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Nuclear Medicine Training: What Now?

Nuclear Medicine Training: What Now?

J Nucl Med. 2017 Aug 17;:

Authors: Mankoff DA, Pryma DA

Abstract
While the multi-disciplinary nature of nuclear medicine and clinical molecular imaging is a key strength of the specialty, the breadth of disciplines involved in the practice of nuclear medicine creates challenges for education and training. The evolution of nuclear medicine science and technology - and the practice of clinical molecular imaging and theranostics - has created a need for changes in the approach to specialty training. The broader US community of imaging physicians has been slow to accept this change, in good part due to historical divides between the nuclear medicine and radiology communities. In this JNM hot topics discussion, we review the historical pathways to training; discuss the training needs for the modern practice of nuclear medicine, clinical molecular imaging, and radionuclide therapy; and suggest a path forward for an approach to training that matches the needs of the evolving clinical specialty.

PMID: 28818993 [PubMed - as supplied by publisher]




Long Half-life (89)Zr Labeled Radiotracers Can Guide In Suite Percutaneous Molecular Imaging PET/CT-guided Biopsies Without Reinjection of Radiotracer.

Long Half-life (89)Zr Labeled Radiotracers Can Guide In Suite Percutaneous Molecular Imaging PET/CT-guided Biopsies Without Reinjection of Radiotracer.

J Nucl Med. 2017 Aug 17;:

Authors: Cornelis FH, Durack J, Pandit-Taskar N, Ulaner GA, Lewis JS, Morris MJ, Solomon SB

Abstract
Rationale: To evaluate the feasibility of in suite Zr89 labeled radiotracer positron emission tomography-computed tomography (PET/CT)-guided biopsies performed without reinjection. Methods: From 2013-2016, 12 patients (7 males, 5 females; mean age 61 years, range 40-75) with suspected metastatic prostate or breast carcinoma on either imaging or biochemical progression underwent 14 percutaneous biopsies after diagnostic PET/CT using (89)Zr labeled radiotracers (mean dose: 180MBq; range: 126-189MBq) targeting prostate specific membrane antigen (PSMA) (n = 7) or human epidermal growth factor receptor 2 (HER2) (n = 5). Biopsies were performed in a PET/CT suite without radiotracer reinjection. Results: Biopsies were performed without complications a mean of 6.2 days (range, 0-13) after injection of radiotracers in bone (n = 7), pleura (n = 3), lymph nodes (n = 2) and liver (n = 2). All biopsies were positive for malignancy on pathology. A concordance between the initial diagnostic imaging findings and biopsies results was observed. The additional radiation (mean dose length product) due to CT procedures was 1581 mGy/cm (379-2686). No complications were reported. Conclusion: Molecular imaging PET/CT-guided biopsies using (89)Zr labeled radiotracers are safe and effective without tracer reinjection.

PMID: 28818992 [PubMed - as supplied by publisher]




Immune Modulation Therapy and Imaging: Workshop Report.

Immune Modulation Therapy and Imaging: Workshop Report.

J Nucl Med. 2017 Aug 17;:

Authors: Shields AF, Jacobs P, Sznol M, Graham MM, Germain R, Lum L, Jaffee E, de Vries EGE, Nimmagadda S, Van den Abbeele AD, Leung D, Wu AM, Sharon E, Shankar LK

Abstract
A workshop at the National Cancer Institute May 2, 2016 considered the current state of imaging in assessment of immunotherapy. Immunotherapy has shown some remarkable and prolonged responses in the treatment of tumors. However, responses are variable and frequently delayed, complicating the evaluation of new immunotherapy agents and customizing treatment for individual patients. Early anatomic imaging may show that a tumor has increased in size, but this could represent pseudoprogression. Based on imaging, clinicians must decide if they should stop, pause, or continue treatment. Other imaging technologies and approaches are being developed to improve the measurement of response in patients receiving immunotherapy. Imaging methods being evaluated include radiomic methods using computed tomography (CT), magnetic resonance imaging (MRI) and (18)F-FDG-PET (fluorodeoxyglucose-positron emission tomography) as well as new radiolabeled small molecules, antibodies, and antibody fragments to image the tumor microenvironment, immune status and changes over the course of therapy. Current studies of immunotherapy can take advantage of these available imaging options to explore and validate their use. Collection of CT, PET, and MR images along with outcomes from trials are critical to develop improved methods of assessment.

PMID: 28818991 [PubMed - as supplied by publisher]




Clinical Use and Utility of Amyloid Imaging.

Clinical Use and Utility of Amyloid Imaging.

J Nucl Med. 2017 Aug 17;:

Authors: Barthel H, Sabri O

Abstract
Currently, three amyloid PET tracers are approved and commercially available for clinical use. They allow for the accurate in vivo detection of amyloid plaques, one hallmark of Alzheimer's disease (AD). Here, we review the current knowledge on the clinical use and utility of amyloid imaging. Appropriate use criteria for the clinical application of amyloid imaging are established, and most currently available data point to their validity. Visual amyloid image analysis is highly standardized. Disclosure of amyloid imaging results is desired by many cognitively impaired subjects, and seems to be safe once appropriate education is delivered to the disclosing clinicians. Regarding clinical utility, increasing evidence points i) to a change of diagnosis via amyloid imaging in ~30% of cases, ii) to an increase of diagnostic confidence in ~60% of cases, iii) to a change of patient management in ~60% of cases, and specifically iv) to a change of medication in ~40% of cases. Also, amyloid imaging results seem to relevantly impact care-givers. Further, initial simulation studies point to a potential positive patient outcome effect and cost-effectiveness of amyloid imaging. These features, however, will require confirmation in prospective clinical trials. More work is also required to determine the clinical utility of amyloid imaging specifically in subjects with mild cognitive impairment, and in comparison/conjunction with other AD biomarkers. Taken together, the clinical use of amyloid imaging is being studied, and the currently available data point to a relevant clinical utility of this imaging technique. Ongoing research will determine whether this accurate and non-invasive approach to amyloid plaque load detection will translate into a benefit to cognitively impaired subjects.

PMID: 28818990 [PubMed - as supplied by publisher]




Metabolic Imaging of Infection.

Metabolic Imaging of Infection.

J Nucl Med. 2017 Aug 17;:

Authors: Lawal I, Zeevaart JR, Ebenhan T, Ankrah A, Vorster M, Kruger H, Govender T, Sathekge M

Abstract
Metabolic imaging of infection has come to occupy a prominent place in the diagnosis and management of microbial infection. Molecular probes available for infection imaging have undergone a rapid evolution starting with the use of non-specific agents that accumulate similarly in infection, sterile inflammation and neoplastic tissue to more targeted probes that seek to identify specific microbial species. This focus review describes the metabolic and molecular imaging techniques currently available for clinical use in infection imaging and those that have demonstrated promising results in preclinical studies with the potential for clinical applications.

PMID: 28818989 [PubMed - as supplied by publisher]




Multiregional tumor drug-uptake imaging by PET and microvascular morphology in end-stage diffuse intrinsic pontine glioma.

Multiregional tumor drug-uptake imaging by PET and microvascular morphology in end-stage diffuse intrinsic pontine glioma.

J Nucl Med. 2017 Aug 17;:

Authors: Veldhuijzen van Zanten SEM, Sewing ACP, van Lingen A, Hoekstra OS, Wesseling P, Meel MH, van Vuurden DG, Kaspers GJL, Hulleman E, Bugiani M

Abstract
Inadequate tumor uptake of the vascular endothelial growth factor (VEGF) antibody bevacizumab could explain lack of effect in diffuse intrinsic pontine glioma (DIPG). Methods: By combining data from a positron emission tomography (PET) imaging study using zirconium-89((89)Zr)-labeled bevacizumab and an autopsy study, a 1-on-1 analysis of multiregional in vivo and ex vivo (89)Zr-bevacizumab uptake, tumor histology and vascular morphology in a DIPG patient was performed. Results: In vivo (89)Zr-bevacizumab measurements showed heterogeneity between lesions. Additional ex vivo measurements and immunohistochemistry of cervicomedullary metastasis samples, showed highest uptake in the area with marked microvascular proliferation. In the primary pontine tumor all samples showed similar vascular morphology. Other histological features were similar between samples studied. Conclusion: In vivo bevacizumab-PET serves to identify heterogeneous uptake between tumor lesions, while subcentimeter intra-lesional heterogeneity could only be identified by ex vivo measurements. Bevacizumab uptake is enhanced by vascular proliferation, although our results suggest it is not the only determinant of intra-lesional uptake heterogeneity.

PMID: 28818988 [PubMed - as supplied by publisher]




Response assessment of (68)Ga-DOTA-E-[c(RGDfK)]2 PET/CT for lung adenocarcinoma patients treated with nintedanib plus docetaxel.

Response assessment of (68)Ga-DOTA-E-[c(RGDfK)]2 PET/CT for lung adenocarcinoma patients treated with nintedanib plus docetaxel.

J Nucl Med. 2017 Aug 17;:

Authors: Arrieta O, Garcia-Perez FO, Michel-Tello D, Ramirez-Tirado LA, Pitalua-Cortes Q, Cruz-Rico G, Macedo-Perez EO, Cardona AF, de la Garza-Salazar J

Abstract
Nintedanib is an oral angiokinase inhibitor used as a second-line treatment for non-small-cell lung cancer (NSCLC). New radiotracers, such as (68)Ga-DOTA-E-[c(RGDfK)]2, that target αvβ3 integrin might impact the clinical practice as a non-invasive method for assessing angiogenesis inhibitors. Methods: From July 2014 through October 2015, 38 patients received second-line nintedanib plus docetaxel. All the patients underwent PET/CT with (68)Ga-DOTA-E-[c(RGDfK)]2 radiotracer and blood-sample tests to quantify angiogenesis factors (FGF, VEGF and PDGF-AB) prior to and after completing 2 therapy cycles. Results: Of the 38 patients, 31 had available baseline and follow-up PET/CT. Baseline lung tumoral volume addressed with (68)Ga-DOTA-E-[c(RGDfK)]2 PET/CT correlated with VEGF serum levels, while the baseline Lung/Liver SUVmax-Index correlated with PDGF-AB. After treatment, the overall response rate (ORR) and disease control rate (DCR) were 7.9% and 47.3%, respectively. A greater decrease in the lung tumoral volume (-37.2% vs. -27.6%) was associated with a better DCR in patients (P = 0.005). Median progression-free survival (PFS) was 3.7 months. Non-smokers and patients with a higher baseline lung tumoral volume were more likely to have a higher PFS (6.4 vs. 3.74; P = 0.023 and 6.4 vs. 2.1; P = 0.003; respectively). Overall survival (OS) was non-reached (NR). Patients with a greater decrease in Lung SUVmax (NR vs. 7.1 months; P = 0.016) and a greater decrease in the Lung/Spleen SUVmax Index (NR vs. 7.1; P = 0.043) were more likely to have a longer OS. Conclusion:(68)Ga-DOTA-E-[c(RGDfK)]2 PET/CT is a potentially useful imaging tool to assess responses related to angiogenesis inhibitors. Further analysis and novel studies with (68)Ga-DOTA-E-[c(RGDfK)]2 are warranted to identify patients who might benefit from this therapy.

PMID: 28818987 [PubMed - as supplied by publisher]




David vs. the Goliaths for the detection of bone metastases.

David vs. the Goliaths for the detection of bone metastases.

J Nucl Med. 2017 Aug 17;:

Authors: Ulaner GA

PMID: 28818986 [PubMed - as supplied by publisher]




Somatostatin Antagonists for Radioligand Therapy of Non-Endocrine Tumors.

Somatostatin Antagonists for Radioligand Therapy of Non-Endocrine Tumors.

J Nucl Med. 2017 Aug 17;:

Authors: Hindie E, Zanotti-Fregonara P, Morgat C

PMID: 28818985 [PubMed - as supplied by publisher]




Pseudo-reference regions for glial imaging with (11)C-PBR28: investigation in two clinical cohorts.

Pseudo-reference regions for glial imaging with (11)C-PBR28: investigation in two clinical cohorts.

J Nucl Med. 2017 Aug 17;:

Authors: Albrecht DS, Normandin MD, Shcherbinin S, Wooten DW, Schwarz AJ, Zurcher NR, Barth VN, Guehl NJ, Johnson-Akeju O, Atassi N, Veronese M, Turkheimer F, Hooker JM, Loggia ML

Abstract
The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. While TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudo-reference approaches can minimize within-group variability, and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing two different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received (11)C-PBR28 PET scans. Occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudo-reference regions by testing for the absence of group differences in Standardized Uptake Value (SUV) and distribution volume (VT) estimated with an arterial input function (AIF). SUV from target regions (cLBP study - thalamus; ALS study - precentral gyrus) was normalized with SUV from candidate pseudo-reference regions to obtain SUVRoccip, SUVRcereb, and SUVRWB The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without AIF (refDVR), and VT Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudo-reference VT or SUV, excepting whole-brain VT, which was higher in cLBP patients than controls. Target VT elevations in patients (P = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVRoccip and SUVRWB, and by refDVR and blDVR (less reliably by SUVRcereb). In voxelwise analyses, SUVRoccip, but not SUVRcereb, identified regional group differences initially observed with SUVRWB, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with VT While important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology-related group differences in (11)C-PBR28 signal as classic kinetic modeling techniques. Occipital cortex may be a suitable pseudo-reference region, at least for the populations evaluated, pending further validation in larger cohorts.

PMID: 28818984 [PubMed - as supplied by publisher]




CURRENT CONCEPTS IN (68)Ga-DOTATATE NEN IMAGING: INTERPRETATION, BIODISTRIBUTION, DOSIMETRY AND MOLECULAR STRATEGIES.

CURRENT CONCEPTS IN (68)Ga-DOTATATE NEN IMAGING: INTERPRETATION, BIODISTRIBUTION, DOSIMETRY AND MOLECULAR STRATEGIES.

J Nucl Med. 2017 Aug 17;:

Authors: Bodei L, Ambrosini V, Herrmann K, Modlin I

Abstract
(68)Ga-DOTATATE PET/CT provides information of the location(s) of somatostatin receptor expressing tumors. Integrating this imaging data effectively in patient care requires the clinical history, the histopathology and biomarker information as well as grade, stage and prior imaging. Previous therapies and technical aspects of the study should be considered, given their ability to alter the interpretation of the images. This includes physiologic biodistribution of the radiotracer, as well as conditions that engender false positive results. This CME document provides a guide to the performance and interpretation of (68)Ga-DOTATATE PET/CT and describes its role in the diagnostic algorithm of neuroendocrine neoplasms (NEN) and is overall utility in their management.

PMID: 28818983 [PubMed - as supplied by publisher]




Forward to the Past: The Case for Quantitative PET Imaging.
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Forward to the Past: The Case for Quantitative PET Imaging.

J Nucl Med. 2017 Jul;58(7):1019-1024

Authors: Lammertsma AA

Abstract
PET was developed in the 1970s as an in vivo method to measure regional pathophysiologic processes. In the 1990s the focus moved to the detection of local increases in uptake, first in the brain (activation studies) and later in oncology (finding metastases), with (18)F-FDG emerging as a highly sensitive staging technique. This focus on sensitivity has overshadowed the other main characteristic of PET, its quantitative nature. In recent years there has been a shift. PET is now seen as a promising tool for drug development and precision medicine-that is, a method to monitor or even predict response to therapy. Quantification is essential for precision medicine, but many studies today use simplified semiquantitative methods without properly validating them. This review provides several examples illustrating that simplified methods may lead to less accurate or even misleading results. Simplification is important for routine clinical practice, but finding the optimal balance between accuracy and simplicity requires careful studies. It is argued that the use of simplified approaches without proper validation not only may waste time and resources but also may raise ethical questions, especially in drug development studies.

PMID: 28522743 [PubMed - indexed for MEDLINE]




Molecular Imaging of PARP.
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Molecular Imaging of PARP.

J Nucl Med. 2017 Jul;58(7):1025-1030

Authors: Carney B, Kossatz S, Reiner T

Abstract
The poly(adenosine diphosphate-ribose)polymerase (PARP) family of enzymes is an important factor in the cellular DNA damage response and has gained much attention for its role in many diseases, particularly cancer. Targeted molecular imaging of PARP using fluorescent or radiolabeled tags has followed on the success of therapeutic inhibitors and gained momentum over the past few years. This review covers PARP imaging from the very first imaging agents up to the current state of the technology, with a focus on the clinical applications made possible by these agents.

PMID: 28473593 [PubMed - indexed for MEDLINE]




(18)F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi.
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(18)F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi.

J Nucl Med. 2017 Jul;58(7):1094-1099

Authors: Lohrke J, Siebeneicher H, Berger M, Reinhardt M, Berndt M, Mueller A, Zerna M, Koglin N, Oden F, Bauser M, Friebe M, Dinkelborg LM, Huetter J, Stephens AW

Abstract
Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks, and pulmonary embolism are major causes of morbidity and mortality worldwide. Glycoprotein IIb/IIIa (GPIIb/IIIa) is the key receptor involved in platelet aggregation and is a validated target for therapeutic approaches and diagnostic imaging. The aim of this study was to develop and characterize a specific small-molecule tracer for PET imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches. Methods: Binding of (18)F-GP1 to GPIIb/IIIa receptors was investigated in competition binding assays and autoradiography using a fresh cardiac thrombus from an explanted human heart. The clot-to-blood ratio for (18)F-GP1 was investigated by an in vitro blood flow model. Biodistribution and thrombus detection was investigated in cynomolgus monkeys after insertion of a roughened catheter into either the vena cava or the aorta. Results:(18)F-GP1 is an (18)F-labeled small molecule for PET imaging of thrombi. The half maximal inhibitory concentration of (18)F-GP1 to GPIIb/IIIa was 20 nM. (18)F-GP1 bound to thrombi with a mean clot-to-blood ratio of 95. Binding was specific and can be displaced by excess nonradioactive derivative. Binding was not affected by anticoagulants such as aspirin or heparin. (18)F-GP1 showed rapid blood clearance and a low background after intravenous injection in cynomolgus monkeys. Small arterial, venous thrombi, thrombotic depositions on damaged endothelial surface, and small cerebral emboli were detected in vivo by PET imaging. Conclusions:(18)F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Because of its favorable preclinical characteristics, (18)F-GP1 is currently being investigated in a human clinical study.

PMID: 28302764 [PubMed - indexed for MEDLINE]




Performance Characteristics of the Whole-Body Discovery IQ PET/CT System.
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Performance Characteristics of the Whole-Body Discovery IQ PET/CT System.

J Nucl Med. 2017 Jul;58(7):1155-1161

Authors: Reynés-Llompart G, Gámez-Cenzano C, Romero-Zayas I, Rodríguez-Bel L, Vercher-Conejero JL, Martí-Climent JM

Abstract
The aim of this study was to assess the physical performance of a new PET/CT system, the Discovery IQ with 5-ring detector blocks. Methods: Performance was measured using the National Electrical Manufacturers Association NU2-2012 methodology. Image quality was extended by accounting for different acquisition parameters (lesion-to-background ratios [8:1, 4:1, and 2:1] and acquisition times) and reconstruction algorithms (VUE-point HD [VPHD], VPHD with point-spread-function modeling [VPHD-S], and Q.Clear). Tomographic reconstruction was also assessed using a Jaszczak phantom. Additionally, 30 patient lesions were analyzed to account for differences in lesion volume and SUV quantification between reconstruction algorithms. Results: Spatial resolution ranged from 4.2 mm at 1 cm to 8.5 mm at 20 cm. Sensitivity measured at the center and at 10 cm was 22.8 and 20.4 kps/kBq, respectively. The noise-equivalent counting rate peak was 124 kcps at 9.1 kBq/cm(3) The scatter fraction was 36.2%. The accuracy of correction for count losses and randoms was 3.9%. In the image quality test, contrast recovery for VPHD, VPHD-S, and Q.Clear ranged from 18%, 18%, and 13%, respectively (hot contrast; 10-mm sphere diameter; ratio, 2:1), to 68%, 67%, and 81%, respectively (cold contrast; 37-mm sphere diameter; ratio, 8:1). Background variability ranged from 3.4%, 3.0%, and 2.1%, respectively (ratio, 2:1), to 5.5%, 4.8%, and 3.7%, respectively (ratio, 8:1). On Q.Clear reconstruction, the decrease in the penalty term (β) increased the contrast recovery coefficients and background variability. With the Jaszczak phantom, image quality increased overall when a reconstruction algorithm modeling the point-spread function was used, and use of Q.Clear increased the signal-to-noise ratio. Lesions analyzed using VPHD-S and Q.Clear had an SUVmean of 6.5 ± 3 and 7 ± 3, respectively (P < 0.01), and an SUVmax of 11 ± 4.8 and 12 ± 4, respectively (P < 0.01). No significant difference in mean lesion volume was found between algorithms. Conclusion: Among the various Discovery bismuth germanium oxide-based PET/CT scanners, the IQ with 5-ring detector blocks has the highest overall performance, with improved sensitivity and counting rate performance. Q.Clear reconstruction improves the PET image quality, with higher recovery coefficients and lower background variability.

PMID: 28302761 [PubMed - indexed for MEDLINE]




Progressive Disintegration of Brain Networking from Normal Aging to Alzheimer Disease: Analysis of Independent Components of (18)F-FDG PET Data.
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Progressive Disintegration of Brain Networking from Normal Aging to Alzheimer Disease: Analysis of Independent Components of (18)F-FDG PET Data.

J Nucl Med. 2017 Jul;58(7):1132-1139

Authors: Pagani M, Giuliani A, Öberg J, De Carli F, Morbelli S, Girtler N, Arnaldi D, Accardo J, Bauckneht M, Bongioanni F, Chincarini A, Sambuceti G, Jonsson C, Nobili F

Abstract
Brain connectivity has been assessed in several neurodegenerative disorders investigating the mutual correlations between predetermined regions or nodes. Selective breakdown of brain networks during progression from normal aging to Alzheimer disease dementia (AD) has also been observed. Methods: We implemented independent-component analysis of (18)F-FDG PET data in 5 groups of subjects with cognitive states ranging from normal aging to AD-including mild cognitive impairment (MCI) not converting or converting to AD-to disclose the spatial distribution of the independent components in each cognitive state and their accuracy in discriminating the groups. Results: We could identify spatially distinct independent components in each group, with generation of local circuits increasing proportionally to the severity of the disease. AD-specific independent components first appeared in the late-MCI stage and could discriminate converting MCI and AD from nonconverting MCI with an accuracy of 83.5%. Progressive disintegration of the intrinsic networks from normal aging to MCI to AD was inversely proportional to the conversion time. Conclusion: Independent-component analysis of (18)F-FDG PET data showed a gradual disruption of functional brain connectivity with progression of cognitive decline in AD. This information might be useful as a prognostic aid for individual patients and as a surrogate biomarker in intervention trials.

PMID: 28280223 [PubMed - indexed for MEDLINE]




Evaluation of Antiatherogenic Properties of Ezetimibe Using (3)H-Labeled Low-Density-Lipoprotein Cholesterol and (99m)Tc-cAbVCAM1-5 SPECT in ApoE(-/-) Mice Fed the Paigen Diet.
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Evaluation of Antiatherogenic Properties of Ezetimibe Using (3)H-Labeled Low-Density-Lipoprotein Cholesterol and (99m)Tc-cAbVCAM1-5 SPECT in ApoE(-/-) Mice Fed the Paigen Diet.

J Nucl Med. 2017 Jul;58(7):1088-1093

Authors: Dumas LS, Briand F, Clerc R, Brousseau E, Montemagno C, Ahmadi M, Bacot S, Soubies A, Perret P, Riou LM, Devoogdt N, Lahoutte T, Barone-Rochette G, Fagret D, Ghezzi C, Sulpice T, Broisat A

Abstract
The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E(-/-) mice. Methods: Apolipoprotein E(-/-) mice were fed the Paigen diet (1.25% cholesterol, 0.5% cholic acid, and 15% fat) without or with ezetimibe (7 mg/kg/d) for 6 wk. In a first set of mice (n = 15), we intravenously injected (3)H-cholesteryl oleate-labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set (n = 20), we used the imaging agent (99m)Tc-cAbVCAM1-5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set (n = 21), we compared VCAM-1 expression with (99m)Tc-cAbVCAM1-5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL-cholesteryl ester plasma disappearance rate (P < 0.001 vs. control) after (3)H-cholesteryl oleate-labeled LDL injection. At 96 h after injection, the hepatic fraction of (3)H-tracer was 61% lower in mice treated with ezetimibe (P < 0.001). Meanwhile, LDL-derived (3)H-cholesterol excretion in the feces was 107% higher (P < 0.001). The antiatherogenic effect of ezetimibe monitored by (99m)Tc-cAbVCAM1-5 SPECT showed a 49% reduction in aortic tracer uptake (percentage injected dose per cubic centimeter, 0.95 ± 0.04 vs. 1.87 ± 0.11; P < 0.01). In addition to hypercholesterolemia, the proinflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues, including the aorta, and this expression correlated strongly with (99m)Tc-cAbVCAM1-5 uptake (r = 0.75; P < 0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes antiatherosclerotic effects through increased LDL cholesterol catabolism and LDL-derived cholesterol fecal excretion and reduces inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding ezetimibe to a statin therapy.

PMID: 28280218 [PubMed - indexed for MEDLINE]




Effect of MPTP on Serotonergic Neuronal Systems and Mitochondrial Complex I Activity in the Living Brain: A PET Study on Conscious Rhesus Monkeys.
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Effect of MPTP on Serotonergic Neuronal Systems and Mitochondrial Complex I Activity in the Living Brain: A PET Study on Conscious Rhesus Monkeys.

J Nucl Med. 2017 Jul;58(7):1111-1116

Authors: Kanazawa M, Ohba H, Nishiyama S, Kakiuchi T, Tsukada H

Abstract
The objective of the present PET study was to compare the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on serotonergic neuronal systems and mitochondrial complex I (MC-I) activity with that of dopamine in conscious rhesus monkeys (Macaca mulatta). Methods: A Parkinson disease monkey model was prepared by repeated administration of MPTP. For the PET measurements, normal and MPTP-treated conscious monkeys received an intravenous injection of (11)C-DASB for serotonin transporter, (18)F-MPPF for serotonin 1A receptor, (11)C-PE2I for dopamine transporter, (11)C-6MemTyr for dopamine synthesis, (11)C-raclopride for dopamine D2 receptor, or (18)F-BCPP-EF for MC-I. Serotonin and dopamine parameters were calculated using time-activity curves in the cerebellum as the input function. The total distribution volume of (18)F-BCPP-EF was assessed using Logan plot graphical analysis with metabolite-corrected plasma as the input function. Results: MPTP-induced diffuse reductions in MC-I activity were observed throughout the brain, except the cerebellum. Significant reductions in the presynaptic dopamine parameters-dopamine transporter and dopamine synthesis-were detected in the striatum and substantia nigra pars compacta of MPTP-treated monkeys, whereas no significant differences in postsynaptic dopamine D2 receptor binding were observed. Serotonin transporter binding was reduced by MPTP not only in striatal regions but also in extrastriatal regions. In contrast, serotonin 1A receptor binding was unaffected by MPTP anywhere in the brain. In the cortex, the reduction of serotonin transporter binding correlated with that of MC-I. Conclusion: The results obtained by multiparametric PET measurements in a Parkinson disease monkey model demonstrated that chronic MPTP treatment induced reductions not only in the dopaminergic system in the nigrostriatal pathway but also in serotonin transporter in the cortical and subcortical regions. These results suggest that the neurotoxicity of MPTP is not exclusive to the nigrostriatal pathway, as predicted from MC-I damage in the extrastriatal regions of the brain.

PMID: 28280215 [PubMed - indexed for MEDLINE]




Qualification of National Cancer Institute-Designated Cancer Centers for Quantitative PET/CT Imaging in Clinical Trials.
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Qualification of National Cancer Institute-Designated Cancer Centers for Quantitative PET/CT Imaging in Clinical Trials.

J Nucl Med. 2017 Jul;58(7):1065-1071

Authors: Scheuermann JS, Reddin JS, Opanowski A, Kinahan PE, Siegel BA, Shankar LK, Karp JS

Abstract
The National Cancer Institute developed the Centers for Quantitative Imaging Excellence (CQIE) initiative in 2010 to prequalify imaging facilities at all of the National Cancer Institute-designated comprehensive and clinical cancer centers for oncology trials using advanced imaging techniques, including PET. Here we review the CQIE PET/CT scanner qualification process and results in detail. Methods: Over a period of approximately 5 y, sites were requested to submit a variety of phantoms, including uniform and American College of Radiology-approved phantoms, PET/CT images, and examples of clinical images. Submissions were divided into 3 distinct time periods: initial submission (T0) and 2 requalification submissions (T1 and T2). Images were analyzed using standardized procedures, and scanners received a pass or fail designation. Sites had the opportunity to submit new data for scanners that failed. Quantitative results were compared across scanners within a given time period and across time periods for a given scanner. Results: Data from 65 unique PET/CT scanners across 56 sites were submitted for CQIE T0 qualification; 64 scanners passed the qualification. Data from 44 (68%) of those 65 scanners were submitted for T2. From T0 to T2, the percentage of scanners passing the CQIE qualification on the first attempt rose from 38% for T1 to 67% for T2. The most common reasons for failure were SUV outside specifications, incomplete submission, and uniformity issues. Uniform phantom and American College of Radiology-approved phantom results between scanner manufacturers were similar. Conclusion: The results of the CQIE process showed that periodic requalification may decrease the frequency of deficient data submissions. The CQIE project also highlighted the concern within imaging facilities about the burden of maintaining different qualifications and accreditations. Finally, for quantitative imaging-based trials, further evaluation of the relationships between the level of the qualification (e.g., bias or precision) and the quality of the image data, accrual rates, and study power is needed.

PMID: 28254874 [PubMed - indexed for MEDLINE]




Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by (18)F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).
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Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by (18)F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).

J Nucl Med. 2017 Jul;58(7):1045-1053

Authors: Vera P, Thureau S, Chaumet-Riffaud P, Modzelewski R, Bohn P, Vermandel M, Hapdey S, Pallardy A, Mahé MA, Lacombe M, Boisselier P, Guillemard S, Olivier P, Beckendorf V, Salem N, Charrier N, Chajon E, Devillers A, Aide N, Danhier S, Denis F, Muratet JP, Martin E, Riedinger AB, Kolesnikov-Gauthier H, Dansin E, Massabeau C, Courbon F, Farcy Jacquet MP, Kotzki PO, Houzard C, Mornex F, Vervueren L, Paumier A, Fernandez P, Salaun M, Dubray B

Abstract
See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant (18)F-misonidazole ((18)F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The (18)F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In (18)F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were (18)F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the (18)F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the (18)F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the (18)F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. (18)F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

PMID: 28254869 [PubMed - indexed for MEDLINE]




Detection Efficacy of Hybrid (68)Ga-PSMA Ligand PET/CT in Prostate Cancer Patients with Biochemical Recurrence After Primary Radiation Therapy Defined by Phoenix Criteria.
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Detection Efficacy of Hybrid (68)Ga-PSMA Ligand PET/CT in Prostate Cancer Patients with Biochemical Recurrence After Primary Radiation Therapy Defined by Phoenix Criteria.

J Nucl Med. 2017 Jul;58(7):1081-1087

Authors: Einspieler I, Rauscher I, Düwel C, Krönke M, Rischpler C, Habl G, Dewes S, Ott A, Wester HJ, Schwaiger M, Maurer T, Eiber M

Abstract
The aim of this retrospective study was to evaluate the detection rate of Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)] ((68)Ga-PSMA ligand; PSMA is prostate-specific membrane antigen) PET/CT in patients with biochemical recurrent prostate cancer defined by Phoenix criteria after external-beam radiotherapy or brachytherapy as primary treatment. Methods: One hundred eighteen patients with a median prostate-specific antigen (PSA) of 6.4 ng/mL (range, 2.2-158.4 ng/mL; interquartile range, 4.2-10.2 ng/mL) were finally eligible for this retrospective analysis. Seventy-seven and 41 patients had been treated by external-beam radiotherapy or brachytherapy, respectively. Of the 118 patients, 45 were receiving androgen-deprivation therapy (ADT) within at least 6 mo before the PET/CT. The detection rates were stratified by PSA. The influence of primary Gleason score and ADT was assessed. Relationships between SUV and clinical as well as pathologic features in patients with positive findings were analyzed using univariate and multivariable linear regression models. Results: One hundred seven of 118 patients (90.7%) showed pathologic findings indicative for tumor recurrence in (68)Ga-PSMA ligand PET/CT. The detection rates were 81.8% (36/44), 95.3% (41/43), and 96.8% (30/31) for PSA of 2 to <5, 5 to <10, and ≥10 ng/mL, respectively (P = 0.0377). (68)Ga-PSMA ligand PET/CT indicated local recurrence in 68 of 107 patients (63.5%), distant lesions in 64 of 107 patients (59.8%), and local recurrence as well as distant lesions in 25 of 107 patients (23.4%). The detection rate was significantly higher in patients with ADT (97.7%) versus without ADT (86.3%, P = 0.0381), but independent from primary Gleason score ≥ 8 (92.0%) versus ≤ 7 (90.2%, P = 0.6346). SUVmax and SUVmean were significantly associated with PSA and ADT (P = 0.018 and 0.004 for SUVmax, respectively; P = 0.025 and 0.007 for SUVmean, respectively). Conclusion:(68)Ga-PSMA ligand PET/CT demonstrates high detection rates in patients with biochemical recurrence of prostate cancer after primary radiation therapy. The detection rate was positively associated to increasing PSA as well as concomitant ADT. (68)Ga-PSMA ligand PET/CT enables discrimination of local versus metastatic disease and thus might have a crucial impact on further clinical management. A major limitation of this study is the lack of histopathologic proof in most patients.

PMID: 28209912 [PubMed - indexed for MEDLINE]




Multiparametric Imaging of Tumor Hypoxia and Perfusion with (18)F-Fluoromisonidazole Dynamic PET in Head and Neck Cancer.
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Multiparametric Imaging of Tumor Hypoxia and Perfusion with (18)F-Fluoromisonidazole Dynamic PET in Head and Neck Cancer.

J Nucl Med. 2017 Jul;58(7):1072-1080

Authors: Grkovski M, Schöder H, Lee NY, Carlin SD, Beattie BJ, Riaz N, Leeman JE, O'Donoghue JA, Humm JL

Abstract
Tumor hypoxia and perfusion are independent prognostic indicators of patient outcome. We developed the methodology for and investigated the utility of multiparametric imaging of tumor hypoxia and perfusion with (18)F-fluoromisonidazole ((18)F-FMISO) dynamic PET (dPET) in head and neck cancer. Methods: One hundred twenty head and neck cancer patients underwent 0- to 30-min (18)F-FMISO dPET in a customized immobilization mask, followed by 10-min static acquisitions starting at 93 ± 6 and 160 ± 13 min after injection. A total of 248 lesions (≥2 cm(3)) were analyzed. Voxelwise pharmacokinetic modeling was conducted using an irreversible 1-plasma 2-tissue-compartment model to calculate surrogate biomarkers of tumor hypoxia (k3), perfusion (K1), and (18)F-FMISO distribution volume. The analysis was repeated with truncated dPET datasets. Results: Substantial inter- and intratumor heterogeneity was observed for all investigated metrics. Equilibration between the blood and unbound (18)F-FMISO was rapid in all tumors. (18)F-FMISO distribution volume deviated from the expected value of unity, causing discrepancy between k3 maps and total (18)F-FMISO uptake and reducing the dynamic range of total (18)F-FMISO uptake for quantifying the degree of hypoxia. Both positive and negative trends between hypoxia and perfusion were observed in individual lesions. All investigated metrics were reproducible when calculated from a truncated 20-min dataset. Conclusion:(18)F-FMISO dPET provides the data necessary to generate parametric maps of tumor hypoxia, perfusion, and radiotracer distribution volume. These data clarify the ambiguity in interpreting (18)F-FMISO uptake and improve the characterization of lesions. We show total acquisition times can be reduced to 20 min, facilitating the translation of (18)F-FMISO dPET into the clinic.

PMID: 28183993 [PubMed - indexed for MEDLINE]




Localization of Unknown Primary Site with (68)Ga-DOTATOC PET/CT in Patients with Metastatic Neuroendocrine Tumor.
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Localization of Unknown Primary Site with (68)Ga-DOTATOC PET/CT in Patients with Metastatic Neuroendocrine Tumor.

J Nucl Med. 2017 Jul;58(7):1054-1057

Authors: Menda Y, O'Dorisio TM, Howe JR, Schultz M, Dillon JS, Dick D, Watkins GL, Ginader T, Bushnell DL, Sunderland JJ, Zamba GKD, Graham M, O'Dorisio MS

Abstract
Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent (68)Ga-DOTATOC PET/CT in a single-site prospective study. The (68)Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the (68)Ga-DOTATOC-positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if (68)Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion:(68)Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET.

PMID: 28153957 [PubMed - indexed for MEDLINE]




Active Brown Fat During (18)F-FDG PET/CT Imaging Defines a Patient Group with Characteristic Traits and an Increased Probability of Brown Fat Redetection.
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Active Brown Fat During (18)F-FDG PET/CT Imaging Defines a Patient Group with Characteristic Traits and an Increased Probability of Brown Fat Redetection.

J Nucl Med. 2017 Jul;58(7):1104-1110

Authors: Gerngroß C, Schretter J, Klingenspor M, Schwaiger M, Fromme T

Abstract
Brown adipose tissue (BAT) provides a means of nonshivering thermogenesis. In humans, active BAT can be visualized by (18)F-FDG uptake as detected by PET combined with CT. The retrospective analysis of clinical scans is a valuable source to identify anthropometric parameters that influence BAT mass and activity and thus the potential efficacy of envisioned drugs targeting this tissue to treat metabolic disease. Methods: We analyzed 2,854 (18)F-FDG PET/CT scans from 1,644 patients and identified 98 scans from 81 patients with active BAT. We quantified the volume of active BAT depots (mean values in mL ± SD: total BAT, 162 ± 183 [n = 98]; cervical, 40 ± 37 [n = 53]; supraclavicular, 66 ± 68 [n = 71]; paravertebral, 51 ± 53 [n = 69]; mediastinal, 43 ± 40 [n = 51]; subphrenic, 21 ± 21 [n = 29]). Because only active BAT is detectable by (18)F-FDG uptake, these numbers underestimate the total amount of BAT. Considering only 32 scans of the highest activity as categorized by a visual scoring strategy, we determined a mean total BAT volume of 308 ± 208 mL. In 30 BAT-positive patients with 3 or more repeated scans, we calculated a much higher mean probability to redetect active BAT (52% ± 25%) as compared with the overall prevalence of 4.9%. We calculated a BAT activity index (BFI) based on volume and intensity of individual BAT depots. Results: We detected higher total BFI in younger patients (P = 0.009), whereas sex, body mass index, height, mass, outdoor temperature, and blood parameters did not affect total or depot-specific BAT activity. Surprisingly, renal creatinine clearance as estimated from mass, age, and plasma creatinine was a significant predictor of BFI on the total (P = 0.005) as well as on the level of several individual depots. In summary, we detected a high amount of more than 300 mL of BAT tissue. Conclusion: BAT-positive patients represent a group with a higher than usual probability to activate BAT during a scan. Estimated renal creatinine clearance correlated with the extent of activated BAT in a given scan. These data imply an efficacy of drugs targeting BAT to treat metabolic disease that is at the same time higher and subject to a larger individual variation than previously assumed.

PMID: 28104743 [PubMed - indexed for MEDLINE]




Recombinant Human Thyroid-Stimulating Hormone Versus Thyroid Hormone Withdrawal in (124)I PET/CT-Based Dosimetry for (131)I Therapy of Metastatic Differentiated Thyroid Cancer.
Related Articles Recombinant Human Thyroid-Stimulating Hormone Versus Thyroid Hormone Withdrawal in (124)I PET/CT-Based Dosimetry for (131)I Therapy of Metastatic Differentiated Thyroid Cancer. J Nucl Med. 2017 Jul;58(7):1146-1154 Authors: Plyku D, Hobbs RF, Huang K, Atkins F, Garcia C, Sgouros G, Van Nostrand D Abstract Patients with metastatic differentiated thyroid cancer (DTC) may be prepared using either thyroid-stimulating hormone withdrawal (THW) or recombinant human thyroid-stimulating hormone (rhTSH) injections before (131)I administration for treatment. The objective of this study was to compare the absorbed dose to the critical organs and tumors determined by (124)I PET/CT-based dosimetry for (131)I therapy of metastatic DTC when the same patient was prepared with and imaged after both THW and rhTSH injections. Methods: Four DTC patients at MedStar Washington Hospital Center were first prepared using the rhTSH method and imaged by (124)I PET/CT at 2, 24, 48, 72, and 96 h after administration of approximately 30-63 MBq of (124)I. After 5-8 wk, the same patients were prepared using the THW method and imaged as before. The (124)I PET/CT images acquired as part of a prospective study were used to perform retrospective dosimetric calculations for (131)I therapy for the normal organs with the dosimetry package 3D-RD. The absorbed doses from (131)I for the lungs, liver, heart, kidneys, and bone marrow were obtained for each study (rhTSH and THW). Twenty-two lesions in 3 patients were identified. The contours were drawn on each PET image of each study. Time-integrated activity coefficients were calculated and used as input in OLINDA/EXM sphere dose calculator to obtain the absorbed dose to tumors. Results: The THW-to-rhTSH organ absorbed dose ratio averaged over 5 organs for the first 3 patients was 1.5, 2.5, and 0.64, respectively, and averaged over 3 organs for the fourth patient was 1.1. The absorbed dose per unit administered activity to the bone marrow was 0.13, 0.086, 0.33, and 0.068 mGy/MBq after rhTSH and 0.11, 0.14, 0.22, and 0.080 mGy/MBq after THW for each patient, respectively. With the exception of 3 lesions of 1 patient, the absorbed dose per unit administered activity of (131)I was higher in the THW study than in the rhTSH study. The ratio of the average tumor absorbed dose after stimulation by THW compared with stimulation by rhTSH injections was 3.9, 27, and 1.4 for patient 1, patient 2, and patient 3, respectively. The ratio of mean tumor to bone marrow absorbed dose per unit administered activity of (131)I, after THW and rhTSH, was 232 and 62 (patient 1), 12 and 0.78 (patient 2), and 22 and 11 (patient 3), respectively. Conclusion: The results suggest a high patient variability in the overall absorbed dose to the normal organs per MBq of (131)I administered, between the 2 TSH stimulation methods. The tumor-to-dose-limiting-organ (bone marrow) absorbed dose ratio, that is, the therapeutic index, was higher in the THW-aided than rhTSH-aided administrations. Additional comparison for tumor and normal organ absorbed dose in patients prepared using both methods is needed before definitive conclusions may be drawn regarding rhTSH versus THW patient preparation methods for (131)I therapy of metastatic DTC. PMID: 28104741 [PubMed - indexed for MEDLINE] [...]



Dissociation Between Brown Adipose Tissue (18)F-FDG Uptake and Thermogenesis in Uncoupling Protein 1-Deficient Mice.
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Dissociation Between Brown Adipose Tissue (18)F-FDG Uptake and Thermogenesis in Uncoupling Protein 1-Deficient Mice.

J Nucl Med. 2017 Jul;58(7):1100-1103

Authors: Hankir MK, Kranz M, Keipert S, Weiner J, Andreasen SG, Kern M, Patt M, Klöting N, Heiker JT, Brust P, Hesse S, Jastroch M, Fenske WK

Abstract
(18)F-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis, which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain, however, whether BAT (18)F-FDG uptake is a reliable surrogate measure of UCP1-mediated heat production. Methods: UCP1 knockout (KO) and wild-type (WT) mice housed at thermoneutrality were treated with the selective β3 adrenergic receptor agonist CL 316, 243 and underwent metabolic cage, infrared thermal imaging and (18)F-FDG PET/MRI experiments. Primary brown adipocytes were additionally examined for their bioenergetics by extracellular flux analysis as well as their uptake of 2-deoxy-(3)H-glucose. Results: In response to CL 316, 243 treatments, oxygen consumption, and BAT thermogenesis were diminished in UCP1 KO mice, but BAT (18)F-FDG uptake was fully retained. Isolated UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-(3)H-glucose uptake rates were largely unaffected. Conclusion: Adrenergic stimulation can increase BAT (18)F-FDG uptake independently of UCP1 thermogenic function.

PMID: 28082439 [PubMed - indexed for MEDLINE]




Whole-Body (18)F-FDG PET/CT Is Superior to CT as First-Line Diagnostic Imaging in Patients Referred with Serious Nonspecific Symptoms or Signs of Cancer: A Randomized Prospective Study of 200 Patients.
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Whole-Body (18)F-FDG PET/CT Is Superior to CT as First-Line Diagnostic Imaging in Patients Referred with Serious Nonspecific Symptoms or Signs of Cancer: A Randomized Prospective Study of 200 Patients.

J Nucl Med. 2017 Jul;58(7):1058-1064

Authors: Lebech AM, Gaardsting A, Loft A, Graff J, Markova E, Bertelsen AK, Madsen JL, Andersen KF, Benzon EV, Helms M, Mathiesen LR, David KP, Kronborg G, Kjaer A

Abstract
A fast-track pathway has been established in Denmark to investigate patients with serious nonspecific symptoms and signs of cancer (NSSC), who are not eligible to enter an organ-specific cancer program. The prevalence of cancer in this cohort is approximately 20%. The optimal screening strategy in patients with NSSC remains unknown. The aim of the study was to investigate whether (18)F-FDG PET/CT was superior to CT as an initial imaging modality in patients with NSSC. In a randomized prospective trial, the imaging modalities were compared with regard to diagnostic performance. Methods: Two hundred patients were randomized 1:1 to whole-body (18)F-FDG PET/CT or CT of the thorax and abdomen as the imaging modality. A tentative diagnosis was established after first-line imaging. The final referral diagnosis was adjudicated by the physician, when sufficient data were available. Results: One hundred ninety-seven patients were available for analysis because 3 patients withdrew consent before scanning. Thirty-nine (20%) patients were diagnosed with cancer, 10 (5%) with an infection, 15 (8%) with an autoimmune disease, and 76 (39%) with other diseases. In the remaining 57 patients (28%), no specific disease was found. (18)F-FDG PET/CT had a higher specificity (96% vs. 85%; P = 0.028) and a higher accuracy (94% vs. 82%; P = 0.017) than CT. However, there were no statistically significant differences in sensitivity (83% vs. 70%) or negative predictive values (96% vs. 92%). No difference in days to final referral diagnosis according to randomization group could be shown (7.2 vs. 7.6 d). However, for the subgroups in which the imaging modality showed a suggestion of malignancy, there was a significant delay to final diagnosis in the CT group compared with the (18)F-FDG PET/CT group (11.6 vs. 5.7 d; P = 0.02). Conclusion: Compared with CT, we found a higher diagnostic specificity and accuracy of (18)F-FDG PET/CT for detecting cancer in patients with NSSC. (18)F-FDG PET/CT should therefore be considered as first-line imaging in this group of patients.

PMID: 28082437 [PubMed - indexed for MEDLINE]




The Effect of Susceptibility Artifacts Related to Metallic Implants on Adjacent-Lesion Assessment in Simultaneous TOF PET/MR.
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The Effect of Susceptibility Artifacts Related to Metallic Implants on Adjacent-Lesion Assessment in Simultaneous TOF PET/MR.

J Nucl Med. 2017 Jul;58(7):1167-1173

Authors: Svirydenka H, Delso G, De Galiza Barbosa F, Huellner M, Davison H, Fanti S, Veit-Haibach P, Ter Voert EEGW

Abstract
Metalic implants may affect attenuation correction (AC) in PET/MR imaging. The purpose of this study was to evaluate the effect of susceptibility artifacts related to metallic implants on adjacent metabolically active lesions in clinical simultaneous PET/MR scanning for both time-of-flight (TOF) and non-TOF reconstructed PET images. Methods: We included 27 patients without implants but with confirmed (18)F-FDG-avid lesions adjacent to common implant locations. In all patients, a clinically indicated whole-body (18)F-FDG PET/MR scan was acquired. Baseline non-TOF and TOF PET images were reconstructed. Reconstruction was repeated after the introduction of artificial signal voids in the AC map to simulate metallic implants in standard anatomic areas. All reconstructed images were qualitatively and quantitatively assessed and compared with the baseline images. Results: In total, 51 lesions were assessed. In 40 and 50 of these cases (non-TOF and TOF, respectively), the detectability of the lesions did not change; in 9 and 1 cases, the detectability changed; and in 2 non-TOF cases, the lesions were no longer visible after the introduction of metallic artifacts. The inclusion of TOF information significantly reduced artifacts due to simulated implants in the femoral head, sternum, and spine (P = 0.01, 0.01, and 0.03, respectively). It also improved image quality in these locations (P = 0.02, 0.01, and 0.01, respectively). The mean percentage error was -3.5% for TOF and -4.8% for non-TOF reconstructions, meaning that the inclusion of TOF information reduced the percentage error in SUVmax by 28.5% (P < 0.01). Conclusion: Qualitatively, there was a significant reduction of artifacts in the femoral head, sternum, and spine. There was also a significant qualitative improvement in image quality in these locations. Furthermore, our study indicated that simulated susceptibility artifacts related to metallic implants have a significant effect on small, moderately (18)F-FDG-avid lesions near the implant site that possibly may go unnoticed without TOF information. On larger, highly (18)F-FDG-avid lesions, the metallic implants had only a limited effect. The largest significant quantitative difference was found in artifacts of the sternum. There was only a weak inverse correlation between lesions affected by artifacts and distance from the implant.

PMID: 28062597 [PubMed - indexed for MEDLINE]




Whole-Body (18)F-FDG PET and (18)F-FDG PET/CT in Patients with Suspected Paraneoplastic Syndrome: A Systematic Review and Meta-Analysis of Diagnostic Accuracy.
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Whole-Body (18)F-FDG PET and (18)F-FDG PET/CT in Patients with Suspected Paraneoplastic Syndrome: A Systematic Review and Meta-Analysis of Diagnostic Accuracy.

J Nucl Med. 2017 Jul;58(7):1031-1036

Authors: Sheikhbahaei S, Marcus CV, Fragomeni RS, Rowe SP, Javadi MS, Solnes LB

Abstract
The purpose of this study was to assess the diagnostic performance of whole-body (18)F-FDG PET or (18)F-FDG PET/CT for detection of underlying malignancy in patients with clinically suspected neurologic and nonneurologic paraneoplastic syndromes. Methods: A systematic search was performed in PubMed (Medline), Embase, and Scopus (last updated November 2016) to identify relevant published studies reporting the performance of (18)F-FDG PET or (18)F-FDG PET/CT in patients with suspected paraneoplastic syndrome. Histopathologic confirmation or clinical follow-up was considered as the reference standard. Pooled estimates, with 95% confidence intervals (CIs), of sensitivity, specificity, and diagnostic odds ratio were calculated. A summary receiver-operating-characteristic curve was constructed, and the area under the curve (AUC) was determined along with the Q* index. Results: Twenty-one studies including a total of 1,293 individual patients suspected of having a paraneoplastic syndrome and who underwent (18)F-FDG PET or (18)F-FDG PET/CT examinations met our inclusion criteria. There was moderate to high heterogeneity among the included studies. The pooled sensitivity, specificity, and diagnostic odds ratio of (18)F-FDG PET or (18)F-FDG PET/CT for the detection of underlying malignancy were 0.81 (95% CI, 0.76-0.86), 0.88 (95% CI, 0.86-0.90), and 34.03 (95% CI, 18.76-61.72), respectively. The AUC and the Q* index were 0.916 (SE, 0.018) and 0.849, indicating excellent diagnostic accuracy. The diagnostic accuracy was slightly improved after studies with high applicability concerns were excluded (AUC, 0.931; SE, 0.020). In a subgroup analysis, (18)F-FDG PET/CT was found to have a significantly higher specificity (0.89 vs. 0.79) than (18)F-FDG PET alone, with no evidence of significant difference in the overall performance (AUC, 0.930 vs. 0.891; 2-tailed P value for difference, 0.31). Conclusion: This meta-analysis of available studies demonstrates that whole-body (18)F-FDG PET or (18)F-FDG PET/CT has high diagnostic accuracy and moderate to high sensitivity and specificity for detection of underlying malignancy in patients suspected of having a paraneoplastic syndrome.

PMID: 27980049 [PubMed - indexed for MEDLINE]




Influence of Animal Heating on PET Imaging Quantification and Kinetics: Biodistribution of (18)F-Tetrafluoroborate and (18)F-FDG in Mice.
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Influence of Animal Heating on PET Imaging Quantification and Kinetics: Biodistribution of (18)F-Tetrafluoroborate and (18)F-FDG in Mice.

J Nucl Med. 2017 Jul;58(7):1162-1166

Authors: Goetz C, Podein M, Braun F, Weber WA, Choquet P, Constantinesco A, Mix M

Abstract
Different environmental conditions under anesthesia may lead to unstable homeostatic conditions in rodents and therefore may alter kinetics. In this study, the impact of different heating conditions on PET imaging quantification was evaluated. Methods: Two groups of 6 adult female BALB/c nude mice with subcutaneously implanted tumors underwent microPET imaging after injection of (18)F-labeled tetrafluoroborate or (18)F-FDG. Dynamic scans were acquired under optimal and suboptimal heating conditions. Time-activity curves were analyzed to calculate uptake and washout time constants. Results: With (18)F-labeled tetrafluoroborate, optimal animal heating led to a stable heart rate during acquisition (515 ± 35 [mean ± SD] beats/min), whereas suboptimal heating led to a lower heart rate and a higher SD (470 ± 84 beats/min). Both uptake and washout time constants were faster (P < 0.01) in animals maintained with optimal heating. Conclusion: Although the difference in heart rates was slight, optimal heating yielded significantly faster uptake and washout kinetics than suboptimal heating in all organs for both tracers.

PMID: 27980048 [PubMed - indexed for MEDLINE]




PET Quantification of the Norepinephrine Transporter in Human Brain with (S,S)-(18)F-FMeNER-D2.
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PET Quantification of the Norepinephrine Transporter in Human Brain with (S,S)-(18)F-FMeNER-D2.

J Nucl Med. 2017 Jul;58(7):1140-1145

Authors: Moriguchi S, Kimura Y, Ichise M, Arakawa R, Takano H, Seki C, Ikoma Y, Takahata K, Nagashima T, Yamada M, Mimura M, Suhara T

Abstract
Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-(11)C-MRB and (S,S)-(18)F-FMeNER-D2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-(11)C-MRB and defluorination with (S,S)-(18)F-FMeNER-D2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated (18)F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using (S,S)-(18)F-FMeNER-D2 PET. Methods: We analyzed our previous (S,S)-(18)F-FMeNER-D2 PET data of 10 healthy volunteers dynamically acquired for 240 min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time-activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of (S,S)-(18)F-FMeNER-D2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time-activity curve ratios of 70- to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using (S,S)-(18)F-FMeNER-D2 These results suggest that we can accurately quantify NET density with a 90-min (S,S)-(18)F-FMeNER-D2 scan in broad brain areas.

PMID: 27980046 [PubMed - indexed for MEDLINE]




Kinetic Modeling of the Tau PET Tracer (18)F-AV-1451 in Human Healthy Volunteers and Alzheimer Disease Subjects.
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Kinetic Modeling of the Tau PET Tracer (18)F-AV-1451 in Human Healthy Volunteers and Alzheimer Disease Subjects.

J Nucl Med. 2017 Jul;58(7):1124-1131

Authors: Barret O, Alagille D, Sanabria S, Comley RA, Weimer RM, Borroni E, Mintun M, Seneca N, Papin C, Morley T, Marek K, Seibyl JP, Tamagnan GD, Jennings D

Abstract
(18)F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate (18)F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. Methods:(18)F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects. Subjects were imaged for 3.5 h, with arterial blood samples obtained throughout. PET data were analyzed using plasma and reference tissue-based methods to estimate the distribution volume, binding potential (BPND), and SUVR. BPND and SUVR were calculated using the cerebellar cortex as a reference region and were compared across the different methods and across the 3 groups (YHV, AHV, and AD). Results: AD demonstrated increased (18)F-AV-1451 retention compared with YHV and AHV based on both invasive and noninvasive analyses in cortical regions in which paired helical filament tau accumulation is expected in AD. A correlation of R(2) > 0.93 was found between BPND (130 min) and SUVR-1 at all time intervals. Cortical SUVR curves reached a relative plateau around 1.0-1.2 for YHV and AHV by approximately 50 min, but increased in AD by up to approximately 20% at 110-130 min and approximately 30% at 160-180 min relative to 80-100 min. Distribution volume (130 min) was lower by 30%-35% in the YHV than AHV. Conclusion: Our data suggest that although (18)F-AV-1451 SUVR curves do not reach a plateau and are still increasing in AD, an SUVR calculated over an imaging window of 80-100 min (as currently used in clinical studies) provides estimates of paired helical filament tau burden in good correlation with BPND, whereas SUVR sensitivity to regional cerebral blood changes needs further investigation.

PMID: 27908967 [PubMed - indexed for MEDLINE]




Prospective Clinical Trial of (18)F-Fluciclovine PET/CT for Determining the Response to Neoadjuvant Therapy in Invasive Ductal and Invasive Lobular Breast Cancers.
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Prospective Clinical Trial of (18)F-Fluciclovine PET/CT for Determining the Response to Neoadjuvant Therapy in Invasive Ductal and Invasive Lobular Breast Cancers.

J Nucl Med. 2017 Jul;58(7):1037-1042

Authors: Ulaner GA, Goldman DA, Corben A, Lyashchenko SK, Gönen M, Lewis JS, Dickler M

Abstract
(18)F-labeled 1-amino-3-fluorocyclobutane-1-carboxylic acid ((18)F-fluciclovine) is a leucine analog radiotracer that depicts amino acid transport into cells. (18)F-fluciclovine PET/CT visualizes malignancy, including prostate cancer, invasive ductal breast cancer, and invasive lobular breast cancer. Whether changes in (18)F-fluciclovine avidity reflect changes in tumor burden resulting from treatment has not been shown. In this prospective clinical trial (clinical trials.gov: NCT01864083), changes in (18)F-fluciclovine avidity after neoadjuvant therapy were compared to breast cancer therapy response, as determined by residual tumor burden on pathology, were evaluated. Methods: Twenty-four women with a new diagnosis of locally advanced invasive ductal breast cancer (n = 18) or invasive lobular breast cancer (n = 6) underwent (18)F-fluciclovine PET/CT before and after the completion of neoadjuvant systemic therapy. SUVmax, SUVmean, metabolic tumor volume, and total lesion avidity were obtained for the primary breast tumor, axillary lymph nodes, and extraaxillary lymph nodes on each examination and corrected for background (18)F-fluciclovine avidity. The relationship between changes in (18)F-fluciclovine avidity and the percentage of reduction of tumor on pathology was assessed with the Spearman rank correlation. Results: The median decrease in the corrected SUVmax of the primary breast lesions was 99% (range, 33%-100%). The median reduction of tumor on pathology was 92% (range, 10%-100%). Changes in (18)F-fluciclovine avidity were strongly correlated with the percentage of reduction of tumor on pathology (Spearman ρ, 0.79; 95% CI, 0.56-0.90; P < 0.001). Conclusion: Changes in (18)F-fluciclovine avidity strongly correlated with the tumor response on pathology in this pilot study.

PMID: 27856630 [PubMed - indexed for MEDLINE]




Analysis of Extrastriatal (123)I-FP-CIT Binding Contributes to the Differential Diagnosis of Parkinsonian Diseases.
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Analysis of Extrastriatal (123)I-FP-CIT Binding Contributes to the Differential Diagnosis of Parkinsonian Diseases.

J Nucl Med. 2017 Jul;58(7):1117-1123

Authors: Joling M, Vriend C, van den Heuvel OA, Raijmakers PGHM, Jones PA, Berendse HW, Booij J

Abstract
(123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123)I-FP-CIT) SPECT can visualize and quantify striatal dopamine transporter (DAT) binding in vivo. In addition, (123)I-FP-CIT has modest affinity for the serotonin transporter (SERT), predominantly represented in extrastriatal binding. On the basis of previous imaging studies that have suggested more pronounced degeneration of other monoaminergic systems in multiple-system atrophy (MSA) and progressive supranuclear palsy (PSP) than in Parkinson disease (PD), we hypothesized that, in addition to striatal DAT binding, there would be differences in extrastriatal (123)I-FP-CIT SPECT binding to SERT between MSA, PSP, and PD. Methods: We included patients with parkinsonian type MSA (multiple-system atrophy with predominantly parkinsonism [MSA-P], n = 9), cerebellar type MSA (MSA-C, n = 7), PSP (n = 13), and PD (n = 30). (123)I-FP-CIT binding was analyzed using region-of-interest (ROI)- as well as voxel-based methods in both the DAT-rich striatum (caudate nucleus and putamen) and the SERT-rich extrastriatal brain regions (thalamus, hypothalamus, and pons). For SERT analysis, patients on selective serotonin reuptake inhibitor were excluded (n = 48 remained). Results: In the ROI analyses, extrastriatal (123)I-FP-CIT binding ratios in the hypothalamus were significantly lower in PSP than in MSA-C patients, and we observed significantly lower striatal (123)I-FP-CIT binding ratios in the caudate nucleus of PSP patients than in that of both PD and MSA-C patients. In the posterior putamen, binding ratios were significantly lower in MSA-P, PSP, and PD than MSA-C patients. Striatal ROI outcomes were confirmed by the voxel-based analyses that additionally showed a significantly lower hypothalamic binding in PSP and MSA-P than PD. Conclusion: Striatal (123)I-FP-CIT binding to DAT and hypothalamic (123)I-FP-CIT binding to SERT are significantly lower in MSA-P and PSP than in PD and MSA-C patients and might therefore be of interest for differential diagnosis.

PMID: 27856628 [PubMed - indexed for MEDLINE]