RODES software for dose assessment of rats and mice contaminated with radionuclides.

In order to support animal experiments of chronic radionuclides intake with realistic dosimetry, voxel-based three-dimensional computer models of mice and rats of both sexes and three ages were built from magnetic resonance imaging. Radiation transport of mono-energetic photons of 11 energies and electrons of 7 energies was simulated with MCNPX 2.6c to assess specific absorbed fractions (SAFs) of energy emitted from 13 source regions and absorbed in 28 target regions. RODES software was developed to combine SAF with radiation emission spectra and user-supplied biokinetic data to calculate organ absorbed doses per nuclear transformation of radionuclides in source regions (S-factors) and for specific animal experiments with radionuclides. This article presents the design of RODES software including the simulation of the particles in the created rodent voxel phantoms. SAF and S-factor values were compared favourably with published results from similar studies. The results are discussed for rodents of different ages and sexes.

A mouse model of cytogenetic analysis to evaluate caesium137 radiation dose exposure and contamination level in lymphocytes.

In case of external overexposure to ionizing radiation, an estimation of its genotoxic effects on exposed individuals can be made retrospectively by the measurement of radiation-induced chromosome aberrations on circulating lymphocytes. Compared with external irradiation, intakes of radionuclides may, however, lead to specific features influencing dose distribution at the scale of body, of tissue or even of cell. Therefore, in case of internal contamination by radionuclides, experimental studies, particularly using animal models, are required to better understand mechanisms of their genotoxic effects and to better estimate the absorbed dose. The present study was designed to evaluate a cytogenetic method in mouse peripheral blood lymphocytes that would allow determination of yields and complexities of chromosome aberrations after low-dose rate exposure to (137)Cs delivered in vitro either by irradiation or by contamination. By using M-FISH analysis, we compared the low-dose rate responses observed in mouse to the high-dose rate responses observed both in mouse and in human. Promising similarities between the two species in the relative biological effect evaluation show that our cytogenetic model established in mouse might be useful to evaluate various radiation exposures, particularly relevant in case of intakes of radionuclides.

Two new δ-globin gene variants: Hb A(2)-Saint-Etienne [δ14(A11)Leu→Pro (HBD: c.44T>C)] and Hb A(2)-Marseille [δ22(B4) Ala→Lys (HBD: c.67G>A;68C>A)].

We report two new variants of the δ-globin gene: Hb A(2)-Saint-Etienne [δ14(A11)Leu→Pro] and Hb A(2)-Marseille [δ22(B4)Ala→Lys]. The first variant has a low rate of expression, the second results from a double nucleotide mutation on the same codon.

A mobile high-resolution gamma camera for therapeutic dose control during radionuclide therapy.

Objective.Molecular radiotherapy is the most used treatment modality against malign and benign diseases of thyroid. In that context, the large heterogeneity of therapeutic doses in patients and the range of effects observed show that individualized dosimetry is essential for optimizing treatments according to the targeted clinical outcome.Approach.We developed a high-resolution mobile gamma camera specifically designed to improve the quantitative assessment of the distribution and biokinetics of131I at patients's bedside after treatment of thyroid diseases. The first prototype has a field of view of 5 × 5 cm2and consists of a high-energy parallel-hole collimator made of 3D-printed tungsten, coupled to a 6 mm thick CeBr3scintillator readout by an array of silicon photomultiplier detectors. The intrinsic and overall imaging performance of the camera was evaluated with133Ba and131I sources. In order to test its quantification capability in realistic clinical conditions, two different 3D-printed thyroid phantoms homogeneously filled with131I were used. Both single view and conjugate view approaches have been applied, with and without scatter correction technique.Main Results.The camera exhibits high imaging performance with an overall energy resolution of 7.68 ± 0.01%, a submillimetric intrinsic spatial resolution of 0.74 ± 0.28 mm and a very low spatial distortion 0.15 ± 0.10 mm. The complete calibration of the camera shows an overall spatial resolution of 3.14 ± 0.03 mm at a distance of 5 cm and a corresponding sensitivity of 1.23 ± 0.01 cps/MBq, which decreases with distance and slightly changes with source size due to the influence of scattering. Activity recovery factors better than 97% were found with the thyroid phantoms.Significance.These preliminary results are very encouraging for the use of our camera as a tool for accurate quantification of absorbed doses and currently motivates the development of a fully operational clinical camera with a 10 × 10 cm2field of view and improved imaging capabilities.

OpenDose: Open-Access Resource for Nuclear Medicine Dosimetry.

Radiopharmaceutical dosimetry depends on the localization in space and time of radioactive sources and requires the estimation of the amount of energy emitted by the sources deposited within targets. In particular, when computing resources are not accessible, this task can be performed using precomputed tables of specific absorbed fractions (SAFs) or S values based on dosimetric models. The aim of the OpenDose collaboration is to generate and make freely available a range of dosimetric data and tools. Methods: OpenDose brings together resources and expertise from 18 international teams to produce and compare traceable dosimetric data using 6 of the most popular Monte Carlo codes in radiation transport (EGSnrc/EGS++, FLUKA, GATE, Geant4, MCNP/MCNPX, and PENELOPE). SAFs are uploaded, together with their associated statistical uncertainties, in a relational database. S values are then calculated from monoenergetic SAFs on the basis of the radioisotope decay data presented in International Commission on Radiological Protection Publication 107. Results: The OpenDose collaboration produced SAFs for all source region and target combinations of the 2 International Commission on Radiological Protection Publication 110 adult reference models. SAFs computed from the different Monte Carlo codes were in good agreement at all energies, with SDs below individual statistical uncertainties. Calculated S values were in good agreement with OLINDA/EXM 2.0 (commercial) and IDAC-Dose 2.1 (free) software. A dedicated website (www.opendose.org) has been developed to provide easy and open access to all data. Conclusion: The OpenDose website allows the display and downloading of SAFs and the corresponding S values for 1,252 radionuclides. The OpenDose collaboration, open to new research teams, will extend data production to other dosimetric models and implement new free features, such as online dosimetric tools and patient-specific absorbed dose calculation software, together with educational resources.

Development of a dosimetric model for in vitro labelled cells with ß + emitters in PET tracking studies.

Positron emission tomography (PET) offers an effective method for tracking ß + emitters-labeled cells in vivo. However, in vitro high labelling activities used may cause cell damage or death. Our understanding of the impact of such procedure remains limited by the fact that the biological effects are usually linked to the activity per cell rather than the absorbed dose. To assess the dose delivered to the cells during the radiolabelling, a multi-cellular dosimetry computational tool was developed, allowing the study of two key parameters: the cell density and the labelling efficiency. Through a hybrid method based on Monte Carlo simulations (MCNP6 code) and an analytical approach implemented in Python, the mean absorbed dose received by a target cell was calculated for distributions with a very large number of cells-up to hundreds of millions. An advanced investigation of in vitro cell labelling with ß-emitting radionuclides was carried out via (i) a systematic study of the effects of the labelling parameters on the cell absorbed dose for 18F, 64Cu and 68Ga, and (ii) a quantitative comparison between cellular and conventional dosimetry. The results provided a thorough analysis of how the dose (self, cross and extracellular medium dose contributions) varies with the initial labelling parameters selected and highlighted the conditions where the cellular dosimetry is required over the conventional dosimetry. The dosimetric model was finally applied to real conditions of 18F-FDG labelling on the basis of eight reported studies. The results showed that similar activity per cell can lead to significantly different absorbed dose and pointed out differences between cellular and conventional dosimetry up to a factor of 5.

223Ra-dichloride therapy of bone metastasis: optimization of SPECT images for quantification.

BACKGROUND: 223Ra imaging is crucial to evaluate the successfulness of the therapy of bone metastasis of castration-resistant prostate cancer (CRPC). The goals of this study were to establish a quantitative tomographic 223Ra imaging protocol with clinically achievable conditions, as well as to investigate its usefulness and limitations. We performed several experiments using the Infinia Hawkeye 4 gamma camera (GE) and physical phantoms in order to assess the optimal image acquisition and reconstruction parameters, such as the windows setting, as well as the iteration number and filter of the reconstruction algorithm. Then, based on the MIRD pamphlet 23, we used a NEMA phantom and an anthropomorphic TORSO® phantom to calibrate the gamma camera and investigate the accuracy of quantification. RESULTS: Experiences showed that the 85 keV ± 20%, 154 keV ± 10%, and 270 keV ± 10% energy windows are the most suitable for 223Ra imaging. The study with the NEMA phantom showed that the OSEM algorithm with 2 iterations, 10 subsets, and the Butterworth filter offered the best compromise between contrast and noise. Moreover, the calibration factors for different sphere sizes (26.5 ml, 11.5 ml, and 5.6 ml) were constant for 223Ra concentrations ranging between 6.5 and 22.8 kBq/ml. The values found are 73.7 cts/s/MBq, 43.8 cts/s/MBq, and 43.4 cts/s/MBq for 26.5 ml, 11.5 ml, and 5.6 ml sphere, respectively. For concentration lower than 6.5 kBq/ml, the calibration factors exhibited greater variability pointing out the limitations of SPECT/CT imaging for quantification. By the use of a TORSO® phantom, we simulated several tumors to normal tissue ratios as close as possible to clinical conditions. Using the calibration factors obtained with the NEMA phantom, for 223Ra concentrations higher than 8 kBq/ml, we were able to quantify the activity with an error inferior to 18.8% in a 5.6 ml lesion. CONCLUSIONS: Absolute quantitative 223Ra SPECT imaging appears feasible once the dimension of the target is determined. Further evaluation should be needed to apply the calibration factor-based quantitation to clinical 223Ra SPECT/CT imaging. This will open the possibility for patient-specific 223Ra treatment planning and therapeutic outcome prediction in patients.

The potential of a radiosensitive intracerebral probe to monitor 18F-MPPF binding in mouse hippocampus in vivo.

UNLABELLED: As mouse imaging has become more challenging in preclinical research, efforts have been made to develop dedicated PET systems. Although these systems are currently used for the study of physiopathologic murine models, they present some drawbacks for brain studies, including a low temporal resolution that limits the pharmacokinetic study of radiotracers. The aim of this study was to demonstrate the ability of a radiosensitive intracerebral probe to measure the binding of a radiotracer in the mouse brain in vivo. METHODS: The potential of a probe 0.25 mm in diameter for pharmacokinetic studies was assessed. First, Monte Carlo simulations followed by experimental studies were used to evaluate the detection volume and sensitivity of the probe and its adequacy for the size of loci in the mouse brain. Second, ex vivo autoradiography of 5-hydroxytryptamine receptor 1A (5-HT(1A)) receptors in the mouse brain was performed with the PET radiotracer 2'-methoxyphenyl-(N-2'-pyridinyl)-p-(18)F-fluorobenzamidoethylpiperazine ((18)F-MPPF). Finally, the binding kinetics of (18)F-MPPF were measured in vivo in both the hippocampus and the cerebellum of mice. RESULTS: Both the simulations and the experimental studies demonstrated the feasibility of using small probes to measure radioactive concentrations in specific regions of the mouse brain. Ex vivo autoradiography showed a heterogeneous distribution of (18)F-MPPF consistent with the known distribution of 5-HT(1A) in the mouse brain. Finally, the time-activity curves obtained in vivo were reproducible and validated the capacity of the new probe to accurately measure (18)F-MPPF kinetics in the mouse hippocampus. CONCLUSION: Our results demonstrate the ability of the tested radiosensitive intracerebral probe to monitor binding of PET radiotracers in anesthetized mice in vivo, with high temporal resolution suited for compartmental modeling.

Evaluation of Functionalized Polysaccharide Microparticles Dosimetry for SPECT Imaging Based on Biodistribution Data of Rats.

PURPOSE: Technetium-99 m (Tc-99 m)-labelled microparticles, functionalized with fucoidan to present a high affinity for P-Selectin, or [(99m)Tc] MP-fucoidan, were developed as a novel SPECT radiotracer for abdominal aortic aneurysm (AAA). As a prerequisite step forwards a clinical trial, the biodistribution and dosimetry of these [(99m)Tc] MP-fucoidan microparticles were performed in rats in order to estimate the absorbed and effective dose in humans. PROCEDURES: Microparticles with a maximum hydrodynamic diameter of 4 µm were obtained by crosslinking polysaccharides dextran and pullulan. They were functionalized with fucoidan then radiolabelled with Tc-99 m. A mean labelling efficiency of 92 ± 1% was measured. [(99m)Tc] MP-fucoidan (43 ± 2 MBq) was injected to 24 rats via the penis vein. Rats were euthanized at 30, 60, 120 and 240 min after injection (4 rats at each time point). Samples of each organ, as well as the injected microparticle suspensions, were aliquoted for counting. Four animals were sacrificed for blood clearance studies and four were sacrificed for image analysis and quantification of the cortical, medullary, papillary kidney, and pelvis uptake. A compartmental model was realised using SAAM II and organ data were fitted. The area under the curve was then used to compute the residence times in each rat organs and converted to human residence time values. Absorbed and effective human doses in organs were estimated using (1) the OLINDA/EXM 1.1 software with the hermaphroditic mathematical phantoms and (2) the OEDIPE software associated to the MCNPX Monte Carlo code and the ICRP reference computational male and female phantoms, using the updated tissue weighting factors in the ICRP Publication 103. RESULTS: The highest human residence times were found in the liver, kidneys, and urinary bladder wall. The largest doses were found in the kidneys and then in the urinary bladder wall and liver. The human effective doses were 6.06 µSv/MBq for the hermaphroditic mathematical phantom and 5.95 µSv/MBq for the ICRP adult reference computational phantom. CONCLUSIONS: Animal-based human dose estimates support a future first-in-human testing of [(99m)Tc] MP-fucoidan following IV injection.

Combining the radiosensitive Beta MicroProbe to nuclear magnetic resonance: theoretical approach for in vivo studies in small animals.

In vivo small animal imaging with multiple modalities has become an important tool in modern biomedical research. Indeed, combining exploratory techniques allows simultaneous recording of complementary data, which is required to elucidate complex physiopathological mechanisms. In this field, because of strict technical constraints in vivo, an exciting challenge remains in the combination of Nuclear Magnetic Resonance (NMR) and Positron Emission Tomography (PET). Coupling NMR with a radiosensitive Beta MicroProbe offers therefore a very interesting technical alternative. Here, we assessed the feasibility of this new combination by theoretically evaluating the ability of the Beta MicroProbe to monitor radioactivity in a magnet. To that aim, we modelled with Geant4 the effect of an intense magnetic field on the probe field of view and showed that the field should not have an impact on the global efficiency of the probe.

Three-dimensional personalized Monte Carlo dosimetry in 90Y resin microspheres therapy of hepatic metastases: nontumoral liver and lungs radiation protection considerations and treatment planning optimization.

UNLABELLED: In the last decades, selective internal radiation therapy (SIRT) has become a real alternative in the treatment of unresectable hepatic cancers. In practice, the activity prescription is limited by the irradiation of organs at risk (OAR), such as the lungs and nontumoral liver (NTL). Its clinical implementation is therefore highly dependent on dosimetry. In that context, a 3-dimensional personalized dosimetry technique--personalized Monte Carlo dosimetry (PMCD)-based on patient-specific data and Monte Carlo calculations was developed and evaluated retrospectively on clinical data. METHODS: The PMCD method was evaluated with data from technetium human albumin macroaggregates ((99m)Tc-MAA) evaluations of 10 patients treated for hepatic metastases. Region-of-interest outlines were drawn on CT images to create patient-specific voxel phantoms using the OEDIPE software. Normalized 3-dimensional matrices of cumulated activity were generated from (99m)Tc-SPECT data. Absorbed doses at the voxel scale were then obtained with the MCNPX Monte Carlo code. The maximum-injectable activity (MIA) for tolerance criteria based on either OAR mean absorbed doses (D(mean)) or OAR dose-volume histograms (DVHs) was determined using OEDIPE. Those MIAs were compared with the one recommended by the partition model (PM) with D(mean) tolerance criteria. Finally, OEDIPE was used to evaluate the absorbed doses delivered if those activities were injected to the patient and to generate the corresponding isodose curves and DVHs. RESULTS: The MIA recommended using D(mean) tolerance criteria is, in average, 27% higher with the PMCD method than with the PM. If tolerance criteria based on DVHs are used along with the PMCD, an increase of at least 40% of the MIA is conceivable, compared with the PM. For MIAs calculated with the PMCD, D(mean) delivered to tumoral liver (TL) ranged from 19.5 to 118 Gy for D(mean) tolerance criteria whereas they ranged from 26.6 to 918 Gy with DVH tolerance criteria. Thus, using the PMCD method, which accounts for fixation heterogeneities, higher doses can be delivered to TL. Finally, absorbed doses to the lungs are not the limiting criterion for activity prescription. However, D(mean) to the lungs can reach 15.0 Gy. CONCLUSION: Besides its feasibility and applicability in clinical routine, the interest for treatment optimization of a personalized Monte Carlo dosimetry in the context of SIRT was confirmed in this study.

Three dosimetry models of lipoma arborescens treated by 90Y synovectomy.

PURPOSE: Lipoma arborescens (LA) is a benign intra-articular lipomatous proliferation of the synovial membrane. This extremely rare condition has previously been treated by intra-articular (90)Y radiosynoviorthesis but dosimetry literature on this form of radionuclide therapy is nonexistent. The authors detail methodology for successful treatment of LA and provide for the first time estimates of radiation dosimetry. The authors also analyze the biodistribution of the radiopharmaceutical over the course of the patient's treatment through sequential imaging. METHODS: A patient with bilateral LA underwent intracavity injection of (90)Y citrate colloid to the right and left knee joint spaces (181 and 198 MBq, respectively). SPECT/CT datasets were acquired over 9 days to quantify the biodistribution and kinetics of the radiopharmaceutical. Radiation dosimetry was performed using the MIRD schema (through OLINDA software), a custom voxel-based method, and a direct Monte Carlo calculation (OEDIPE). RESULTS: Follow-up MRI showed marked reduction in LA size in both knees. Mean absorbed doses to the LA were 21.2 ± 0.8 and 42.9 ± 2.3 Gy using OLINDA, 8.1 ± 0.3 and 16.7 ± 0.5 Gy using voxel based methodology, and 8.2 ± 0.3 and 15.7 ± 0.5 Gy for OEDIPE in the right and left LA, respectively. Distribution of the radiopharmaceutical within the joint space alters over the imaging period, with less than 1% of the remaining activity having moved posteriorly in the knee cavity. No uptake was detected outside of the joint space after assessment with whole-body scintigraphy. CONCLUSIONS: An activity of approximately 185 MBq successfully relieved clinical symptoms of LA. There was good correlation between direct Monte Carlo and voxel based techniques, but OLINDA was shown to overestimate the absorbed dose to the tumor. Accurate dosimetry may help select an activity more tailored to the specific size and location of the LA.

Evaluation of absorbed and effective doses to patients from radiopharmaceuticals using the ICRP 110 reference computational phantoms and ICRP 103 formulation.

In diagnostic nuclear medicine, mean absorbed doses to patients' organs and effective doses are published for standard stylised anatomic models. To provide more realistic and detailed geometries of the human morphology, the International Commission on Radiological Protection (ICRP) has recently adopted male and female voxel phantoms to represent the reference adult. This work investigates the impact of the use of these new computational phantoms. The absorbed doses were calculated for 11 different radiopharmaceuticals currently used in diagnostic nuclear medicine. They were calculated for the ICRP 110 reference computational phantoms using the OEDIPE software and the MCNP extended Monte Carlo code. The biokinetic models were issued from ICRP Publications 53, 80 and 106. The results were then compared with published values given in these ICRP Publications. To discriminate the effect of anatomical differences on organ doses from the effect of the calculation method, the Monte Carlo calculations were repeated for the reference adult stylised phantom. The voxel effect, the influence of the use of different densities and nuclear decay data were also investigated. Effective doses were determined for the ICRP 110 adult reference computational phantom with the tissue weighting factor of ICRP Publication 60 and the tissue weighting factors of ICRP Publication 103. The calculation method and, in particular, the simulation of the electron transport have a significant influence on the calculated doses, especially, for small and walled organs. Overestimates of >200 % were observed for the urinary bladder wall of the stylised phantom compared with the computational phantoms. The unrealistic organ topology of the stylised phantom leads to important dose differences, sometimes by an order of magnitude. The effective doses calculated using the new computational phantoms and the new tissue weighting factors are globally lower than the published ones, except for some radiopharmaceuticals, where the differences can reach 60 % higher than the published values. This study analyses the first set of absorbed and effective doses with the new ICRP male and female reference computational phantoms for different radiopharmaceuticals. It highlights the importance of taking into account the electron transport and the realism of the shape and inter-organ distances of the anthropomorphic model used.

Creation of ORNL NURBS-based phantoms: evaluation of the voxel effect on absorbed doses from radiopharmaceuticals.

Doses from radiopharmaceuticals absorbed by organs can be assessed using Monte Carlo simulations and computational phantoms. Patient-based voxel phantoms improve the realism of organ topology but present unrealistic stair-stepped surfaces. The goal of this research was to study the voxel effect on the basis of creation and voxelisation of a series of non-uniform rational B-spline (NURBS) reference phantoms issued from the publication of the Oak Ridge National Laboratory (ORNL). Absorbed doses from various radiopharmaceuticals were calculated and compared with the values obtained for the corresponding analytical phantoms for models of an adult male and a 5-y-old child. Dose differences lower than 12.5 % were observed when the critical structure of the skin was excluded. Moreover, the highest differences were noted for small organs and walls. Finally, all NURBS phantoms of the ORNL series, their voxelised version and the corresponding Monte Carlo N-Particle eXtended input files were programmed and are available for further simulations.