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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: [15O]H2O, [18F]FDG and [64Cu]Cu-DOTATATE, were used in development and testing of the algorithm. Delay time 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-[15O]H2O tracers. Testing on synthetically produced time activity curves it displays 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 [15O]H2O, [18F]FDG and [64Cu]Cu-DOTATATE, and hence is a viable option offering the ability for delay correction across various organs and tracers in use with kinetic modeling., 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: [15O]H2O, [18F]FDG and [64Cu]Cu-DOTATATE, were used in development and testing of the algorithm. Delay time 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-[15O]H2O tracers. Testing on synthetically produced time activity curves it displays 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 [15O]H2O, [18F]FDG and [64Cu]Cu-DOTATATE, and hence is a viable option offering the ability for delay correction across various organs and tracers in use with kinetic modeling.

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 (SUVmax), reference normal organ or tissue mean SUV (SUVmean) and tumor-to-normal tissue ratios (TTN) calculated from SUVmax/ SUVmeanResults 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 expan

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 SUVmax 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 vol

Overexpression of somatostatin receptors in patients with neuroendocrine neoplasms (NEN) is utilized for both diagnosis and treatment. Receptor density may reflect tumor differentiation and thus be associated with prognosis. Non-invasive visualization and quantification of somatostatin receptor density is possible by somatostatin receptor imaging (SRI) using positron emission tomography (PET). Recently, we introduced 64Cu-DOTATATE for SRI and we hypothesized that uptake of this tracer could be associated with overall (OS) and progression-free survival (PFS). Methods: We evaluated patients with NEN that had a 64Cu-DOTATATE PET/CT SRI performed in two prospective studies. Tracer uptake was determined as the maximal standardized uptake value (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 was calculated for prediction of outcome at 24 months after 64Cu-DOTATATE PET/CT. Results: A total of 128 patients with NEN were included and followed for a median of 73 (1-112) months. During follow-up, 112 experienced disease progression and 69 patients died. The optimal cutoff for 64Cu-DOTATATE SUVmax was 43.3 for prediction of PFS with a hazard ratio of 0.56 (95% CI: 0.38-0.84) for patients with SUVmax > 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 (0.32-0.77) for PFS. The accuracy was moderate for predicting PFS (57%) at 24 months after 64Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of 64Cu-DOTATATE PET/CT and outcome in patients with NEN, tumor somatostatin receptor density visualized with 64Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 months after 64Cu-DOTATATE PET/CT SRI was moderate limiting the valu

Background: In 2012 we introduced the somatostatin receptor imaging ligand 64Cu-DOTATATE. A potential benefit compared to SPECT tracers and 68Ga-labeled PET tracers included a better spatial image resolution. In addition, when compared to 68Ga-labeled tracers, the longer half-life of 64Cu (13h) compared to 68Ga (1h) could potentially make logistics easier, in particular in high-throughput centers. Here we present our experience having scanned more than 500 neuroendocrine tumor patients. Methods: Description of performance and practical workflow based on the first 500 patients. Data summarized from both results obtained as part of our routine as well as from the clinical protocols for evaluation of diagnostic performance we have performed until now. Results: The PET tracer 64Cu-DOTATATE is produced in batches for up to ten patient doses. These batches are released in the morning and the product has an approved shelf life of 24h. Accordingly, for practical purposes the patients may be scanned during the day and evening on the day of tracer production. Due to the long half-life, patients showing up late are no longer a major concern with regard to PET tracer use. Compared to 68Ga-labeled tracers, which we used previously and that typically are produced for 1-2 patients at a time, we have freed up radiochemist time at our department. Imaging is typically performed 1h after injection of approximately 200 MBq of 64Cu-DOTATATE but based on our first-in-human study, we have documented that image acquisition may be performed any time between 1 and 3h post injection. With regard to diagnostic performance, we have undertaken two head-to-head comparison studies with 111In-DTPA-octreotide and 68Ga-DOTATOC, respectively. On a lesion basis, 64Cu-DOTATATE was superior to both 111In-DTPA-octreotide and 68Ga-DOTATOC . Based on the first 112 patients, the sensitivity and specificity when using a composite standard of truth (CT only, follow up on imaging/biopsy) were

Somatostatin receptor imaging is a valuable tool in the diagnosis, follow-up and treatment planning of neuroendocrine tumor (NET) patients. Positron emission tomography (PET) based tracers using (68)Ga as the radioisotope have in most centers replaced single-photon emission tomography (SPECT) based tracers as the gold standard. (64)Cu-DOTATATE is a new PET tracer that has been shown to be far superior compared to the SPECT tracer (111)In-DTPA-octreotide. Due to advantages of (64)Cu compared to (68)Ga, we hypothesize that the tracer could have 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 both with (64)Cu-DOTATATE and (68)Ga-DOTATOC PET and computed tomography (CT) and compared on a head-to-head basis. Discordant lesions were verified during at least 30 months of follow-up.RESULTS: A total of 701 lesions were concordantly detected on both (64)Cu-DOTATATE and (68)Ga-DOTATOC PET/CT scans while 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 only found on 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 possesses advantages in the detection of lesions in NET patients compared to (68)Ga-DOTATOC. Although patient based sensitivity was the same for (64)Cu-DOTATATE and (68)Ga-DO

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.

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, suggestin

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.

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.

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.

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.

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.

Udgivelsesdato: 2009-Dec, 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 wor