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The role of somatostatin receptor (SSTR) PET/CT, using 68 Ga-based tracers or [ 64 Cu]Cu-DOTATATE ( 64 Cu-DOTATATE), in the management of patients with neuroendocrine neoplasm (NEN) is guided by appropriate use criteria (AUC). In this study, we performed systematic analyses of referral patterns and image findings of routine 64 Cu-DOTATATE PET/CT scans to support AUC development. Methods: We included all clinical routine 64 Cu-DOTATATE PET/CT scans performed between April 10, 2018 (start of clinical use), and May 2, 2022, at Copenhagen University Hospital-Rigshospitalet. We reviewed the referral text and image report of each scan and classified the indication according to clinical scenarios as listed in the AUC. Results: In total, 1,290 patients underwent 2,249 64 Cu-DOTATATE PET/CT scans. Monitoring of patients with NEN seen both on conventional imaging and on SSTR PET without clinical evidence of progression was the most common indication (defined as "may be appropriate" in the AUC) and accounted for 703 (31.3%) scans. Initial staging after NEN diagnosis ("appropriate" in the AUC) and restaging after curative-intent surgery ("may be appropriate" in the AUC) accounted for 221 (9.8%) and 241 (10.7%) scans, respectively. Selection of patients eligible for peptide receptor radionuclide therapy ("appropriate" in the AUC) and restaging after peptide receptor radionuclide therapy completion ("appropriate" in the AUC) accounted for 95 (4.2%) and 115 (5.1%) scans, respectively. The number of scans performed for indications not defined in the AUC was 371 (16.5%). Image result analysis revealed no disease in 669 scans (29.7%), stable disease in 582 (25.9%), and progression in 461 (20.5%). In 99 of the 461 (21.5%) scans, progression was detected on PET but not on CT. Conclusion: Our study provided real-life data that may contribute to support development of 64 Cu-DOTATATE/SSTR PET/CT guidelines including AUC. Some scenarios listed as "may be appropriate" in the current AUC were frequent in our data. Monitoring of patients with NEN without clinical evidence of progression was the most frequent indication for 64 Cu-DOTATATE PET/CT, in which disease progression was detected in more than one third, and a large proportion was visible by PET only. We therefore conclude that this scenario could potentially be classified as appropriate., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: We present an algorithm to estimate the delay between a tissue time-activity curve and a blood input curve at a single-voxel level tested on whole-body data from a long-axial field-of-view scanner with tracers of different noise characteristics., Methods: Whole-body scans of 15 patients divided equally among three tracers, namely [ 15 O]H 2 O, [ 18 F]FDG and [ 64 Cu]Cu-DOTATATE, which were used in development and testing of the algorithm. Delay times were estimated by fitting the cumulatively summed input function and tissue time-activity curve with special considerations for noise. To evaluate the performance of the algorithm, it was compared against two other algorithms also commonly applied in delay estimation: name cross-correlation and a one-tissue compartment model with incorporated delay. All algorithms were tested on both synthetic time-activity curves produced with the one-tissue compartment model with increasing levels of noise and delays between the tissue activity curve and the blood input curve. Whole-body delay maps were also calculated for each of the three tracers with data acquired on a long-axial field-of-view scanner with high time resolution., Results: Our proposed model performs better for low signal-to-noise ratio time-activity curves compared to both cross-correlation and the one-tissue compartment models for non-[ 15 O]H 2 O tracers. Testing on synthetically produced time-activity curves showed only a small and even residual delay, while the one-tissue compartment model with included delay showed varying residual delays., Conclusion: The algorithm is robust to noise and proves applicable on a range of tracers as tested on [ 15 O]H 2 O, [ 18 F]FDG and [ 64 Cu]Cu-DOTATATE, and hence is a viable option offering the ability for delay correction across various organs and tracers in use with kinetic modeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Nielsen, Lindberg, Bordallo, Johnbeck, Law, Fischer, Andersen and Andersen.)

Frequent somatostatin receptor PET, for example, 64 Cu-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 64 Cu-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 64 Cu-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 64 Cu-DOTATATE PET images corresponding to 25% (PET 25% ), or about 48 MBq, of the injected activity of the reference full dose (PET 100% ), or about 191 MBq, to generate denoised PET images (PET AI ). 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 PET AI /PET 100% versus PET 25% /PET 100% 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 PET AI and PET 100% 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 (C 1 , definite lesion; C 0 , lesion-suspicious focus) and matched with PET 100% as the reference. True-positive (TP), false-positive (FP), and false-negative (FN) lesions were assessed. Results: For PET AI /PET 100% versus PET 25% /PET 100% , 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 PET 100% and PET AI , respectively . Total number of detected lesions was 118 on PET 100% and 115 on PET AI Only 78 PET AI 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 C 1 , suggesting a definite lesion. Conclusion: PET AI improved visual similarity with PET 100% compared with PET 25% , and PET AI and PET 100% had similar Likert scale-defined image quality. However, lesion detection analysis performed by physicians showed high proportions of FP and FN lesions on PET AI , highlighting the need for clinical validation of AI algorithms., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Patients with neuroendocrine neoplasms (NEN) engage in lifelong follow-up with frequent somatostatin receptor PET, e.g. [ 64 Cu]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 [ 64 Cu]Cu-DOTATATE dose while maintaining image quality and lesion detection rate., Procedures: We included scans from 38 patients with NEN referred to routine [ 64 Cu]Cu-DOTATATE PET/CT. Using reconstruction of under-sampled PET list-mode data, we simulated [ 64 Cu]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% (PET 75% ), 50% (PET 50% ), and 25% (PET 25% ) of the full-dose 191 MBq [169;209] (PET 100% ). 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 PET 75-25% were compared with PET 100% ., Results: The median [ 64 Cu]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 PET 75% and PET 50% . Overall sensitivity for detection of NEN was 100% (26/26) for both PET 75% and PET 50% , and overall specificities were 92% (11/12) and 100% (12/12) for PET 75 and PET 50 , respectively. Following dose-blinded post hoc review, the PET 75% specificity was adjusted to 100% (12/12)., Conclusions: The [ 64 Cu]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., (© 2022. World Molecular Imaging Society.)

Background: Segmentation of neuroendocrine neoplasms (NENs) in [ 64 Cu]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 [ 64 Cu]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., (© 2022. The Author(s).)

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 64 Cu-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, 64 Cu-DOTATATE uptake would be more prognostic, and we developed a semiautomatic method for evaluating this hypothesis. Methods: Patients with NENs underwent 64 Cu-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 SUV mean 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 SUV mean and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, whereas SUV max was significant only for PFS. In multivariate Cox analyses, both minimum SUV mean and total tumor volume remained statistically significant. Minimum SUV mean 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 SUV mean Patients with a low total tumor volume and high minimum SUV mean 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 SUV mean ). Conclusion: We propose a standardized semiautomatic tumor delineation method to identify the lesion with the lowest 64 Cu-DOTATATE uptake and total tumor volume. Assessment of the lowest, rather than the highest, lesion uptake greatly increases prognostication by 64 Cu-DOTATATE PET/CT. Combining lesion uptake and total tumor volume, we derived a novel prognostic classification system for patients with NENs., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Accurate grading of patients with neuroendocrine neoplasms (NENs) is essential for risk stratification and optimal choice of therapy. Currently, grading is based on histologically assessed degree of tumor proliferation. The aim of the present study was to assess the long-term prognostic value of 18 F-FDG PET imaging for risk stratification of NENs and compare it with tumor grading (World Health Organization 2010 classification). Methods: We conducted a prospective cohort study evaluating the prognostic value of 18 F-FDG PET imaging and compared it with histologic grading. Enrolled were 166 patients of all grades and with histologically confirmed NENs of gastroenteropancreatic origin. The primary endpoint was overall survival (OS). Progression-free survival (PFS) was a secondary endpoint. In addition, OS in relation to peptide receptor radionuclide therapy (PRRT) was analyzed as an exploratory endpoint. The median follow-up time was 9.8 y. Results: Analysis of the whole cohort revealed that a positive 18 F-FDG PET scan was associated with a shorter OS than a negative 18 F-FDG PET scan (hazard ratio: 3.8; 95% CI: 2.4-5.9; P < 0.001). In G1 and G2 patients ( n = 140), a positive 18 F-FDG PET scan was the only identifier of high risk for death (hazard ratio: 3.6; 95% CI, 2.2-5.9; P < 0.001). In multivariate analysis, 18 F-FDG PET, G3 tumor, ≥2 liver metastases, and ≥2 prior therapies were independent prognostic factors for OS, and 18 F-FDG PET, G3 tumor, and ≥3 liver metastases were independent prognostic factors for PFS. For patients receiving PRRT, 18 F-FDG-negative cases had a significantly longer survival than 18 F-FDG-positive cases, whereas no difference was identified for tumor grading. 18 F-FDG-positive patients receiving PRRT had a significantly longer median survival than patients not receiving PRRT (4.4 vs. 1.4 y, P = 0.001), whereas no difference was seen for 18 F-FDG-negative patients. Conclusion: 18 F-FDG PET is useful for risk stratification of all NEN grades and is superior to histologic grading. 18 F-FDG PET could differentiate G1 and G2 tumors into low- and high-risk groups. In the selection of therapy and for risk stratification of NEN patients, 18 F-FDG PET status should be considered., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

PET/computed tomography (CT) imaging increasingly is used in neuroendocrine neoplasms (NENs) for diagnosis, staging, monitoring, prognostication, and choosing treatment. Somatostatin PET analog tracers have added to the specificity by obtaining higher affinity to somatostatin receptors with 68 Ga-labeled or 64 Cu-labeled DOTA peptides compared with single-photon emission CT imaging isotopes. PET uptake correlates to tumor grade and is an essential part of theranostics with peptide receptor radionuclide treatment. This article focuses on the literature on head-to-head studies and meta-analyses of different combinations of peptide agonists and a few antagonists. Overall, the published data support the diagnostic capability of PET/CT imaging in NENs., Competing Interests: Disclosure of commercial or financial conflicts of interest and any funding sources The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 64 Cu-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 64 Cu-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 64 Cu-DOTATATE PET.

64 Cu-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 64 Cu-DOTATATE PET/CT images from 35 patients with NENs scanned 1 and 3 h after injection of 200 MBq of 64 Cu-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 64 Cu-DOTATATE PET images) were considered true if found on simultaneous CT or later MR, CT, or somatostatin receptor imaging. We measured lesion SUV max , reference normal-organ or -tissue SUV mean , and tumor-to-normal-tissue ratios calculated from SUV max and SUV mean Results: We found 822 concordant lesions (visible on both 1-h and 3-h 64 Cu-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 64 Cu-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 64 Cu-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 64 Cu-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., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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 64 Cu-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 64 Cu-DOTATATE PET/CT SRI in 2 prospective studies. Tracer uptake was determined as the maximal SUV (SUV max ) for each patient. Kaplan-Meier analysis with log-rank was used to determine the predictive value of 64 Cu-DOTATATE SUV max for OS and PFS. Specificity, sensitivity, and accuracy were calculated for prediction of outcome at 24 mo after 64 Cu-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 64 Cu-DOTATATE SUV max 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 SUV max 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 SUV max 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 64 Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of 64 Cu-DOTATATE PET/CT and outcome in patients with NENs, tumor SSTR density as visualized with 64 Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 mo after 64 Cu-DOTATATE PET/CT SRI was moderate, limiting the value on an individual-patient basis., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Somatostatin receptor imaging is a valuable tool in the diagnosis, follow-up, and treatment planning of neuroendocrine tumor (NET). PET-based tracers using 68 Ga as the radioisotope have in most centers replaced SPECT-based tracers as the gold standard. 64 Cu-DOTATATE is a new PET tracer that has been shown to be far superior to the SPECT tracer 111 In-diethylenetriaminepentaacetic acid-octreotide. Because of the advantages of 64 Cu over 68 Ga, we hypothesized that the tracer has a higher sensitivity than 68 Ga-based tracers. To test this hypothesis, we compared on a head-to-head basis the diagnostic performance of 64 Cu-DOTATATE with that of 68 Ga-DOTATOC in NET patients. Methods: Fifty-nine NET patients were scanned with both 64 Cu-DOTATATE and 68 Ga-DOTATOC PET/CT and compared on a head-to-head basis. Discordant lesions were verified during at least 30 mo of follow-up. Results: A total of 701 lesions were concordantly detected on both 64 Cu-DOTATATE and 68 Ga-DOTATOC PET/CT scans, whereas an additional 68 lesions were found by only one of the scans. 64 Cu-DOTATATE showed 42 lesions not found on 68 Ga-DOTATOC, of which 33 were found to be true-positive on follow-up. 68 Ga-DOTATOC showed 26 lesions not found on 64 Cu-DOTATATE, of which 7 were found to be true-positive on follow-up. False-positives were mainly lymph node lesions. Accordingly, 83% of the additional true lesions found on only one of the scans were found by 64 Cu-DOTATATE. On a patient-basis, additional true lesions were found by 64 Cu-DOTATATE and 68 Ga-DOTATOC in 13 and 3 patients, respectively. All patients with additional lesions also had concordant lesions found by both scans. Conclusion: 64 Cu-DOTATATE has advantages over 68 Ga-DOTATOC in the detection of lesions in NET patients. Although patient-based sensitivity was the same for 64 Cu-DOTATATE and 68 Ga-DOTATOC in this cohort, significantly more lesions were detected by 64 Cu-DOTATATE. Furthermore, the shelf life of more than 24 h and the scanning window of at least 3 h make 64 Cu-DOTATATE favorable and easy to use in the clinical setting., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors arising in various organs and with a large span of aggressiveness and survival rates. The Ki-67 proliferation index is presently used as the key marker of prognosis, and treatment guidelines are largely based on this index. 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) is a proliferation tracer for PET imaging valuable in the monitoring of disease progression and treatment response in various types of cancer. However, until now only data from 10 patients with NEN were available in the literature. The aim of the present study was to investigate 18 F-FLT PET as a prognostic marker for NENs in comparison with 18 F-FDG PET and Ki-67 index., Methods: One hundred patients were PET-scanned with both 18 F-FLT and 18 F-FDG within the same week, and the prognostic value of a positive scan was examined in terms of progression-free survival (PFS) and overall survival (OS). The correlation between the Ki-67 index and 18 F-FLT uptake was also investigated., Results: Thirty-seven percent of patients had a positive 18 F-FLT PET scan, and 49% had 18 F-FDG PET-positive foci. Patients with a high 18 F-FLT uptake had a significantly shorter OS and PFS than patients with low or no 18 F-FLT uptake. No correlation was found between Ki-67 index and 18 F-FLT uptake. In a multivariate analysis 18 F-FLT, 18 F-FDG, and Ki-67 all were significant prognostic markers of PFS. For OS, only 18 F-FDG and Ki-67 remained significant., Conclusion: 18 F-FLT PET has prognostic value in NEN patients but when 18 F-FDG PET and Ki-67 index are also available, a multivariate model revealed that 18 F-FLT PET only adds information regarding PFS but not OS, whereas 18 F-FDG PET remains predictive of both PFS and OS. However, a clinically robust algorithm including 18 F-FLT in addition to 18 F-FDG and Ki-67 could not be found. Accordingly, the exact role, if any, of 18 F-FLT PET in NENs remains to be established., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: The somatostatin receptor subtype 2 is expressed on macrophages, an abundant cell type in the atherosclerotic plaque. Visualization of somatostatin receptor subtype 2, for oncologic purposes, is frequently made using the DOTA-derived somatostatin analogs DOTATOC or DOTATATE for PET. We aimed to compare the uptake of the PET tracers (68)Ga-DOTATOC and (64)Cu-DOTATATE in large arteries, in the assessment of atherosclerosis by noninvasive imaging technique, combining PET and CT. Further, the correlation of uptake and cardiovascular risk factors was investigated., Methods: Sixty consecutive patients with neuroendocrine tumors underwent both (68)Ga-DOTATOC and (64)Cu-DOTATATE PET/CT scans, in random order. For each scan, the maximum and mean standardized uptake values (SUVs) were calculated in 5 arterial segments. In addition, the blood-pool-corrected target-to-background ratio was calculated. Uptake of the tracers was correlated with cardiovascular risk factors collected from medical records., Results: We found detectable uptake of both tracers in all arterial segments studied. Uptake of (64)Cu-DOTATATE was significantly higher than (68)Ga-DOTATOC in the vascular regions both when calculated as maximum and mean uptake. There was a significant association between Framingham risk score and the overall maximum uptake of (64)Cu-DOTATATE using SUV (r = 0.4; P = 0.004) as well as target-to-background ratio (r = 0.3; P = 0.04), whereas no association was found with (68)Ga-DOTATOC. The association of risk factors and maximum SUV of (64)Cu-DOTATATE was found driven by body mass index, smoking, diabetes, and coronary calcium score (P < 0.001, P = 0.01, P = 0.005, and P = 0.03, respectively)., Conclusion: In a series of oncologic patients, vascular uptake of (68)Ga-DOTATOC and (64)Cu-DOTATATE was found, with highest uptake of the latter. Uptake of (64)Cu-DOTATATE, but not of (68)Ga-DOTATOC, was correlated with cardiovascular risk factors, suggesting a potential role for (64)Cu-DOTATATE in the assessment of atherosclerosis., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention., Objective: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis., Methods and Results: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta., Conclusions: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis., (© 2015 American Heart Association, Inc.)

Heart muscle cells produce peptide hormones such as natriuretic peptides. Developing hearts also express the gene for the classic intestinal hormone cholecystokinin (CCK) in amounts similar to those in the intestine and brain. However, cardiac expression of peptides other than natriuretic peptides has only been suggested using transcriptional measures or methods, with the post-translational phase of gene expression unaddressed. In this study, we examined the cardiac expression of the CCK gene in adult mammals and its expression at the protein level. Using quantitative PCR, a library of sequence-specific pro-CCK assays, peptide purification, and mass spectrometry, we demonstrate that the mammalian heart expresses pro-CCK in amounts comparable to natriuretic prohormones and processes it to a unique, triple-sulfated, and N-terminally truncated product distinct from intestinal and cerebral CCK peptides. Isoprenaline rapidly stimulated cardiac CCK gene expression in vitro and in vivo, which suggests that the cardiac-specific truncated pro-CCK may have pathophysiological relevance as a new marker of heart failure. The suggestion is confirmed by measurement of plasma from heart failure patients., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Neuroendocrine tumors have shown rising incidence mainly due to higher clinical awareness and better diagnostic tools over the last 30 years. Functional imaging of neuroendocrine tumors with PET tracers is an evolving field that is continuously refining the affinity of new tracers in the search for the perfect neuroendocrine tumor imaging tracer. (68)Ga-labeled tracers coupled to synthetic somatostatin analogs with differences in affinity for the five somatostatin receptor subtypes are now widely applied in Europe. Comparison of sensitivity between the most used tracers - (68)Ga-DOTA-Tyr3-octreotide, (68)Ga-DOTA-Tyr3-octreotate and (68)Ga-DOTA-l-Nal3-octreotide - shows little difference and expertise on the specific tracer used, and knowledge regarding physiological uptake might be more important than in vitro-proven differences in affinity. Using isotopes such as (18)F or (64)Cu might improve these PET tracers further.

Introduction: The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging., Methods: The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily) for 10 days. PET/CT scans were repeated at day 1,3 and 10., Results: Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016), day 7 (164±7% vs. 226±13%; p<0.001) and at day 10 (194±10% vs. 281±18%; p<0.001). Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034), 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019) and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001) and day 10 (r2 = 0.58; P = 0.027)., Conclusion: Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.

Background: Belinostat is a histone deacetylase inhibitor with anti-tumor effect in several pre-clinical tumor models and clinical trials. The aim of the study was to evaluate changes in cell proliferation and glucose uptake by use of 3'-deoxy-3'-[(18)F]fluorothymidine ([18F]FLT) and 2-deoxy-2-[(18)F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) following treatment with belinostat in ovarian cancer in vivo models., Methods: In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) were studied after treatment with belinostat. Mice were divided in 2 groups receiving either belinostat (40 mg/kg ip twice daily Day 0-4 and 6-10) or vehicle. Baseline [18F]FLT or [18F]FDG scans were made before treatment (Day 0) and repeated at Day 3, 6 and 10. Tracer uptake was quantified using small animal PET/CT., Results: Tumors in the belinostat group had volumes that were 462 ± 62% (640 mm(3)) at Day 10 relative to baseline which was significantly different (P = 0.011) from the control group 769 ± 74% (926 mm(3)). [18F]FLT SUVmax increased from baseline to Day 10 (+30 ± 9%; P = 0.048) in the control group. No increase was observed in the treatment group. [18F]FDG SUVmean was significantly different in the treatment group compared to the control group (P = 0.0023) at Day 10. Within treatment groups [18F]FDG uptake and to a lesser extent [18F]FLT uptake at Day 3 were significantly correlated with tumor growth at Day 10., Conclusions: [18F]FDG uptake early following treatment initiation predicted tumor sizes at Day 10, suggesting that [18F]FDG may be a valuable biomarker for non-invasive assessment of anti-tumor activity of belinostat.

Combined PET/MRI systems are now commercially available and are expected to change the medical imaging field by providing combined anato-metabolic image information. We believe this will be of particular relevance in imaging of cancer patients. At the Department of Clinical Physiology, Nuclear Medicine & PET at Rigshospitalet in Copenhagen we installed an integrated PET/MRI in December 2011. Here, we describe our first clinical PET/MR cases and discuss some of the areas within oncology where we envision promising future application of integrated PET/MR imaging in clinical routine. Cases described include brain tumors, pediatric oncology as well as lung, abdominal and pelvic cancer. In general the cases show that PET/MRI performs well in all these types of cancer when compared to PET/CT. However, future large-scale clinical studies are needed to establish when to use PET/MRI. We envision that PET/MRI in oncology will prove to become a valuable addition to PET/CT in diagnosing, tailoring and monitoring cancer therapy in selected patient populations.

Introduction: APO866 is a new anti-tumor compound inhibiting nicotinamide phosphoribosyltransferase (NAMPT). APO866 has an anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of this study was non-invasively to study effect of APO866 treatment on [18F]FLT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake., Methods: In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment. Baseline [18F]FLT or [18F]FDG scans were made before treatment and repeated after 24 hours, 48 hours and 7 days. Tumor volume was followed with computed tomography (CT). Tracer uptake was quantified using small animal PET/CT. One hour after iv injection of tracer, static PET scans were performed. Imaging results were compared with Ki67 immunohistochemistry., Results: Tumors treated with APO866 had volumes that were 114% (24 h), 128% (48 h) and 130% (Day 7) relative to baseline volumes at Day 0. In the control group tumor volumes were 118% (24 h), 145% (48 h) and 339% (Day 7) relative to baseline volumes Day 0. Tumor volume between the treatment and control group was significantly different at Day 7 (P = 0.001). Compared to baseline, [18F]FLT SUVmax was significantly different at 24 h (P<0.001), 48 h (P<0.001) and Day 7 (P<0.001) in the APO866 group. Compared to baseline, [18F]FDG SUVmax was significantly different at Day 7 (P = 0.005) in the APO866 group., Conclusions: APO866 treatment caused a significant decrease in [18F]FLT uptake 24 and 48 hours after treatment initiation. The early reductions in tumor cell proliferation preceded decrease in tumor volume. The results show the possibility to use [18F]FLT and [18F]FDG to image treatment effect early following treatment with APO866 in future clinical studies.

The aim of our study was to perform a prospective study that compared the diagnostic ability of V/Q single photon emission computer tomography (V/Q-SPECT), V/Q-SPECT combined with low-dose computed tomography (CT) and pulmonary multidetector computed tomography(MDCT)-angiography in patients suspected of having pulmonary embolism (PE) using a dedicated combined SPECT/MDCT-scanner. V/Q-SPECT in combination with low-dose CT had a sensitivity of 97% and a specificity of 100%. MDCT angiography had a sensitivity of 68% and a specificity of 100%. We conclude that V/Q-SPECT in combination with low-dose CT without contrast has an excellent diagnostic performance and should be considered the first-line imaging technique in the work-up of PE in most cases.

Unlabelled: The diagnosis of pulmonary embolism (PE) is usually established by a combination of clinical assessment, D-dimer testing, and imaging with either pulmonary ventilation-perfusion (V/Q) scintigraphy or pulmonary multidetector CT (MDCT) angiography. Both V/Q SPECT and MDCT angiography seem to have high diagnostic accuracy. However, only limited data directly comparing these 2 modalities are available. Hybrid gamma-camera/MDCT systems have been introduced and allow simultaneous 3-dimensional lung V/Q SPECT and MDCT angiography, suitable for diagnosing PE. The aim of our study was to compare, in a prospective design, the diagnostic ability of V/Q SPECT, V/Q SPECT combined with low-dose CT, and pulmonary MDCT angiography obtained simultaneously using a combined SPECT/MDCT scanner in patients suspected of having PE., Methods: Consecutive patients from June 2006 to February 2008 suspected of having acute PE were referred to the Department of Nuclear Medicine at Rigshospitalet or Frederiksberg Hospital, Denmark, for V/Q SPECT as a first-line imaging procedure. The number of eligible patients was 196. Patients with positive D-dimer results (>0.5 mmol/mL) or a clinical assessment with a Wells score greater than 2 were included and underwent V/Q SPECT, low-dose CT, and pulmonary MDCT angiography in a single session. Patient follow-up was 6 mo., Results: A total of 81 simultaneous studies were available for analysis, of which 38% were from patients with PE. V/Q SPECT had a sensitivity of 97% and a specificity of 88%. When low-dose CT was added, the sensitivity was still 97% and the specificity increased to 100%. Perfusion SPECT with low-dose CT had a sensitivity of 93% and a specificity of 51%. MDCT angiography alone had a sensitivity of 68% and a specificity of 100%., Conclusion: We conclude that V/Q SPECT in combination with low-dose CT without contrast enhancement has an excellent diagnostic performance and should therefore probably be considered first-line imaging in the work-up of PE in most cases.