⁶⁴Cu-DOTATATE PET/CT imaging 1 hour (h) post-injection (p.i.) is excellent for lesion detection in patients with neuroendocrine neoplasms (NEN). We hypothesized that the imaging time window can be extended up to 3h p.i. 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 NEN scanned 1h and 3h p.i. of 200 MBq ⁶⁴Cu-DOTATATE. The number of lesions on both scans were counted and grouped according to organs or regions and compared with negative binomial regression. Discordant lesions (visible on the 1h or 3h p.i. ⁶⁴Cu-DOTATATE PET but not the other) were considered true if found on simultaneous CT or later MR, CT or somatostatin receptor imaging. We measured lesion maximal standardized uptake values (SUV_max), reference normal organ or tissue mean SUV (SUV_mean) and tumor-to-normal tissue ratios (TTN) calculated from SUV_max/ SUV_mean. Results We found 822 concordant lesions (visible on both the 1h and 3h p.i. ⁶⁴Cu-DOTATATE PET) and five discordant lesions of which four were considered true. One discordant case in one patient involved a discordant organ system (lymph node) detected on the 3h p.i. but not the 1h p.i. 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 the 1h and 3h p.i. ⁶⁴Cu-DOTATATE PET. Throughout the 1-3 h p.i. imaging window, TTN (mean [95% confidence interval]) remained high in all key organs: Liver (1h p.i.: 12.6 [10.2; 14.9] , 3h p.i.: 11.0 [8.7; 13.4]), intestines (1h p.i.: 24.2 [14.9; 33.4], 3h p.i.: 28.2 [16.5; 40.0]), pancreas (1h p.i.: 42.4 [12.3; 72.5], 3h p.i.: 41.1 [8.7; 73.4]) and bone (1h p.i.: 103.0 [38.6; 167.4], 3h p.i.: 124.2 [57.1; 191.2]). Conclusion The imaging time window of ⁶⁴Cu-DOTATATE PET/CT of patients with NEN can be expanded from 1h p.i. to 1-3 hours p.i. without significant differences in the number of lesions detected.

The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Non-invasive 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-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 120 patients with NENs of all grades of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was acquired 20 minutes after injection of approximately 200 MBq ⁶⁸Ga-NOTA-AE105. uPAR target-to-liver ratio (uPAR TLR) was used to define lesions as uPAR positive when lesion SUV_max /liver SUVmean ≥ 2. Patients were followed for at least 1 year to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The majority of patients had small intestinal NEN (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 disease (NEN G3). During follow-up (median 28 months), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as uPAR TLR above median, had a hazard ratio (95% confidence interval) of 1.87 (1.11-3.17) and 2.64 (1.19-5.88) for PFS and OS, respectively (p<0.05 for both). CONCLUSION: Using ⁶⁸Ga-NOTA-AE105 PET for imaging uPAR in patients with NEN, uPAR positive lesions were seen in the majority of patients and most notably in patients with both low and high grade NEN. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and uPAR may be a promising target for therapy in patients with NEN.

Patients with neuroendocrine neoplasms (NEN) 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, e.g. 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 lowest, rather than highest, ⁶⁴Cu-DOTATATE uptake would be more prognostic and developed a semi-automatic method for evaluating this. Methods: Patients with NEN underwent ⁶⁴Cu-DOTATATE PET/CT. A standardized semi-automatic tumor delineation method was developed and used to identify the lesion with the lowest uptake, i.e. lowest of lesion mean standardized uptake values (SUV)mean. Additionally, we assessed total tumor volume derived from the semi-automatic tumor delineation. Kaplan-Meier and Cox regression analyses were used to determine association with OS and PFS. Results: In 116 patients with NEN, median PFS (95% confidence interval) was 23 (20-31) months and median OS was 85 (68-113) months. Minimum SUVmean and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, while SUV_max was only significant 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/low total tumor volume and high/low minimum SUVmean. Patients with low total tumor volume and high minimum SUVmean had a hazard ratio (95% confidence interval) of 0.32 (0.20-0.51) for PFS and 0.24 (0.13-0.43) for OS, both P<0.001 (reference: high total tumor volume and low minimum SUVmean). Conclusion: We propose a standardized semi-automatic tumor delineation method to identify the lesion with lowest ⁶⁴Cu-DOTATATE uptake and total tumor volume. Assessment of lowest, rather than highest lesion uptake greatly increases prognostication by ⁶⁴Cu-DOTATATE PET/CT. Combing lesion uptake and total tumor volume, we derived a novel prognostic classification of patients with NEN.

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 α_vβ₃. [⁶⁸Ga]Ga-NODAGA-E[(cRGDyK)]₂ ([⁶⁸Ga]Ga-RGD) is a promising PET-radiotracer reflecting angiogenesis by binding to integrin α_vβ₃. 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 α_vβ₃ was evaluated using immunohistochemistry. The staining showed higher α_vβ₃ 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.