Characterizing the voxel-based approaches in radioembolization dosimetry with reDoseMC.

BACKGROUND: Yttrium-90 ( 90 Y $^{90}{\rm {Y}}$ ) represents the primary radioisotope used in radioembolization procedures, while holmium-166 ( 166 Ho $^{166}{\rm {Ho}}$ ) is hypothesized to serve as a viable substitute for 90 Y $^{90}{\rm {Y}}$ due to its comparable therapeutic potential and improved quantitative imaging. Voxel-based dosimetry for these radioisotopes relies on activity images obtained through PET or SPECT and dosimetry methods, including the voxel S-value (VSV) and the local deposition method (LDM). However, the evaluation of the accuracy of absorbed dose calculations has been limited by the use of non-ideal reference standards and investigations restricted to the liver. The objective of this study was to expand upon these dosimetry characterizations by investigating the impact of image resolutions, voxel sizes, target volumes, and tissue materials on the accuracy of 90 Y $^{90}{\rm {Y}}$ and 166 Ho $^{166}{\rm {Ho}}$ dosimetry techniques. METHODS: A specialized radiopharmaceutical dosimetry software called reDoseMC was developed using the Geant4 Monte Carlo toolkit and validated by benchmarking the generated 90 Y $^{90}{\rm {Y}}$ kernels with published data. The decay spectra of both 90 Y $^{90}{\rm {Y}}$ and 166 Ho $^{166}{\rm {Ho}}$ were also compared. Multiple VSV kernels were generated for the liver, lungs, soft tissue, and bone for isotropic voxel sizes of 1 mm, 2 mm, and 4 mm. Three theoretical phantom setups were created with 20 or 40 mm activity and mass density inserts for the same three voxel sizes. To replicate the limited spatial resolutions present in PET and SPECT images, image resolutions were modeled using a 3D Gaussian kernel with a Full Width at Half Maximum (FWHM) ranging from 0 to 16 mm and with no added noise. The VSV and LDM dosimetry methods were evaluated by characterizing their respective kernels and analyzing their absorbed dose estimates calculated on theoretical phantoms. The ground truth for these estimations was calculated using reDoseMC. RESULTS: The decay spectra obtained through reDoseMC showed less than a 1% difference when compared to previously published experimental data for energies below 1.9 MeV in the case of 90 Y $^{90}{\rm {Y}}$ and less than 1% for energies below 1.5 MeV for 166 Ho $^{166}{\rm {Ho}}$ . Additionally, the validation kernels for 90 Y $^{90}{\rm {Y}}$ VSV exhibited results similar to those found in published Monte Carlo codes, with source dose depositions having less than a 3% error margin. Resolution thresholds ( FWHM thresh s ${\rm {FWHM}}_\mathrm{thresh}{\rm {s}}$ ), defined as resolutions that resulted in similar dose estimates between the LDM and VSV methods, were observed for 90 Y $^{90}{\rm {Y}}$ . They were 1.5 mm for bone, 2.5 mm for soft tissue and liver, and 8.5 mm for lungs. For 166 Ho $^{166}{\rm {Ho}}$ , the accuracy of absorbed dose deposition was found to be dependent on the contributions of absorbed dose from photons. Volume errors due to variations in voxel size impacted the final dose estimates. Larger target volumes yielded more accurate mean doses than smaller volumes. For both radioisotopes, the radial dose profiles for the VSV and LDM approximated but never matched the reference standard. CONCLUSIONS: reDoseMC was developed and validated for radiopharmaceutical dosimetry. The accuracy of voxel-based dosimetry was found to vary widely with changes in image resolutions, voxel sizes, chosen target volumes, and tissue material; hence, the standardization of dosimetry protocols was found to be of great importance for comparable dosimetry analysis.

A simple method to shorten the apparent dead time in the dosimetry of Lu-177 for targeted radionuclide therapy using a gamma camera.

BACKGROUND: The dead-time loss reportedly degrades the accuracy of dosimetry using a gamma camera for targeted radionuclide therapy with Lu-177; therefore, the dead-time loss needs to be corrected. However, the correction is challenging. In this study, we propose a novel and simple method to shorten the apparent dead time rather than correcting it through experiments and Monte Carlo simulations. METHODS: An energy window of 208 keV ± 10 % is generally used for the imaging of Lu-177. Lower-energy gamma photons and X-rays of Lu-177 do not contribute to image formation but lead to dead-time losses. In our proposed method, a thin lead sheet was used to shield gamma photons and X-rays with energies lower than 208 keV, while detecting 208 keV gamma photons that penetrated the thin sheet. We measured and simulated the energy spectra and count rate characteristics of a clinical gamma camera system using a cylindrical phantom filled with a Lu-177 solution. Lead sheets of 1.0- and 0.5-mm thicknesses were used as thin shields, and the dead-time losses in tumour imaging with consumed Lu-177 were simulated. RESULTS: The apparent dead times with lead sheets of 1.0- and 0.5-mm thicknesses and without a lead sheet were 1.7, 1.9, and 5.8 µs for an energy window of 208 keV ± 10 %, respectively. The dead-time losses could be reduced from 10 % to 1.3 % using the 1.0-mm thick lead sheet in the simulated imaging of tumour. CONCLUSION: Our method is promising in clinical situations and studies on Lu-177 dosimetry for tumours.

Membrane and Nuclear Absorbed Doses from 177Lu and 161Tb in Tumor Clusters: Effect of Cellular Heterogeneity and Potential Benefit of Dual Targeting-A Monte Carlo Study.

Early use of targeted radionuclide therapy to eradicate tumor cell clusters and micrometastases might offer cure. However, there is a need to select appropriate radionuclides and assess the potential impact of heterogeneous targeting. Methods: The Monte Carlo code CELLDOSE was used to assess membrane and nuclear absorbed doses from 177Lu and 161Tb (ß--emitter with additional conversion and Auger electrons) in a cluster of 19 cells (14-µm diameter, 10-µm nucleus). The radionuclide distributions considered were cell surface, intracytoplasmic, or intranuclear, with 1,436 MeV released per labeled cell. To model heterogeneous targeting, 4 of the 19 cells were unlabeled, their position being stochastically determined. We simulated situations of single targeting, as well as dual targeting, with the 2 radiopharmaceuticals aiming at different targets. Results: 161Tb delivered 2- to 6-fold higher absorbed doses to cell membranes and 2- to 3-fold higher nuclear doses than 177Lu. When all 19 cells were targeted, membrane and nuclear absorbed doses were dependent mainly on radionuclide location. With cell surface location, membrane absorbed doses were substantially higher than nuclear absorbed doses, both with 177Lu (38-41 vs. 4.7-7.2 Gy) and with 161Tb (237-244 vs. 9.8-15.1 Gy). However, when 4 cells were not targeted by the cell surface radiopharmaceutical, the membranes of these cells received on average only 9.6% of the 177Lu absorbed dose and 2.9% of the 161Tb dose, compared with a cluster with uniform cell targeting, whereas the impact on nuclear absorbed doses was moderate. With an intranuclear radionuclide location, the nuclei of unlabeled cells received only 17% of the 177Lu absorbed dose and 10.8% of the 161Tb dose, compared with situations with uniform targeting. With an intracytoplasmic location, nuclear and membrane absorbed doses to unlabeled cells were one half to one quarter those obtained with uniform targeting, both for 177Lu and for 161Tb. Dual targeting was beneficial in minimizing absorbed dose heterogeneities. Conclusion: To eradicate tumor cell clusters, 161Tb may be a better candidate than 177Lu. Heterogeneous cell targeting can lead to substantial heterogeneities in absorbed doses. Dual targeting was helpful in reducing dose heterogeneity and should be explored in preclinical and clinical studies.

S-values for radium-223 and absorbed doses estimates for 223RACL2 using three computational phantoms.

Radium-223 dichloride (223RaCl2), approved by FDA (Food and Drug Administration) in 2013 and in Brazil by ANVISA (Agência Nacional de Vigilância Sanitária) in 2016, offers a new therapeutic option for bone metastases from castration-resistant prostate cancer (CRPC). The advantages of radionuclide therapy for bone metastases include the simultaneous treatment of multiple lesions at the same time. The activity prescription is based on the patient's body weight, disregarding the absorbed dose limit of 2 Gy in the organ at risk: bone marrow. This study focuses on Internal Dosimetry for 223RaCl2 therapy aiming to apply biokinetic models described in the literature to estimate absorbed doses in the organs of interests, especially for the bone marrow. For this purpose, the present paper compares and validates the GATE Monte Carlo simulation with the Radioactive Decay Module (RDM) and calculates a set of S-values for Radium-223 radionuclide using male and female XCAT computational models. Moreover, a comparison of S-values for Radium-223 for three male computational models with different anatomies is also evaluated, Male (standard), Pat1 (lower body weight) and Pat2 (highest body weight). A comprehensive set of S-values was calculated for the Male model, 30 source-regions and 47 target-regions, and for Female model, 30 source-regions and 42 target-regions for Radium-223 and its decay scheme: Radon-219, Polonium-215, Lead-211, Bismuth- 211, Polonium-211 and Thallium-207. The new set of S-values will facilitate absorbed dose calculations for Radium-223 therapy. In addition, Absorbed Dose Evaluation for 223RaCl2 therapy was estimated for three different biodistributions described in the literature within three male computational models. For all biodistributions, the Pat2 phantom has a greatest absorbed dose within the red marrow, when compared with Male and Pat1.

Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment.

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.

Dosimetry assessment of theranostic Auger-emitting radionuclides in a micron-sized multicellular cluster model: A Monte Carlo study using Geant4-DNA simulations.

The present work is aimed at improving the multicellular dosimetry of several Auger radionuclides of interest for targeted cancer therapy, including 99mTc, 111In, 123I, 125I, and 201Tl. For this purpose, using the Geant4-DNA Monte Carlo code, a cluster of 13 similar spherical cells with a hexagonal packed arrangement was modeled, and the mean absorbed doses per unit cumulated activity (S-values) were calculated by considering two target←source configurations, cell←cell and nucleus←nucleus. The obtained ratios of cross-dose to self-dose S-value in terms of the distance between the source and target regions were evaluated and also compared to those estimated by the Medical Internal Radiation Dose (MIRD) method. Besides, the contribution of the Coster-Kronig, Auger and internal conversion electrons to the S-values was provided for each radionuclide. According to the results, it can be concluded that in contrast to self-absorption, the cross-absorption due to the Auger-emitters has not a significant role in the total energy deposition within a cell in the cluster.

Fast beta-emitter Monte Carlo simulations and full patient dose calculations of targeted radionuclide therapy: introducing egs_mird.

BACKGROUND: Targeted radionuclide therapy (TRT) is a fast-growing field garnering much interest, with several clinical trials currently underway, that has a steady increase in development of treatment techniques. Unfortunately, within the field and many clinical trials, the dosimetry calculation techniques used remain relatively simple, often using a mix of S-value calculations and kernel convolutions. PURPOSE: The common TRT calculation techniques, although very quick, can often ignore important aspects of patient anatomy and radionuclide distribution, as well as the interplay there-in. This paper introduces egs_mird, a new Monte Carlo (MC) application built in EGSnrc which allows users to model full patient tissue and density (using clinical CT images) and radionuclide distribution (using clinical PET images) for fast and detailed dose TRT calculation. METHODS: The novel application egs_mird is introduced along with a general outline of the structure of egs_mird simulations. The general structure of the code, and the track-length (TL) estimator scoring implementation for variance reduction, is described. A new egs++ source class egs_internal_source, created to allow detailed patient-wide source distribution, and a modified version of egs_radionuclide_source, changed to be able to work with egs_internal_source, are also described. The new code is compared to other MC calculations of S-values kernels of 131 I, 90 Y, and 177 Lu in the literature, along with further self-validation using a histogram variant of the electron Fano test. Several full patient prostate 177 Lu TRT prostate cancer treatment simulations are performed using a single set of patient DICOM CT and [18 F]-DCFPyL PET data. RESULTS: Good agreement is found between S-value kernels calculated using egs_mird with egs_internal_source and those found in the literature. Calculating 1000 doses (individual voxel uncertainties of ∼0.05%) in a voxel grid Fano test for monoenergetic 500 keV electrons and 177 Lu electrons results in 94% and 99% of the doses being within 0.1% of the expected dose, respectively. For a hypothetical 177 Lu treatment, patient prostate, rectum, bone marrow, and bladder dose volume histograms (DVHs) results did not vary significantly when using the TL estimator and not modeling electron transport, modeling bone marrow explicitly (rather than using generic tissue compositions), and reducing activity to voxels containing partial or full calcifications to half or none, respectively. Dose profiles through different regions demonstrate there are some differences with model choices not seen in the DVH. Simulations using the TL estimator can be completed in under 15 min (∼30 min when using standard interaction scoring). CONCLUSION: This work shows egs_mird to be a reliable MC code for computing TRT doses as realistically as the patient Computed Tomography (CT) and Positron Emission Tomography (PET) data allow. Furthermore, the code can compute doses to sub-1% uncertainty within 15 min, with little to no optimization. Thus, this work supports the use of egs_mird for dose calculations in TRT.

Dosimetry in targeted alpha therapy. A systematic review: current findings and what is needed.

Objective. A systematic review of dosimetry in Targeted Alpha Therapy (TAT) has been performed, identifying the common issues.Approach. The systematic review was performed in accordance with the PRISMA guidelines, and the literature was searched using the Scopus and PubMed databases.Main results. From the systematic review, three key points should be considered when performing dosimetry in TAT. (1) Biodistribution/Biokinetics: the accuracy of the biodistribution data is a limit to accurate dosimetry in TAT. The biodistribution of alpha-emitting radionuclides throughout the body is difficult to image directly, with surrogate radionuclide imaging, blood/faecal sampling, and animal studies able to provide information. (2) Daughter radionuclides: the decay energy of the alpha-emissions is sufficient to break the bond to the targeting vector, resulting in a release of free daughter radionuclides in the body. Accounting for daughter radionuclide migration is essential. (3) Small-scale dosimetry and microdosimetry: due to the short path length and heterogeneous distribution of alpha-emitters at the target site, small-scale/microdosimetry are important to account for the non-uniform dose distribution in a target region, organ or cell and for assessing the biological effect of alpha-particle radiation.Significance. TAT is a form of cancer treatment capable of delivering a highly localised dose to the tumour environment while sparing the surrounding healthy tissue. Dosimetry is an important part of treatment planning and follow up. Being able to accurately predict the radiation dose to the target region and healthy organs could guide the optimal prescribed activity. Detailed dosimetry models accounting for the three points mentioned above will help give confidence in and guide the clinical application of alpha-emitting radionuclides in targeted cancer therapy.

Super-selective intra-arterial platinum-based chemotherapy concurrent with low-dose-rate plaque brachytherapy in the treatment of retinoblastoma: A simulation study.

OBJECTIVE: Retinoblastoma is the most common cancer among children under 5 years of age. The common conventional methods for the treatment of retinoblastoma include chemotherapy and brachytherapy (BT). This study investigated the concurrent use of BT with 125I and 103Pd sources and chemotherapy with platinum-based chemotherapy drugs for retinoblastoma. MATERIALS AND METHODS: The absorbed doses in different parts of the eye were measured with and without platinum. Platinum concentrations of 5, 7.5, 10, and 15 mg/g were evaluated, and the dose enhancement factors (DEFs) were calculated for different cases. RESULTS: For the 125I source, the DEFs at the tumor apex were 1.49, 1.67, 1.81, and 1.97 at concentrations of 5, 7.5, 10, and 15 mg/g, respectively. The DEF decreased dramatically beyond the apex at 0.85 cm from tumor base and was 0.87, 0.82, 0.76, and 0.63 for the abovementioned concentrations, respectively. For the 103Pd source, the DEFs were 1.15, 1.24, 1.21, and 1.07, respectively, at the apex and 0.76, 0.65, 0.56, and 0.39, respectively, beyond the apex. CONCLUSIONS: Our results showed that the concurrent use of low-dose-rate plaque BT and platinum-based chemotherapy significantly increased the tumor-absorbed dose and decreased the absorbed dose in areas outside the tumor and the treatment time.

In silico dosimetry of low-dose rate brachytherapy using radioactive nanoparticles.

PURPOSE: Nanoparticles (NPs) with radioactive atoms incorporated within the structure of the NP or bound to its surface, functionalized with biomolecules are reported as an alternative to low-dose-rate seed-based brachytherapy. In this study, authors report a mathematical dosimetric study on low-dose rate brachytherapy using radioactive NPs. METHOD: Single-cell dosimetry was performed by calculating cellular S-values for spherical cell model using Au-198, Pd-103 and Sm-153 NPs. The cell survival and tumor volume versus time curves were calculated and compared to the experimental studies on radiotherapeutic efficiency of radioactive NPs published in the literature. Finally, the radiotherapeutic efficiency of Au-198, Pd-103 and Sm-153 NPs was tested for variable: administered radioactivity, tumor volume and tumor cell type. RESULT: At the cellular level Sm-153 presented the highest S-value, followed by Pd-103 and Au-198. The calculated cell survival and tumor volume curves match very well with the published experimental results. It was found that Au-198 and Sm-153 can effectively treat highly aggressive, large tumor volumes with low radioactivity. CONCLUSION: The accurate knowledge of uptake rate, washout rate of NPs, radio-sensitivity and tumor repopulation rate is important for the calculation of cell survival curves. Self-absorption of emitted radiation and dose enhancement due to AuNPs must be considered in the calculations. Selection of radionuclide for radioactive NP must consider size of tumor, repopulation rate and radiosensitivity of tumor cells. Au-198 NPs functionalized with Mangiferin are a suitable choice for treating large, radioresistant and rapidly growing tumors.

A Monte Carlo Investigation of Dose Point Kernel Scaling for α-Emitting Radionuclides.

Background: Density-based dose point kernel (DPK) scaling accuracy was investigated in various homogeneous tissue media. Methods: Using GEometry ANd Tracking 4 Monte Carlo code, DPKs were generated for 5, 8 MeV monoenergetic α particles and 223Ra, 225Ac, and 227Th. Dose was scored in 1 µm thick concentric shells and DPKs were scaled based on the tissue's mass density and compared with the water DPK. Results: Scaled kernels agreed within ±5% except near the Bragg peaks, where they differed up to 25%. Conclusions: The authors conclude that kernel scaling based on mass density of the transport medium can be utilized accurately up to 5%, excluding Bragg peak regions.

The Impact of Tissue Type and Density on Dose Point Kernels for Patient-Specific Voxel-Wise Dosimetry: A Monte Carlo Investigation.

We report the generation of dose point kernels for clinically-relevant radionuclide beta decays and monoenergetic electrons in various tissues to understand the impact of tissue type on dose point kernels. Currently available voxel-wise dosimetry approaches using dose point kernels ignore tissue composition and density heterogeneities. Therefore, the study on the impact of tissue type on dose point kernels is warranted. Simulations were performed using the GATE Monte Carlo toolkit, which encapsulates GEANT4 libraries. Dose point kernels were simulated in phantoms of water, compact bone, lung, adipose tissue, blood and red marrow for radionuclides 90Y, 188Re, 32P, 89Sr, 186Re, 153Sm and 177Lu and monoenergetic electrons (0.015-10 MeV). All simulations were performed by assuming an isotropic point source of electrons at the center of a homogeneous spherical phantom. Tissue-specific differences between kernels were investigated by normalizing kernels for effective pathlength. Transport of 20 million particles was found to provide sufficient statistical precision in all simulated kernels. The simulated dose point kernels demonstrate excellent agreement with other Monte Carlo packages. Deviation from kernels reported in the literature did not exceed a 10% global difference, which is consistent with the variability among published results. There are no significant differences between the dose point kernel in water and kernels in other tissues that have been scaled to account for density; however, tissue density predictably demonstrated itself to be a significant variable in dose point kernel distribution.

Assessment of Therapy-Related Myeloid Neoplasms in Patients With Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy: A Systematic Review.

Importance: Peptide receptor radionuclide therapy (PRRT) is a tumor-targeted treatment that uses radiation to induce tumor cell death in neuroendocrine tumors (NET) via ß particle-emitting radionuclide linked to a somatostatin peptide analog. Therapy-related myeloid neoplasm (t-MN) has been reported as a potential long-term and frequently lethal adverse event after PRRT. However, the incidence, time of diagnosis, and nature of t-MN is unclear. Therefore, a systematic review is helpful to study the incidence and characteristics of t-MN after PRRT in patients with NET. Objective: To systematically evaluate the literature and report the incidence, time of diagnosis, and nature of t-MN after PRRT. Evidence Review: MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for articles and abstracts reporting studies of different designs studying more than 1 patient (randomized clinical trials, prospective phase I or phase II, retrospective studies, and case series) were searched from database inception through April 2019. Studies of interest included patients with NET who were treated with PRRT and reported the incidence of t-MN, if any. The primary outcome was the incidence of t-MN. Findings: Twenty-eight articles were identified comprising 7334 patients who were treated with PRRT for NET. The main reason of exclusion was not reporting the t-MN incidence. The incidence of t-MN was variable between studies with mean (SD) incidence of 2.61% (4.38%). Of all 134 cases, cytogenetic abnormalities were reported in 32 patients with the most common abnormality being complex cytogenetics, consistent with myeloid neoplasms following exposure to alkylating agents or irradiation. Conclusions and Relevance: The risk of t-MN after PRRT is small but not insignificant given the poor prognosis after t-MN diagnosis. Close monitoring is warranted to identify such patients early in the disease course when hematologic abnormalities persist.

A cell-based dosimetry model for radium-223 dichloride therapy using bone micro-CT images and GATE simulations.

Dosimetry at the cellular level has outperformed macrodosimetry in terms of agreement with toxicity effects in clinical studies. This fact has encouraged dosimetry studies aiming to quantify the absorbed doses needed to reach radiotoxicity at the cellular level and to inform recommendations on the administration of radium-223. The aim of this work is to qualitatively and quantitatively evaluate the absorbed doses of radium-223 and the interactions of the doses at the cellular level. The analysis was performed by Monte Carlo simulations in GATE using micro-CT image of a mouse. Two physics lists available in the GATE code were tested. The influence of single and multiple scattering models on the absorbed dose distribution and number of particle hits was also studied. In addition, the fuzzy c-means clustering method was used for data segmentation. The segmentation method was suitable for these analyses, particularly given that it was unsupervised. There was no significant difference in the estimated absorbed dose between the two proposed physics lists. The absorbed dose values were not significantly influenced by scattering, although single scattering resulted in twice as many interactions as multiple scattering. The absorbed dose histogram at the voxel level shows heterogeneous absorbed dose values within each shell, but the observations from the graph of the medians were comparable to those in the literature. The interaction histogram indicates 104 events, although some voxels had no interactions with alpha particles. However, the voxels did not show absorbed doses capable of deterministic effects in the deepest part of the bone marrow. The absorbed dose distribution in images of mouse trabecular bone was compatible with simple geometric models, with absorbed doses capable of deterministic effects near the bone surface. The interaction distributions need to be correlated with in vivo studies for better interpretation.

A deep learning approach to radiation dose estimation.

Currently methods for predicting absorbed dose after administering a radiopharmaceutical are rather crude in daily clinical practice. Most importantly, individual tissue density distributions as well as local variations of the concentration of the radiopharmaceutical are commonly neglected. The current study proposes machine learning techniques like Green's function-based empirical mode decomposition and deep learning methods on U-net architectures in conjunction with soft tissue kernel Monte Carlo (MC) simulations to overcome current limitations in precision and reliability of dose estimations for clinical dosimetric applications. We present a hybrid method (DNN-EMD) based on deep neural networks (DNN) in combination with empirical mode decomposition (EMD) techniques. The algorithm receives x-ray computed tomography (CT) tissue density maps and dose maps, estimated according to the MIRD protocol, i.e. employing whole organ S-values and related time-integrated activities (TIAs), and from measured SPECT distributions of 177Lu radionuclei, and learns to predict individual absorbed dose distributions. In a second step, density maps are replaced by their intrinsic modes as deduced from an EMD analysis. The system is trained using individual full MC simulation results as reference. Data from a patient cohort of 26 subjects are reported in this study. The proposed methods were validated employing a leave-one-out cross-validation technique. Deviations of estimated dose from corresponding MC results corroborate a superior performance of the newly proposed hybrid DNN-EMD method compared to its related MIRD DVK dose calculation. Not only are the mean deviations much smaller with the new method, but also the related variances are much reduced. If intrinsic modes of the tissue density maps are input to the algorithm, variances become even further reduced though the mean deviations are less affected. The newly proposed hybrid DNN-EMD method for individualized radiation dose prediction outperforms the MIRD DVK dose calculation method. It is fast enough to be of use in daily clinical practice.

A novel 169 Yb-based dynamic-shield intensity modulated brachytherapy delivery system for prostate cancer.

PURPOSE: Intensity modulated brachytherapy (IMBT) is a novel high dose rate brachytherapy (HDR BT) technique which incorporates static or dynamic shielding to increase tumor coverage and/or spare healthy tissues. The purpose of this study is to present a novel delivery system (AIM-Brachy) design that can enable dynamic-shield IMBT for prostate cancer. METHODS: The AIM-Brachy system dynamically controls the rotation of platinum shields, placed within interstitial catheters, which partially collimate the radiation emitted from an 169 Yb source. Conventional HDR BT (10 Ci 192 Ir) and IMBT (18 Ci 169 Yb) plans were generated for 12 patients using an in-house column generation-based optimizer, coupled to a Geant4-based dose calculation engine, RapidBrachyMC. Treatment plans were normalized to match the same PTV D90 coverage as the clinical plan. Intershield attenuation effects were taken into account. A sensitivity analysis was performed to evaluate the dosimetric impact of systematic longitudinal source positioning errors ( ± 1 mm, ± 2 mm, and ± 3 mm) and rotational errors ( ± 5 ∘ , ± 10 ∘ , and ± 15 ∘ ) on clinically relevant parameters (PTV D90 and urethra D10 ). RESULTS: The platinum shield reduced the dose rate on the shielded side at 1 cm to 18.1% of the dose rate on the unshielded side. For equal PTV D90 coverage, the urethral D10 was reduced by 13.3%  ±  4.7%, without change to other plan quality indices (PTV V100 , V150, V200 , bladder V75 , rectum V75 , HI, COIN). Delivery times for HDR BT and IMBT were 9.2 ± 1.6 min and 18.6 ± 4.0 min, respectively. In general, the PTV D90 was more sensitive to source positioning errors than rotational errors, while the urethral D10 was more sensitive to rotational errors than source positioning errors. For a typical range of positioning errors ( ± 1 mm, ± 5 ∘ ), the overall tolerance was <2%. CONCLUSIONS: The AIM-Brachy system was proposed to deliver dynamic-shield IMBT for prostate cancer with the potential to create a low dose tunnel within the urethra. The urethra-sparing properties are desirable to minimize the occurrence and severity of urethral strictures or, alternatively, to provide a method for dose escalation.

Dose point kernels for 2,174 radionuclides.

PURPOSE: Rapid adoption of targeted radionuclide therapy as an oncologic intervention has motivated the development of patient-specific voxel-wise approaches to radiation dosimetry. These approaches often rely on pretabulated dose point kernels for convolution-based calculations; however, these dose kernels are sparse in literature and often have suboptimal characteristics. The purpose of this work was to generate an extensive library of dose point kernels with sufficient size and resolution for general clinical application of voxel-wise dosimetry. METHODS: Nuclear data were acquired for 2174 radionuclides from the National Nuclear Data Center (Brookhaven National Laboratory, accessed March 2018). Based on these data, isotropic point sources of radioactivity in water were simulated using Monte Carlo N-Particle transport v6.2 (MCNP6.2, Los Alamos National Laboratory). Simulations were separated by emission type for each radionuclide - photons (γ-rays, x rays), beta particles (positrons, electrons); and discrete electrons (conversion electrons, Auger electrons, Coster-Kronig electrons). Dose was tallied in concentric spherical shells about the point source using an energy deposition pulse-height tally (MCNP *F8 tally). Bins were spaced every 0.1 mm until a radius of 10 cm, and every 1 mm until a radius of 2 m. Positron emissions where treated as electrons for transport, with annihilation photons generated at the origin within the photon simulation. Alpha particle emissions were not simulated since their energy is deposited within ~0.2 mm of the source. Neutron and spallation effects were not considered. A subset of the resultant dose point kernels (11 C, 18 F, 32 P, 52g Mn, 64 Cu, 67 Ga, 89 Sr, 89 Zr, 90 Y, 99m Tc, 111 In, 117m Sn, 123 I, 124 I, 125 I, 131 I, 153 Sm, 177 Lu, 186 Re, 188 Re, 211 As, 212 Pb, 213 Bi, 223 Ra, and 225 Ac) were evaluated for accuracy based on conservation of energy, comparison to kernels in the literature, and statistical precision. RESULTS: Among dose point kernels that were manually reviewed, good agreement with previously published dose point kernels was observed. Energy within the kernels was found to be conserved to within 1% of the value expected from nuclear data, suggesting that a radius of 2 m was sufficient to capture the almost all of the energy released during decay for all isotopes considered. Local dosimetric uncertainty, evaluated at the radius of 99% energy deposition, was found to be less than 9% for all radioisotopes evaluated. Rebinning data more coarsely by a factor of 10, similar to what would be done for a clinical dose calculation, results in all evaluated kernels having a relative error of less than 1.1% at R50% , 1.5% at R90% , and 2.7% at R99% (the radius corresponding to 50%, 90%, and 99% of total energy deposition, respectively). The kernels produced in this work have been made freely available (https://zenodo.org/record/2564036). CONCLUSIONS: An extensive library of high-resolution radial dose kernels was generated and validated against published data. In addition to enabling patient-specific voxel-wise internal dosimetry by convolution superposition, the generated dose point kernels data may prove useful to the wider health physics community.

Texture analysis in 177Lu SPECT phantom images: Statistical assessment of uniformity requirements using texture features.

The purpose of this study was to apply texture analysis (TA) to evaluate the uniformity of SPECT images reconstructed with the 3D Ordered Subsets Expectation Maximization (3D-OSEM) algorithm. For this purpose, a cylindrical homogeneous phantom filled with 177Lu was used and a total of 24 spherical volumes of interest (VOIs) were considered inside the phantom. The location of the VOIs was chosen in order to define two different configurations, i.e. gravity and radial configuration. The former configuration was used to investigate the uniformity of distribution of 177Lu inside the phantom, while the latter configuration was used to investigate the lack of uniformity from center towards edge of the images. For each VOI, the trend of different texture features considered as a function of 3D-OSEM updates was investigated in order to evaluate the influence of reconstruction parameters. TA was performed using CGITA software. The equality of the average texture feature trends in both spatial configurations was assumed as the null hypothesis and was tested by functional analysis of variance (fANOVA). With regard to the gravity configuration, no texture feature rejected the null hypothesis when the number of subsets increased. For the radial configuration, the statistical analysis revealed that, depending on the 3D-OSEM parameters used, a few texture features were capable of detecting the non-uniformity of 177Lu distribution inside the phantom moving from the center of the image towards its edge. Finally, cross-correlation coefficients were calculated to better identify the features that could play an important role in assessing quality assurance procedures performed on SPECT systems.

Comparison between Targeted Radionuclide Therapy of Bone Metastases Based on ß-Emitting and α-Emitting Radionuclides.

INTRODUCTION: The α- and ß-emitter radionuclides are used for palliative treatment of bone metastasis. Our objective was to compare the dosimetric parameters of radionuclides used in bone pain palliation therapy. METHODS: Monte Carlo code, MCNPX, was used to simulate radiation transport. Dosimetric calculations were performed for monoenergetic electrons with energies of 0.1-3 MeV, α-particles with energies of 3-10 MeV, and several radionuclides 32P, 89Sr, 153Sm, 177Lu, 223Ra, and its progeny. The simulated phantom consisted of bone marrow, an endosteal layer, bone, and soft tissue. Source tissues included bone marrow, endosteal layer, and bone. Absorbed fractions and specific absorbed fractions were calculated for target regions. Absorbed doses were calculated for investigated radionuclides. RESULTS: The obtained results demonstrated that the dosimetric parameters vary depending on the source or target size, particle energy, and location of the source. The ß-emitter radionuclides were able to penetrate the bone marrow region, whereas the α-emitter radionuclides gave a higher and localized dose to the bone and endosteal layer in comparison. CONCLUSION: 223Ra and 177Lu have fewer side effects on the bone marrow, and they may be a better choice for use in bone pain palliation radiotherapy.

Evaluación del riesgo radiológico en la radiosinoviortesis y el tratamiento mielosupresor de la policitemia vera / Radiological risk assessment in radiosynoviorthesis and the myelosupressor treatment of polycythemia vera

Introducción: La aplicación del método de la matriz de riesgo para la evaluación del riesgo radiológico en la medicina permite identificar de manera proactiva debilidades en las etapas del proceso y hacer un plan de acciones de mejora para la seguridad y calidad. Objetivo: Evaluar los riesgos radiológicos de la radiosinoviortesis y el tratamiento mielosupresor con Fósforo-32 de la policitemia vera. Método: Se utilizó el método de matriz de riesgo y se realizó el análisis y tratamiento de los riesgos radiológicos por medio del código cubano SECURE-MR-FMEA 3.0. Resultados: El 17 por ciento del riesgo alto se eliminó con las medidas adicionales adoptadas; predominaron las consecuencias medias para los trabajadores y el público, 30 por ciento y el 14 por ciento, respectivamente. Las defensas más importantes fueron: levantamiento radiológico inicial de las áreas del departamento; revisión independiente del proyecto con las regulaciones de seguridad aplicables; inspección de trabajos de construcción civil y montaje de equipos antes de iniciar la operación del departamento; capacitación de los médicos nucleares en los tratamientos; existencia de protocolos de tratamiento; análisis de lecciones aprendidas de incidentes radiológicos; levantamiento radiológico periódico de las áreas del servicio y procedimiento de emergencia para reducir la dosis en órganos críticos en caso de administración errónea de radiofármacos. Se creó una base de datos de incidentes utilizada como referencia para el modelo utilizado. El factor humano fue la causa mayor de los sucesos radiológicos analizados (88 por ciento). Conclusiones: Estos resultados facilitan la toma de decisiones para el mejor desempeño de la radiosinoviortesis y el tratamiento de la policitemia vera con Fósforo-32 en Cuba. Se sugiere elaborar el plan de mejora de la seguridad con especial atención a las operaciones de administración del radiofármaco en ambos casos.(AU)

Introduction: The application of risk matrix for ionizing radiation medicine allow identify in proactive way the weakness of the process' step, which implies in the design of safety and quality improvement plan for this. Method: Risk matrix method applied for radiosynoviorthesis and the myelosupressor treatment with Phosphorus-32 of polycythemia vera. The Cuban code SECURE-MR-FMEA 3.0 is used. Results: It was eliminated the 17 percent of the high risk with additional measures, and the medium consequences for workers and public are 30 percent and 14 percent, respectively. The most important identified safety measures were the initial radiological monitoring from different nuclear medicine department areas; the project revision based on the applicable safety regulations; a survey of civil construction works and equipment assembly before work began; training of nuclear medicine doctors in related aspects of nuclear medicine treatments; existence of treatment protocols; the analysis of learned lessons from radiological incidents; the periodical radiological monitoring from different services areas and the emergency procedure for the cases of mistake in the radiopharmaceuticals administration. Human factor was the major cause in analyzed radiological events (88 percent). Conclusions: These results facilitate taking decisions for the best performance of radiosynoviorthesis and the myelosupressor treatment with Phosphorus-32 of polycythemia vera in Cuba. It is recommended to elaborate the safety improvement plan from these and focussing in the radiopharmaceutical administration operations in both cases.(AU)