Improved positron emission tomography imaging of glioblastoma cancer using novel 68Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR).

The urokinase-type plasminogen activator receptor (uPAR) is overexpressed in several cancers including glioblastoma (GBM) and is an established biomarker for metastatic potential. The uPAR-targeting peptide AE105-NH2 (Ac-Asp-Cha-Phe-(D)Ser-(D)Arg-Tyr-Leu-Trp-Ser-CONH2) is a promising candidate for non-invasive positron emission tomography (PET) imaging of uPAR. Despite the optimal physical properties of 68Ga for peptide-based PET imaging, low tumor uptakes have previously been reported using 68Ga-labeled AE105-NH2-based tracers. In an attempt to optimize the tumor uptake, we developed three novel tracers with alkane (AOC) and polyethylene glycol (PEG) spacers inserted between AE105-NH2 and the radio metal chelator 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA). The resulting tracers NODAGA-AOC-AE105-NH2, NODAGA-PEG3-AE105-NH2 and NODAGA-PEG8-AE105-NH2 were compared to the non-spacer version, NODAGA-AE105-NH2. Following radiolabeling with 68Ga, we evaluated the in vitro and in vivo performance in mice bearing subcutaneous tumors derived from the uPAR-expressing human GBM cell line U87MG. In vivo PET/CT imaging showed that introduction of PEG spacers more than doubled the in vivo tumor uptake after 1 h compared with the non-spacer version: 68Ga-NODAGA-PEG3-AE105-NH2 (2.08 ± 0.37%ID/g) and 68Ga-NODAGA-PEG8-AE105-NH2 (2.01 ± 0.22%ID/g) vs. 68Ga-NODAGA-AE105-NH2 (0.70 ± 0.40%ID/g), p < 0.05. In addition, 68Ga-NODAGA-PEG8-AE105-NH2 showed significantly higher (p < 0.05) tumor-to-background contrast (3.68 ± 0.23) than the other tracers. The specific tumor-targeting property of 68Ga-NODAGA-PEG8-AE105-NH2 was established by effectively blocking the tumor uptake with co-injection of unlabeled AE105-NH2 (1 h: unblocked 2.01 ± 0.22%ID/g vs. blocked 1.24 ± 0.09%ID/g, p < 0.05). Ex vivo biodistribution confirmed the improved tumor uptakes of the PEG-modified tracers. 68Ga-NODAGA-PEG8-AE105-NH2 is thus a promising candidate for human translation for PET imaging of GBM.

Preclinical Study on GRPR-Targeted (68)Ga-Probes for PET Imaging of Prostate Cancer.

Gastrin-releasing peptide receptor (GRPR) targeted positron emission tomography (PET) is a highly promising approach for imaging of prostate cancer (PCa) in small animal models and patients. Developing a GRPR-targeted PET probe with excellent in vivo performance such as high tumor uptake, high contrast, and optimal pharmacokinetics is still very challenging. Herein, a novel bombesin (BBN) analogue (named SCH1) based on JMV594 peptide modified with an 8-amino octanoic acid spacer (AOC) was thus designed and conjugated with the metal chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA). The resulting NODAGA-SCH1 was then radiolabeled with (68)Ga and evaluated for PET imaging of PCa. Compared with (68)Ga-NODAGA-JMV594 probe, (68)Ga-NODAGA-SCH1 exhibited excellent PET/CT imaging properties on PC-3 tumor-bearing nude mice, such as high tumor uptake (5.80 ± 0.42 vs 3.78 ± 0.28%ID/g, 2 h) and high tumor/muscle contrast (16.6 ± 1.50 vs 8.42 ± 0.61%ID/g, 2 h). Importantly, biodistribution data indicated a relatively similar accumulation of (68)Ga-NODAGA-SCH1 was observed in the liver (4.21 ± 0.42%ID/g) and kidney (3.41 ± 0.46%ID/g) suggesting that the clearance is through both the kidney and the liver. Overall, (68)Ga-NODAGA-SCH1 showed promising in vivo properties and is a promising candidate for translation into clinical PET-imaging of PCa patients.

Prospective Phase II Trial of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT Imaging of Integrin αvß3 for Prognostication in Patients with Neuroendocrine Neoplasms.

Integrin αvß3, a subtype of the arginine-glycine-aspartate (RGD)-recognizing cell surface integrins, is upregulated on endothelial cells during angiogenesis and on tumor cells. Because of involvement in tumor growth, invasiveness and metastases, and angiogenesis, integrin αvß3 is an attractive target in cancers. In this study, we applied 68Ga-NODAGA-E[c(RGDyK)]2 for imaging of integrin αvß3 in patients with neuroendocrine neoplasms (NENs) and its potential use for prognostication. We hypothesized that 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT would show tumor lesion uptake and that higher tumor lesion uptake was associated with a poorer prognosis. Methods: Between December 2017 and November 2020 we prospectively enrolled 113 patients with NEN of all grades (2019 World Health Organization classification) for 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT. The scan was acquired 45 min after injection of 200 MBq of 68Ga-NODAGA-E[c(RGDyK)]2 Board-certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUVmax in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUVmax for each patient was used as a predictor of outcome. Patients were followed for at least 1 y to assess progression-free survival and overall survival. Results: Of 113 patients enrolled in the trial, 99 underwent 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT, with 97 patients having evaluable lesions. The patients predominantly had small intestinal (64%) or pancreatic (20%) NEN and most had metastatic disease (93%). Most patients had low-grade tumors (78%), whereas 22% had high-grade tumors. During a median follow-up of 31 mo (interquartile range, 26-38 mo), 62 patients (64%) experienced disease progression and 25 (26%) patients died. In total, 76% of patients had positive tumor lesions, and of the patients with high-grade tumors 91% had positive tumor lesions. High integrin αvß3 expression, defined as an SUVmax of at least 5.25, had a hazard ratio of 2.11 (95% CI, 1.18-3.78) and 6.95 (95% CI, 1.64-29.51) for progression-free survival and overall survival, respectively (P = 0.01 for both). Conclusion: Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)]2 was evident in patients with all grades of NEN. High uptake was associated with a poorer prognosis. Further studies are warranted to establish whether 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin αvß3.

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.

Prospective Phase II Trial of Prognostication by 68Ga-NOTA-AE105 uPAR PET in Patients with Neuroendocrine Neoplasms: Implications for uPAR-Targeted Therapy.

The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Noninvasive tools to improve prognostication and guide decisions on treatment are warranted. Expression of urokinase plasminogen activator receptor (uPAR) is present in many cancer types and associated with a poor outcome. Therefore, using an in-house-developed uPAR PET tracer [68Ga]Ga-NOTA-Asp-Cha-Phe-D-Ser-D-Arg-Tyr-Leu-Trp-Ser-OH (68Ga-NOTA-AE105), we aimed to assess uPAR expression in NENs. We hypothesized that uPAR expression was detectable in a significant proportion of patients and associated with a poorer outcome. In addition, as uPAR-targeted radionuclide therapy has previously proven effective in preclinical models, the study would also indicate the potential for uPAR-targeted radionuclide therapy in NEN patients. Methods: In a prospective clinical phase II trial, we included 116 patients with NENs of all grades, of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was performed 20 min after injection of approximately 200 MBq of 68Ga-NOTA-AE105. uPAR target-to-liver ratio was used to define lesions as uPAR-positive when lesion SUVmax-to-liver SUVmean ratio was at least 2. Patients were followed for at least 1 y to assess progression-free and overall survival. Results: Most patients had small intestinal NENs (n = 61) and metastatic disease (n = 86). uPAR-positive lesions were seen in 68% (n = 65) of all patients and in 75% (n = 18) of patients with high-grade (grade 3) NENs. During follow-up (median, 28 mo), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as a uPAR target-to-liver ratio above median, had a hazard ratio of 1.87 (95% CI, 1.11-3.17) and 2.64 (95% CI, 1.19-5.88) for progression-free and overall survival, respectively (P < 0.05 for both). Conclusion: When 68Ga-NOTA-AE105 PET was used to image uPAR in patients with NENs, uPAR-positive lesions were seen in most patients, notably in patients with both low-grade and high-grade NENs. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and that uPAR may be a promising target for therapy in patients with NENs.

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 convolutional neural network for total tumor segmentation in [64Cu]Cu-DOTATATE PET/CT of patients with neuroendocrine neoplasms.

BACKGROUND: Segmentation of neuroendocrine neoplasms (NENs) in [64Cu]Cu-DOTATATE positron emission tomography makes it possible to extract quantitative measures useable for prognostication of patients. However, manual tumor segmentation is cumbersome and time-consuming. Therefore, we aimed to implement and test an artificial intelligence (AI) network for tumor segmentation. Patients with gastroenteropancreatic or lung NEN with [64Cu]Cu-DOTATATE PET/CT performed were included in our training (n = 117) and test cohort (n = 41). Further, 10 patients with no signs of NEN were included as negative controls. Ground truth segmentations were obtained by a standardized semiautomatic method for tumor segmentation by a physician. The nnU-Net framework was used to set up a deep learning U-net architecture. Dice score, sensitivity and precision were used for selection of the final model. AI segmentations were implemented in a clinical imaging viewer where a physician evaluated performance and performed manual adjustments. RESULTS: Cross-validation training was used to generate models and an ensemble model. The ensemble model performed best overall with a lesion-wise dice of 0.850 and pixel-wise dice, precision and sensitivity of 0.801, 0.786 and 0.872, respectively. Performance of the ensemble model was acceptable with some degree of manual adjustment in 35/41 (85%) patients. Final tumor segmentation could be obtained from the AI model with manual adjustments in 5 min versus 17 min for ground truth method, p < 0.01. CONCLUSION: We implemented and validated an AI model that achieved a high similarity with ground truth segmentation and resulted in faster tumor segmentation. With AI, total tumor segmentation may become feasible in the clinical routine.

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.

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.

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.

Semiautomatic Tumor Delineation for Evaluation of 64Cu-DOTATATE PET/CT in Patients with Neuroendocrine Neoplasms: Prognostication Based on Lowest Lesion Uptake and Total Tumor Volume.

Patients with neuroendocrine neoplasms (NENs) have heterogeneous somatostatin receptor expression, with highly differentiated lesions having higher expression. Receptor expression of the total tumor burden may be visualized by somatostatin receptor imaging, such as with 64Cu-DOTATATE PET/CT. Assessment of maximal lesion uptake is associated with progression-free survival (PFS) but not overall survival (OS). We hypothesized that the lesion with the lowest, rather than the highest, 64Cu-DOTATATE uptake would be more prognostic, and we developed a semiautomatic method for evaluating this hypothesis. Methods: Patients with NENs underwent 64Cu-DOTATATE PET/CT. A standardized semiautomatic tumor delineation method was developed and used to identify the lesion with the lowest uptake, that is, with the lowest SUVmean Additionally, we assessed total tumor volume derived from the semiautomatic tumor delineation. Kaplan-Meier and Cox regression analyses were used to determine whether there was any association with OS and PFS. Results: In 116 patients with NENs, median PFS (95% CI) was 23 mo (range, 20-31 mo) and median OS was 85 mo (range, 68-113 mo). Minimum SUVmean and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, whereas SUVmax was significant only for PFS. In multivariate Cox analyses, both minimum SUVmean and total tumor volume remained statistically significant. Minimum SUVmean and total tumor volume were then dichotomized by their median, and patients were categorized into 4 groups: high or low total tumor volume and high or low minimum SUVmean Patients with a low total tumor volume and high minimum SUVmean had a hazard ratio of 0.32 (95% CI, 0.20-0.51) for PFS and 0.24 (95% CI, 0.13-0.43) for OS, both with P values of less than 0.001 (reference: high total tumor volume and low minimum SUVmean). Conclusion: We propose a standardized semiautomatic tumor delineation method to identify the lesion with the lowest 64Cu-DOTATATE uptake and total tumor volume. Assessment of the lowest, rather than the highest, lesion uptake greatly increases prognostication by 64Cu-DOTATATE PET/CT. Combining lesion uptake and total tumor volume, we derived a novel prognostic classification system for patients with NENs.

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.

[68Ga]Ga-NODAGA-E[(cRGDyK)]2 Angiogenesis PET/MR in a Porcine Model of Chronic Myocardial Infarction.

Angiogenesis is crucial in tissue repair and prevents scar tissue formation following an ischemic event such as myocardial infarction. The ischemia induces formation of new capillaries, which have high expression of integrin αvß3. [68Ga]Ga-NODAGA-E[(cRGDyK)]2 ([68Ga]Ga-RGD) is a promising PET-radiotracer reflecting angiogenesis by binding to integrin αvß3. A Göttingen mini-pig underwent transient catheter-induced left anterior descending artery (LAD) occlusion for 120 min, and after 8 weeks was imaged on a Siemens mMR 3T PET/MR system. A large antero-septal infarction was evident by late gadolinium enhancement (LGE) on the short axis and 2-4 chamber views. The infarcted area corresponded to the area with high [68Ga]Ga-RGD uptake on the fused PET/MR images, with no uptake in the healthy myocardium. To support the hypothesis that [68Ga]Ga-RGD uptake reflects angiogenesis, biopsies were sampled from the infarct border and healthy myocardium. Expression of αvß3 was evaluated using immunohistochemistry. The staining showed higher αvß3 expression in the capillaries of the infarct border compared to those in the healthy myocardium. These initial data confirm in vivo detection of angiogenesis using [68Ga]Ga-RGD PET in a translational model, which overall support the method applicability when evaluating novel cardio-protective therapies.

64Cu-DOTATATE PET/CT and Prediction of Overall and Progression-Free Survival in Patients with Neuroendocrine Neoplasms.

Overexpression of somatostatin receptors (SSTRs) in patients with neuroendocrine neoplasms (NENs) is used for both diagnosis and treatment. Receptor density may reflect tumor differentiation and thus be associated with prognosis. Noninvasive visualization and quantification of SSTR density is possible by SSTR imaging (SRI) using PET. Recently, we introduced 64Cu-DOTATATE for SRI, and we hypothesized that uptake of this tracer could be associated with overall survival (OS) and progression-free survival (PFS). Methods: We evaluated patients with NENs who underwent 64Cu-DOTATATE PET/CT SRI in 2 prospective studies. Tracer uptake was determined as the maximal SUV (SUVmax) for each patient. Kaplan-Meier analysis with log-rank was used to determine the predictive value of 64Cu-DOTATATE SUVmax for OS and PFS. Specificity, sensitivity, and accuracy were calculated for prediction of outcome at 24 mo after 64Cu-DOTATATE PET/CT. Results: In total, 128 patients with NENs were included and followed for a median of 73 mo (range, 1-112 mo). During follow-up, 112 experienced disease progression, and 69 died. The optimal cutoff for 64Cu-DOTATATE SUVmax was 43.3 for prediction of PFS, with a hazard ratio of 0.56 (95% confidence interval, 0.38-0.84) for patients with an SUVmax of more than 43.3. However, no significant cutoff was found for prediction of OS. In multiple Cox regression adjusted for age, sex, primary tumor site, and tumor grade, the SUVmax cutoff hazard ratio was 0.50 (range, 0.32-0.77) for PFS. The accuracy was moderate for predicting PFS (57%) at 24 mo after 64Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of 64Cu-DOTATATE PET/CT and outcome in patients with NENs, tumor SSTR density as visualized with 64Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 mo after 64Cu-DOTATATE PET/CT SRI was moderate, limiting the value on an individual-patient basis.

Multimodality Hyperpolarized C-13 MRS/PET/Multiparametric MR Imaging for Detection and Image-Guided Biopsy of Prostate Cancer: First Experience in a Canine Prostate Cancer Model.

PURPOSE: To assess whether simultaneous hyperpolarized C-13 magnetic resonance spectroscopy (MRS)/positron emission tomography (PET)/multiparametric magnetic resonance (mpMR) imaging is feasible in an orthotopic canine prostate cancer (PCa) model using a clinical PET/MR system and whether the combined imaging datasets can be fused with transrectal ultrasound (TRUS) in real time for multimodal image fusion-guided targeted biopsy of PCa. PROCEDURES: Institutional Animal Care and Use Committee approval was obtained for this study. Canine prostate adenocarcinoma (Ace-1) cells were orthotopically injected into the prostate of four dogs. Once tumor engraftment was confirmed by TRUS, simultaneous hyperpolarized C-13 MRS of [1-13C]pyruvate, PET (2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), [68Ga]NODAGA-SCH1), and mpMR (T2W, DWI) imaging was performed using a clinical PET/MR system. Multimodality imaging data sets were then fused with TRUS and image-guided targeted biopsy was performed. Imaging results were then correlated with histological findings. RESULTS: Successful tumor engraftment was histologically confirmed in three of the four dogs (dogs 2, 3, and 4) and simultaneous C-13 MRS/PET/mpMR was feasible in all three. In dog 2, C-13 MRS showed increased lactate signal in the tumor (lactate/totalC = 0.47) whereas mpMR did not show any signal changes. In dog 3, [18F]FDG-PET (SUVmean = 1.90) and C-13 MRS (lactate/totalC = 0.59) showed elevated metabolic activity in the tumor. In dog 4, [18F]FDG (SUVmean = 2.43), [68Ga]NODAGA-SCH1 (SUVmean = 0.75), and C-13 MRS (Lac/totalC = 0.53) showed elevated uptake in tumor compared to control tissue and multimodal image fusion-guided biopsy of the tumor was successfully performed. CONCLUSION: Simultaneous C-13 MRS/PET/mpMR imaging and multimodal image fusion-guided biopsy is feasible in a canine PCa model.

The CPC Risk Calculator: A New App to Predict Prostate-specific Antigen Recurrence During Follow-up After Radical Prostatectomy.

BACKGROUND: It can be challenging to predict the risk of biochemical recurrence (BR) during follow-up after radical prostatectomy (RP) in men who have undetectable prostate-specific antigen (PSA), even years after surgery. OBJECTIVE: To establish and validate a contemporary nomogram that predicts the absolute risk of BR every year after RP in men with undetectable PSA while accounting for competing risks of death. DESIGN, SETTING, AND PARTICIPANTS: A total of 3746 patients from Rigshospitalet (Copenhagen, Denmark) and Stanford Urology (Stanford, CA, USA) who underwent RP between 1995 and 2013 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to BR was defined as the first PSA result ≥0.2 ng/ml. BR risk was computed using multiple cause-specific Cox regression including preoperative PSA, pT category, RP Gleason score (GS), and surgical margin (R) status. Death without BR was considered a competing event. The nomogram presents the future risk of BR for a man who is alive and without BR at the time of follow-up. Validation assessed the discrimination and accuracy using time-dependent area under the curve and Brier scores. RESULTS AND LIMITATIONS: The nomogram predicts risk of BR up to 12 yr after RP at an individual level. As example, the risk of BR for a man with pT3a, R-, GS 3 + 4, and preoperative PSA ≤10 ng/ml followed for 5 yr with undetectable PSA is 18% for the next 5 yr. External validation demonstrated both high accuracy and discrimination. The CPC Risk Calculator is available as a free Android and iOS App. Declining discrimination and accuracy after 7 yr of follow-up is the main limitation. CONCLUSIONS: This nomogram can be used as a tool to inform men with undetectable PSA during follow-up after RP about their future risk of BR, and may aid in decisions on the necessity for further follow-up. The nomogram is the first to be available as a free app. PATIENT SUMMARY: We developed an easily interpretable nomogram to evaluate the risk of prostate-specific antigen elevation (cancer recurrence) following complete removal of the prostate (radical prostatectomy). The tool can aid both physicians and patients in evaluating the future risk of cancer recurrence during follow-up after surgery. The model is available as a free mobile app that can be downloaded from the App Store.

Temporal Trends in Clinical and Pathological Characteristics for Men Undergoing Radical Prostatectomy Between 1995 and 2013 at Rigshospitalet, Copenhagen, Denmark, and Stanford University Hospital, United States.

PURPOSE: To analyze how prostate-specific antigen (PSA) screening and practice patterns has affected trends in tumor characteristics in men undergoing radical prostatectomy (RP) in the United States and Denmark. Unlike in the United States, PSA screening has not been recommended in Denmark. PATIENTS AND METHODS: We performed an observational register study using pre- and postoperative data on 2168 Danish patients from Rigshospitalet, Copenhagen, Denmark, and 2236 patients from Stanford University Hospital, Stanford, CA, who underwent RP between 1995 and 2013. Patients were stratified according to Cancer of the Prostate Risk Assessment-Postsurgical (CAPRA-S) risk groups and D'Amico risk classification and were clustered into 4 time periods (1995-1999, 2000-2004, 2005-2009, and 2010-2013). Temporal trends in the proportions of patients of a given variable at the 2 institutions were evaluated with Cochran-Armitage test for trends and chi-square testing. RESULTS: A total of 4404 patients were included. Temporal changes in preoperative PSA, age, grade, and stage was found in both cohorts. Median preoperative PSA declined in both cohorts, while median age increased, with the Danish cohort showing the greatest changes in both PSA and age. In both cohorts, there was a trend for higher-risk preoperative features before RP over time. In 2010-2013, 27.7% and 21.8% of the patients were in the D'Amico high-risk group at Copenhagen and Stanford, respectively. CONCLUSION: Despite recommendation against PSA screening in Denmark, Danish men undergoing RP at Rigshospitalet to a considerable extent now resemble American men undergoing RP at Stanford. At both sites, there is continued trend to reduce the number of men undergoing RP for low-risk prostate cancer.