MCF7 breast cancer cell line. A 2.4 × 2.4 cm2 square area of a T25 flask was irradiated by a Varian Novalis accelerator delivering 6 MV photons. Cell survival inside the irradiation field, in the dose gradient zone and in the peripheral zone, was determined using a clonogenic assay for different radiation doses at the isocenter. Increased cell survival was observed inside the irradiation area for doses of 2, 10, and 20 Gy when nonirradiated cells were present at the periphery, while the cells at the periphery showed decreased survival compared to controls. Increased survival was also observed at the edge of the dose gradient zone for cells receiving 0.02 to 0.01 Gy when compared with cells at the periphery of the same flask, whatever the isocenter dose. These data are the first to report cell survival in the dose gradient zone. Radiotherapists must be aware of this nonlinearity in dose response.

Evaluation of [18F]FNM biodistribution and dosimetry based on whole-body PET imaging of rats

INTRODUCTION The aim of this work was to study the biodistribution, metabolism and radiation dosimetry of rats injected with [18F]FNM using PET/CT images. This novel radiotracer targeting NMDA receptor has potential for investigation for neurological and psychiatric diseases. METHODS Free fraction and stability in fresh human plasma were determined in vitro. PET/CT was performed on anesthetized rats. Organs were identified and 3D volumes of interest (VOIs) were manually drawn on the CT in the center of each organ. Time activity curves (TACs) were created with these VOIs, enabling the calculation of residence times. To confirm these values, ex vivo measurements of organs were performed. Plasma and urine were also collected to study in vivo metabolism. Data was extrapolated to humans, effective doses were estimated using ICRP-60 and ICRP-89 dosimetric models and absorbed doses were estimated using OLINDA/EXM V1.0 and OLINDA/EXM V2.0 (which use weighting factors from ICRP-103 to do the calculations). RESULTS The [18F]FNM was stable in human plasma and the diffusible free fraction was 53%. As with memantine, this tracer is poorly metabolized in vivo. Ex vivo distributions validated PET/CT data as well as demonstrating a decrease of radiotracer uptake in the brain due to anesthesia. Total effective dose was around 6.11 μSv/MBq and 4.65 μSv/MBq for female and male human dosimetric models, respectively. CONCLUSIONS This study shows that the presented compound exhibits stability in plasma and plasma protein binding very similar to memantine. Its dosimetry shows that it is suitable for use in humans due to a low total effective dose compared to other PET radiotracers.

Treatment planning of microbrachytherapy with 3D NSGA-II

An innovative form of radiotherapy, microbrachytherapy, is under development for solid, inoperable, radioresistant tumors. A method of treatment planning is proposed using a multi-objective algorithm, NSGA-II.

Voxel‐based multimodel fitting method for modeling time activity curves in SPECT images

Purpose: Estimating the biodistribution and the pharmacokinetics from time‐sequence SPECT images on a per‐voxel basis is useful for studying activity nonuniformity or computing absorbed dose distributions by convolution of voxel kernels or Monte‐Carlo radiation transport. Current approaches are either region‐based, thus assuming uniform activity within the region, or voxel‐based but using the same fitting model for all voxels. Methods: We propose a voxel‐based multimodel fitting method (VoMM) that estimates a fitting function for each voxel by automatically selecting the most appropriate model among a predetermined set with Akaike criteria. This approach can be used to compute the time integrated activity (TIA) for all voxels in the image. To control fitting optimization that may fail due to excessive image noise, an approximated version based on trapezoid integration, named restricted method, is also studied. From this comparison, the number of failed fittings within images was estimated and analyzed. Numerical experiments were used to quantify uncertainties and feasibility was demonstrated with real patient data. Results: Regarding numerical experiments, root mean square errors of TIA obtained with VoMM were similar to those obtained with bi‐exponential fitting functions, and were lower (< 5% vs. > 10%) than with single model approaches that consider the same fitting function for all voxels. Failure rates were lower with VoMM and restricted approaches than with single‐model methods. On real clinical data, VoMM was able to fit 90% of the voxels and led to less failed fits than single‐model approaches. On regions of interest (ROI) analysis, the difference between ROI‐based and voxel‐based TIA estimations was low, less than 4%. However, the computation of the mean residence time exhibited larger differences, up to 25%. Conclusions: The proposed voxel‐based multimodel fitting method, VoMM, is feasible on patient data. VoMM leads organ‐based TIA estimations similar to conventional ROI‐based method. However, for pharmacokinetics analysis, studies of spatial heterogeneity or voxel‐based absorbed dose assessment, VoMM could be used preferentially as it prevents model overfitting.