Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: subgroup analysis of a Swiss-wide prospective registry study.

PURPOSE: To assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy. METHODS: Single-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021-01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan-Meier methodology (log-rank test). RESULTS: Between 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4-26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09-0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07-0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16-0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01-0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02-0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively). CONCLUSION: Six weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice.

Prospective Study Comparing [99mTc]Tc-DP-FAPI Quantitative SPECT/CT with [68Ga]Ga-FAPI-04 PET/CT in Patients with Gastrointestinal Tumors.

Over the past decade, [68Ga]Ga-FAPI-04 positron emission tomography (PET)/CT imaging has been widely used for the treatment of various tumors. However, the application of 99mTC-labeled fibroblast activation protein inhibitors in tumors has been less studied. Our team previously demonstrated the safe biological distribution of [99mTc]Tc-DP-FAPI in the human body. Based on this, this study reports the accuracy of [99mTc]Tc-DP-FAPI in the imaging diagnosis of gastrointestinal tumors and compares it with that of [68Ga]Ga-FAPI-04 to evaluate the differences. A total of 24 patients with clinically diagnosed gastrointestinal tumors were prospectively included. All patients received [99mTc]Tc-DP-FAPI quantitative SPECT/CT imaging on the first day and [68Ga]Ga-FAPI-04 PET/CT imaging on the second day. And the effectiveness of the two imaging probes in detecting suspicious lesions was analyzed and compared. The primary tumors of all 24 patients were well detected by two imaging probes, and the sensitivity of [99mTc]Tc-DP-FAPI and [68Ga]Ga-FAPI-04 to the primary lesions was 100%. [99mTc]Tc-DP-FAPI examined 21 lymph nodes with a sensitivity and specificity of 32.8% and 10.9%, and [68Ga]Ga-FAPI-04 detected 57 lymph nodes with a sensitivity and specificity of 89.1% and 67.2%, respectively. Three distant metastases were detected by [99mTc]Tc-DP-FAPI and nine metastases by [68Ga]Ga-FAPI-04. The study showed that [99mTc]Tc-DP-FAPI is highly sensitive to detecting primary lesions of gastrointestinal tumors. Compared with [68Ga]Ga-FAPI-04, [99mTc]Tc-DP-FAPI has the same sensitivity in detecting primary tumors but has certain limitations in detecting metastases. [99mTc]Tc-DP-FAPI is of great value for preliminary screening of tumor lesions and early diagnosis of disease in patients who are suspected of having gastrointestinal tumors.

A Simple Kit Formulation for Preparation and Exploratory Human Studies of a Novel 99mTc-Labeled Fibroblast Activation Protein Inhibitor Tracer for Imaging of the Fibroblast Activation Protein in Cancers.

Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment because it is selectively expressed on the cell membrane of cancer-associated fibroblasts in most solid tumor stroma. The aim of this study was to develop a 99mTc-labeled fibroblast activation protein inhibitor (FAPI) tracer, evaluate its imaging efficacy in nude mice, and further explore its biodistribution in healthy volunteers and uptake in tumor patients. An FAPI-derived ligand (DP-FAPI) containing d-proline was designed and synthesized as a linker, and a stable hydrophilic 99mTc-labeled complex ([99mTc]Tc-DP-FAPI) was obtained by kit formulation. In vitro cellular uptake and saturation binding assays were performed in FAP-transfected HT-1080 cells (FAP-HT-1080). The biodistribution was characterized, and micro-single-photon emission computed tomography (SPECT) imaging was performed in BALB/c nude mice bearing U87 MG tumors. Furthermore, a first-in-man application was performed in four healthy volunteers and three patients with gastrointestinal tumors. In vitro, the nanomolar Kd values of [99mTc]Tc-DP-FAPI indicated that it had significantly high target affinity for FAP. Biodistribution and micro-SPECT imaging studies showed that [99mTc]Tc-DP-FAPI exhibited high uptake and high tumor-to-nontargeted ratios. The calculated effective dose for [99mTc]Tc-DP-FAPI was approximately <5 mSv in four healthy volunteers. In three patients with gastrointestinal tumors, [99mTc]Tc-DP-FAPI quantitative SPECT/CT revealed high and reliable uptake. [99mTc]Tc-DP-FAPI exhibited high selectivity and affinity for FAP in vitro. The safety and effectiveness of [99mTc]Tc-DP-FAPI in primary tumor imaging have been confirmed by animal and clinical studies, revealing the potential clinical application value of this tracer.

Quantify total activity by volume-of-interest expansion with clinical SPECT/CT systems, a phantom study.

PURPOSE: Quantitative measurements of activity in SPECT are important for radioisotope therapy planning and disease diagnosis. The aim of this manuscript is to develop a robust method to quantify the total activity in a volume-of-interest (VOI) of different quantitative SPECT reconstructions and validate the estimation accuracy. METHODS: We customized an IEC body phantom using 3D printing technology and made six sphere inserts of 1-6 cm in diameter with at least 3 cm separation. The activity concentration within the spheres was in the range of patient lesion/organ activity. The background activity was then increased from zero to a sphere/background activity concentration of 8:1, 4:1, and 2:1. SPECT data were acquired with Philips Brightview and GE Discovery 670 SPECT/computed tomography (CT) systems under clinical acquisition protocols. Quantitative SPECT images were reconstructed with Hermes SUV-SPECT (both Philips and GE data) and GE Q.Metrix (GE data only). The quantitative SPECT reconstructions are iterative with scatter, CT attenuation correction, and resolution recovery. We quantified the total activity by expanding the sphere VOI to include a spill-out region. Background correction was applied by sampling a region outside the spill-out region. The true fractions (TFs) (total activity/true activity) were measured for all six spheres for all SPECT acquisitions. RESULTS: The TF is close to 100% for 2-6 cm spheres for zero background, 8:1 and 4:1 sphere/background activity ratios. The TF was found to be unreliable for the 1-cm sphere because of the limit of phantom design. TF accuracy for 2:1 sphere/background ratio was degraded due to significantly large background, inadequate scatter correction and detector count loss. CONCLUSIONS: The results demonstrated that the proposed quantification method is accurate for objects of different sizes in currently clinical quantitative reconstruction and has the potential for improving the accuracy for therapeutic treatment planning or radiation dosimetry calculations.

Quantitative myocardial perfusion SPECT/CT for the assessment of myocardial tracer uptake in patients with three-vessel coronary artery disease: Initial experiences and results.

BACKGROUND: To evaluate quantitative myocardial perfusion SPECT/CT datasets for routine clinical reporting and the assessment of myocardial tracer uptake in patients with severe TVCAD. METHODS: MPS scans were reconstructed as quantitative SPECT datasets using CTs from internal (SPECT/CT, Q_INT) and external (PET/CT, Q_EXT) sources for attenuation correction. TPD was calculated and compared to the TPD from non-quantitative SPECT datasets of the same patients. SUVmax, SUVpeak, and SUVmean were compared between Q_INT and Q_EXT SPECT datasets. Global SUVmax and SUVpeak were compared between patients with and without TVCAD. RESULTS: Quantitative reconstruction was feasible. TPD showed an excellent correlation between quantitative and non-quantitative SPECT datasets. SUVmax, SUVpeak, and SUVmean showed an excellent correlation between Q_INT and Q_EXT SPECT datasets, though mean SUVmean differed significantly between the two groups. Global SUVmax and SUVpeak were significantly reduced in patients with TVCAD. CONCLUSIONS: Absolute quantification of myocardial tracer uptake is feasible. The method seems to be robust and principally suitable for routine clinical reporting. Quantitative SPECT might become a valuable tool for the assessment of severe coronary artery disease in a setting of balanced ischemia, where potentially life-threatening conditions might otherwise go undetected.

Cardiac Resynchronization Therapy for Improving Non-Uniform Thickening of Left Ventricular Wall: Assessment by Quantitative Gated Myocardial Perfusion SPECT.

Cardiac resynchronization therapy (CRT) improves cardiac dyssynchrony in heart failure patients with a wide QRS electrocardiogram (ECG). Assessment of left ventricular (LV) dyssynchrony using echocardiography or other imaging modalities is important to predict CRT effectiveness. In this study, we retrospectively evaluated cardiac nuclear imaging of ECG-gated myocardial perfusion single-photon emission computed tomography (SPECT) with 99mTc-sestamibi for CRT candidate (n = 120) with severe heart failure and wide QRS (> 120 msec) in ECG. To analyze LV non-uniformity, we used the quantitative gated SPECT (QGS) software to calculate changes in regional LV wall thickness during a cardiac cycle (i.e., wall thickening scores). Cardiac events (heart failure, ventricular arrhythmias and cardiac death) after CRT during 38 ± 22 (SD) months were also evaluated. In 97 of 120 patients who underwent QGS before and 6 months after CRT, CRT homogenized non-uniform wall thickening between septal and lateral of the LV especially in CRT responders. This observation was indicated as increase in the lateral deflection (XWT) of wall thickening scores before CRT and its decrease after CRT. In 120 patients with QGS before CRT, the larger XWT before CRT (≥ 16.5) predicted better prognoses after CRT. This finding was similarly observed even in patients with narrower baseline QRS (≤ 140 msec; n = 41 of 120), who usually have less benefits from CRT. In conclusion, CRT improved non-uniformity of wall thickening between the LV septal and lateral regions evaluated using QGS, which is predictive of better prognosis in the chronic phase after CRT.

Quantitative bone SPECT/CT: high specificity for identification of prostate cancer bone metastases.

PURPOSE: Bone scintigraphy with 99mTc-labeled diphosphonates can identify prostate cancer bone metastases with high sensitivity, but relatively low specificity, because benign conditions such as osteoarthritis can also trigger osteoblastic reactions. We aimed to investigate the diagnostic performance of 99mTc-2,3-dicarboxy propane-1,1-diphosphonate (99mTc-DPD) uptake quantification by single-photon emission computed tomography coupled with computed tomography (SPECT/CT) for distinguishing prostate cancer bone metastases from spinal and pelvic osteoarthritic lesions. METHODS: We retrospectively assessed 26 bone scans from 26 patients with known prostate cancer bone metastases and 13 control patients with benign spinal and pelvic osteoarthritic changes without known neoplastic disease. Quantitative SPECT/CT (xSPECT, Siemens Symbia Intevo, Erlangen, Germany) was performed and standardized uptake values (SUVs) were quantified with measurements of SUVmax and SUVmean (g/mL) in all bone metastases for the prostate cancer group and in spinal and pelvic osteoarthritic changes for the control group. We used receiver operating characteristics (ROC) curves to determine the optimum SUVmax cutoff value to distinguish between bone metastases and benign spinal and pelvic lesions. RESULTS: In total, 264 prostate cancer bone metastases were analyzed, showing a mean SUVmax and SUVmean of 34.6 ± 24.6 and 20.8 ± 14.7 g/mL, respectively. In 24 spinal and pelvic osteoarthritic lesions, mean SUVmax and SUVmean were 14.2 ± 3.8 and 8.9 ± 2.2 g/mL, respectively. SUVmax and SUVmean were both significantly different between the bone metastases and osteoarthritic groups (p ≤ 0.0001). Using a SUVmax cutoff of 19.5 g/mL for prostate cancer bone metastases in the spine and pelvis, sensitivity, specificity, positive and negative predictive values were 87, 92, 99 and 49%, respectively. CONCLUSION: This study showed significant differences in quantitative 99mTc-DPD uptake on bone SPECT/CT between prostate cancer bone metastases and spinal and pelvic osteoarthritic changes, with higher SUVmax and SUVmean in metastases. Using a SUVmax cutoff of 19.5 g/mL, high specificity and positive predictive value for metastases identification in the spine and pelvis were found, thus increasing accuracy of bone scintigraphy.

[Effect of Misregistration between SPECT and CT Images on Attenuation Correction for Quantitative Bone SPECT Imaging].

PURPOSE: The aim of this study was to evaluate the effect of misregistration between single-photon emission computed tomography (SPECT) and computed tomography (CT) images on bone SPECT. METHODS: We acquired SPECT and CT images of a body phantom filled with bone-equivalent solution and 99mTc for evaluation of bone SPECT. SPECT images were reconstructed using attenuation correction maps obtained by shifting the attenuation coefficients from non-shifted values (reference). Activity concentrations, SPECT standardized uptake values (SPECT-SUVs), and tumor background ratios (TBRs) were evaluated. RESULTS: Activity concentrations and SPECT-SUVs decreased with decreasing attenuation coefficient. The difference in attenuation coefficient was especially large between the shifted-to-lung (0.085 cm-1) and reference (0.249 cm-1) values. Non-shifted and shifted-to-lung SPECT-SUVs were 11.5±1.0 and 2.3±0.2, respectively. TBR also decreased with decreasing attenuation coefficient. The maximum percentage change in TBR was 86% in the shifted-to-lung value. CONCLUSIONS: Our results indicate that the accuracy of activity concentration and lesion detectability was commonly affected by misalignment between SPECT and CT images. Although the impact of SPECT/CT misregistration on bone SPECT is case-specific and difficult to predict, it is important to reduce the incidence of misregistration errors for quantitative bone SPECT imaging.

Comparison of a 3D CZT and conventional SPECT/CT system for quantitative Lu-177 SPECT imaging.

PURPOSE: Next-generation SPECT/CT systems with CdZnTe (CZT) digital detectors in a ring-like setup are emerging to perform quantitative Lu-177 SPECT imaging in clinical routine. It is essential to assess how the shorter acquisition time might affect the image quality and uncertainty on the mean absorbed dose of the tumors and organs at risk compared to a conventional system. METHODS: A NEMA Image Quality phantom was scanned with a 3D CZT SPECT/CT system (Veriton, by Spectrum Dynamics) using 6 min per bed position and with a conventional SPECT/CT system (Symbia T16, by Siemens) using 16 min per bed position. The sphere-to-background ratio was 12:1 and the background activity concentration ranged from 0.52 to 0.06 MBq/mL. A clinical reconstruction protocol for dosimetry purposes was determined for both systems by maximizing the sphere-to-background ratio while keeping the coefficient of variation of the background as low as possible. The corresponding image resolution was determined by the matching filter method and used for a dose uncertainty assessment of both systems following an established uncertainty model.. RESULTS: The optimized iterative reconstruction protocol included scatter and attenuation correction for both systems and detector response modeling for the Siemens system. For the 3D CZT system, 6 iterations and 8 subsets were combined with a Gaussian post-filter of 3 mm Full Width Half Maximum (FWHM) for post-smoothing. For the conventional system, 16 iterations and 16 subsets were applied with a Gaussian post-smoothing filter of 1 mm FWHM. For these protocols, the sphere-to-background ratio was 18.5% closer to the true ratio for the conventional system compared to the 3D CZT system when considering the four largest spheres. Meanwhile, the background coefficient of variation was very similar for both systems. These protocols resulted in SPECT image resolution of 14.8 mm and 13.6 mm for the 3D CZT and conventional system respectively. Based on these resolution estimates, a 50% dose uncertainty corresponded to a lesion volume of 28 mL for the conventional system and a lesion volume of 33 mL for the 3D CZT system. CONCLUSIONS: An optimized reconstruction protocol for a Veriton system with 6 min of acquisition time per bed position resulted in slightly higher dose uncertainties than a conventional Symbia system using 16 min of acquisition time per bed position. Therefore, a 3D CZT SPECT/CT allows to significantly reduce the acquisition times with only a very limited impact on dose uncertainties such that quantitative Lu-177 SPECT/CT imaging becomes much more accessible for treatment concurrent dosimetry. Nevertheless, the uncertainty of SPECT-based dose estimates remains high.

Pareto optimization of SPECT acquisition and reconstruction settings for 177Lu activity quantification.

BACKGROUND: The aim was to investigate the noise and bias properties of quantitative 177Lu-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 177Lu 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 177Lu-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 177Lu 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.

In vivoquantitative SPECT imaging of actinium-226: feasibility and proof-of-concept.

Objective.225Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy, however,225Ac (t1/2= 9.9 d) lacks direct gamma emissions forin vivoimaging.226Ac (t1/2= 29.4 h) is a promising element-equivalent matched diagnostic radionuclide for preclinical evaluation of225Ac radiopharmaceuticals.226Ac has two gamma emissions (158 keV and 230 keV) suitable for SPECT imaging. This work is the first feasibility study forin vivoquantitative226Ac SPECT imaging and validation of activity estimation.Approach.226Ac was produced at TRIUMF (Vancouver, Canada) with its Isotope Separator and Accelerator (ISAC) facility. [226Ac]Ac3+was radiolabelled with the bioconjugate crown-TATE developed for therapeutic targeting of neuroendocrine tumours. Mice with AR42J tumour xenografts were injected with either 2 MBq of [226Ac]Ac-crown-TATE or 4 MBq of free [226Ac]Ac3+activity and were scanned at 1, 2.5, 5, and 24 h post injection in a preclinical microSPECT/CT. Quantitative SPECT images were reconstructed from the 158 keV and 230 keV photopeaks with attenuation, background, and scatter corrections. Image-based226Ac activity measurements were assessed from volumes of interest within tumours and organs of interest. Imaging data was compared withex vivobiodistribution measured via gamma counter.Main results. We present, to the best of our knowledge, the first everin vivoquantitative SPECT images of226Ac activity distributions. Time-activity curves derived from SPECT images quantify thein vivobiodistribution of [226Ac]Ac-crown-TATE and free [226Ac]Ac3+activity. Image-based activity measurements in the tumours and organs of interest corresponded well withex vivobiodistribution measurements.Significance. Here in, we established the feasibility ofin vivo226Ac quantitative SPECT imaging for accurate measurement of actinium biodistribution in a preclinical model. This imaging method could facilitate more efficient development of novel actinium labelled compounds by providing accurate quantitativein vivopharmacokinetic information essential for estimating toxicities, dosimetry, and therapeutic potency.

Kidney dosimetry in [177Lu]Lu-DOTA-TATE therapy based on multiple small VOIs.

PURPOSE: The aim was to investigate the use of multiple small VOIs for kidney dosimetry in [177Lu]Lu-DOTA-TATE therapy. METHOD: The study was based on patient and simulated SPECT images in anthropomorphic geometries. Images were reconstructed using two reconstruction programs (local LundaDose and commercial Hermia) using OS-EM with and without resolution recovery (RR). Five small VOIs were placed to determine the average activity concentration (AC) in each kidney. The study consisted of three steps: (i) determination of the number of iterations for AC convergence based on simulated images; (ii) determination of recovery-coefficients (RCs) for 2 mL VOIs using a separate set of simulated images; (iii) assessment of operator variability in AC estimates for simulated and patient images. Five operators placed the VOIs, using for guidance: a) SPECT/CT with RR, b) SPECT/CT without RR, and c) CT only. For simulated images, time-integrated ACs (TIACs) were evaluated. For patient images, estimated ACs were compared with results of a previous method based on whole-kidney VOIs. RESULTS: Eight iterations and ten subsets were sufficient for both programs and reconstruction settings. Mean RCs (mean ± SD) with RR were 1.03 ± 0.02 (LundaDose) and 1.10 ± 0.03 (Hermia), and without RR 0.91 ± 0.03 (LundaDose) and 0.94 ± 0.03 (Hermia). Most stable and accurate estimates of the AC were obtained using five 2-mL VOIs guided by SPECT/CT with RR, applying them to images without RR, and including an explicit RC for recovery correction. CONCLUSION: The small VOI method based on five 2-mL VOIs was found efficient and sufficiently accurate for kidney dosimetry in [177Lu]Lu-DOTA-TATE therapy.

Quantitative SPECT imaging of 155Tb and 161Tb for preclinical theranostic radiopharmaceutical development.

BACKGROUND: Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, 155Tb (t1/2 = 5.32 d) and 161Tb (t1/2 = 6.89 d) have been proposed as a theranostic pair for their respective applications in single photon emission computed tomography (SPECT) imaging and targeted beta therapy. Our study assessed the performance of preclinical quantitative SPECT imaging with 155Tb and 161Tb. A hot rod resolution phantom with rod diameters ranging between 0.85 and 1.70 mm was filled with either 155Tb (21.8 ± 1.7 MBq/mL) or 161Tb (23.6 ± 1.9 MBq/mL) and scanned with the VECTor preclinical SPECT/CT scanner. Image performance was evaluated with two collimators: a high energy ultra high resolution (HEUHR) collimator and an extra ultra high sensitivity (UHS) collimator. SPECT images were reconstructed from photopeaks at 43.0 keV, 86.6 keV, and 105.3 keV for 155Tb and 48.9 keV and 74.6 keV for 161Tb. Quantitative SPECT images of the resolution phantoms were analyzed to report inter-rod contrast, recovery coefficients, and contrast-to-noise metrics. RESULTS: Quantitative SPECT images of the resolution phantom established that the HEUHR collimator resolved all rods for 155Tb and 161Tb, and the UHS collimator resolved rods ≥ 1.10 mm for 161Tb and ≥ 1.30 mm for 155Tb. The HEUHR collimator maintained better quantitative accuracy than the UHS collimator with recovery coefficients up to 92%. Contrast-to-noise metrics were also superior with the HEUHR collimator. CONCLUSIONS: Both 155Tb and 161Tb demonstrated potential for applications in preclinical quantitative SPECT imaging. The high-resolution collimator achieves < 0.85 mm resolution and maintains quantitative accuracy in small volumes which is advantageous for assessing sub organ activity distributions in small animals. This imaging method can provide critical quantitative information for assessing and optimizing preclinical Tb-radiopharmaceuticals.

Prognostic Value of [99mTc]Tc-DPD Quantitative SPECT/CT in Patients with Suspected and Confirmed Amyloid Transthyretin-Related Cardiomyopathy and Preserved Left Ventricular Function.

Quantitative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]Tc-DPD) SPECT may be used for risk-stratifying patients with amyloid transthyretin-related cardiomyopathy (ATTR-CM). We aimed to analyze the predictive value of quantitative [99mTc]Tc-DPD SPECT/CT in suspected and confirmed ATTR-CM according to different disease stages. Methods: The study enrolled consecutive patients with suspected ATTR-CM who were referred to a single tertiary center and underwent quantitative [99mTc]Tc-DPD SPECT/CT allowing SUVmax and SUVpeak analysis. Patients were divided into 2 groups according to left ventricular ejection fraction (LVEF) at baseline (i.e., ≥50% and <50%). Clinical, laboratory, and echocardiographic parameters and major adverse cardiac events (i.e., all-cause death, sustained ventricular tachyarrhythmia, hospitalization for heart failure, implantation of a cardioverter defibrillator) were investigated for any correlation with quantitative uptake values. Results: In total, 144 patients with suspected ATTR-CM were included in the study (98 with LVEF ≥ 50% and 46 with LVEF < 50%), of whom 99 were diagnosed with ATTR-CM (68.8%; 69 with LVEF ≥ 50% and 30 with LVEF < 50%). A myocardial SUVmax of at least 7 was predictive of major adverse cardiac events at 21.9 ± 13.0 mo of follow-up (hazard ratio, 2.875; 95% CI, 1.23-6.71; P = 0.015) in patients with suspected or confirmed ATTR-CM (global χ2 = 6.892, P = 0.02) and an LVEF of at least 50%. SUVmax was not predictive in patients with an LVEF of less than 50% and suspected or confirmed ATTR-CM. Conclusion: In patients with suspected or confirmed ATTR-CM and preserved LVEF, representing an early disease stage, quantitative [99mTc]Tc-DPD SPECT should be considered to improve early-stage risk stratification.

Effect of kilovoltage and quality reference mAs on CT-based attenuation correction in 177Lu SPECT/CT imaging: a phantom study.

INTRODUCTION: CT-based attenuation correction (CT-AC) plays a major role in accurate activity quantification by SPECT/CT imaging. However, the effect of kilovoltage peak (kVp) and quality-reference mAs (QRM) on the attenuation coefficient image (µ-map) and volume CT dose index (CTDIvol) have not yet been systematically evaluated. Therefore, the aim of this study was to fill this gap and investigate the influence of kVp and QRM on CT-AC in 177Lu SPECT/CT imaging. METHODS: Seventy low-dose CT acquisitions of an Electron Density Phantom (seventeen inserts of nine tissue-equivalent materials) were acquired using various kVp and QRM combinations on a Siemens Symbia Intevo Bold SPECT/CT system. Using manufacturer reconstruction software, 177Lu µ-maps were generated for each CT image, and three low-dose CT related aspects were examined. First, the µ-map-based attenuation values (µmeasured) were compared with theoretical values (µtheoretical). Second, changes in 177Lu activity expected due to changes in the µ-map were calculated using a modified Chang method. Third, the noise in the µ-map was assessed by measuring the coefficient of variation in a volume of interest in the homogeneous section of the Electron Density Phantom. Lastly, two phantoms were designed to simulate attenuation in four tissue-equivalent materials for two different source geometries (1-mL and 10-mL syringes). 177Lu SPECT/CT imaging was performed using three different reconstruction algorithms (xSPECT Quant, Flash3D, STIR), and the SPECT-based activities were compared against the nominal activities in the sources. RESULTS: The largest relative errors between µmeasured and µtheoretical were observed in the lung inhale insert (range: 18%-36%), while it remained below 6% for all other inserts. The resulting changes in 177Lu activity quantification were -3.5% in the lung inhale insert and less than -2.3% in all other inserts. Coefficient of variation and CTDIvol ranged from 0.3% and 3.6 mGy (130 kVp, 35 mAs) to 0.4% and 0.9 mGy (80 kVp, 20 mAs), respectively. The SPECT-based activity quantification using xSPECT Quant reconstructions outperformed all other reconstruction algorithms. CONCLUSION: This study shows that kVp and QRM values in low-dose CT imaging have a minimum effect on quantitative 177Lu SPECT/CT imaging, while the selection of low values of kVp and QRM reduce the CTDIvol.

3D printed non-uniform anthropomorphic phantoms for quantitative SPECT.

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 177Lu and 99mTc 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 177Lu (kidneys) or 99mTc (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 177Lu and 99mTc, 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.

From SPECT/CT towards absolute quantification? - the case of unilateral condylar hyperplasia of the mandible.

BACKGROUND: Unilateral condylar hyperplasia (UCH) of the mandible is a rare condition characterized by asymmetric growth of the mandibular condyles. Bone scintigraphy with SPECT(/CT) is commonly used to diagnose UCH and guide treatment. Still, varying results have been reported using the traditional threshold of 55%:45% in relative tracer uptake. While absolute quantification of uptake on SPECT/CT could improve results, optimal correction and reconstruction settings are currently unknown. METHODS: Three anthropomorphic phantoms representing UCH were developed from patient CT volumes and produced using 3D printing technology. Fillable spherical inserts of different sizes (Ø: 8-15 mm) were placed in the condylar positions representing symmetrical and asymmetrical distributions. Recovery coefficients were determined for SPECT/CT using various reconstruction corrections, including attenuation and scatter correction (ACSC), resolution modeling (RM), and partial volume correction (PVC) using phantom measurements. Uptake ratios between condyles and condyle to clivus were evaluated. Finally, the impact of these correction techniques on absolute activity and diagnostic accuracy was assessed in a retrospective patient cohort for the diagnostic threshold of 55%:45%. RESULTS: The activity was only partially recovered in all spherical inserts (range: 22.5-64.9%). However, RM improved relative recovery by 20.2-62.3% compared to ACSC. In the symmetric phantoms, the 95% confidence interval (CI) of condyle ratios included the diagnostic threshold (57.6%:42.4%) for UCH when using ACSC potentially leading to false positives, but not for ACSCRM datasets. Partial volume corrections coefficients from the NEMA IQ phantom was positionally dependent, with improvements seen performing PVC using coefficients derived from anthropomorphic phantoms. Retrospective application in a patient cohort showed only a weak linear correlation (R²: 0.25-0.67) and large limits of agreement (9.6-12.5%) between different reconstructions. Up to 44% of patients were reclassified using the 55%:45% threshold. Using clinical outcome data, ACSCRM had highest sensitivity (91%; 95% CI 59-100%) and specificity (66%; 95% CI 47-81%), significantly improving specificity (P = 0.038). CONCLUSIONS: Anthropomorphic phantoms were shown to be essential in determining optimal settings for acquisition, reconstruction, and analysis. SPECT/CT reconstructions with attenuation and scatter correction and resolution modeling are recommended and could improve specificity when using the 55%:45% threshold to assess condylar growth.

Position dependence of recovery coefficients in 177Lu-SPECT/CT reconstructions - phantom simulations and measurements.

BACKGROUND: Although the importance of quantitative SPECT has increased tremendously due to newly developed therapeutic radiopharmaceuticals, there are still no accreditation programs to harmonize SPECT imaging. Work is currently underway to develop an accreditation for quantitative 177Lu SPECT/CT. The aim of this study is to verify whether the positioning of the spheres within the phantom has an influence on the recovery and thus needs to be considered in SPECT harmonization. In addition, the effects of these recovery coefficients on a potential partial volume correction as well as absorbed-dose estimates are investigated. METHODS: Using a low-dose CT of a SPECT/CT acquisition, a computerized version of the NEMA body phantom was created using a semi-automatic threshold-based method. Based on the mass-density map, the detector orbit, and the sphere centers, realistic SPECT acquisitions of all possible 720 sphere configurations of both the PET and the SPECT versions of the NEMA Body Phantom were generated using Monte Carlo simulations. SPECT reconstructions with different numbers of updates were performed without (CASToR) and with resolution modeling (STIR). Recovery coefficients were calculated for all permutations, reconstruction methods, and phantoms, and their dependence on the sphere positioning was investigated. Finally, the simulation-based findings were validated using SPECT/CT acquisitions of six different sphere configurations. RESULTS: Our analysis shows that sphere positioning has a significant impact on the recovery for both of the reconstruction methods and the phantom type. Although resolution modeling resulted in significantly higher recovery, the relative variation in recovery within the 720 permutations was even larger. When examining the extreme values of the recovery, reconstructions without resolution modeling were influenced primarily by the sphere position, while with resolution modeling the volume of the two adjacent spheres had a larger influence. The SPECT measurements confirmed these observations, and the recovery curves showed good overall agreement with the simulated data. CONCLUSION: Our study shows that sphere positioning has a significant impact on the recovery obtained in NEMA sphere phantom measurements and should therefore be considered in a future SPECT accreditation. Furthermore, the single-measurement method normally performed for PVC should be reconsidered to account for the position dependency.

ISIT-QA: In Silico Imaging Trial to Evaluate a Low-Count Quantitative SPECT Method Across Multiple Scanner-Collimator Configurations for 223Ra-Based Radiopharmaceutical Therapies.

Personalized dose-based treatment planning requires accurate and reproducible noninvasive measurements to ensure safety and effectiveness. Dose estimation using SPECT is possible but challenging for alpha (α)-particle-emitting radiopharmaceutical therapy (α-RPT) because of complex γ-emission spectra, extremely low counts, and various image-degrading artifacts across a plethora of scanner-collimator configurations. Through the incorporation of physics-based considerations and skipping of the potentially lossy voxel-based reconstruction step, a recently developed projection-domain low-count quantitative SPECT (LC-QSPECT) method has the potential to provide reproducible, accurate, and precise activity concentration and dose measures across multiple scanners, as is typically the case in multicenter settings. To assess this potential, we conducted an in silico imaging trial to evaluate the LC-QSPECT method for a 223Ra-based α-RPT, with the trial recapitulating patient and imaging system variabilities. Methods: A virtual imaging trial titled In Silico Imaging Trial for Quantitation Accuracy (ISIT-QA) was designed with the objectives of evaluating the performance of the LC-QSPECT method across multiple scanner-collimator configurations and comparing performance with a conventional reconstruction-based quantification method. In this trial, we simulated 280 realistic virtual patients with bone-metastatic castration-resistant prostate cancer treated with 223Ra-based α-RPT. The trial was conducted with 9 simulated SPECT scanner-collimator configurations. The primary objective of this trial was to evaluate the reproducibility of dose estimates across multiple scanner-collimator configurations using LC-QSPECT by calculating the intraclass correlation coefficient. Additionally, we compared the reproducibility and evaluated the accuracy of both considered quantification methods across multiple scanner-collimator configurations. Finally, the repeatability of the methods was evaluated in a test-retest study. Results: In this trial, data from 268 223RaCl2 treated virtual prostate cancer patients, with a total of 2,903 lesions, were used to evaluate LC-QSPECT. LC-QSPECT provided dose estimates with good reproducibility across the 9 scanner-collimator configurations (intraclass correlation coefficient > 0.75) and high accuracy (ensemble average values of recovery coefficients ranged from 1.00 to 1.02). Compared with conventional reconstruction-based quantification, LC-QSPECT yielded significantly improved reproducibility across scanner-collimator configurations, accuracy, and test-retest repeatability ([Formula: see text] Conclusion: LC-QSPECT provides reproducible, accurate, and repeatable dose estimations in 223Ra-based α-RPT as evaluated in ISIT-QA. These findings provide a strong impetus for multicenter clinical evaluations of LC-QSPECT in dose quantification for α-RPTs.

The impact of different reconstruction parameters on quantitative 99mTc-DPD SPECT/CT values in the assessment of cardiac transthyretin amyloidosis.

AIM: To assess in a phantom and in a clinical study the influence of different reconstruction parameters on quantitative SPECT/CT values in the assessment of cardiac transthyretin amyloidosis (ATTR-CA). METHOD: A hybrid SPECT/CT camera with a proprietary software for SPECT/CT-based quantification of myocardial uptake of 99mTc-DPD was used. Images were reconstructed with 6 different protocols, differing in iterations, subset and Gaussian filter. Quantitative values were tested in phantom and clinical studies across different reconstruction protocols. Values were automatically calculated both as kBq/ml and as maximum, mean and peak standardized uptake value (SUV). RESULTS: The standard parameters provided by the manufacturer (reconstruction 1) yielded higher accuracy in quantifying, with measuring 97.1% of the expected activity in the phantom. Reconstructions with higher Gaussian filter caused a systematic underestimation of quantified values of 27.2% (p < 0.01). Results were replicated in the clinical study consisting of 155 patients with suspected ATTR-CA, wherein changing the number of iterations and subsets was not associated with a statistically significant difference in quantitative values compared to reconstruction 1, while a higher Gaussian filter caused inaccurate quantification with up to 24% of difference measured. CONCLUSION: Different reconstruction parameters can impact quantitative values on 99mTc-DPD SPECT/CT. Therefore, parameters should be maintained consistently across different acquisitions and different centres.