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First-in-human assessment of the novel LAT1 targeting PET probe 18F-FIMP.
Nozaki, S, Nakatani, Y, Mawatari, A, Hume, WE, Wada, Y, Ishii, A, Tanaka, M, Tsuyuguchi, N, Doi, H, Watanabe, Y
Biochemical and biophysical research communications. 2022;:83-87
Abstract
In the first-in-human PET study, we evaluated the biodistribution and tumor accumulation of the novel PET probe, (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP), which targets the tumor-related L-type amino acid transporter 1 (LAT1), and compared it with L-[methyl-11C]methionine (11C-MET) and 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG). 18F-FIMP biodistribution was revealed by whole-body and brain scans in 13 healthy controls. Tumor accumulation of 18F-FIMP was evaluated in 7 patients with a brain tumor, and compared with those of 11C-MET and 18F-FDG. None of the subjects had significant problems due to probe administration, such as adverse effects or abnormal vital signs. 18F-FIMP was rapidly excreted from the kidneys to the urinary bladder. There was no characteristic physiological accumulation in healthy controls. 18F-FIMP PET resulted in extremely clear images in patients with suspected glioblastoma compared with 11C-MET and 18F-FDG. 18F-FIMP could be a useful novel PET probe for LAT1-positive tumor imaging including glioblastoma.
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Overexpression of miR-375 and L-type Amino Acid Transporter 1 in Pheochromocytoma and Their Molecular and Functional Implications.
Manso, J, Bertazza, L, Barollo, S, Mondin, A, Censi, S, Carducci, S, Ferrara, AM, Boschin, IM, Zovato, S, Schiavi, F, et al
International journal of molecular sciences. 2022;(5)
Abstract
Pheochromocytoma (Pheo) is a tumor derived from chromaffin cells. It can be studied using 18F-dihydroxyphenylalanine (DOPA)-positron emission tomography (PET) due to its overexpression of L-type amino acid transporters (LAT1 and LAT2). The oncogenic pathways involved are still poorly understood. This study examined the relationship between 18F-DOPA-PET uptake and LAT1 expression, and we explored the role of miR-375 and putative target genes. A consecutive series of 58 Pheo patients were retrospectively analyzed, performing 18F-DOPA-PET in 32/58 patients. Real-time quantitative PCR was used to assess the expression of LAT1, LAT2, phenylethanolamine N-methyltransferase (PNMT), miR-375, and the major components of the Hippo and Wingless/Integrated pathways. Principal germline mutations associated with hereditary Pheo were also studied. Pheo tissues had significantly higher LAT1, LAT2, and PNMT mRNA levels than normal adrenal tissues. MiR-375 was strongly overexpressed. Yes-associated protein 1 and tankyrase 1 were upregulated, while beta-catenin, axin2, monocarboxylate transporter 8, and Frizzled 8 were downregulated. A positive relationship was found between 18F-DOPA-PET SUV mean and LAT1 gene expression and for 24 h-urinary norepinephrine and LAT1. This is the first experimental evidence of 18F-DOPA uptake correlating with LAT1 overexpression. We also demonstrated miR-375 overexpression and downregulated (Wnt) signaling and identified the Hippo pathway as a new potentially oncogenic feature of Pheo.
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The value of four imaging modalities to distinguish malignant from benign solitary pulmonary nodules: a study based on 73 cohorts incorporating 7956 individuals.
Wu, Q, Zhong, L, Xie, X
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2021;(2):296-310
Abstract
BACKGROUND Solitary pulmonary nodules (SPNs) frequently bother oncologists. The differentiation of malignant from benign nodules with non-invasive approach remains a tough challenge. This study was designed to assess the diagnostic accuracy of dynamic computed tomography (CT), dynamic magnetic resonance imaging (MRI), fluorine 18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET), and technetium 99 m (99mTc) depreotide single photon emission computed tomography (SPECT) for SPNs. METHODS Electronic databases of MEDLINE, PubMed, EMBASE, and Cochrane Library were searched to identify relevant trials. The primary evaluation index of diagnostic accuracy was areas under the summary receiver-operating characteristic (SROC) curve. The results were analyzed utilizing Stata 12.0 statistical software. RESULTS Seventy-three trials incorporating 7956 individuals were recruited. Sensitivities, specificities, positive likelihood ratios, negative likelihood ratios, diagnostic score, diagnostic odds ratios, and areas under the SROC curve with 95% confidence intervals were, respectively, 0.92 (0.89-0.95), 0.64 (0.54-0.74), 2.60 (1.98-3.42), 0.12 (0.08-0.17), 3.10 (2.62-3.59), 22.24 (13.67-36.17), and 0.91 (0.88-0.93) for CT; 0.92 (0.86-0.95), 0.85 (0.77-0.90), 6.01 (3.90-9.24), 0.10 (0.06-0.17), 4.12 (3.41-4.82), 61.39 (30.41-123.93), and 0.94 (0.92-0.96) for MRI; 0.90 (0.86-0.93), 0.73 (0.65-0.79), 3.28 (2.56-4.20), 0.14 (0.10-0.19), 3.16 (2.69-3.64), 23.68 (14.74-38.05), and 0.90 (0.87-0.92) for 18F-FDG PET; and 0.93 (0.88-0.96), 0.70 (0.56-0.81), 3.12 (2.03-4.81), 0.10 (0.06-0.17), 3.43 (2.63-4.22), 30.74 (13.84-68.27), and 0.93 (0.91-0.95) for 99mTc-depreotide SPECT. CONCLUSION The dynamic MRI, dynamic CT, 18F-FDG PET, and 99mTc-depreotide SPECT were favorable non-invasive approaches to distinguish malignant SPNs from benign. Moreover, from the viewpoint of cost-effectiveness and avoiding radiation, the dynamic MRI was recommendable for SPNs.
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Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[18F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design.
Florea, A, Kooi, ME, Mess, W, Schurgers, LJ, Bucerius, J, Mottaghy, FM
Nutrients. 2021;(3)
Abstract
INTRICATE is a prospective double-blind placebo-controlled feasibility study, assessing the influence of combined vitamin K2 and vitamin D3 supplementation on micro-calcification in carotid artery disease as imaged by hybrid Sodium [18F]Fluoride (Na[18F]F) positron emission tomography (PET)/ magnetic resonance imaging (MRI). Arterial calcification is an actively regulated process and results from the imbalance between calcification promoting and inhibiting factors. Considering the recent advancements in medical imaging, ultrasound (US), PET/MRI, and computed tomography (CT) can be used for the selection and stratification of patients with atherosclerosis. Fifty-two subjects with asymptomatic carotid artery disease on at least one side of the neck will be included in the study. At baseline, an Na[18F]F PET/MRI and CT examination will be performed. Afterwards, subjects will be randomized (1:1) to a vitamin K (400 µg MK-7/day) and vitamin D3 (80 µg/day) or to placebo. At the 3-month follow-up, subjects will undergo a second Na[18F]F PET/MRI and CT scan. The primary endpoint is the change in Na[18F]F PET/MRI (baseline vs. after 3 months) in the treatment group as compared to the placebo arm. Secondary endpoints are changes in plaque composition and in blood-biomarkers. The INTRICATE trial bears the potential to open novel avenues for future large scale randomized controlled trials to intervene in the plaque development and micro-calcification progression.
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Design and rationale of the randomized trial of comprehensive lifestyle modification, optimal pharmacological treatment and utilizing PET imaging for quantifying and managing stable coronary artery disease (the CENTURY study).
Kitkungvan, D, Johnson, NP, Kirkeeide, R, Haynie, M, Carter, C, Patel, MB, Bui, L, Madjid, M, Mendoza, P, Roby, AE, et al
American heart journal. 2021;:135-146
Abstract
BACKGROUND The literature reports no randomized trial in chronic coronary artery disease (CAD) of a comprehensive management strategy integrating intense lifestyle management, maximal medical treatment to specific goals and high precision quantitative cardiac positron emission tomography (PET) for identifying high mortality risk patients needing essential invasive procedures. We hypothesize that this comprehensive strategy achieves greater risk factor reduction, lower major adverse cardiovascular events and fewer invasive procedures than standard practice. METHODS The CENTURY Study (NCT00756379) is a randomized-controlled-trial study in patients with stable or at high risk for CAD. Patients are randomized to standard of care (Standard group) or intense comprehensive lifestyle-medical treatment to targets and PET guided interventions (Comprehensive group). Comprehensive Group patients are regularly consulted by the CENTURY team implementing diet/lifestyle/exercise program and medical treatment to target risk modification. Cardiac PET at baseline, 24-, and 60-months quantify the physiologic severity of CAD and guide interventions in the Comprehensive group while patients and referring physicians of the Standard group are blinded to PET results. The primary end-point is the CENTURY risk score reduction during 5 years follow-up. The secondary endpoint is a composite of death, non-fatal myocardial infarction, stroke, and coronary revascularization. CONCLUSIONS The CENTURY Study is the first study in stable CAD to test the incremental benefit of a comprehensive strategy integrating intense lifestyle modification, medical treatment to specific goals, and high-precision quantitative myocardial perfusion imaging to guide revascularization. A total of 1028 patients have been randomized, and the 5 years follow-up will conclude in 2022.
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Aggregated Tau Measured by Visual Interpretation of Flortaucipir Positron Emission Tomography and the Associated Risk of Clinical Progression of Mild Cognitive Impairment and Alzheimer Disease: Results From 2 Phase III Clinical Trials.
Lu, M, Pontecorvo, MJ, Devous, MD, Arora, AK, Galante, N, McGeehan, A, Devadanam, C, Salloway, SP, Doraiswamy, PM, Curtis, C, et al
JAMA neurology. 2021;(4):445-453
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Abstract
IMPORTANCE Flortaucipir positron emission tomography (PET) scans, rated with a novel, US Food and Drug Administration-approved, clinically applicable visual interpretation method, provide valuable information regarding near-term clinical progression of patients with Alzheimer disease (AD) or mild cognitive impairment (MCI). OBJECTIVE To evaluate the association between flortaucipir PET visual interpretation and patients' near-term clinical progression. DESIGN/SETTING/PARTICIPANTS Two prospective, open-label, longitudinal studies were conducted from December 2014 to September 2019. Study 1 screened 298 patients and enrolled 160 participants who had a flortaucipir scan at baseline visit. Study 2 selected 205 participants from the AMARANTH trial, which was terminated after futility analysis. Out of the 2218 AMARANTH participants, 424 had a flortaucipir scan around randomization, but 219 did not complete 18-month clinical dementia rating (CDR) assessments and thus were excluded. In both studies, all participants were diagnosed as clinically impaired, and they were longitudinally followed up for approximately 18 months after baseline. MAIN OUTCOMES AND MEASURES Flortaucipir scans were rated as either advanced or nonadvanced AD pattern using a predetermined visual interpretation method. The CDR sum of box (CDR-SB) score was used as primary clinical end point measurement in both studies. RESULTS Of the 364 study participants who had readable scans, 48% were female (n = 174 of 364), and the mean (SD) age was 71.8 (8.7) years. Two hundred forty participants were rated as having an advanced AD pattern. At 18 months follow-up, 70% of those with an advanced AD pattern (n = 147 of 210) had 1 point or more increase in CDR-SB, an event predefined as clinically meaningful deterioration. In contrast, only 46% of those with a nonadvanced AD pattern scan (n = 48 of 105) experienced the same event (risk ratio [RR], 1.40; 95% CI, 1.11-1.76; P = .005). The adjusted mean CDR-SB changes were 2.28 and 0.98 for advanced and nonadvanced AD pattern groups, respectively (P < .001). Analyses with other clinical end point assessments, as well as analyses with each individual study's data, consistently indicated a higher risk of clinical deterioration associated with an advanced AD scan pattern. CONCLUSIONS AND RELEVANCE These results suggest that flortaucipir PET scans, when interpreted with an US Food and Drug Administration-approved, clinically applicable visual interpretation method, may provide valuable information regarding the risk of clinical deterioration over 18 months among patients with AD and MCI. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02016560 and NCT03901105.
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Total-body PET Imaging: A New Frontier for the Assessment of Metabolic Disease and Obesity.
Chondronikola, M, Sarkar, S
PET clinics. 2021;(1):75-87
Abstract
Obesity and associated metabolic syndrome are a global public health issue. Understanding the pathophysiology of this systemic disease is of critical importance for the development of future therapeutic interventions to improve clinical outcomes. The multiorgan nature of the pathophysiology of obesity presents a unique challenge. Total-body PET imaging, either static or dynamic, provides a vital set of tools to study organ crosstalk. The visualization and quantification of tissue metabolic kinetics with total-body PET in health and disease provides essential information to better understand disease physiology and potentially develop diagnostic and therapeutic modalities.
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Final Results of the Prospective Biomarker Trial PETra: [11C]-MET-Accumulation in Postoperative PET/MRI Predicts Outcome after Radiochemotherapy in Glioblastoma.
Seidlitz, A, Beuthien-Baumann, B, Löck, S, Jentsch, C, Platzek, I, Zöphel, K, Linge, A, Kotzerke, J, Petr, J, van den Hoff, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(5):1351-1360
Abstract
PURPOSE This prospective trial investigates the association of time to recurrence (TTR) in glioblastoma with [11C]methionine (MET) tracer uptake before postoperative radiochemotherapy (RCT) aiming to guide radiotherapy boost regions. EXPERIMENTAL DESIGN Between 2013 and 2016, 102 patients with glioblastoma were recruited. RCT was performed with concurrent and adjuvant temozolomide to a total dose of 60 Gy. Tumor residues in postresection PET and MRI were together defined as gross tumor volumes for radiotherapy treatment planning. [11C]methionine (MET)-PET/MRI was performed before RCT and at each follow-up. RESULTS The primary hypothesis of a longer TTR for patients without increased tracer accumulation in postoperative MET-PET was confirmed in 89 patients. With 18.9 months (95% confidence interval, 9.3-28.5 months), median TTR was significantly (P < 0.001) longer for patients without (n = 29, 32.6%) as compared with 6.3 months (3.6-8.9) for patients with MET accumulation (n = 60, 67.4%) in pre-RCT PET. Although MRI often did not detect all PET-positive regions, an unfavorable impact of residual tumor in postsurgical MRI (n = 38, 42.7%) on TTR was observed [4.6 (4.2-5.1) vs. 15.5 months (6.0-24.9), P < 0.001]. Significant multivariable predictors for TTR were MRI positivity, PET-positive volume, and O6-methylguanine DNA methyltransferase (MGMT) hypermethylation. CONCLUSIONS Postsurgical amino acid PET has prognostic value for TTR after RCT in glioblastoma. Because of the added value of the metabolic beyond the pure structural information, it should complement MRI in radiotherapy planning if available with reasonable effort, at least in the context of maximal therapy. Furthermore, the spatial correlation of regions of recurrence with PET-positive volumes could provide a bioimaging basis for further trials, for example, testing local radiation dose escalation.
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Parametric imaging of dual-time window [18F]flutemetamol and [18F]florbetaben studies.
Heeman, F, Yaqub, M, Hendriks, J, Bader, I, Barkhof, F, Gispert, JD, van Berckel, BNM, Lopes Alves, I, Lammertsma, AA
NeuroImage. 2021;:117953
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Abstract
Optimal pharmacokinetic models for quantifying amyloid beta (Aβ) burden using both [18F]flutemetamol and [18F]florbetaben scans have previously been identified at a region of interest (ROI) level. The purpose of this study was to determine optimal quantitative methods for parametric analyses of [18F]flutemetamol and [18F]florbetaben scans. Forty-six participants were scanned on a PET/MR scanner using a dual-time window protocol and either [18F]flutemetamol (N=24) or [18F]florbetaben (N=22). The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two-step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90-110 min post injection interval. All parametric images were assessed visually. Regional outcome measures were compared with those from a validated ROI method, i.e. DVR derived using RLogan. Visually, RPM, and SRTM2 performed best across tracers and, in addition to SUVR, provided highest AUC values for differentiating between Aβ-positive vs Aβ-negative scans ([18F]flutemetamol: range AUC=0.96-0.97 [18F]florbetaben: range AUC=0.83-0.85). Outcome parameters of most methods were highly correlated with the reference method (R2≥0.87), while lowest correlation were observed for MRTM2 (R2=0.71-0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. The optimal parametric method differed per evaluated aspect; however, the best compromise across aspects was found for MRTM0 followed by SRTM2, for both tracers. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression.
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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.