In-vivo inhibition of neutral endopeptidase 1 results in higher absorbed tumor doses of [177Lu]Lu-PP-F11N in humans: the lumed phase 0b study.

BACKGROUND: A new generation of radiolabeled minigastrin analogs delivers low radiation doses to kidneys and are considered relatively stable due to less enzymatic degradation. Nevertheless, relatively low tumor radiation doses in patients indicate limited stability in humans. We aimed at evaluating the effect of sacubitril, an inhibitor of the neutral endopeptidase 1, on the stability and absorbed doses to tumors and organs by the cholecystokinin-2 receptor agonist [177Lu]Lu-PP-F11N in patients. In this prospective phase 0 study eight consecutive patients with advanced medullary thyroid carcinoma and a current somatostatin receptor subtype 2 PET/CT scan were included. Patients received two short infusions of ~ 1 GBq [177Lu]Lu-PP-F11N in an interval of ~ 4 weeks with and without Entresto® pretreatment in an open-label, randomized cross-over order. Entresto® was given at a single oral dose, containing 48.6 mg sacubitril. Adverse events were graded and quantitative SPECT/CT and blood sampling were performed. Absorbed doses to tumors and relevant organs were calculated. RESULTS: Pretreatment with Entresto® showed no additional toxicity and increased the stability of [177Lu]Lu-PP-FF11N in blood significantly (p < 0.001). Median tumor-absorbed doses were 2.6-fold higher after Entresto® pretreatment (0.74 vs. 0.28 Gy/GBq, P = 0.03). At the same time, an increase of absorbed doses to stomach, kidneys and bone marrow was observed, resulting in a tumor-to-organ absorbed dose ratio not significantly different with and without Entresto®. CONCLUSIONS: Premedication with Entresto® results in a relevant stabilization of [177Lu]Lu-PP-FF11N and consecutively increases radiation doses in tumors and organs. Trial registration clinicaltrails.gov, NCT03647657. Registered 20 August 2018.

Active and passive dosimetry for beta-emitting radiopharmaceutical therapy agents in a custom SPECT/CT compatible phantom.

Objective. This work introduces a novel approach to performing active and passive dosimetry for beta-emitting radionuclides in solution using common dosimeters. The measurements are compared to absorbed dose to water (Dw) estimates from Monte Carlo (MC) simulations. We present a method for obtaining absorbed dose to water, measured with dosimeters, from beta-emitting radiopharmaceutical agents using a custom SPECT/CT compatible phantom for validation of Monte Carlo based absorbed dose to water estimates.Approach. A cylindrical, acrylic SPECT/CT compatible phantom capable of housing an IBA EFD diode, Exradin A20-375 parallel plate ion chamber, unlaminated EBT3 film, and thin TLD100 microcubes was constructed for the purpose of measuring absorbed dose to water from solutions of common beta-emitting radiopharmaceutical therapy agents. The phantom is equipped with removable detector inserts that allow for multiple configurations and is designed to be used for validation of image-based absorbed dose estimates with detector measurements. Two experiments with131I and one experiment with177Lu were conducted over extended measurement intervals with starting activities of approximately 150-350 MBq. Measurement data was compared to Monte Carlo simulations using the egs_chamber user code in EGSnrc 2019.Main results. Agreement withink= 1 uncertainty between measured and MC predictedDwwas observed for all dosimeters, except the A20-375 ion chamber during the second131I experiment. Despite the agreement, the measured values were generally lower than predicted values by 5%-15%. The uncertainties atk = 1 remain large (5%-30% depending on the dosimeter) relative to other forms of radiation therapy.Significance. Despite high uncertainties, the overall agreement between measured and simulated absorbed doses is promising for the use of dosimeter-based RPT measurements in the validation of MC predictedDw.

Exploring the Limitations of Hybrid Adiabatic Quantum Computing for Emission Tomography Reconstruction.

Our study explores the feasibility of quantum computing in emission tomography reconstruction, addressing a noisy ill-conditioned inverse problem. In current clinical practice, this is typically solved by iterative methods minimizing a L2 norm. After reviewing quantum computing principles, we propose the use of a commercially available quantum annealer and employ corresponding hybrid solvers, which combine quantum and classical computing to handle more significant problems. We demonstrate how to frame image reconstruction as a combinatorial optimization problem suited for these quantum annealers and hybrid systems. Using a toy problem, we analyze reconstructions of binary and integer-valued images with respect to their image size and compare them to conventional methods. Additionally, we test our method's performance under noise and data underdetermination. In summary, our method demonstrates competitive performance with traditional algorithms for binary images up to an image size of 32×32 on the toy problem, even under noisy and underdetermined conditions. However, scalability challenges emerge as image size and pixel bit range increase, restricting hybrid quantum computing as a practical tool for emission tomography reconstruction until significant advancements are made to address this issue.

Myocardial perfusion imaging with retrospective gating and integrated correction of attenuation, scatter, respiration, motion, and arrhythmia.

BACKGROUND: Absolute quantitative myocardial perfusion SPECT requires addressing of aleatory and epistemic uncertainties in conjunction with providing image quality sufficient for lesion detection and characterization. Iterative reconstruction methods enable the mitigation of the root causes of image degradation. This study aimed to determine the feasibility of a new SPECT/CT method with integrated corrections attempting to enable absolute quantitative cardiac imaging (xSPECT Cardiac; xSC). METHODS: We compared images of prototype xSC and conventional SPECT (Flash3DTM) acquired at rest from 56 patients aged 71 ± 12 y with suspected coronary heart disease. The xSC prototype comprised list-mode acquisitions with continuous rotation and subsequent iterative reconstructions with retrospective electrocardiography (ECG) gating. Besides accurate image formation modeling, patient-specific CT-based attenuation and energy window-based scatter correction, additionally we applied mitigation for patient and organ motion between views (inter-view), and within views (intra-view) for both the gated and ungated reconstruction. We then assessed image quality, semiquantitative regional values, and left ventricular function in the images. RESULTS: The quality of all xSC images was acceptable for clinical purposes. A polar map showed more uniform distribution for xSC compared with Flash3D, while lower apical count and higher defect contrast of myocardial infarction (p = 0.0004) were observed on xSC images. Wall motion, 16-gate volume curve, and ejection fraction were at least acceptable, with indication of improvements. The clinical prospectively gated method rejected beats ≥20% in 6 patients, whereas retrospective gating used an average of 98% beats, excluding 2% of beats. We used the list-mode data to create a product equivalent prospectively gated dataset. The dataset showed that the xSC method generated 18% higher count data and images with less noise, with comparable functional variables of volume and LVEF (p = ns). CONCLUSIONS: Quantitative myocardial perfusion imaging with the list-mode-based prototype xSPECT Cardiac is feasible, resulting in images of at least acceptable image quality.

Validation of Monte Carlo simulated absorbed-dose-to-water inside a custom SPECT/CT phantom using active and passive dosimeters: a feasibility study using99mTc.

Objective.This project aims to provide a novel method for performing dosimetry measurements on TRT radionuclides using a custom-made SPECT/CT compatible phantom, common active and passive detectors, and Monte Carlo simulations. In this work we present a feasibility study using99mTc for a novel approach to obtaining reproducible measurements of absorbed-dose-to-water from radionuclide solutions using active and passive detectors in a custom phantom for the purpose of benchmarking Monte Carlo-based absorbed-dose-to-water estimates.Approach. A cylindrical, acrylic SPECT/CT compatible phantom capable of housing an IBA EFD diode, SNC600c Farmer type ion chamber, and TLD-100 microcubes was designed and built for the purpose of assessing internal absorbed-dose-to-water at various points within a solution of99mTc. The phantom is equipped with removable inserts that allow for numerous detector configurations and is designed to be used for verification of SPECT/CT-based absorbed-dose estimates with traceable detector measurements at multiple locations. Three experiments were conducted with exposure times ranging from 11 to 21 h with starting activities of approximately 10-16 GBq. Measurement data was compared to Monte Carlo simulations using the egs_chamber user code in EGSnrc 2019.Main results. In general, the ionization chamber measurements agreed with the Monte Carlo simulations withink= 1 uncertainty values (±4% and ±7%, respectively). Measurements from the TLDs yielded results withink= 1 agreement of the MC prediction (±6% and ±5%, respectively). Agreement withink= 1 uncertainty (±6% and ±7%, respectively) was obtained for the diode for one of three conducted experiments.Significance. While relatively large uncertainties remain, the agreement between measured and simulated absorbed-doses provides proof of principal that dosimetry of radionuclide solutions with active detectors may be performed using this type of phantom with potential modifications for beta-emitting radionuclides to be introduced in future work.

A Prospective Comparative Study of Using Ultrasonography, 4D-CT and Parathyroid Dual-Phase Scintigraphy with SPECT in Patients with Primary Hyperparathyroidism.

Thirty-one consecutive patients were included in this study who were planned for parathyroidectomy due to primary hyperparathyroidism. They were studied with US, 4D-CT and dual-phase scintigraphy including SPECT/CT, and possible adenomas were identified in each imaging modality. Imaging data were quantified with US, CT and SPECT. Parathyroidectomies were performed as minimally invasive according to preoperative imaging findings. A total of 16 adenomas were found in 15 patients, and the surgery was negative in four patients. The imaging results were compared with each other and correlated to histology findings and blood biochemistry (S-Ca and P-PTH). Quantitative SPECT found a strong correlation between the quantification methods-Conjugate Gradient with Attenuation and Scatter Correction with a zone map (CGZAS) and Conjugate Gradient with Attenuation and Scatter Correction (CGAS)-measured as SUVmax and kBq/mL. However, a statistically significant correlation between the quantitative parameters (CGZAS and CGAS) and serum biomarkers (S-PTH and S-Ca) was not observed. The sensitivities of the imaging methods were calculated using histopathology as a gold standard. SPECT/CT demonstrated 93% sensitivity, 4D-CT 93% sensitivity and ultrasonography 73% sensitivity. The imaging methods were compared with each other using parathyroid regions because findings and locations varied between the modalities. Our prospective study supports that quantitative SPECT/CT is useful for presurgical assessment of primary hyperparathyroidism.

Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 µg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion:177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.

IQ·SPECT technology and its clinical applications using multicenter normal databases.

IQ·SPECT (Siemens Medical Solutions) is a solution for high-sensitivity and short-time acquisition imaging of the heart for a variable angle general purpose gamma camera. It consists of a multi-focal collimator, a cardio-centric orbit and advanced iterative reconstruction, modeling the image formation physics accurately. The multi-focal collimator enables distance-dependent enlargement of the center region while avoiding truncation at the edges. With the specified configuration and a cardio-centric orbit it can obtain a fourfold sensitivity increase for the heart at the center of the scan orbit. Since IQ·SPECT shows characteristic distribution patterns in the myocardium, appropriate acquisition and processing conditions are required, and normal databases are convenient for quantification of both normal and abnormal perfusion images. The use of prone imaging can be a good option when X-ray computed tomography (CT) is not available for attenuation correction. CT-based attenuation correction changes count distribution significantly in the inferior wall and around the apex, hence image interpretation training and additional use of normal databases are recommended. Recent reports regarding its technology, Japanese Society of Nuclear Medicine working group activities, and clinical studies using 201Tl and 99mTc-perfusion tracers in Japan are summarized.

Fully Automated Data-Driven Respiratory Signal Extraction From SPECT Images Using Laplacian Eigenmaps.

We propose a data-driven method for extracting a respiratory surrogate signal from SPECT list-mode data. The approach is based on dimensionality reduction with Laplacian Eigenmaps. By setting a scale parameter adaptively and adding a series of post-processing steps to correct polarity and normalization between projections, we enable fully-automatic operation and deliver a respiratory surrogate signal for the entire SPECT acquisition. We validated the method using 67 patient scans from three acquisition types (myocardial perfusion, liver shunt diagnostic, lung inhalation/perfusion) and an Anzai pressure belt as a gold standard. The proposed method achieved a mean correlation against the Anzai of 0.81 ± 0.17 (median 0.89). In a subsequent analysis, we characterize the performance of the method with respect to count rates and describe a predictor for identifying scans with insufficient statistics. To the best of our knowledge, this is the first large validation of a data-driven respiratory signal extraction method published thus far for SPECT, and our results compare well with those reported in the literature for such techniques applied to other modalities such as MR and PET.

Dose reduction in half-time myocardial perfusion SPECT-CT with multifocal collimation.

BACKGROUND: Recent technological advances in myocardial perfusion imaging may warrant the use of lower injected activity. We evaluated whether quantitative measures of stress myocardial perfusion defects using Tc-99m sestamibi and low-energy high-resolution (LEHR) collimators are equivalent to lower dose SPECT-CT with cardiac multifocal collimators and software (IQ·SPECT). METHODS: 93 patients underwent one-day rest-stress gated SPECT-CT. Following conventional rest imaging, 925-1100 MBq (25-30 mCi) of Tc-99m sestamibi was injected during stress testing. Stress SPECT-CT images were acquired two ways: with LEHR (13 minutes) and IQ·SPECT (7 minutes). Low-dose IQ·SPECT stress was simulated by subsampling the full-dose data to half-, quarter-, and eighth-count levels. Abnormalities were quantified using the total perfusion deficit (TPD) score and dose-specific databases. RESULTS: The mean ± SD of the differences between LEHR and IQ·SPECT TPD scores were -1.01 ± 5.36%, -0.10 ± 5.81%, 1.78 ± 4.81%, and 1.75 ± 6.05% at full, half, quarter, and eighth doses, respectively. Differences were statistically significant for quarter and eighth doses. Correlation between LEHR and IQ·SPECT was excellent at all doses (R ≥ 0.93). Bland-Altman plots demonstrated minimal bias. CONCLUSIONS: With IQ·SPECT, quantitative stress SPECT-CT imaging is possible with half of the standard injected activity in half the time.

Beyond current guidelines: reduction in minimum administered radiopharmaceutical activity with preserved diagnostic image quality in pediatric hepatobiliary scintigraphy.

PURPOSE: To determine if the minimum administered radiopharmaceutical activity for hepatobiliary scintigraphy can be reduced while preserving diagnostic image quality using enhanced planar processing (EPP). METHODS: A total of 40 infants between 10 and 270 days old (body mass 2.2 - 6.5 kg) had hepatobiliary scintigraphy during the period 2004 - 2010 following the intravenous administration of either (99m)Tc-mebrofenin (18 patients) or (99m)Tc-disofenin (22 patients). Due to the small size of these patients, they all received the minimum administered activity of 18.5 MBq consistent with the North American Consensus Guidelines. Six nuclear medicine physicians subjectively graded the acceptability of the image quality for clinical interpretation using a four-point scale (not acceptable, fair, good, excellent). Each physician independently graded seven image sets including the original study (full activity) and simulated reduced activity studies using binomial subsampling (50% of full activity, 25% of full activity and activity reduced by weight), with and without EPP. RESULTS: For full-activity studies, 98% were deemed acceptable by the six physicians for clinical interpretation. The percentages of acceptable 50% reduced activity studies with and without EPP were not significantly different from the percentage of acceptable full-activity studies (P = 0.193 and P = 0.998, respectively). The percentage of acceptable 25% reduced activity studies without EPP was significantly different from the percentage of acceptable full-activity studies (P < 0.001); however, this difference vanished when EPP was applied (P = 0.482). The activity reduced by weight ranged from 1.85 to 4.81 MBq (10% to 26% of full dose) and the percentages of acceptable studies with and without EPP were significantly different from the percentage of acceptable full-activity studies (P < 0.001 and P = 0.02, respectively). CONCLUSION: Clinically interpretable hepatobiliary scintigraphy images can be obtained in infants when the minimum administered activity is substantially reduced. Without EPP, clinically acceptable images may be produced with a reduction of 50%, and with EPP, a reduction of 75% or more may be possible.

Reduction in radiation dose in mercaptoacetyltriglycerine renography with enhanced planar processing.

PURPOSE: To determine the minimum dose of technetium 99m ((99m)Tc) mercaptoacetyltriglycerine (MAG3) needed to perform dynamic renal scintigraphy in the pediatric population without loss of diagnostic quality or accurate quantification of renal function and to investigate whether adaptive noise reduction could help further reduce the minimum dose required. MATERIALS AND METHODS: Approval for this retrospective study was obtained from the institutional review board, with waiver of informed consent. A retrospective review was conducted in 33 pediatric patients consecutively referred for a (99m)Tc-MAG3 study. In each patient, a 20-minute dynamic study was performed after administration of 7.4 MBq/kg. Binomial subsampling was used to simulate studies performed with 50%, 30%, 20%, and 10% of the administered dose. Four nuclear medicine physicians independently reviewed the original and subsampled images, with and without noise reduction, for image quality. Two observers independently performed a quantitative analysis of renal function. Subjective rater confidence was analyzed by using a logistic regression model, and the quantitative analysis was performed by using the paired Student t test. RESULTS: Reducing the administered dose to 30% did not substantially affect image quality, with or without noise reduction. When the dose was reduced to 20%, there was a slight but significant decrease (P = .0074) in image quality, which resolved with noise reduction. Reducing the dose to 10% caused a decrease in image quality (P = .0003) that was not corrected with noise reduction. However, the dose could be reduced to 10% without a substantial change in the quantitative evaluation of renal function independent of the application of noise reduction. CONCLUSION: Decreasing the dose of (99m)Tc-MAG3 from 7.4 to 2.2 MBq/kg did not compromise image quality. With noise reduction, the dose can be reduced to 1.5 MBq/kg without subjective loss in image quality. The quantitative evaluation of renal function was not substantially altered, even with a theoretical dose as low as 0.74 MBq/kg.

Pediatric 99mTc-MDP bone SPECT with ordered subset expectation maximization iterative reconstruction with isotropic 3D resolution recovery.

PURPOSE: To perform a preliminary evaluation of the image quality of pediatric technetium 99m ((99m)Tc) methylene diphosphonate (MDP) bone single photon emission computed tomography (SPECT) by using iterative reconstruction-ordered subset expectation maximization with three-dimensional resolution recovery (OSEM-3D)-and to assess whether any improvements with use of this technique could lead to a reduction in patient dose or a shortening in imaging time. MATERIALS AND METHODS: Institutional advisory board approval was obtained for this investigation. Fifty (99m)Tc-MDP SPECT studies of the spine were evaluated (36 female and 14 male patients; mean age, 15.5 years). Each study was acquired by using a dual-detector camera, with each detector rotating 360°. By using filtered back projection (FBP) and OSEM-3D, images were reconstructed from data generated by both detectors. Likewise, OSEM-3D was used to reconstruct data from a single detector simulating half the administered radiopharmaceutical activity. Two nuclear medicine physicians, blinded to the patient data, reviewed the images for image quality in four different categories by using a four-point scale: artifacts (category 1), lesions (category 2), noise (category 3), and image sharpness (category 4). RESULTS: Compared with FBP, images reconstructed by using OSEM-3D with one or two detectors showed significant improvement in image quality with regard to lesion detection, noise level, and image sharpness (P < .02, .01, and .001, respectively). With OSEM-3D, no significant differences were observed when either one or two detectors were used. CONCLUSION: Improved image quality of skeletal SPECT with either a 50% reduction in radiation dose or a 50% reduction in acquisition time or combination of the two can be achieved by using OSEM-3D.

Pediatric 99mTc-DMSA SPECT performed by using iterative reconstruction with isotropic resolution recovery: improved image quality and reduced radiopharmaceutical activity.

PURPOSE: To compare two methods of reconstructing technetium 99m (99mTc) dimercaptosuccinic acid (DMSA) renal single photon emission computed tomographic (SPECT) data--ordered subset expectation maximization with three-dimensional resolution recovery (OSEM-3D) and filtered back projection (FBP)--in children in terms of improving image quality and reducing the radiopharmaceutical activity and radiation dose. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the requirement for informed patient consent. Fifty sequential pediatric patient 99mTc-DMSA SPECT studies of 98 kidneys were retrospectively analyzed by using a dual-detector gamma camera. FBP reconstruction with data from both detectors was compared with OSEM-3D reconstruction with half the gamma photon counts (ie, data from only one detector). Two nuclear medicine physicians blinded to the patients' medical histories and reconstruction techniques evaluated the studies. Scores for image quality, renal size, and relative function were compared by using paired t tests. Total scores for renal cortical defects were compared by using the Wilcoxon signed rank test. The kappa coefficient was calculated as an indicator of the concordance between the OSEM-3D and FBP reconstruction methods. RESULTS: Image quality was significantly enhanced with OSEM-3D (P < .001, paired t test). Cortical defects were identified better on OSEM-3D images than on FBP images. Of the 98 kidney SPECT studies analyzed, 19 showed identical cortical defects and 75 showed none at both OSEM-3D and FBP. In four kidneys, OSEM-3D depicted cortical defects that were not seen with FBP. No significant difference in relative renal function between the two methods was observed (P = .973). CONCLUSION: Compared with FBP, OSEM-3D yielded superior image quality in the evaluation of 99mTc-DMSA renal SPECT data, with the potential for markedly reduced radiation doses and/or shorter scanning times for patients.