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Effect of 26 Weeks of Liraglutide Treatment on Coronary Artery Inflammation in Type 2 Diabetes Quantified by [64Cu]Cu-DOTATATE PET/CT: Results from the LIRAFLAME Trial.
Jensen, JK, Zobel, EH, von Scholten, BJ, Rotbain Curovic, V, Hansen, TW, Rossing, P, Kjaer, A, Ripa, RS
Frontiers in endocrinology. 2021;:790405
Abstract
BACKGROUND Quantification of coronary artery inflammation and atherosclerosis remains a challenge in high-risk individuals. In this study we sought to investigate if the glucagon like peptide-1 receptor agonist liraglutide has a direct anti-inflammatory effect in the coronary arteries using positron emission tomography (PET) with a radioactive tracer targeting activated macrophages in the vessel-wall. METHODS Thirty randomly selected participants with type 2 diabetes from the placebo-controlled trial LIRAFLAME were enrolled in this sub-study. Participants were, prior to enrollment in this sub-study, randomized to either treatment with daily liraglutide (n=15) or placebo (n=15). Both groups underwent a combined [64Cu]Cu-DOTATATE positron emission tomography and computed tomography scan of the heart at baseline and after 26 weeks of treatment. Coronary artery uptake of [64Cu]Cu-DOTATATE were measured as maximum standardized uptake values (SUVmax); and means of the maximum values (mSUVmax), both values were calculated at the level of each participant and each individual coronary-segment. RESULTS SUVmax and mSUVmax values decreased significantly in the liraglutide group both at the participant level (SUVmax: p=0.013; mSUVmax: p=0.004) and at the coronary-segment level (SUVmax: p=0.001; mSUVmax: p<0.0001). No change was observed in the placebo group neither at the participant level (SUVmax: p=0.69; mSUVmax: p=0.67) or at the coronary-segment level (SUVmax: p=0.49; mSUVmax: p=0.30). When comparing the mean change in uptake values between the two groups at both the participant level (SUVmax: p=0.076; mSUVmax: p=0.077) and the coronary segment level (SUVmax: p=0.13; mSUVmax: p=0.11) a borderline significant difference was observed. Baseline SUVmax [64Cu]Cu-DOTATATE uptake values showed a weak positive correlation with the inflammatory biomarker high-sensitivity c-reactive protein (τ =0.26, p=0.045). CONCLUSION Liraglutide treatment for 26-weeks caused a significant reduction in [64Cu]Cu-DOTATATE uptake in the coronary arteries whereas this was not seen in the placebo treated group. In addition, [64Cu]Cu-DOTATATE PET/CT as a marker of coronary inflammation correlated with the systemic inflammation marker hs-CRP.
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Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus: The SIMPLE Trial.
Jürgens, M, Schou, M, Hasbak, P, Kjær, A, Wolsk, E, Zerahn, B, Wiberg, M, Brandt-Jacobsen, NH, Gæde, P, Rossing, P, et al
Journal of the American Heart Association. 2021;(15):e020418
Abstract
Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A1c by 0.76% (95% CI, 1.0-0.5; P<0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; P<0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.
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Bone mineralisation adjacent to cemented and uncemented acetabular cups: analysis by [18F]-fluoride-PET in a randomised clinical trial.
Ullmark, G, Sörensen, J, Nilsson, O, Maripuu, E
Hip international : the journal of clinical and experimental research on hip pathology and therapy. 2020;(6):745-751
Abstract
PURPOSE We present a randomised clinical trial using F-PET/CT to analyse new bone metabolic mineralisation adjacent to acetabular cups following total hip arthoplasty (THA). PATIENTS AND METHODS THA was performed on 26 patients (26 cases) with hip OA. Patients with hip osteoarthritis (OA) were randomly assigned to operations with cemented or uncemented acetabular components. The contralateral, healthy acetabulum was used as referent for normal bone metabolism. The patients were analysed with radiography, clinical scoring, and F-PET/CT preoperatively, and at 6 weeks and 6 months postoperatively. RESULTS No major complications were recorded, and clinical results were good in all patients. Radiography showed all cups to be stable. The bone-forming activity, as measured by F-PET/CT, was quantified as standardised uptake values (SUV). The mean SUV was 4.6 (6 weeks) and 3.5 (6 months) around the uncemented cups, and 4.8 and 4.0, respectively, for the cemented cups. Normal healthy bone metabolism in the referent was 2.8 and 2.7 SUV at 6 weeks and 6 months, respectively. P < 0.01 for the cemented group at 6 weeks and 6 months, for the uncemented group only at 6 weeks. INTERPRETATION An acetabulum affected by OA has elevated SUV activity. Both cemented and uncemented cups had elevated bone metabolic activity at 6 weeks. The raised activity was interpreted as an effect from bone mineralisation secondary to surgical trauma and healing, and to the OA. At 6 months, activity was more normalised for the uncemented group than for the cemented, suggesting healing may terminate faster in the uncemented group. Postoperative bone metabolic activity can be analysed in detail by F-PET/CT.ClinicalTrials.gov Identifier: NCT01623687.
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Fingerprint pattern of bone mineralisation on cemented and uncemented femoral stems: analysis by [18F]-fluoride-PET in a randomised clinical trial.
Ullmark, G, Sörensen, J, Maripuu, E, Nilsson, O
Hip international : the journal of clinical and experimental research on hip pathology and therapy. 2019;(6):609-617
Abstract
PURPOSE We present a randomised clinical study using 18F-fluoride positron emission tomography/computed tomography (F-PET/CT) to analyse the osteoblastic part of bone metabolism (new bone mineralisation) in periprosthetic bone adjacent to femoral stems following total hip arthoplasty (THA) surgery. Patients with hip osteoarthritis were randomly assigned to THA surgery with cemented or uncemented femoral components. PATIENTS AND METHODS THA was performed on 26 patients (26 cases) with hip osteoarthritis. The patients received either an uncemented HA-coated femoral stem or a cemented one. The contralateral healthy femur was used as referent for normal bone metabolism. The patients were analysed with clinical score, radiography and F-PET/CT preoperatively, and postoperatively at 6 weeks and 6 months. After 2 years, clinical score and radiography was analysed again. We used the Polar Map system for analysing and presenting the PET results in 13 regions of interest adjacent to the whole stem. RESULTS The clinical results were good in all patients; there were no major complications. Radiographically, all stems were stable. PET analyses after 6 weeks showed that bone mineralising activity was significantly higher around the uncemented stems, both compared to the cemented group and to the contralateral healthy reference femur group. The cemented group also had elevated activity but only at a barely significant level. INTERPRETATION Mineralising activity analysed with F-PET/CT was significantly higher for the uncemented group and also decreased at a slower rate. F-PET/CT is a useful new tool for analysing secondary stabilisation of femoral stems after THA. The study was registered at ClinicalTrials.gov (identifier NCT01623687).
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Effect of cocoa on the brain and gut in healthy subjects: a randomised controlled trial.
Fox, M, Meyer-Gerspach, AC, Wendebourg, MJ, Gruber, M, Heinrich, H, Sauter, M, Woelnerhanssen, B, Koeberle, D, Juengling, F
The British journal of nutrition. 2019;(6):654-661
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Abstract
Dark chocolate is claimed to have effects on gastrointestinal function and to improve well-being. This randomised controlled study tested the hypothesis that cocoa slows gastric emptying and intestinal transit. Functional brain imaging identified central effects of cocoa on cortical activity. Healthy volunteers (HV) ingested 100 g dark (72 % cocoa) or white (0 % cocoa) chocolate for 5 d, in randomised order. Participants recorded abdominal symptoms and stool consistency by the Bristol Stool Score (BSS). Gastric emptying (GE) and intestinal and colonic transit time were assessed by scintigraphy and marker studies, respectively. Combined positron emission tomography-computed tomography (PET-CT) imaging assessed regional brain activity. A total of sixteen HV (seven females and nine males) completed the studies (mean age 34 (21-58) years, BMI 22·8 (18·5-26·0) kg/m2). Dark chocolate had no effect on upper gastrointestinal function (GE half-time 82 (75-120) v. 83 (60-120) min; P=0·937); however, stool consistency was increased (BSS 3 (3-5) v. 4 (4-6); P=0·011) and there was a trend to slower colonic transit (17 (13-26) v. 21 (15-47) h; P=0·075). PET-CT imaging showed increased [18F]fluorodeoxyglucose (FDG) in the visual cortex, with increased FDG uptake also in somatosensory, motor and pre-frontal cortices (P<0·001). In conclusion, dark chocolate with a high cocoa content has effects on colonic and cerebral function in HV. Future research will assess its effects in patients with functional gastrointestinal diseases with disturbed bowel function and psychological complaints.
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Metformin Discontinuation prior to FDG PET/CT: A Randomized Controlled Study to Compare 24- and 48-hour Bowel Activity.
Hamidizadeh, R, Eftekhari, A, Wiley, EA, Wilson, D, Alden, T, Bénard, F
Radiology. 2018;(2):418-425
Abstract
Purpose To investigate the relationship of 24- and 48-hour metformin discontinuation to bowel uptake of fluorine 18 fluorodeoxyglucose (FDG) on PET/CT scans. Materials and Methods Patients with diabetes who were treated with metformin and referred for FDG PET/CT were randomized to three equal groups based on duration of metformin discontinuation: 24 hours, 48 hours, and no discontinuation (control group). Two interpreters blinded to the study groups assessed FDG uptake in multiple segments of small and large bowel qualitatively and semiquantitatively by using maximum standardized uptake values (SUVsmax). Differences in age, sex, weight, dose of metformin, duration of metformin treatment, blood glucose levels, and FDG dose injected were assessed. Data were analyzed with analysis of variance when passing normality, and by nonparametric testing when not. Results Ninety study participants (62 male, 28 female; median age, 70 years) were enrolled from July 2010 through March 2012. There were no differences between study groups in weight, blood glucose levels 3 days prior to scanning, or normal organ uptake. Large bowel SUVmax was lower after 24 hours (4.10 ± 2.00 vs 5.42 ± 2.36; P = .020) and 48 hours (2.63 ± 0.88 vs 5.42 ± 2.36; P ˂ .001) of metformin discontinuation than for no discontinuation (control), and for 48 hours versus 24 hours of discontinuation (P = .0015). Small bowel SUVmax was lower after 24 hours (2.86 ± 0.67 vs 3.73 ± 1.08 [control]; P ˂ .001) and 48 hours (2.78 ± 0.73 vs 3.73 ± 1.08 [control]; P ˂ .001) of metformin discontinuation versus no metformin discontinuation, but not for 48 hours versus 24 hours of discontinuation (P = .57). Examination-day blood glucose levels increased after 48-hour withdrawal of metformin (8.41 mmol/L ± 2.86 vs 6.83 mmol/L ± 2.13 [control]; P = .002). Conclusion Metformin discontinuation for 48 hours prior to PET/CT was associated with lower accumulation of fluorodeoxyglucose in the bowel, compared to when there was no discontinuation (control group) or 24-hour discontinuation of metformin. © RSNA, 2018.
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18F-Alfatide II PET/CT for Identification of Breast Cancer: A Preliminary Clinical Study.
Wu, J, Wang, S, Zhang, X, Teng, Z, Wang, J, Yung, BC, Niu, G, Zhu, H, Lu, G, Chen, X
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018;(12):1809-1816
Abstract
18F-alfatide II has been proven to have excellent clinical translational potential. In this study, we investigated 18F-alfatide II for identifying breast cancer and compared the performances between 18F-alfatide II and 18F-FDG. Methods: Forty-four female patients with suspected primary breast cancer were recruited. PET/CT images using 18F-alfatide II and 18F-FDG were acquired within 7 d. Tracer uptake in breast lesions was evaluated by visual analysis, and semiquantitative analysis with SUVmax and SUVmeanResults: Forty-two breast cancer lesions and 11 benign breast lesions were confirmed by histopathology in 44 patients. Both 18F-alfatide II and 18F-FDG had higher uptake in breast cancer lesions than in benign breast lesions (P < 0.05 for 18F-alfatide II, P < 0.05 for 18F-FDG). The area under the curve of 18F-alfatide II was slightly less than that of 18F-FDG. Both 18F-alfatide II and 18F-FDG had high sensitivity (88.1% vs. 90.5%), high positive predictive value (88.1% vs. 88.4%), moderate specificity (54.5% vs. 54.5%), and moderate negative predictive value (54.5% vs. 60.0%) for differentiating breast cancer from benign breast lesions. By combining 18F-alfatide II and 18F-FDG, the sensitivity and negative predictive value significantly increased to 97.6% and 85.7%, respectively, with positive predictive value slightly increased to 89.1% and no change to the specificity (54.5%). The uptake of 18F-alfatide II (SUVmax: 3.77 ± 1.78) was significantly lower than that of 18F-FDG (SUVmax: 7.37 ± 4.48) in breast cancer lesions (P < 0.05). 18F-alfatide II uptake in triple-negative subtype was significantly lower than that in luminal A and luminal B subtypes. By contrast, human epidermal growth factor receptor-2 (HER-2)-overexpressing subtype had higher 18F-FDG uptake than the other 3 subtypes. There were 8 breast cancer lesions with higher 18F-alfatide II uptake than 18F-FDG uptake, which all had a common characteristic that HER-2 expression was negative and estrogen receptor expression was strongly positive. Conclusion:18F-alfatide II is suitable for clinical use in breast cancer patients. 18F-alfatide II is of good performance, but not superior to 18F-FDG in identifying breast cancer. 18F-alfatide II may have superiority to 18F-FDG in detecting breast cancer with strongly positive estrogen receptor expression and negative HER-2 expression.
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Estimation of Severity of Moyamoya Disease with [15O]Water-Positron Emission Tomography Compared with Magnetic Resonance Imaging and Angiography.
Roder, C, Bürkle, E, Ebner, FH, Tatagiba, M, Ernemann, U, Buck, A, Meyer, PT, Khan, N
World neurosurgery. 2018;:e75-e81
Abstract
BACKGROUND Moyamoya disease is a steno-occlusive disease of the circle of Willis with growth of pathologic collaterals. We compared functional perfusion imaging ([15O]water-positron emission tomography [PET] with acetazolamide challenge) with conventional magnetic resonance imaging (MRI) and angiography for determining indication for cerebral revascularization in patients with moyamoya. METHODS We performed a retrospective blinded analysis of individual imaging modalities (MRI, angiography, PET) and scored each modality for severity of disease in 21 untreated patients with moyamoya with 78 affected vascular territories. RESULTS Positive predictive value to identify insufficient perfusion on angiography and MRI together was 98.3% as proven on combined PET/computed tomography. Negative predictive value to identify sufficient perfusion on angiography and/or MRI only was 60%. Negative predictive value to predict good perfusion on PET based on MRI (no infarctions in the respective territory) was only 17%. An assumed good perfusion based on the suggestion of good collaterals on angiography was correct in only 13.4% of cases. Positive predictive value (angiography of main vessel and weak or no collateralization) to predict insufficient perfusion on PET/computed tomography was 76.9%; negative predictive value (angiography of main vessel and strong collateralization) to identify good perfusion was 13.4%. CONCLUSIONS Reliable evaluation of cerebral blood flow might not be possible with angiography and basic MRI alone. We strongly recommend additional functional imaging (e.g., [15O]water-PET with acetazolamide challenge) to precisely evaluate the indication for cerebral revascularization.
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[(68)Ga]DOTATATE PET/MRI and [(18)F]FDG PET/CT are complementary and superior to diffusion-weighted MR imaging for radioactive-iodine-refractory differentiated thyroid cancer.
Vrachimis, A, Stegger, L, Wenning, C, Noto, B, Burg, MC, Konnert, JR, Allkemper, T, Heindel, W, Riemann, B, Schäfers, M, et al
European journal of nuclear medicine and molecular imaging. 2016;(10):1765-72
Abstract
PURPOSE The purpose of this study was to determine whether [(68)Ga]DOTATATE PET/MRI with diffusion-weighted imaging (DWI) can replace or complement [(18)F]FDG PET/CT in patients with radioactive-iodine (RAI)-refractory differentiated thyroid cancer (DTC). METHODS The study population comprised 12 patients with elevated thyroglobulin and a negative RAI scan after thyroidectomy and RAI remnant ablation who underwent both [(18)F]FDG PET/CT and [(68)Ga]DOTATATE PET/MRI within 8 weeks of each other. The presence of recurrent cancer was evaluated on a per-patient, per-organ and per-lesion basis. Histology, and prior and follow-up examinations served as the standard of reference. RESULTS Recurrent or metastatic tumour was confirmed in 11 of the 12 patients. [(68)Ga]DOTATATE PET(/MRI) correctly identified the tumour burden in all 11 patients, whereas in one patient local relapse was missed by [(18)F]FDG PET/CT. In the lesion-based analysis, overall lesion detection rates were 79/85 (93 %), 69/85 (81 %) and 27/82 (33 %) for [(18)F]FDG PET/CT, [(68)Ga]DOTATATE PET/MRI and DWI, respectively. [(18)F]FDG PET(/CT) was superior to [(68)Ga]DOTATATE PET(/MRI) in the overall evaluation and in the detection of pulmonary metastases. In the detection of extrapulmonary metastases, [(68)Ga]DOTATATE PET(/MRI) showed a higher sensitivity than [(18)F]FDG PET(/CT), at the cost of lower specificity. DWI achieved only poor sensitivity and was significantly inferior to [(18)F]FDG PET in the lesion-based evaluation in the detection of both extrapulmonary and pulmonary metastases. CONCLUSION [(18)F]FDG PET/CT was more sensitive than [(68)Ga]DOTATATE PET/MRI in the evaluation of RAI-refractory DTC, mostly because of its excellent ability to detect lung metastases. In the evaluation of extrapulmonary lesions, [(68)Ga]DOTATATE PET(/MRI) was more sensitive and [(18)F]FDG PET(/CT) more specific. Furthermore, DWI did not provide additional information and cannot replace [(18)F]FDG PET for postoperative monitoring of patients with suspected RAI-refractory DTC.