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This paper describes a stack phantom useful for imaging complex activity distributions. It is based on images printed with radioactive ink using a commercial ink-jet printer. The application for the phantom is in the evaluation of planar and SPECT scintillation camera images and for validation of Monte Carlo simulated images. The accuracy in generating the activity distributions on paper sheets is especially important. Here we describe the calibration procedure for the ink-jet printer. The goal of the printer calibration is to find the relationship between the digital image count (voxel grey level) and its corresponding activity on the paper sheets (radioactivity). The relationship between the voxel grey level and the radioactivity on the paper sheets (measured by scanning technique and well counter) was found to be logarithmic, and a 3rd degree polynomial was found to fit the relationship. The distribution of radioactivity in the ink cartridge was investigated by pinhole SPECT. The distribution of 99mTc solution was found to be homogeneous in the ink solution. Experimental studies were done directly on Monte Carlo simulated heart images from the NCAT phantom. The result showed that the simulated images are similar to the images measured using the ink-jet technique. This stack phantom could be a promising solution with an advantage that the exact geometry generated in Monte Carlo could be imitated in the phantom. The phantom is a very flexible device and clearly much more versatile than conventional phantoms which have a fixed geometry and spatial limitation. [ABSTRACT FROM AUTHOR]

Biallelic variants in PISD cause a phenotypic spectrum ranging from short stature with spondyloepimetaphyseal dysplasia (SEMD) to a multisystem disorder affecting eyes, ears, bones, and brain. PISD encodes the mitochondrial-localized enzyme phosphatidylserine decarboxylase. The PISD precursor is self-cleaved to generate a heteromeric mature enzyme that converts phosphatidylserine to the phospholipid phosphatidylethanolamine. We describe a 17-year-old male patient, born to unrelated healthy parents, with disproportionate short stature and SEMD, featuring platyspondyly, prominent epiphyses, and metaphyseal dysplasia. Trio genome sequencing revealed compound heterozygous PISD variants c.569C>T; p.(Ser190Leu) and c.799C>T; p.(His267Tyr) in the patient. Investigation of fibroblasts showed similar levels of the PISD precursor protein in both patient and control cells. However, patient cells had a significantly higher proportion of fragmented mitochondria compared to control cells cultured under basal condition and after treatment with 2-deoxyglucose that represses glycolysis and stimulates respiration. Structural data from the PISD orthologue in Escherichia coli suggest that the amino acid substitutions Ser190Leu and His267Tyr likely impair PISD's autoprocessing activity and/or phosphatidylethanolamine biosynthesis. Based on the data, we propose that the novel PISD p.(Ser190Leu) and p.(His267Tyr) variants likely act as hypomorphs and underlie the pure skeletal phenotype in the patient., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Objective: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease., Methods: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years., Results: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years)., Interpretation: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions., Competing Interests: Declaration of competing interest Dr. Adang is an advisor to Takeda Pharmaceuticals (enzyme replacement study for MLD), Orchard Therapeutics (gene therapy development for MLD), and is a site sub-investigator for the Takeda trial (enzyme replacement study); Dr. Gröschel is an advisor Takeda and Orchard Therapeutics; Dr. Bonkowsky is a site principal investigator for the Takeda trial; Dr. Bernard is a site principal investigator for the Takeda trial; Dr. Weller Grønborg is a consultant to Orchard Therapeutics; Dr. Orchard is a consultant to Orchard Therapeutics. Dr. Krägeloh-Mann is an advisor to Takeda, Orchard Therapeutics; Dr. Vanderver is an advisor to Takeda, Passagebio, Orchard; and is site PI Takeda trial; Dr. Escolar is an advisor to Takeda, Janssen; she is employed by Forge Biologics; Dr. Fumagalli is the license holder of OTL-200, I Orchard Therapeutics trial, advisor Orchard, Takeda, funding Telethon Foundation, GSK, Orchard. Dr. Eichler, Dr. Fatemi, Dr. Gavazzi, Dr. Sevagamoorthy, Ms. Mutua, Ms. Muirhead, Ms. Schmidt, Ms. Pizzino, Ms. Yu, Ms. Jin, Mr. Vincent, Ms. Grzyb, Mr. D'Aiello, Mr. Sherbini, Mr. Bronner, Mr. Patel, Dr. Fraser, Dr. Emrick, Dr. Van Haren, Dr. Ruzhnikov, Dr. Keller, Ms. Uebergang, Ms. Poe, Dr. Yazdani, Dr. Bernat, Dr. Lindstrom, Dr. Stutterd, Dr. Gupta, Dr. Boulanger, Dr. Sylvain, Dr. Nguyen, Dr. Potic, Dr. Ljungberg, Dr. Zambon, Ms. Locatelli, Ms. Elgün, Dr. Kehrer, and Dr. Shults have no relevant disclosures., (Copyright © 2024. Published by Elsevier Inc.)

Background: The aim was to investigate the noise and bias properties of quantitative 177 Lu-SPECT with respect to the number of projection angles, and the number of subsets and iterations in the OS-EM reconstruction, for different total acquisition times., Methods: Experimental SPECT acquisition of six spheres in a NEMA body phantom filled with 177 Lu was performed, using medium-energy collimators and 120 projections with 180 s per projection. Bootstrapping was applied to generate data sets representing acquisitions with 20 to 120 projections for 10 min, 20 min, and 40 min, with 32 noise realizations per setting. Monte Carlo simulations were performed of 177 Lu-DOTA-TATE in an anthropomorphic computer phantom with three tumours (2.8 mL to 40.0 mL). Projections representing 24 h and 168 h post administration were simulated, each with 32 noise realizations. Images were reconstructed using OS-EM with compensation for attenuation, scatter, and distance-dependent resolution. The number of subsets and iterations were varied within a constrained range of the product number of iterations × number of projections ≤ 2400 . Volumes-of-interest were defined following the physical size of the spheres and tumours, the mean activity-concentrations estimated, and the absolute mean relative error and coefficient of variation (CV) over noise realizations calculated. Pareto fronts were established by analysis of CV versus mean relative error., Results: Points at the Pareto fronts with low CV and high mean error resulted from using a low number of subsets, whilst points at the Pareto fronts associated with high CV but low mean error resulted from reconstructions with a high number of subsets. The number of projection angles had limited impact., Conclusions: For accurate estimation of the 177 Lu activity-concentration from SPECT images, the number of projection angles has limited importance, whilst the total acquisition time and the number of subsets and iterations are parameters of importance., (© 2024. The Author(s).)

Purpose: This study aimed to assess the accuracy of patient-specific absorbed dose calculations for tumours and organs at risk in radiopharmaceutical therapy planning, utilizing hybrid planar-SPECT/CT imaging., Methods: Three Monte Carlo (MC) simulated digital patient phantoms were created, with time-activity data for mIBG labelled to I-123 (LEHR and ME collimators) and I-131 (HE collimator). The study assessed the accuracy of the mean absorbed doses for I-131-mIBG therapy treatment planning. Multiple planar whole-body (WB) images were simulated (between 1 to 72 h post-injection (p.i)). The geometric-mean image of the anterior and posterior WB images was calculated, with scatter and attenuation corrections applied. Time-activity curves were created for regions of interest over the liver and two tumours (diameters: 3.0 cm and 5.0 cm) in the WB images. A corresponding SPECT study was simulated at 24 h p.i and reconstructed using the OS-EM algorithm, incorporating scatter, attenuation, collimator-detector response, septal scatter and penetration corrections. MC voxel-based absorbed dose rate calculations used two image sets, (i) the activity distribution represented by the SPECT images and (ii) the activity distribution from the SPECT images distributed uniformly within the volume of interest. Mean absorbed doses were calculated considering photon and charged particle emissions, and beta emissions only. True absorbed doses were calculated by MC voxel-based dosimetry of the known activity distributions for reference., Results: Considering photon and charged particle emissions, mean absorbed dose accuracies across all three radionuclide-collimator combinations of 3.8 ± 5.5% and 0.1 ± 0.9% (liver), 5.2 ± 10.0% and 4.3 ± 1.7% (3.0 cm tumour) and 15.0 ± 5.8% and 2.6 ± 0.6% (5.0 cm tumour) were obtained for image set (i) and (ii) respectively. Considering charged particle emissions, accuracies of 2.7 ± 4.1% and 5.7 ± 0.7% (liver), 3.2 ± 10.2% and 9.1 ± 1.7% (3.0 cm tumour) and 13.6 ± 5.7% and 7.0 ± 0.6% (5.0 cm tumour) were obtained for image set (i) and (ii) respectively., Conclusion: The hybrid WB planar-SPECT/CT method proved accurate for I-131-mIBG dosimetry, suggesting its potential for personalized treatment planning., (© 2024. The Author(s).)

Objectives  The purpose of a parallel-hole collimator in a scintillation camera system is to transmit only those photons that have an emission angle close to the direction of the hole. This makes it possible to receive spatial information about the origin of the emission, that is, radioactivity decay. The dimension, shape, and intrahole thickness determine the spatial resolution and, by a tradeoff, sensitivity. The composition of the collimator material also plays an important role in determining a proper collimator. In this study, we compared tungsten alloys as a potential collimator material replacement for the conventional lead antimony material used in most of the current camera systems. Materials and Methods  Monte Carlo simulations of a commercial scintillation camera system with low energy high resolution (LEHR), medium-energy (ME), and high-energy (HE) collimators of lead, tungsten, and tungsten-based alloy were simulated for different I-131, Lu-177, I-123, and Tc-99m sources, and a Deluxe rod phantom using the SIMIND Monte Carlo code. Planar images were analyzed regarding spatial resolution, image contrast in a cold source case, and system sensitivity for each collimator configuration. The hole dimensions for the three collimators were those specified in the vendor's datasheet. Results  Using Pb, W, and tungsten alloy (Wolfmet) as collimator materials, the full width at half maximum (FWHM) measures for total counts (T) for LEHR with Tc-99m source (6.9, 6.8, and 6.8 mm), for ME with Lu-177 source (11.7, 11.5, and 11.6 mm), and for HE with I-131 (6.2, 13.1, and 13.1 mm) were obtained, and the system sensitivities were calculated as 89.9, 86.1, and 89.8 cps T /MBq with Tc-99m source; 42.7, 17.4, and 20.9 cps T /MBq with Lu-177 source; and 40.1, 69.7, and 77.4 cps T /MBq with I-131 source. The collimators of tungsten and tungsten alloy (97.0% W, 1.5% Fe, 1.5% Ni) provided better spatial resolution and improved image contrast when compared with conventional lead-based collimators. This was due to lower septal penetration. Conclusion  The results suggest that development of a new set of ME and HE tungsten and tungsten alloy collimators could improve imaging of I-131, Lu-177, and I-123., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: A 3D printing grid-based method was developed to construct anthropomorphic phantoms with non-uniform activity distributions, to be used for evaluation of quantitative SPECT images. The aims were to characterize the grid-based method and to evaluate its capability to provide realistically shaped phantoms with non-uniform activity distributions., Methods: Characterization of the grid structures was performed by printing grid-filled spheres. Evaluation was performed by micro-CT imaging to investigate the printing accuracy and by studying the modulation contrast ([Formula: see text]) in SPECT images for 177 Lu and 99m Tc as a function of the grid fillable-volume fraction (FVF) determined from weighing. The grid-based technique was applied for the construction of two kidney phantoms and two thyroid phantoms, designed using templates from the XCAT digital phantoms. The kidneys were constructed with a hollow outer container shaped as cortex, an inner grid-based structure representing medulla and a solid section representing pelvis. The thyroids consisted of two lobes printed as grid-based structures, with void hot spots within the lobes. The phantoms were filled with solutions of 177 Lu (kidneys) or 99m Tc (thyroids) and imaged with SPECT. For verification, Monte Carlo simulations of SPECT imaging were performed for activity distributions corresponding to those of the printed phantoms. Measured and simulated SPECT images were compared qualitatively and quantitatively., Results: Micro-CT images showed that printing inaccuracies were mainly uniform across the grid. The relationships between the FVF from weighing and [Formula: see text] were found to be linear (r = 0.9995 and r = 0.9993 for 177 Lu and 99m Tc, respectively). The FVF-deviations from the design were up to 15% for thyroids and 4% for kidneys, mainly related to possibilities of cleaning after printing. Measured and simulated SPECT images of kidneys and thyroids exhibited similar activity distributions and quantitative comparisons agreed well, thus verifying the grid-based method., Conclusions: We find the grid-based technique useful for the provision of 3D printed, realistically shaped, phantoms with non-uniform activity distributions, which can be used for evaluation of different quantitative methods in SPECT imaging., (© 2024. The Author(s).)

Background: In image processing for activity quantification, the end goal is to produce a metric that is independent of the measurement geometry. Photon attenuation needs to be accounted for and can be accomplished utilizing spectral information, avoiding the need of additional image acquisitions. The aim of this work is to investigate the feasibility of 177 Lu activity quantification with a small CZT-based hand-held gamma-camera, using such an attenuation correction method., Methods: A previously presented dual photopeak method, based on the differential attenuation for two photon energies, is adapted for the three photopeaks at 55 keV, 113 keV, and 208 keV for 177 Lu. The measurement model describes the count rates in each energy window as a function of source depth and activity, accounting for distance-dependent system sensitivity, attenuation, and build-up. Parameter values are estimated from characterizing measurements, and the source depth and activity are obtained by minimizing the difference between measured and modelled count rates. The method is applied and evaluated in phantom measurements, in a clinical setting for superficial lesions in two patients, and in a pre-clinical setting for one human tumour xenograft. Evaluation is made for a LEHR and an MEGP collimator., Results: For phantom measurements at clinically relevant depths, the average (and standard deviation) in activity errors are 17% ± 9.6% (LEHR) and 2.9% ± 3.6% (MEGP). For patient measurements, deviations from activity estimates from planar images from a full-sized gamma-camera are 0% ± 21% (LEHR) and 16% ± 18% (MEGP). For mouse measurements, average deviations of - 16% (LEHR) and - 6% (MEGP) are obtained when compared to a small-animal SPECT/CT system. The MEGP collimator appears to be better suited for activity quantification, yielding a smaller variability in activity estimates, whereas the LEHR results are more severely affected by septal penetration., Conclusions: Activity quantification for 177 Lu using the hand-held camera is found to be feasible. The readily available nature of the hand-held camera may enable more frequent activity quantification in e.g., superficial structures in patients or in the pre-clinical setting., (© 2024. The Author(s).)

Introduction: Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using 133 Ba as a surrogate for 131 I imaging., Materials and Methods: Two sets of four traceable 133 Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68-107.4 mL). Corresponding hollow cylinders to be filled with liquid 131 I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of 133 Ba sources and liquid 131 I., Results: As anticipated, the 131 I pseudo-image calibration factors (cps/MBq) were higher than those for 133 Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12-1.5%. The site-specific cross-calibration method also showed agreement between 133 Ba and 131 I for all cylinder volumes, which highlights the potential use of 133 Ba sources to calculate recovery coefficients for partial volume correction., Conclusion: This comparison exercise demonstrated that traceable solid 133 Ba sources can be used as surrogate for liquid 131 I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with 131 I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals., (© 2023. The Author(s).)

SPECT systems distinguish radionuclides by using multiple energy windows. For CZT detectors, the energy spectrum has a low energy tail leading to additional crosstalk between the radionuclides. Previous work developed models to correct the scatter and crosstalk for CZT-based dedicated cardiac systems with similar 99m Tc/ 123 I tracer distributions. These models estimate the primary and scatter components by solving a set of equations employing the MLEM approach. A penalty term is applied to ensure convergence. The present work estimates the penalty term for any 99m Tc/ 123 I activity level. An iterative approach incorporating Monte Carlo into the iterative image reconstruction loops was developed to estimate the penalty terms. We used SIMIND and XCAT phantoms in this study. Distribution of tracers in the myocardial tissue and blood pool were varied to simulate a dynamic acquisition. Evaluations of the estimated and the real penalty terms were performed using simulations and large animal data. The myocardium to blood pool ratio was calculated using ROIs in the myocardial tissue and the blood pool for quantitative analysis. All corrected images yielded a good agreement with the gold standard images. In conclusion, we developed a CZT crosstalk correction method for quantitative imaging of 99m Tc/ 123 I activity levels by dynamically estimating the penalty terms., Competing Interests: All authors declare that they have no known conflicts of interest in terms of competing financial interests or personal relationships that could have an influence or are relevant to the work reported in this paper.

Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia., Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22)., Findings: Forty-two participants received TransCon CNP at doses of 6 μg (n = 10; 7 female), 20 μg (n = 11; 3 female), 50 μg (n = 10; 3 female), or 100 μg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 μg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 μg CNP/kg/week., Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial., Funding: Ascendis Pharma, A/S., Competing Interests: RS reports participation on advisory boards with Ascendis and BioMarin and consulting role for BridgeBio. AGH reports research funding from, speaker's bureau support for, and grants from Zimvie; patents and stock options with, consulting for, and travel support from Orthopediatrics; and honoraria from BioMarin. ML reports consulting role with and travel support from Ascendis. CAB reports research funding from Ascendis, BioMarin, Ionis, NIH, and Roche; board member for the American Board of Medical Genetics and Genomics; author for 8 chapters in Genetics in UpToDate. MBB reports research funding from Ascendis, BioMarin, QED, and Therachon/Pfizer; consulting fees from Tyra; honoraria from Novo Nordisk; participation on a data and safety monitoring board (DSMB) for BioMarin, QED, and Therachon/Pfizer; and leadership for SDMC. JML reports research funding and honoraria from BioMarin and travel support from Ascendis. WH reports research funding and consulting fees from Ascendis and consulting fees from BioMarin. TQ reports research funding from Ascendis, Janssen, Merck, NIH, and Provention Bio; consulting fees from Janssen and Provention Bio; honoraria from Merck and MH Life Sciences; expert testimony payment from Janssen; and travel support from Provention Bio. MJA reports research funding from Ascendis, Lumos, MannKind, Medtronic, Novo Nordisk, Rhythm, and Soleno; participation on a DSMB for Ascendis, Broad Group, Rhythm, and Pfizer; and leadership with Raymond A Wood Foundation. KKW reports honoraria from BioMarin; patents with UpToDate; and research funding from Ascendis, BioMarin, Pfizer, and Ultragenyx. NSM reports research funding from and consulting role for Ascendis. DS reports honoraria from Hexal/Sandoz, Kyowa Kirin, Novo Nordisk, and Pfizer; travel support from Ascendis and Novo Nordisk; participation on a DSMB for Ascendis, BioMarin, Hexal/Sandoz, Kyowa Kirin, and Novo Nordisk; and leadership with German Society for Pediatric Endocrinology and Diabetes. SBS reports honoraria from and advisory role for Ascendis and BioMarin; honoraria from Kiowa Kirin; and travel support from BioMarin. MM, AS, MC, AG, BW, BV, and ADS report employment and stock options with Ascendis. CM reports research funding and travel support from Ascendis; consulting role with BioMarin; travel support from Pfizer; leadership with International Society of Children's Bone Health. YAZ and PLH have no conflicts to disclose., (© 2023 The Author(s).)

Background: Dosimetry in radionuclide therapy often requires the calculation of average absorbed doses within and between spatial regions, for example, for voxel-based dosimetry methods, for paired organs, or across multiple tumors. Formation of such averages can be made in different ways, starting from different definitions., Purpose: The aim of this study is to formally specify different averaging strategies for absorbed doses, and to compare their results when applied to absorbed dose distributions that are non-uniform within and between regions., Methods: For averaging within regions, two definitions of the average absorbed dose are considered: the simple average over the region (the region average) and the average when weighting by the mass density (density-weighted region average). The latter is shown to follow from the definition of mean absorbed dose according to the ICRU, and to be consistent with the MIRD formalism. For averaging between different spatial regions, three definitions follow: the volume-weighted, the mass-weighted, and the unweighted average. With respect to characterizing non-uniformity, the different average definitions lead to the use of dose-volume histograms (DVHs) (region average), dose-mass histograms (DMHs) (density-weighted region average), and unweighted histograms (unweighted average). Average absorbed doses are calculated for three worked examples, starting from the different definitions. The first, schematic, example concerns the calculation of the average absorbed dose between two regions with different volumes or mass densities. The second, stylized, example concerns voxel-based dosimetry, for which the average absorbed-dose rate within a region is calculated. The geometries studied include three 177 Lu-filled voxelized spheres, where the sphere masses are held constant while the material compositions, densities, and volumes are varied. For comparison, the mean absorbed-dose rates obtained using unit-density sphere S-values are also included. The third example concerns SPECT/CT-based tumor dosimetry for five patients undergoing therapy with 177 Lu-PSMA and six patients undergoing therapy with 177 Lu-DOTA-TATE, for which the average absorbed-dose rates across multiple tumors are calculated. For the second and third examples, analyses also include representations by histograms., Results: Example 1 shows that the average absorbed doses, calculated using different definitions, can differ considerably if the masses and absorbed doses for two regions are markedly different. From example 2 it is seen that the density-weighted region average is stable under different activity and density distributions and is also in line with results using S-values. In contrast, the region average varies as function of the activity distribution. In example 3, the absorbed dose rates for individual tumors differ by (1.1 ± 4.3)% and (-0.1 ± 0.4)% with maximum deviations of +34.4% and -1.4% for 177 Lu-PSMA and 177 Lu-DOTA-TATE, respectively, when calculated as region averages or density-weighted region averages, with largest deviations obtained when the density is non-uniform. The average absorbed doses calculated across all tumors are similar when comparing mass-weighted and volume-weighted averages but these differ substantially from unweighted averages., Conclusion: Different strategies for averaging of absorbed doses within and between regions can lead to substantially different absorbed-dose estimates. At reporting of radionuclide therapy dosimetry, it is important to specify the averaging strategy applied., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objectives  Collimators have a significant role in image quality and detectability in single-photon emission computed tomography (SPECT) imaging. Using an appropriate alloy that effectively absorbs scattered photons, without induced secondary x-rays, and with proper rigidity and weight may provide an effective approach to the image improvement that conventionally collimators made of lead (Pb). Materials and Methods  A Siemens E.CAM SPECT imaging system equipped with low-energy high-resolution (LEHR) collimator was simulated by the Simulating Medical Imaging Nuclear Detectors Monte Carlo program. Experimental and simulated data were compared based on a 2-mm 99m Tc point source in an acrylic cylindrical Deluxe phantom (Data Spectrum, Inc). Seven types of tungsten (W) alloys (Wolfmet), with W content from 90 to 97% by weight, were then used as collimator materials of the simulated system. Camera parameters, such as energy- and spatial resolution, image contrast, and collimator-related parameters, such as fraction of septal penetration, scatter-to-primary ratios, and percentage of induced secondary x-rays, due to interactions in the collimator, were evaluated. Results  Acceptable conformity was found for the simulated and experiment systems in terms of energy spectra, 10.113 and 10.140%, full width at half-maximum (FWHM) of the point spread function (PSF) curves, 8.78 and 9.06 mm, sensitivity, 78.46 and 78.34 cps/MBq, and contrast in images of 19.1 mm cold spheres in the Deluxe phantom, 79.17 and 78.97%, respectively. Results on the parameters of the simulated system with LEHR collimator made from the alloys showed that the alloy consisting of 90% W, 6% nickel, and 4% copper provided an FWHM of 8.76 mm, resulting in a 0.2% improvement in spatial resolution. Furthermore, all the Wolfmet collimators showed a 48% reduction in the amount of X-rays production compared to the Pb. Conclusion  A Wolfmet LEHR collimator, made by a combination of W (90%), Ni (6%), and Cu (6%) provides a better image quality and detectability compared to the Pb., Competing Interests: Conflicts of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: The autistic population is growing and ageing and this also applies to the parents. Despite this, research about parental experiences is still relatively scarce. Even though studies show, compared with adults with other disabilities, parents of autistic adolescents and adults report a decrease in well-being and that caregiving is often a lifelong commitment., Method: This scoping review maps, synthesises and identifies gaps in previous research as regards the experiences of parental caregivers of adult autistic children. The review was based on Arksey and Malley's framework and six databases were searched., Results: The results show how the research has focused on the well-being and consequences of daily caregiving for an American middle-class mother who co-resides with an adult son., Conclusion: To enhance knowledge about formal services and service needs, more research is necessary on different welfare regimes and social contexts., (© 2023 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

One example of a PET exam that suffers from noise problems is [ 68 Ga]Ga-DOTA-TOC, where patients are generally administered between 100 and 200 MBq [ 68 Ga]Ga-DOTA-TOC, irrespective of size. However, a fixed activity can result in low signal-to-noise ratios (SNRs) in larger patients. This study aimed to evaluate the impact on image quality with respect to injected activity and patient habitus through Monte Carlo (MC) simulation. Eight anthropomorphic computer phantoms with body mass indices (BMIs) between 19 kg/m 2 and 38 kg/m 2 and tumours distributed in the liver were simulated using the MC software Gate v8.2 with an activity distribution defined according to [ 68 Ga]Ga-DOTA-TOC standardised uptake values. Three activity-administration protocols were simulated: (i) with a fixed activity of 100 MBq, (ii) with the activity scaled by 2 MBq/kg, and (iii) with the activity scaled by a body size-dependent power-function based on the SNR obtained with (ii). BMI, weight, body surface area, and abdominal circumference were evaluated body size parameters. Images were reconstructed with the CASToR software and evaluated for background SNR and lesion contrast-to-noise ratio (CNR). Large SNR variabilities were obtained with protocols (i) and (ii), while (iii) generated good consistency. Several tumours failed to reach a CNR of 5 for large phantoms with protocol (i), but the CNR was generally improved by (ii) and (iii). An activity scaled by patient habitus generate better image quality consistency, which increases the likelihood that patients receive a similar standard of care., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: We developed a method of standardizing the heart-to-mediastinal ratio in 123 I-labeled meta-iodobenzylguanidine (MIBG) images using a conversion coefficient derived from a dedicated phantom. This study aimed to create a machine-learning (ML) model to estimate conversion coefficients without using a phantom., Methods: 210 Monte Carlo (MC) simulations of 123 I-MIBG images to obtain conversion coefficients using collimators that differed in terms of hole diameter, septal thickness, and length. Simulated conversion coefficients and collimator parameters were prepared as training datasets, then a gradient-boosting ML was trained to estimate conversion coefficients from collimator parameters. Conversion coefficients derived by ML were compared with those that were MC simulated and experimentally derived from 613 phantom images., Results: Conversion coefficients were superior when estimated by ML compared with the classical multiple linear regression model (root mean square deviations: 0.021 and 0.059, respectively). The experimental, MC simulated, and ML-estimated conversion coefficients agreed, being, respectively, 0.54, 0.55, and 0.55 for the low-; 0.74, 0.70, and 0.72 for the low-middle; and 0.88, 0.88, and 0.88 for the medium-energy collimators., Conclusions: The ML model estimated conversion coefficients without the need for phantom experiments. This means that conversion coefficients were comparable when estimated based on collimator parameters and on experiments., (© 2023. The Author(s).)

Background: Immunotherapy of hepatocellular carcinoma (HCC) is an emerging method with promising results. Immunotherapy can have an antitumor effect without affecting tumor size, calling for functional imaging methods for response evaluation., Purpose: To evaluate the response to intratumoral injections with the immune primer ilixadencel in HCCs with diffusion-weighted magnetic resonance imaging (DW-MRI) using intravoxel incoherent motion (IVIM) and histogram analysis., Material and Methods: A total of 17 patients with advanced HCC were treated with intratumoral injections with ilixadencel on three occasions 2-5 weeks apart. The patients were examined with IVIM before each injection as well as approximately three months after the first injection., Results: The 10th percentile of perfusion-related parameter D* decreased significantly after the first and second intratumoral injections of ilixadencel compared to baseline ( P < 0.05). There was a non-significant trend of lower median region of interest f (perfusion fraction) before injection 2 compared to baseline ( P  = 0.07). There were significant correlations between the 10th percentile and median of D at baseline and change in tumor size after three months ( r  = 0.79, P < 0.01 and r  = 0.72, P < 0.05, respectively)., Conclusion: DW-MRI with IVIM and histogram analysis revealed significant reductions of D* early after treatment as well as an association between D at baseline and smaller tumor growth at three months. The lower percentiles (10th and 50th) were found more important. Further research is needed to confirm our preliminary findings of reduced perfusion after ilixadencel vaccinations, suggesting a treatment effect on HCC.

Purpose: Radionuclide therapy with 177 Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized 177 Lu-DOTATATE for which the number of cycles varied based on renal dosimetry., Methods: Patients were eligible if they had a progressive, somatostatin receptor-positive neuroendocrine tumor with a Ki 67 labeling index < 20%. They received cycles of 7.4 GBq of 177 Lu-DOTATATE at 10 ± 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0)., Results: Ninety-six patients who had received a median of 5 cycles (range 1-9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1-2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3-4 toxicity occurred in < 10% of patients and was mostly hematological, with no grade 3-4 renal toxicity., Conclusion: Individualized treatment with 177 Lu-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials., Trial Registration: EudraCT 2011-000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078., (© 2022. The Author(s).)

Noninvasive methods to study changes in tumor microstructure enable early assessment of treatment response and thus facilitate personalized treatment. The aim of this study was to evaluate the diffusion MRI model, Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors (VERDICT), for early response assessment to external radiation treatment and to compare the results with those of more studied sets of parameters derived from diffusion-weighted MRI data. Mice xenografted with human small intestine tumors were treated with external radiation treatment, and diffusion MRI experiments were performed on the day before and up to 2 weeks after treatment. The diffusion models VERDICT, ADC, IVIM, and DKI were fitted to MRI data, and the treatment response of each tumor was calculated based on pretreatment tumor growth and post-treatment tumor volume regression. Linear regression and correlation analysis were used to evaluate each model and their respective parameters for explaining the treatment response. VERDICT analysis showed significant changes from day -1 to day 3 for the intracellular and extracellular volume fraction, as well as the cell radius index (p < 0.05; Wilcoxon signed-rank test). The strongest correlation between the diffusion model parameters and the tumor treatment response was seen for the ADC, kurtosis-corrected diffusion coefficient, and intracellular volume fraction on day 3 (τ = 0.47, 0.52, and -0.49, respectively, p < 0.05; Kendall rank correlation coefficient). Of all the tested models, VERDICT held the strongest explanatory value for the tumor treatment response on day 3 (R 2  = 0.75, p < 0.01; linear regression). In conclusion, VERDICT has potential for early assessment of external radiation treatment and may provide further insights into the underlying biological effects of radiation on tumor tissue. In addition, the results suggest that the time window for assessment of treatment response using dMRI may be narrow., (© 2021 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Semiconductor gamma-camera systems based on cadmium zinc telluride (CZT) detectors present new challenges due to an energy-response that includes effects of low-energy tailing. In particular, such energy tails produce effects that need to be considered when imaging radionuclides with multiple emissions such as [Formula: see text]. Monte Carlo simulation can be used to investigate the behaviour of such systems and optimise their use, provided that the detector model closely reflects the real physical detector. The aim of this work is to develop a CZT model applicable for simulation of CZT-based gamma cameras., Methods: The equations describing the charge transport and signal induction are considered in three dimensions and are solved numerically, and the CZT model is then realised by coupling the detector-response to the photon-transport handled by the SIMIND Monte Carlo program. The CZT model is tuned to reproduce experimentally measured energy spectra of a hand-held gamma camera system for multiple radionuclides ([Formula: see text], [Formula: see text] and [Formula: see text]) and parallel-hole collimators (MEGP, LEHR) as well as an uncollimated system., Results: Overall, the model results agree well with measurements across the range of experimental conditions. The applicability of the model is demonstrated by separating energy spectra into components to investigate the interference of high-energy photons on lower energy-windows, where pronounced effects of low-energy tailing for [Formula: see text] are observed., Conclusions: The developed model provides understanding of the specifics of the camera response and is expected to be helpful for future optimisation of gamma camera applications., (© 2022. The Author(s).)

The study aimed to create a pipeline from Monte Carlo simulated projections of a Gate PET system to reconstructed images. The PET system was modelled after the GE Discovery MI (DMI) PET/CT, and the simulated projections were reconstructed with the stand-alone reconstruction software CASToR. Attenuation correction, normalisation calibration, random estimation, and scatter estimation for the simulations were computed with in-house programs. The pipeline was compared in both projection and image space with data acquired on a clinical DMI and reconstructed with GE's off-line PET reconstruction software (PET Toolbox) and CASToR. The simulated and measured data were compared for the number of prompt coincidences, scatter fraction, contrast recovery coefficient (CRC), signal-to-noise ratio (SNR), background variability, residual lung error, and image profiles. A slight discrepancy was noted in the projection space, but good agreements were generally achieved in image space between simulated and measured data. The CRC was found to be 81 % for Gate - CASToR, 84 % for GE - CASToR, and 84 % for GE - PET Toolbox for the largest sphere of the NEMA image quality (IQ) phantom, and the SNR was found to be 98 for Gate - CASToR, 91 for GE - CASToR, and 93 for GE - PET Toolbox. Profiles drawn over the spheres for the NEMA IQ phantom and the Data Spectrum (DS) phantom show a good match between measurement and simulation. The results indicate feasibility to utilise the pipeline as a tool for off-line simulation-based studies. A complete pipeline introduces possibilities to study the impact of single parameters in the whole chain from simulation to reconstructed images., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Purpose: The accuracy and precision of patient positioning is crucial in radiotherapy; however, there are no publications available using synthetic computed tomography (sCT) that evaluate rotations in head and neck (H&N) patients positioning or the effect of translation and rotation combined. The aim of this work was to evaluate the differences between using sCT with the CT for 2D- and 3D-patient positioning in a magnetic resonance imaging (MRI)-only workflow., Methods: This study included 14 H&N cancer patients, with generated sCT data (MRI Planner v2.2) and the CT deformably registered to the MRI. Patient positioning was evaluated by comparing sCT against CT data: 3D cone beam CT (CBCT) was registered to the deformed CT (dCT) and sCT in six degrees of freedom (DoF) with a rigid auto-registration algorithm and bone threshold, and 2D deformed digital reconstructed radiographs (dDRR) and synthetic DRRs (sDRR) were manually registered to orthogonal projections in five DoF by six blinded observers. The difference in displacement in all DoF were calculated for dCT and sCT, as well as for dDRR and sDRR. The interobserver variation was evaluated by separate application of the paired dDRR and sDRR registration matrices to the original coordinates of the planning target volume (PTV) structures and calculation of the Euclidean distance between the corresponding points. The Dice similarity coefficient (DSC) was calculated between dDRR/sDRR-registered PTVs., Results: The mean difference in patient positioning using CBCT was <0.7 mm and <0.3° and using orthogonal projections <0.4 mm and <0.2° in all directions. The maximum Euclidean distance was 5.1 mm, the corresponding mean (1SD) Euclidean distance and mean DSC were 3.5 ± 0.7 mm and 0.93, respectively., Conclusions: This study shows that the sCT-based patient positioning gives a comparable result with that based on CT images, allowing sCT to replace CT as reference for patient treatment positioning., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Somatization, defined as the presence of multiple somatic symptoms, frequently occurs in irritable bowel syndrome (IBS) and may constitute the clinical manifestation of a neurobiological sensitization process. Brain imaging data was acquired with T1 weighted 3 tesla MRI, and gray matter morphometry were analyzed using FreeSurfer. We investigated differences in networks of structural covariance, based on graph analysis, between regional gray matter volumes in IBS-related brain regions between IBS patients with high and low somatization levels, and compared them to healthy controls (HCs). When comparing IBS low somatization (N = 31), IBS high somatization (N = 35), and HCs (N = 31), we found: (1) higher centrality and neighbourhood connectivity of prefrontal cortex subregions in IBS high somatization compared to healthy controls; (2) higher centrality of left cerebellum in IBS low somatization compared to both IBS high somatization and healthy controls; (3) higher centrality of the anterior insula in healthy controls compared to both IBS groups, and in IBS low compared to IBS high somatization. The altered structural covariance of prefrontal cortex and anterior insula in IBS high somatization implicates that prefrontal processes may be more important than insular in the neurobiological sensitization process associated with IBS high somatization.