In Vivo Visualization and Quantification of Neutrophil Elastase in Lungs of COVID-19 Patients: A First-in-Humans PET Study with 11C-NES.

Coronavirus disease 2019 (COVID-19) can cause life-threatening lung inflammation that is thought to be mediated by neutrophils. The aim of the present work was to evaluate a novel PET tracer for neutrophil elastase (NE). Methods: In this first-in-humans study, 4 patients with hypoxia due to COVID-19 and 2 healthy controls were investigated with PET using 11C-NES and 15O-water for visualization and quantification of NE and perfusion in the lungs, respectively. Results: 11C-NES accumulated selectively in lung areas with COVID-19 opacities on CT scans, suggesting high levels of NE there. In the same areas, perfusion was severely reduced in comparison to healthy lung tissue as measured with 15O-water. Conclusion: The data suggest that NE is associated with severe lung inflammation in COVID-19 patients and that inhibition of NE could potentially reduce the acute inflammatory process and improve the condition.

Influence of image reconstruction on quantitative cardiac 15O-water positron emission tomography.

BACKGROUND: The impact on quantitative 15O-water PET/CT of a wide range of different reconstruction settings, including regularized reconstruction by block-sequential regularized expectation maximization (BSREM), was investigated. METHODS: Twenty clinical stress scans from patients referred for assessment of myocardial ischemia were included. Patients underwent a 4-min dynamic stress PET scan with 15O-water on a digital PET/CT scanner. Twenty-two reconstructions were generated from each scan and a clinical reconstruction was used as reference. Varied parameters were number of iterations, filter, exclusion of time-of-flight and point-spread function, and regularization parameter with BSREM. Analyses were performed in aQuant utilizing two different methods and resulting regional myocardial blood flow (MBF), perfusable tissue fraction (PTF), and transmural MBF (MBFt) values were evaluated. RESULTS: Across the two analyses, correlations toward the reference reconstruction were strong for all parameters (ρ ≥ 0.83). Using automated analysis and the diagnostic threshold of hyperemic MBF at 2.3 mL⋅g-1⋅min-1, diagnosis was unchanged irrespective of reconstruction method in all patients except for one, where only four of the most extreme reconstruction methods resulted in a change of diagnosis. CONCLUSION: The low sensitivity of MBF values to reconstruction method and, as previously shown, scanner type and PET/CT misalignment, confirms that diagnostic hyperemic MBF cutoff values can be consistently used for 15O-water.

Comparison of 68Ga-PSMA PET/CT with fluoride PET/CT for detection of bone metastatic disease in prostate cancer.

BACKGROUND: 18F-NaF positron emission tomography/computed tomography (fluoride PET/CT) is considered the most sensitive technique to detect bone metastasis in prostate cancer (PCa). 68Ga-PSMA-11 (PSMA) PET/CT is increasingly used for staging of PCa. This study primarily aimed to compare the diagnostic performance of fluoride PET/CT and gallium-based PSMA PET/CT in identifying bone metastasis followed by a comparison of PSMA PET/CT with contrast-enhanced CT (CE-CT) in identifying soft tissue lesions as a secondary objective. METHODS: Twenty-eight PCa patients with high suspicion of disseminated disease following curative treatment were prospectively evaluated. PET/CT examinations using fluoride and PSMA were performed. All suspicious bone lesions were counted, and the tracer uptake was measured as standardized uptake values (SUV) for both tracers. In patients with multiple findings, ten bone lesions with highest SUVmax were selected from which identical lesions from both scans were considered for direct comparison of SUVmax. Soft tissue findings of local and lymph node lesions from CE-CT were compared with PSMA PET/CT. RESULTS: Both scans were negative for bone lesions in 7 patients (25%). Of 699 lesions consistent with skeletal metastasis in 21 patients on fluoride PET/CT, PSMA PET/CT identified 579 lesions (83%). In 69 identical bone lesions fluoride PET/CT showed significantly higher uptake (mean SUVmax: 73.1 ± 36.8) compared to PSMA PET/CT (34.5 ± 31.4; p < 0.001). Compared to CE-CT, PSMA PET/CT showed better diagnostic performance in locating local (96% vs 61%, p = 0.004) and lymph node (94% vs 46%, p < 0.001) metastasis. CONCLUSION: In this prospective comparative study, PSMA PET/CT detected the majority of bone lesions that were positive on fluoride PET/CT. Further, this study indicates better diagnostic performance of PSMA PET/CT to locate soft tissue lesions compared to CE-CT.

Quantitative comparison of data-driven gating and external hardware gating for 18F-FDG PET-MRI in patients with esophageal tumors.

BACKGROUND: Respiratory motion during PET imaging reduces image quality. Data-driven gating (DDG) based on principal component analysis (PCA) can be used to identify respiratory signals. The use of DDG, without need for external devices, would greatly increase the feasibility of using respiratory gating in a routine clinical setting. The objective of this study was to evaluate data-driven gating in relation to external hardware gating and regular static image acquisition on PET-MRI data with respect to SUVmax and lesion volumes. METHODS: Sixteen patients with esophageal or gastroesophageal cancer (Siewert I and II) underwent a 6-min PET scan on a Signa PET-MRI system (GE Healthcare) 1.5-2 h after injection of 4 MBq/kg 18F-FDG. External hardware gating was done using a respiratory bellow device, and DDG was performed using MotionFree (GE Healthcare). The DDG raw data files and the external hardware-gating raw files were created on a Matlab-based toolbox from the whole 6-min scan LIST-file. For comparison, two 3-min static raw files were created for each patient. Images were reconstructed using TF-OSEM with resolution recovery with 2 iterations, 28 subsets, and 3-mm post filter. SUVmax and lesion volume were measured in all visible lesions, and noise level was measured in the liver. Paired t-test, linear regression, Pearson correlation, and Bland-Altman analysis were used to investigate difference, correlation, and agreement between the methods. RESULTS: A total number of 30 lesions were included in the study. No significant differences between DDG and external hardware-gating SUVmax or lesion volumes were found, but the noise level was significantly reduced in the DDG images. Both DDG and external hardware gating demonstrated significantly higher SUVmax (9.4% for DDG, 10.3% for external hardware gating) and smaller lesion volume (- 5.4% for DDG, - 6.6% for external gating) in comparison with non-gated static images. CONCLUSIONS: Data-driven gating with MotionFree for PET-MRI performed similar to external device gating for esophageal lesions with respect to SUVmax and lesion volume. Both gating methods significantly increased the SUVmax and reduced the lesion volume in comparison with non-gated static acquisition. DDG resulted in reduced image noise compared to external device gating and static images.

Prospective data-driven respiratory gating of [68Ga]Ga-DOTATOC PET/CT.

AIM: The aim of this prospective study was to evaluate a data-driven gating software's performance, in terms of identifying the respiratory signal, comparing [68Ga]Ga-DOTATOC and [18F]FDG examinations. In addition, for the [68Ga]Ga-DOTATOC examinations, tracer uptake quantitation and liver lesion detectability were assessed. METHODS: Twenty-four patients with confirmed or suspected neuroendocrine tumours underwent whole-body [68Ga]Ga-DOTATOC PET/CT examinations. Prospective DDG was applied on all bed positions and respiratory motion correction was triggered automatically when the detected respiratory signal exceeded a certain threshold (R value ≥ 15), at which point the scan time for that bed position was doubled. These bed positions were reconstructed with quiescent period gating (QPG), retaining 50% of the total coincidences. A respiratory signal evaluation regarding the software's efficacy in detecting respiratory motion for [68Ga]Ga-DOTATOC was conducted and compared to [18F]FDG data. Measurements of SUVmax, SUVmean, and tumour volume were performed on [68Ga]Ga-DOTATOC PET and compared between gated and non-gated images. RESULTS: The threshold of R ≥ 15 was exceeded and gating triggered on mean 2.1 bed positions per examination for [68Ga]Ga-DOTATOC as compared to 1.4 for [18F]FDG. In total, 34 tumours were evaluated in a quantitative analysis. An increase of 25.3% and 28.1%, respectively, for SUVmax (P < 0.0001) and SUVmean (P < 0.0001), and decrease of 21.1% in tumour volume (P < 0.0001) was found when DDG was applied. CONCLUSIONS: High respiratory signal was exclusively detected in bed positions where respiratory motion was expected, indicating reliable performance of the DDG software on [68Ga]Ga-DOTATOC PET/CT. DDG yielded significantly higher SUVmax and SUVmean values and smaller tumour volumes, as compared to non-gated images.

Image reconstruction methods affect software-aided assessment of pathologies of [18F]flutemetamol and [18F]FDG brain-PET examinations in patients with neurodegenerative diseases.

PURPOSE: To assess how some of the new developments in brain positron emission tomography (PET) image reconstruction affect quantitative measures and software-aided assessment of pathology in patients with neurodegenerative diseases. METHODS: PET data were grouped into four cohorts: prodromal Alzheimer's disease patients and controls receiving [18F]flutemetamol, and neurodegenerative disease patients and controls receiving [18F]FDG PET scans. Reconstructed images were obtained by ordered-subsets expectation maximization (OSEM; 3 iterations (i), 16/34 subsets (s), 3/5-mm filter, ±time-of-flight (TOF), ±point-spread function (PSF)) and block-sequential regularized expectation maximization (BSREM; TOF, PSF, ß-value 75-300). Standardized uptake value ratios (SUVR) and z-scores were calculated (CortexID Suite, GE Healthcare) using cerebellar gray matter, pons, whole cerebellum and whole brain as reference regions. RESULTS: In controls, comparable results to the normal database were obtained with OSEM 3i/16 s 5-mm reconstruction. TOF, PSF and BSREM either increased or decreased the relative uptake difference to the normal subjects' database within the software, depending on the tracer and chosen reference area, i.e. resulting in increased absolute z-scores. Normalizing to pons and whole brain for [18F]flutemetamol and [18F]FDG, respectively, increased absolute differences between reconstructions methods compared to normalizing to cerebellar gray matter and whole cerebellum when applying TOF, PSF and BSREM. CONCLUSIONS: Software-aided assessment of patient pathologies should be used with caution when employing other image reconstruction methods than those used for acquisition of the normal database.

Evaluation of block-sequential regularized expectation maximization reconstruction of 68Ga-DOTATOC, 18F-fluoride, and 11C-acetate whole-body examinations acquired on a digital time-of-flight PET/CT scanner.

BACKGROUND: Block-sequential regularized expectation maximization (BSREM) is a fully convergent iterative image reconstruction algorithm. We hypothesize that tracers with different distribution patterns will result in different optimal settings for the BSREM algorithm. The aim of this study was to evaluate the image quality with variations in the applied ß-value and acquisition time for three positron emission tomography (PET) tracers. NEMA image quality phantom measurements and clinical whole-body digital time-of-flight (TOF) PET/computed tomography (CT) examinations with 68Ga-DOTATOC (n = 13), 18F-fluoride (n = 10), and 11C-acetate (n = 13) were included. Each scan was reconstructed using BSREM with ß-values of 133, 267, 400, and 533, and ordered subsets expectation maximization (OSEM; 3 iterations, 16 subsets, and 5-mm Gaussian post-processing filter). Both reconstruction methods included TOF and point spread function (PSF) recovery. Quantitative measures of noise, signal-to-noise ratio (SNR), and signal-to-background ratio (SBR) were analysed for various acquisition times per bed position (bp). RESULTS: The highest ß-value resulted in the lowest level of noise, which in turn resulted in the highest SNR and lowest SBR. Noise levels equal to or lower than those of OSEM were found with ß-values equal to or higher than 400, 533, and 267 for 68Ga-DOTATOC, 18F-fluoride, and 11C-acetate, respectively. The specified ß-ranges resulted in increased SNR at a minimum of 25% (P < 0.0001) and SBR at a maximum of 23% (P < 0.0001) as compared to OSEM. At a reduced acquisition time by 25% for 68Ga-DOTATOC and 18F-fluoride, and 67% for 11C-acetate, BSREM with ß-values equal to or higher than 533 resulted in noise equal to or lower than that of OSEM at full acquisition duration (2 min/bp for 68Ga-DOTATOC and 18F-fluoride, 3 min/bp for 11C-acetate). The reduced acquisition time with ß 533 resulted in increased SNR (16-26%, P < 0.003) and SBR (6-18%, P < 0.0001 (P = 0.07 for 11C-acetate)) compared to the full acquisition OSEM. CONCLUSIONS: Within tracer-specific ranges of ß-values, BSREM reconstruction resulted in increased SNR and SBR with respect to conventional OSEM reconstruction. Similar SNR, SBR, and noise levels could be attained with BSREM at relatively shorter acquisition times or, alternatively, lower administered dosages, compared to those attained with OSEM.

Comparison of 68Ga-PSMA-11 PET/CT with 11C-acetate PET/CT in re-staging of prostate cancer relapse.

Positron emission tomography (PET) imaging is used to localize recurrent disease in prostate cancer (PCa). The tracer 68Ga-PSMA-11 visualizes lesions overexpressing prostate-specific membrane antigen (PSMA), while 11C-acetate visualizes lesions with increased anabolic metabolism. The aim of this study was to compare the performance of PSMA-PET and acetate-PET in re-staging patients with biochemical relapse. Thirty PCa patients with prostate-specific antigen (PSA) relapse after primary curative therapy were prospectively evaluated. PET/CT examinations using 11C-acetate and 68Ga-PSMA-11 were performed. Identified lesions were categorized according to anatomical location and PET measurements were correlated with PSA at time of scan. Tumour lesions showed higher semi-quantitative uptake values on PSMA-PET than acetate-PET. PSMA-PET identified more lesions in 11 patients, fewer lesions in eight patients, and identical number of lesions in 11 patients. This study indicates better diagnostic performance of PSMA-PET, particularly in detecting lymph node (81% vs 60%, p = 0.02) and bone metastasis (95% vs 61%, p = 0.0001) compared to acetate-PET. However, 38% of PSMA-expressing metastases appear to be metabolically inactive and 15% of metabolically active metastases lack PSMA expression. Addition of PET with a metabolic tracer, such as 11C-acetate, might be beneficial before making treatment decisions.

Regularized reconstruction of digital time-of-flight 68Ga-PSMA-11 PET/CT for the detection of recurrent disease in prostate cancer patients.

Accurate localization of recurrent prostate cancer (PCa) is critical, especially if curative therapy is intended. With the aim to optimize target-to-background uptake ratio in 68Ga-PSMA-11 PET, we investigated the image quality and quantitative measures of regularized reconstruction by block-sequential regularized expectation maximization (BSREM). Methods: The study encompassed retrospective reconstruction and analysis of 20 digital time-of-flight (TOF) PET/CT examinations acquired 60 min post injection of 2 MBq/kg of 68Ga-PSMA-11 in PCa patients with biochemical relapse after primary treatment. Reconstruction by ordered-subsets expectation maximization (OSEM; 3 iterations, 16 subsets, 5 mm gaussian postprocessing filter) and BSREM (ß-values of 100-1600) were used, both including TOF and point spread function (PSF) recovery. Background variability (BV) was measured by placing a spherical volume of interest in the right liver lobe and defined as the standard deviation divided by the mean standardized uptake value (SUV). The image quality was evaluated in terms of signal-to-noise ratio (SNR) and signal-to-background ratio (SBR), using SUVmax of the lesions. A visual assessment was performed by four observers. Results: OSEM reconstruction produced images with a BV of 15%, whereas BSREM with a ß-value above 300 resulted in lower BVs than OSEM (36% with ß 100, 8% with ß 1300). Decreasing the acquisition duration from 2 to 1 and 0.5 min per bed position increased BV for both reconstruction methods, although BSREM with ß-values equal to or higher than 800 and 1200, respectively, kept the BV below 15%. In comparison of BSREM with OSEM, the mean SNR improved by 25 to 66% with an increasing ß-value in the range of 200-1300, whereas the mean SBR decreased with an increasing ß-value, ranging from 0 to 125% with a ß-value of 100 and 900, respectively. Decreased acquisition duration resulted in ß-values of 800 to 1000 and 1200 to 1400 for 1 and 0.5 min per bed position, respectively, producing improved image quality measures compared with OSEM at a full acquisition duration of 2 min per bed position. The observer study showed a slight overall preference for BSREM ß 900 although the interobserver variability was high. Conclusion: BSREM image reconstruction with ß-values in the range of 400-900 resulted in lower BV and similar or improved SNR and SBR in comparison with OSEM.

Affibody­mediated imaging of EGFR expression in prostate cancer using radiocobalt­labeled DOTA­ZEGFR:2377.

The epidermal growth factor receptor (EGFR) is often overexpressed during prostate cancer (PCa) progression towards androgen­independence after hormone therapy, but the overexpression is lower than in other types of cancers. Despite the low expression, EGFR has emerged as a promising therapeutic target for patients with castration­resistant PCa. Non­invasive methods for determination of EGFR expression in PCa can serve for patient stratification and therapy response monitoring. Radionuclide imaging probes based on affibody molecules (7 kDa) provide high contrast imaging of cancer­associated molecular targets. We hypothesized that the anti­EGFR affibody molecule DOTA­ZEGFR:2377 labeled with 55Co (positron­emitter, T1/2=17.5 h) would enable imaging of EGFR expression in PCa xenografts. The human PCa cell line DU­145 was used for in vitro and in vivo experiments and 57Co was used as a surrogate for 55Co in the present study. Binding of 57Co­DOTA­ZEGFR:2377 to EGFR­expressing xenografts was saturable with anti­EGFR monoclonal antibody cetuximab, which would motivate the use of this tracer for monitoring the receptor occupancy during treatment. A significant dose­dependent difference in radioactivity accumulation in tumors and normal organs was observed when the biodistribution was studied 3 h after the injection of 10 and 35 µg of 57Co­DOTA­ZEGFR:2377: At lower doses the tumor uptake was 2­fold higher although tumor­to­organ ratios were not altered. For clinically relevant organs for PCa, tumor­to­organ ratios increased with time, and at 24 h pi were 2.2±0.5 for colon, 7±2 for muscle, and 4.0±0.7 for bones. Small animal SPECT/CT images confirmed the capacity of radiocobalt labeled DOTA­ZEGFR:2377 to visualize EGFR expression in PCa. In conclusion, the present study demonstrated the feasibility of using the radiocobalt labeled anti­EGFR affibody conjugate ZEGFR:2377 as an imaging agent for in vivo visualization of low EGFR­expressing tumors, like PCa, and for monitoring of receptor occupancy during cetuximab therapy as well as the importance of optimal dosing in order to achieve higher sensitivity molecular imaging.

Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model.

Vascular endothelial growth factor receptor-2 (VEGFR2) is a key mediator of angiogenesis and therefore a promising therapeutic target in malignancies including glioblastoma multiforme (GBM). Molecular imaging of VEGFR2 expression may enable patient stratification for antiangiogenic therapy. The goal of the current study was to evaluate the capacity of the novel anti-VEGFR2 biparatopic affibody conjugate (ZVEGFR2-Bp2) for in vivo visualization of VEGFR2 expression in GBM. Methods: ZVEGFR2-Bp2 coupled to a NODAGA chelator was generated and radiolabeled with indium-111. The VEGFR2-expressing murine endothelial cell line MS1 was used to evaluate in vitro binding specificity and affinity, cellular processing and targeting specificity in mice. Further tumor targeting was studied in vivo in GL261 glioblastoma orthotopic tumors. Experimental imaging was performed. Results: [111In]In-NODAGA-ZVEGFR2-Bp2 bound specifically to VEGFR2 (KD=33±18 pM). VEGFR2-mediated accumulation was observed in liver, spleen and lungs. The tumor-to-organ ratios 2 h post injection for mice bearing MS1 tumors were approximately 11 for blood, 15 for muscles and 78 for brain. Intracranial GL261 glioblastoma was visualized using SPECT/CT. The activity uptake in tumors was significantly higher than in normal brain tissue. The tumor-to-cerebellum ratios after injection of 4 µg [111In]In-NODAGA-ZVEGFR2-Bp2 were significantly higher than the ratios observed for the 40 µg injected dose and for the non-VEGFR2 binding size-matched conjugate, demonstrating target specificity. Microautoradiography of cryosectioned CNS tissue was in good agreement with the SPECT/CT images. Conclusion: The anti-VEGFR2 affibody conjugate [111In]In-NODAGA-ZVEGFR2-Bp2 specifically targeted VEGFR2 in vivo and visualized its expression in a murine GBM orthotopic model. Tumor-to-blood ratios for [111In]In-NODAGA-ZVEGFR2-Bp2 were higher compared to other VEGFR2 imaging probes. [111In]In-NODAGA-ZVEGFR2-Bp2 appears to be a promising probe for in vivo noninvasive visualization of tumor angiogenesis in glioblastoma.

Evaluation of Penalized-Likelihood Estimation Reconstruction on a Digital Time-of-Flight PET/CT Scanner for 18F-FDG Whole-Body Examinations.

The resolution and quantitative accuracy of PET are highly influenced by the reconstruction method. Penalized-likelihood estimation algorithms allow for fully convergent iterative reconstruction, generating a higher image contrast than ordered-subsets expectation maximization (OSEM) while limiting noise. In this study, a type of penalized reconstruction known as block-sequential regularized expectation maximization (BSREM) was compared with time-of-flight OSEM (TOF OSEM). Various strengths of noise penalization factor ß were tested along with various acquisition durations and transaxial fields of view (FOVs) with the aim of evaluating the performance and clinical use of BSREM for 18F-FDG PET/CT, both quantitatively and in a qualitative visual evaluation. Methods: Eleven clinical whole-body 18F-FDG PET/CT examinations acquired on a digital TOF PET/CT scanner were included. The data were reconstructed using BSREM with point-spread function recovery and ß-factors of 133, 267, 400, and 533-and using TOF OSEM with point-spread function-for various acquisition times per bed position and various FOVs. Noise level, signal-to-noise ratio (SNR), signal-to-background ratio (SBR), and SUV were analyzed. A masked evaluation of visual image quality, rating several aspects, was performed by 2 nuclear medicine physicians to complement the analysis. Results: The lowest levels of noise were reached with the highest ß-factor, resulting in the highest SNR, which in turn resulted in the lowest SBR. A ß-factor of 400 gave noise equivalent to TOF OSEM but produced a significant increase in SUVmax (11%), SNR (22%), and SBR (12%). BSREM with a ß-factor of 533 at a decreased acquisition duration (2 min/bed position) was comparable to TOF OSEM at a full acquisition duration (3 min/bed position). Reconstructed FOV had an impact on BSREM outcome measures; SNR increased and SBR decreased when FOV was shifted from 70 to 50 cm. The evaluation of visual image quality resulted in similar scores for reconstructions, although a ß-factor of 400 obtained the highest mean whereas a ß-factor of 267 was ranked best in overall image quality, contrast, sharpness, and tumor detectability. Conclusion: In comparison with TOF OSEM, penalized BSREM reconstruction resulted in an increased tumor SUVmax and an improved SNR and SBR at a matched level of noise. BSREM allowed for a shorter acquisition than TOF OSEM, with equal image quality.