An Investigation of Lesion Detection Accuracy for Artificial Intelligence-Based Denoising of Low-Dose 64Cu-DOTATATE PET Imaging in Patients with Neuroendocrine Neoplasms.

Frequent somatostatin receptor PET, for example, 64Cu-DOTATATE PET, is part of the diagnostic work-up of patients with neuroendocrine neoplasms (NENs), resulting in high accumulated radiation doses. Scan-related radiation exposure should be minimized in accordance with the as-low-as-reasonably achievable principle, for example, by reducing injected radiotracer activity. Previous investigations found that reducing 64Cu-DOTATATE activity to below 50 MBq results in inadequate image quality and lesion detection. We therefore investigated whether image quality and lesion detection of less than 50 MBq of 64Cu-DOTATATE PET could be restored using artificial intelligence (AI). Methods: We implemented a parameter-transferred Wasserstein generative adversarial network for patients with NENs on simulated low-dose 64Cu-DOTATATE PET images corresponding to 25% (PET25%), or about 48 MBq, of the injected activity of the reference full dose (PET100%), or about 191 MBq, to generate denoised PET images (PETAI). We included 38 patients in the training sets for network optimization. We analyzed PET intensity correlation, peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and mean-square error (MSE) of PETAI/PET100% versus PET25%/PET100% Two readers assessed Likert scale-defined image quality (1, very poor; 2, poor; 3, moderate; 4, good; 5, excellent) and identified lesion-suspicious foci on PETAI and PET100% in a subset of the patients with no more than 20 lesions per organ (n = 33) to allow comparison of all foci on a 1:1 basis. Detected foci were scored (C1, definite lesion; C0, lesion-suspicious focus) and matched with PET100% as the reference. True-positive (TP), false-positive (FP), and false-negative (FN) lesions were assessed. Results: For PETAI/PET100% versus PET25%/PET100%, PET intensity correlation had a goodness-of-fit value of 0.94 versus 0.81, PSNR was 58.1 versus 53.0, SSIM was 0.908 versus 0.899, and MSE was 2.6 versus 4.7. Likert scale-defined image quality was rated good or excellent in 33 of 33 and 32 of 33 patients on PET100% and PETAI, respectively. Total number of detected lesions was 118 on PET100% and 115 on PETAI Only 78 PETAI lesions were TP, 40 were FN, and 37 were FP, yielding detection sensitivity (TP/(TP+FN)) and a false discovery rate (FP/(TP+FP)) of 66% (78/118) and 32% (37/115), respectively. In 62% (23/37) of cases, the FP lesion was scored C1, suggesting a definite lesion. Conclusion: PETAI improved visual similarity with PET100% compared with PET25%, and PETAI and PET100% had similar Likert scale-defined image quality. However, lesion detection analysis performed by physicians showed high proportions of FP and FN lesions on PETAI, highlighting the need for clinical validation of AI algorithms.

First-in-Humans PET Imaging of Tissue Factor in Patients with Primary and Metastatic Cancers Using 18F-labeled Active-Site Inhibited Factor VII (18F-ASIS): Potential as Companion Diagnostic.

Tissue factor (TF) expression in cancers correlates with poor prognosis. Recently, the first TF-targeted therapy was approved by the U.S. Food and Drug Administration for cervical cancer. To unfold the potential of TF-targeted therapies, correct stratification and selection of patients eligible for treatments may become important for optimization of patient outcomes. TF-targeted PET imaging based on 18F-radiolabeled active-site inhibited versions of the TF natural ligand coagulation factor VII (18F-ASIS) has in preclinical models convincingly demonstrated its use for noninvasive quantitative measurements of TF expression in tumor tissue. 18F-ASIS PET imaging thus has the potential to act as a diagnostic companion for TF-targeted therapies in the clinical setting. Methods: In this first-in-humans trial, we included 10 cancer patients (4 pancreatic, 3 breast, 2 lung, and 1 cervical cancer) for 18F-ASIS PET imaging. The mean and SD of administered 18F-ASIS activity was 157 ± 35 MBq (range, 93-198 MBq). PET/CT was performed after 1, 2, and 4 h. The primary objectives were to establish the safety, biodistribution, pharmacokinetics, and dosimetry of 18F-ASIS. Secondary objectives included quantitative measurements of SUVs in tumor tissue with PET and evaluation of the correlation (Pearson correlation) between tumor SUVmax and ex vivo TF expression in tumor tissue. Results: Administration of 18F-ASIS was safe, and no adverse events were observed. No clinically significant changes in vital signs, electrocardiograms, or blood parameters were observed after injection of 18F-ASIS. Mean 18F-ASIS plasma half-life was 3.2 ± 0.6 h, and the radiotracer was predominantly excreted in the urine. For injection activity of 200 MBq of 18F-ASIS, effective whole-body dose was 4 mSv and no prohibitive organ-specific absorbed doses were found. Heterogeneous radiotracer uptake was observed across patients and within tumors. We found a trend of a positive correlation between tumor SUVmax and ex vivo TF expression (r = 0.84, P = 0.08, n = 5). Conclusion: 18F-ASIS can be safely administered to cancer patients for PET imaging of TF expression in tumors. The trial marks the first test of a TF-targeted PET radiotracer in humans (first-in-class). The findings represent important first steps toward clinical implementation of 18F-ASIS PET imaging of TF expression.

Activity Dose Reduction in 64Cu-DOTATATE PET in Patients with Neuroendocrine Neoplasms: Impact on Image Quality and Lesion Detection Ability.

PURPOSE: Patients with neuroendocrine neoplasms (NEN) engage in lifelong follow-up with frequent somatostatin receptor PET, e.g. [64Cu]Cu-DOTATATE PET, and continued measures to reduce radiation exposures should be in pursued in accordance with the as-low-as-reasonably-achievable (ALARA) principle. We therefore aimed to determine the lowest achievable [64Cu]Cu-DOTATATE dose while maintaining image quality and lesion detection rate. PROCEDURES: We included scans from 38 patients with NEN referred to routine [64Cu]Cu-DOTATATE PET/CT. Using reconstruction of under-sampled PET list-mode data, we simulated [64Cu]Cu-DOTATATE activity dose-reduced PET equivalents with median [range] 142 MBq [127;157], 95 MBq [85;105], and 48 MBq [42;52], corresponding to 75% (PET75%), 50% (PET50%), and 25% (PET25%) of the full-dose 191 MBq [169;209] (PET100%). Three blinded readers independently assessed image quality (scores 1-5), lesion confidence (scores 0-2), and counted lesions grouped by organs and regions. Number of lesions, proportions of patients with diagnostic image quality (reader-median image quality ≥ 4), diagnostic lesion confidence (reader-median lesion confidence ≥ 1), and per-patient sensitivities and specificities for organ-specific disease on PET75-25% were compared with PET100%. RESULTS: The median [64Cu]Cu-DOTATATE activity dose could be reduced from 191 to 142 MBq without decline in diagnostic image quality (P = 0.62), diagnostic lesion confidence (P = 1.0), or number of lesions detected in major organs or regions (P = 0.19-0.71). Sensitivity and specificity for detection of liver disease were 100% (26/26 patients) and 100% (12/12), respectively, for both PET75% and PET50%. Overall sensitivity for detection of NEN was 100% (26/26) for both PET75% and PET50%, and overall specificities were 92% (11/12) and 100% (12/12) for PET75 and PET50, respectively. Following dose-blinded post hoc review, the PET75% specificity was adjusted to 100% (12/12). CONCLUSIONS: The [64Cu]Cu-DOTATATE activity dose can be reduced from 191 MBq to at least 142 MBq without losing image quality or lesion detection ability and further reduced to 95 MBq without loss of clinically relevant information.

A Randomized, Factorial Phase II Study to Determine the Optimal Dosing Regimen for 68Ga-Satoreotide Trizoxetan as an Imaging Agent in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

68Ga-satoreotide trizoxetan is a novel somatostatin receptor antagonist associated with high sensitivity and reproducibility in neuroendocrine tumor (NET) detection and localization. However, the optimal peptide mass and radioactivity ranges for 68Ga-satoreotide trizoxetan have not yet been established. We therefore aimed to determine its optimal dosing regimen in patients with metastatic gastroenteropancreatic NETs in a prospective, randomized, 2 × 3 factorial, multicenter phase II study. Methods: Patients received 68Ga-satoreotide trizoxetan at a peptide mass of 5-20 µg on day 1 of the study and of 30-45 µg on days 16-22, at 1 of 3 68Ga radioactivity ranges (40-80, 100-140, or 160-200 MBq). Whole-body PET/CT imaging was performed 50-70 min after each injection. The primary endpoint was the detection rate of NET lesions imaged by 68Ga-satoreotide trizoxetan relative to contrast-enhanced CT (for each of the 6 peptide mass and radioactivity range combinations). Results: Twenty-four patients were evaluated in the per-protocol analysis. The median number of lesions detected by 68Ga-satoreotide trizoxetan PET/CT or PET alone was at least twice as high as the number detected by contrast-enhanced CT across the 6 studied peptide mass and radioactivity range combinations. There were no differences between the 2 peptide mass ranges or between the 3 radioactivity ranges in the number of identified lesions. However, a trend toward a lower relative lesion count was noted in the liver for the 40- to 80-MBq range. No relationship was observed between the radioactivity range per patient's body weight (MBq/kg) and the number of lesions detected by 68Ga-satoreotide trizoxetan. The median diagnostic sensitivity of 68Ga-satoreotide trizoxetan PET/CT, based on the number of lesions per patient, ranged from 85% to 87% across the different peptide mass and radioactivity ranges. Almost all reported adverse events were mild and self-limiting. Conclusion: A radioactivity of 100-200 MBq with a peptide mass of up to 50 µg was confirmed as the optimal dosing regimen for 68Ga-satoreotide trizoxetan to be used in future phase III studies.

Initial Experience with 64Cu-DOTATATE Digital PET of Patients with Neuroendocrine Neoplasms: Comparison with Analog PET.

The recent introduction of solid-state detectors in clinical positron emission tomography (PET) scanners has significantly improved image quality and spatial resolution and shortened acquisition time compared to conventional analog PET scanners. In an initial evaluation of the performance of our newly acquired Siemens Biograph Vision 600 PET/CT (digital PET/CT) scanner for 64Cu-DOTATATE imaging, we compared PET/CT acquisitions from patients with neuroendocrine neoplasms (NENs) grades 1 and 2 and stable disease on CT who were scanned on both our Siemens Biograph 128 mCT PET/CT (analog PET/CT) and digital PET/CT within 6 months as part of their routine clinical management. Five patients fulfilled the criteria and were included in the analysis. The digital PET acquisition time was less than 1/3 of the analog PET acquisition time (digital PET, mean (min:s): 08:20 (range, 07:59-09:45); analog PET, 25:28 (24:39-28:44), p < 0.001). All 44 lesions detected on the analog PET with corresponding structural correlates on the CT were also found on the digital PET performed 137 (107-176) days later. Our initial findings suggest that digital 64Cu-DOTATATE PET can successfully be performed in patients with NENs using an image acquisition time of only 1/3 of what is used for an analog 64Cu-DOTATATE PET.

64Cu-DOTATATE PET in Patients with Neuroendocrine Neoplasms: Prospective, Head-to-Head Comparison of Imaging at 1 Hour and 3 Hours After Injection.

64Cu-DOTATATE PET/CT imaging 1 h after injection is excellent for lesion detection in patients with neuroendocrine neoplasms (NENs). We hypothesized that the imaging time window can be extended up to 3 h after injection without significant differences in the number of lesions detected. Methods: From a prospective study, we compared, on a head-to-head basis, sets of 64Cu-DOTATATE PET/CT images from 35 patients with NENs scanned 1 and 3 h after injection of 200 MBq of 64Cu-DOTATATE. The number of lesions on both PET scans was counted and grouped according to organs or regions and compared with negative binomial regression. Discordant lesions (visible on only the 1-h images or only the 3-h 64Cu-DOTATATE PET images) were considered true if found on simultaneous CT or later MR, CT, or somatostatin receptor imaging. We measured lesion SUVmax, reference normal-organ or -tissue SUVmean, and tumor-to-normal-tissue ratios calculated from SUVmax and SUVmeanResults: We found 822 concordant lesions (visible on both 1-h and 3-h 64Cu-DOTATATE PET) and 5 discordant lesions, of which 4 were considered true. One discordant case in 1 patient involved a discordant organ system (lymph node) detected on 3-h but not 1-h 64Cu-DOTATATE PET that did not alter the patient's disease stage (stage IV) because the patient had 11 additional concordant liver lesions. We found no significant differences between the number of lesions detected on 1-h and 3-h 64Cu-DOTATATE PET. Throughout the 1- to 3-h imaging window, the mean tumor-to-normal-tissue ratio remained high in all key organs: liver (1 h: 12.6 [95% confidence interval (CI), 10.2-14.9]; 3 h: 11.0 [95%CI, 8.7-13.4]), intestines (1 h: 24.2 [95%CI, 14.9-33.4]; 3 h: 28.2 [95%CI, 16.5-40.0]), pancreas (1 h: 42.4 [95%CI, 12.3-72.5]; 3 h: 41.1 [95%CI, 8.7-73.4]), and bone (1 h: 103.0 [95%CI, 38.6-167.4]; 3 h: 124.2 [95%CI, 57.1-191.2]). Conclusion: The imaging time window of 64Cu-DOTATATE PET/CT for patients with NENs can be expanded from 1 h to 1-3 h without significant differences in the number of lesions detected.

The stability of myocardial area at risk estimated electrocardiographically in patients with ST elevation myocardial infarction.

In patients with ST-elevation myocardial infarction (STEMI) the amount of myocardial area at risk (MaR) indicates the maximal potential loss of myocardium if the coronary artery remains occluded. During the time course of infarct evolution ischemic MaR is replaced by necrosis, which results in a decrease in ST segment elevation and QRS complex distortion. Recently it has been shown that combining the electrocardiographic (ECG) Aldrich ST and Selvester QRS scores result in a more accurate estimate of MaR than using either method alone. Therefore, we hypothesized that the combined Aldrich and Selvester score, indicating MaR, is stable until myocardial reperfusion therapy. In a retrospective analysis of a study population of 114 patients, 33 patients were included. The combined Aldrich and Selvester score was determined in ECGs recorded in the ambulance (ECG1) and in the hospital before reperfusion (ECG2). The combined Aldrich and Selvester score was considered stable if the difference between ECG1 and ECG2 was <4.5-percentage point. Stability of the combined Aldrich and Selvester score was observed in 12/33 patients (36.4%), and in regards to anterior and inferior ST elevation in 4/14 patients (28.6%) and 8/19 patients (42.1%), respectively. The median time between the recording of ECG1 and ECG2 was 75 minutes, however the changes in ECG scores were independent of the time between ECG recordings. Patients not meeting the stability criterion either had a decrease (9 patients) or increase (12 patients) of the combined Aldrich and Selvester score. In conclusion, the ECG estimated MaR was stable between the earliest recording time and initiation of reperfusion treatment only in a subgroup of the patients with STEMI. The findings of this study may suggest heterogeneity in regards to the development of the MaR and could indicate a potential need for differentiation in the acute treatment.

Availability of a baseline Electrocardiogram changes the application of the Sclarovsky-Birnbaum Myocardial Ischemia Grade.

BACKGROUND AND AIMS: The electrocardiogram (ECG) based Sclarovsky-Birnbaum Ischemia Grade may be used to determine the prognosis of patients with ST-elevation myocardial infarction (STEMI). However, application of the method is based on assumption of the baseline QRS morphology. Thus, the aims of this study were to determine if the baseline QRS morphology was correctly assumed based on an ECG recorded during induced ischemia, and if reference to the baseline ECG altered the designated Ischemia Grade. METHODS: Sixty-three patients with chronic ischemic heart disease that underwent elective percutaneous transluminal coronary angioplasty were included. Baseline ECG and ECG during the procedure were recorded. In the latter, Ischemia Grade was classified according to assumed baseline QRS morphology. Then the baseline ECG was used as reference and Ischemia Grade was determined based on change from the baseline ECG. RESULTS: In 66.6% (42/63) of patients the criteria for STEMI were fulfilled; the incidence was similar between left anterior descending (LAD) and right coronary artery (RCA) occlusion. In LAD patients who fulfilled STEMI criteria, assumption of baseline QRS morphology in involved leads was accurate in only 35% (7/20) and this altered the Ischemia Grade in 10% (2/20) of patients. In RCA patients who fulfilled STEMI criteria, assumption of baseline QRS morphology in involved leads was accurate in 77.3% (17/22) and this altered the Ischemia Grade in 9.1% (2/22) of patients. CONCLUSION: Application of the Sclarovsky-Birnbaum Ischemia Grade with reference to a baseline ECG altered Ischemia Grade in approximately 10% of patients. All patients that were reclassified were assigned a higher Ischemia Grade. Future research is needed to determine the impact of availability of the baseline ECG on the clinical diagnostic and prognostic performances of the Sclarovsky-Birnbaum Ischemia Grade.

A mismatch index based on the difference between measured left ventricular ejection fraction and that estimated by infarct size at three months following reperfused acute myocardial infarction.

BACKGROUND AND AIM: The reduction of left ventricular ejection fraction (LVEF) following ST-segment elevation myocardial infarction (STEMI) is a result of infarcted myocardium and may involve dysfunctional but viable myocardium. An index that may quantitatively determine whether LVEF is reduced beyond the expected value when considering only infarct size (IS) has previously been presented based on cardiac magnetic resonance (CMR). The purpose of this study was to introduce the index based on the electrocardiogram (ECG) and compare indices based on ECG and CMR. METHOD AND RESULTS: In 55 patients ECG and CMR were obtained 3 months after STEMI treated with primary percutaneous coronary intervention. Significant, however moderate inverse relationships were found between measured LVEF and IS. Based on IS and LVEF an IS estimated LVEF was derived and an MI-LVEF mismatch index was calculated as the difference between measured LVEF and IS estimated LVEF. In 41 (74.5%) of the patients there was agreement between the ECG and CMR indices in regards to categorizing indices as >10 or ≤ 10 and generally no significant difference was detected, mean difference of 1.26 percentage points (p = 0.53). CONCLUSION: The study found an overall good agreement between MI-LVEF mismatch indices based on ECG and CMR. The MI-LVEF mismatch index may serve as a tool to identify patients with potentially reversible dysfunctional but viable myocardium, but future studies including both ECG and CMR are needed.

Comparison of Selvester QRS score with magnetic resonance imaging measured infarct size in patients with ST elevation myocardial infarction.

BACKGROUND AND PURPOSE: Recent studies have shown that the Selvester QRS score is significantly correlated with delayed enhancement-magnetic resonance imaging (DE-MRI) measured myocardial infarct (MI) size in reperfused ST elevation MI (STEMI). This study further tests the hypothesis that Selvester QRS score correlates well with MI size determined by DE-MRI in reperfused STEMI. METHODS AND RESULTS: The relationship was evaluated retrospectively in 55 first-time STEMI patients 3 months after receiving primary percutaneous coronary intervention. Selvester QRS score and DE-MRI MI size were significantly correlated, r = 0.41 (P < .01). The difference between the Selvester QRS score and DE-MRI was 5.8% MI of the left ventricle (95% confidence interval, 2.9%-8.6%). Furthermore, increasing difference between Selvester QRS score and DE-MRI was observed with increasing MI size. CONCLUSION: Selvester QRS score correlated only moderately with DE-MRI MI size. Selvester QRS score overestimated MI size.