Search

The diagnosis of bacterial infections at deep body sites benefits from noninvasive imaging of molecular probes that can be traced by positron emission tomography (PET). We specifically labeled bacteria by targeting their iron transport system with artificial siderophores. The cyclen-based probes contain different binding sites for iron and the PET nuclide gallium-68. A panel of 11 siderophores with different iron coordination numbers and geometries was synthesized in up to 8 steps, and candidates with the best siderophore potential were selected by a growth recovery assay. The probes [ 68 Ga] 7 and [ 68 Ga] 15 were found to be suitable for PET imaging based on their radiochemical yield, radiochemical purity, and complex stability in vitro and in vivo. Both showed significant uptake in mice infected with Escherichia coli and were able to discern infection from lipopolysaccharide-triggered, sterile inflammation. The study qualifies cyclen-based artificial siderophores as readily accessible scaffolds for the in vivo imaging of bacteria.

Background: Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers., Methods and Results: Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both 18 F-deoxyglucose ( 18 F-FDG) and the labeled amino acid 11 C-methionine ( 11 C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers 68 Ga-DOTATATE targeting the somatostatin receptor type 2 and 68 Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted 18 F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers., Conclusions: The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent., (© 2019. American Society of Nuclear Cardiology.)

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV 41max ) and SUV 4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUV max approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm 3 using SUV 41max and 460 cm 3 using SUV 4 . For iPET response, the respective thresholds were 46.9% SUV max reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV 41max and SUV 4 , and 29% and 25% for iPET response by ΔSUV max and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV 41max and 3.206 (1.524-6.743) for SUV 4 . At iPET, it was 3.910 (1.891-8.087) for ΔSUV max and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies., (© 2019 John Wiley & Sons, Ltd.)

Background and Aim: Corticosteroids alone or in combination therapy are associated with favorable biochemical responses in metastatic castration-resistant prostate cancer (mCRPC). We speculated that the intermittent addition of dexamethasone may also enhance the antitumor effect of radioligand therapy (RLT) with 177 Lu-prostate-specific membrane antigen (PSMA)-617., Patients and Methods: Seventy-one patients with mCRPC were treated with 1 to 5 cycles of 177 Lu-PSMA-617 (6.0-7.4 GBq per cycle) at 6 to 8 weeks intervals. Based on the clinical decision (eg, in the case of vertebral metastases), 56% of patients received 4 mg of dexamethasone for the first 5 days of each cycle. Biochemical response rates, PSA decline and progression-free survival (PFS) were analyzed after one, three, and five cycles of RLT., Results: PSA response rates were not significantly different between patients receiving 177 Lu-PSMA-617 plus dexamethasone and those receiving 177 Lu-PSMA-617 alone after one, three, and five cycles (33% vs 39%, P = .62; 45% vs 45%, P = 1.0; and 38% vs 42%, P = .81). However, there was a nonsignificant trend for a more pronounced PSA decline in patients with bone metastases receiving adjunct dexamethasone (-21% ± 50% vs +11% ± 90%, P = .08; -21% ± 69% vs +22% ± 116%, P = .07; -13% ± 76% vs +32% ± 119%, P = .07). Median PFS tended to be longer in patients with bone metastases receiving 177 Lu-PSMA-617 plus dexamethasone (146 vs 81 days; hazard ratio: 0.87 [95% confidence interval: 0.47-1.61]; P = .20). Multiple regression analysis showed that age (P = .0110), alkaline phosphatase levels (P = .0380) and adjunct dexamethasone (P = .0285) were independent predictors of changes in PSA in patients with bone metastases., Conclusions: We observed high response rates to 177 Lu-PSMA-617 RLT in men with mCRPC. The short-term addition of dexamethasone to 177 Lu-PSMA-617 had no striking antitumor effect but might enhance biochemical responses in patients with bone metastases. Future trials are warranted to test this hypothesis in a prospective setting., (© 2020 The Authors. The Prostate published by Wiley Periodicals LLC.)

Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with 68 Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from 68 Ga- to 18 F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite 68 Ge/ 68 Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, 18 F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, 18 F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging 18 F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available 18 F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios., Competing Interests: Competing Interests: Martin G. Pomper is a coinventor on a patent covering [18F]DCFPyL and is entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. He has also received research funding from Progenics Phamaceuticals, the licensee of [18F]DCFPyL. Michael A. Gorin has served as a consultant to, and has received research funding from, Progenics Phamaceuticals. Steven P. Rowe has received research funding from Progenics Phamaceuticals., (© The author(s).)

Background and Aims: Atherosclerosis is a chronic inflammatory process of vessel walls responsible for coronary, cerebrovascular and peripheral vascular disease, which together account for the majority of non-infective global deaths. Whilst great emphasis has been placed on lifestyle factors, a growing body of evidence supports an autoimmune component to atherosclerosis. This study evaluates a novel autoantibody against MYC-associated zinc finger protein (MAZ-Ab) as a potential marker of atherosclerosis. It compares MAZ-Ab to activity on whole-body positron-emission tomography/computed tomography (PET/CT) attributable to atherosclerosis., Methods: Antibody screening using protein arrays was performed in patients with angiographically-proven ischaemic heart disease. Following MAZ-Ab detection, an ELISA for large-scale testing was developed. An a priori group of unselected patients attending for unrelated 18 F-fluorodeoxyglucose (FDG) PET/CT was prospectively enrolled. Each completed a structured questionnaire under supervision and provided serum for analysis. PET/CT scans were evaluated for inflammatory arterial lesions. Whole-body arterial inflammatory burden was then correlated with ELISA optical density for MAZ-Ab., Results: Protein array testing identified IgG anti-MAZ antibodies in 4/6 (67%) patients with ischemic heart disease, versus 0/10 controls. Significant positive correlations between MAZ-Ab and both increasing number of PET positive inflammatory atherosclerostic lesions (p = 0.023) and whole-body arterial inflammatory burden (p = 0.002) were shown. No traditional atherosclerotic risk factor correlated with MAZ-Ab., Conclusions: A quantitative association between MAZ-Ab optical density on ELISA and the cumulative inflammatory burden of atherosclerosis on 18 F-FDG PET/CT could be shown. These findings provide further evidence for an autoimmune component in atherosclerosis and suggest MAZ-Abs as a potential biomarker for atherosclerotic disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: High-energy resolution and sensitivity of novel cadmium-zinc-telluride (CZT) detector equipped SPECT systems facilitate simultaneous imaging of multiple isotopes and may enhance the detection of molecular/cellular signals. This may refine the detection of endocarditis. This study was designed to determine the feasibility and diagnostic accuracy of simultaneous imaging of inflammation with 111In-labeled white blood cells (WBCs) and myocardial perfusion with 99mTc-sestamibi, for localization of WBCs relative to the valve plane in suspected endocarditis., Methods and Results: A dedicated cardiac CZT camera (Discovery 530c, GE Healthcare) was employed. Anthropomorphic thorax phantom studies were followed by clinical studies in 34 patients with suspected infection of native valves (n = 12) or implants (n = 22). Simultaneous 111In-WBC/99mTc perfusion imaging was performed, and compared with standard 111In-WBC planar scintigraphy and SPECT-CT. Phantom studies ruled out significant radioisotope crosstalk. Downscatter on 99mTc images was not observed for 111In activity as high as 2.5*99mTc activity. In patients, image quality was superior for CZT imaging vs. conventional SPECT-CT and planar scintigraphy (P < 0.01). Cadmium-zinc-telluride dual isotope imaging improved reader confidence for detection of inflammatory foci. Diagnostic accuracy based on surgery or Duke Criteria during follow-up was highest for CZT imaging (P < 0.001)., Conclusion: Novel CZT SPECT technology improves the accuracy of molecular/cellular cardiac imaging. Simultaneous multi-isotope imaging with 111In and 99mTc is feasible and aids in the workup of suspected endocarditis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objective: Urinary radiotracer excretion of 68 Ga-Labelled prostate-specific membrane antigen (PSMA) ligands may complicate the assessment of the prostate region and differentiation of lymph nodes from ureteral activity. The aim of this study was to assess the value of delayed imaging after forced diuresis., Materials and Methods: Sixty-six patients underwent 68 Ga-PSMA I&T PET/CT for evaluation of prostate cancer at 60 min post-injection. In subgroups of patients, this was amended by delayed imaging after 180 min post-injection, preceded by furosemide and oral hydration early, at the time of tracer injection, or delayed, at 100 min post-injection. Urinary tracer activity within the bladder and focal ureteral activity was analyzed., Results: After forced diuresis, linear and focal visualization of ureters was significantly reduced. After delayed furosemide, mean and peak bladder activity decreased (p < 0.001), and image quality of the prostate region improved on delayed images (p < 0.001). Early furosemide co-injection with tracer resulted in increased mean and peak bladder activity (p < 0.001) and in deteriorated image quality of the prostate region on delayed images (p = 0.008)., Conclusion: Ga-PSMA I&T PET/CT delayed imaging after forced diuresis can improve the assessment of prostate region and pelvic lymph nodes by removing excreted tracer from the lower urinary tract., Key Points: • Forced diuresis can improve image quality in 68 Ga-PSMA I&T. • After forced diuresis, linear and focal visualization of ureters was reduced. • Timing of diuresis relative to 68 Ga-PSMA I&T injection is important. • Early furosemide co-injection with tracer resulted in deteriorated image quality on delayed images. • After delayed furosemide, image quality improved on delayed images.

Objective: Intraplaque neovascularization contributes to the progression and rupture of atherosclerotic lesions. Glutamate carboxypeptidase II (GCPII) is strongly expressed by endothelial cells of tumor neovasculature and plays a major role in hypoxia-induced neovascularization in rodent models of benign diseases. We hypothesized that GCPII expression may play a role in intraplaque neovascularization and may represent a target for imaging of atherosclerotic lesions. The aim of this study was to determine frequency, pattern, and clinical correlates of vessel wall uptake of a 68 Ga-GCPII ligand for positron emission tomographic imaging., Approach and Results: Data from 150 patients undergoing 68 Ga-GCPII ligand positron emission tomography were evaluated. Tracer uptake in various arterial segments was analyzed and was compared with calcified plaque burden, cardiovascular risk factors, and immunohistochemistry of carotid specimens. Focal arterial uptake of 68 Ga-GCPII ligand was identified at 5776 sites in 99.3% of patients. The prevalence of uptake sites was highest in the thoracic aorta; 18.4% of lesions with tracer uptake were colocalized with calcified plaque. High injected dose (P=0.0005) and obesity (P=0.007) were significantly associated with 68 Ga-GCPII ligand accumulation, but other cardiovascular risk factors showed no association. The number of 68 Ga-GCPII ligand uptake sites was significantly associated with overweight condition (P=0.0154). Immunohistochemistry did not show GCPII expression. Autoradiographic blocking studies indicated nonspecific tracer binding., Conclusions: 68 Ga-GCPII ligand positron emission tomography does not identify vascular lesions associated with atherosclerotic risk. Foci of tracer accumulation are likely caused by nonspecific tracer binding and are in part noise-related. Taken together, GCPII may not be a priority target for imaging of atherosclerotic lesions., (© 2016 American Heart Association, Inc.)

Background: Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany., Methods: A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan-Meier curves and uni-variate log rank test Cox models., Findings: Median overall survival of all patients was 59 (95% confidence interval [CI] 49-68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83-5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79-5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41-12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18-0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9-46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71-4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2-1.5% of patients., Interpretation: These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Increased rollout and availability of preclinical imaging provides a foundation for development of novel molecular nuclear imaging agents. The current armamentarium of radiotracers available for nuclear cardiology allows for the interrogation of critical molecular processes involved in a myriad of cardiovascular disorders, including altered metabolism, ventricular remodeling, sympathetic neuronal activation, and systemic inflammation. Effective translational molecular imaging requires coordination of clinical need with tracer development and molecular biology, leading to the identification of ideal translational imaging compounds., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Post-transplant reinnervation is a unique model to study sympathetic neuronal regeneration in vivo. The differential role of subcellular mechanisms of catecholamine handling in nerve terminals has not been investigated., Methods and Results: Three different carbon-11-labeled catecholamines were used for positron emission tomography of transport (C-11 m-hydroxyephedrine, HED), vesicular storage (C-11 epinephrine, EPI), and metabolic degradation (C-11 phenylephrine). A 2-day protocol was used, including quantification of myocardial blood flow by N-13 ammonia. Resting myocardial blood flow and EPI, HED and phenylephrine retention were homogeneous in healthy volunteers (n=7). Washout was only observed for phenylephrine (T(1/2) 49±6 min). In nonrejecting, otherwise healthy heart transplant recipients (>1 year after surgery, n=10), resting myocardial blood flow was also homogenous. Regional catecholamine uptake of varying degrees was observed in the anterior left ventricular wall and septum. Overall, 24±19% of left ventricle showed HED uptake levels comparable with healthy volunteers, whereas it was only 8±7% for EPI (P=0.004 versus HED). Phenylephrine washout was not different from healthy volunteers in the area with restored EPI and HED retention (T(1/2) 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T(1/2) 36±8 min; P=0.008), consistent with inefficient vesicular storage and enhanced metabolic degradation., Conclusions: Regeneration of subcellular components of sympathetic nerve terminal function does not occur simultaneously. In the reinnervating transplanted heart, a region with normal catecholamine transport and vesicular storage is surrounded by a borderzone, where transport is already restored but vesicular storage remains inefficient, suggesting that vesicular storage is a more delicate mechanism. This observation may have implications for other pathologies involving cardiac autonomic innervation., (© 2015 American Heart Association, Inc.)

Purpose: Myelofibrosis is a haematopoietic stem cell neoplasm characterized by bone marrow inflammation, reactive marrow fibrosis and extramedullary haematopoiesis. The aim of this study was to determine if (18)F-FDG PET/CT can be used to noninvasively visualize and quantify the extent and activity of bone marrow involvement., Methods: In 30 patients, the biodistribution of (18)F-FDG was analysed by measuring the standardized uptake value in the bone marrow compartment and spleen. Imaging findings were compared with laboratory, cytogenetic and histopathological data., Results: Retention of (18)F-FDG was observed in bone marrow and spleen. Bone marrow involvement varied, ranging from mildly increased uptake in the central skeleton to extensive uptake in most parts of the skeleton. The extent of bone marrow involvement decreased over time from initial diagnosis (r s  = -0.43, p = 0.019). Metabolic activity of the bone marrow decreased as the histopathological grade of fibrosis increased (r s  = -0.37, p = 0.04). There was a significant positive correlation between the metabolic activity of the bone marrow and that of the spleen (p = 0.04)., Conclusion: (18)F-FDG PET/CT is as a promising technique for the quantitation of bone marrow inflammation in myelofibrosis. Our data indicate that the intensity of bone marrow (18)F-FDG uptake decreases as bone marrow fibrosis increases. Further evaluation in prospective studies is required to determine the potential clinical impact and prognostic significance of PET.

Purpose: Myocardial inflammation is an emerging target for novel therapies and thus for molecular imaging. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) has been employed, but requires an approach for suppression of cardiomyocyte uptake. We tested clinically viable strategies for their suitability in mouse models in order to optimize preclinical imaging protocols., Methods: C57BL/6 mice (n = 56) underwent FDG PET under various conditions. In healthy animals, the effect of low-dose (5 units/kg) or high-dose (500 units/kg, 15 min prior) intravenous heparin, extended fasting (18 h) and the impact of conscious injection with limited, late application of isoflurane anaesthesia after 40 min of conscious uptake were examined in comparison to ketamine/xylazine anaesthesia. Conscious injection/uptake strategies were further evaluated at 3 days after permanent coronary artery occlusion., Results: Under continuous isoflurane anaesthesia, neither heparin administration nor extended fasting significantly impacted myocardial (18)F-FDG accumulation. Injection with 40 min uptake in awake mice resulted in a marked reduction of global myocardial (18)F-FDG uptake compared to standard isoflurane anaesthesia (5.7 ± 1.1 %ID/g vs 30.2 ± 7.9 %ID/g, p < 0.01). Addition of heparin and fasting further reduced uptake compared to conscious injection alone (3.8 ± 1.5 %ID/g, p < 0.01) similar to ketamine/xylazine (2.4 ± 2.2 %ID/g, p < 0.001). In the inflammatory phase, 3 days after myocardial infarction, conscious injection/uptake with and without heparin/fasting identified a marked increase in myocardial (18)F-FDG accumulation that was similar to that observed under ketamine/xylazine., Conclusion: Continuous isoflurane anaesthesia obscures any suppressive effect of heparin or fasting on cardiomyocyte glucose utilization. Conscious injection of FDG in rodents significantly reduces cardiomyocyte uptake and enables further suppression by heparin and fasting, similar to clinical observations. In contrast to ketamine/xylazine, this represents a more physiological, translatable strategy for suppression of cardiomyocyte (18)F-FDG uptake when targeting myocardial inflammation.

Unlabelled: Imaging of inflammation early after myocardial infarction (MI) is a promising approach to the guidance of novel molecular interventions that support endogenous healing processes. (18)F-FDG PET has been used, but may be complicated by physiological myocyte uptake. We evaluated the potential of two alternative imaging targets: lactoferrin binding by (68)Ga-citrate and somatostatin receptor binding by (68)Ga-DOTATATE., Methods: C57Bl/6 mice underwent permanent coronary artery ligation. Serial PET imaging was performed 3 - 7 days after MI using (68)Ga-citrate, (68)Ga-DOTATATE, or (18)F-FDG with ketamine/xylazine suppression of myocyte glucose uptake. Myocardial perfusion was evaluated by (13)N-ammonia PET and cardiac geometry by contrast-enhanced ECG-gated CT., Results: Mice exhibited a perfusion defect of 30 - 40% (of the total left ventricle) with apical anterolateral wall akinesia and thinning on day 7 after MI. (18)F-FDG with ketamine/xylazine suppression demonstrated distinct uptake in the infarct region, as well as in the border zone and remote myocardium. The myocardial standardized uptake value in MI mice was significantly higher than in healthy mice under ketamine/xylazine anaesthesia (1.9 ± 0.4 vs. 1.0 ± 0.1). (68)Ga images exhibited high blood pool activity with no specific myocardial uptake up to 90 min after injection (tissue-to-blood contrast 0.9). (68)Ga-DOTATATE was rapidly cleared from the blood, but myocardial SUV was very low (0.10 ± 0.03)., Conclusion: Neither (68)Ga nor (68)Ga-DOTATATE is a useful alternative to (18)F-FDG for PET imaging of myocardial inflammation after MI in mice. Among the three tested approaches, (18)F-FDG with ketamine/xylazine suppression of cardiomyocyte uptake remains the most practical imaging marker of post-infarct inflammation.

Ventricular tachycardia (VT) is a major cause of sudden cardiac death (SCD) in patients with heart failure (HF). Left ventricular ejection fraction (LVEF) and heart failure class according to the New York Heart association (NYHA) are in most common use to identify patients that may benefit from implantable cardioverter defibrillator (ICD) therapy. But during 3 years of follow up only 35% of patients receive appropriate ICD action. Therefore, there is a continued need for refinement of selection criteria for ICD implantation. In this regard, molecular imaging of the autonomic nervous system, which plays a central role in HF progression and cardiac electro-mechanical regulation, can make a substantial contribution. This article reviews the currently available literature concerning the value of molecular neuronal cardiac imaging for prediction of ventricular arrhythmias in HF patients.

The autonomic nervous system is the primary extrinsic control of cardiac performance, and altered autonomic activity has been recognized as an important factor in the progression of various cardiac pathologies. Molecular imaging techniques have been developed for global and regional interrogation of pre- and postsynaptic targets of the cardiac autonomic nervous system. Building on established work with the guanethidine analogue ¹²³I-metaiodobenzylguanidine (MIBG) for single-photon emission tomography (SPECT), development of radiotracers and protocols for positron emission tomography (PET) investigation of autonomic signaling has expanded. PET is limited in availability and requires specialized centers for radiosynthesis and interpretation, but the higher resolution allows for improved regional analysis and kinetic modeling provides more true quantification than is possible with SPECT. A wider array of radiolabeled catecholamines, analogues of catecholamines, and receptor ligands have been characterized and evaluated. Sympathetic neuronal PET tracers have shown promise in the identification of several cardiac pathologies. In particular, recent studies have elucidated a mechanistic role for heterogeneous sympathetic innervation in the development of lethal ventricular arrhythmias. Evaluation of cardiomyocyte adrenergic receptor expression and the parasympathetic nervous system has been slower to develop, with clinical studies beginning to emerge. This review summarizes the clinical and the experimental PET tracers currently available for autonomic imaging and discusses their application in health and cardiovascular disease, with particular emphasis on the major findings of the last decade.

Unlabelled: (18)F-fluorobenzyl triphenyl phosphonium (FBnTP) has recently been introduced as a myocardial perfusion PET agent. We used a rat model of transient coronary occlusion to determine the stability of the perfusion defect size over time and the magnitude of redistribution., Methods: Wistar rats (n = 15) underwent thoracotomy and 2-min occlusion of the left coronary artery (LCA), followed by reperfusion. During occlusion, (18)F-FBnTP (92.5 MBq) and (201)Tl-thallium chloride (0.74 MBq) were injected intravenously. One minute before the animals were sacrificed at 5, 45, and 120 min after reperfusion, the LCA was occluded again and 2% Evans blue was injected intravenously to determine the ischemic territory. The hearts were excised, frozen, and sliced for serial dual-tracer autoradiography and histology. Dynamic in vivo (18)F-FBnTP PET was performed on a subgroup of animals (n = 4)., Results: (18)F-FBnTP showed stable ischemic defects at all time points after tracer injection and reperfusion. The defects matched the blue dye defect (y = 0.97x+1.5, R(2) = 0.94, y = blue-dye defect, x = (18)F-FBnTP defect). Count density analysis showed no defect fill-in at 45 min but slightly increased activity at 120 min (LCA/remote uptake ratio = 0.19 ± 0.02, 0.19 ± 0.05, and 0.34 ± 0.06 at 5, 45, and 120 min, respectively, P < 0.05). For comparison, (201)Tl showed complete redistribution at 120 min (LCA/remote = 0.42 ± 0.04, 0.72 ± 0.03, and 0.97 ± 0.05 at 5, 45, and 120 min, respectively, P < 0.001). Persistence of the (18)F-FBnTP defect over time was confirmed by in vivo dynamic small-animal PET., Conclusion: In a transient coronary occlusion model, perfusion defect size using the new PET agent (18)F-FBnTP remained stable for at least 45 min and matched the histologically defined ischemic area. This lack of significant redistribution suggests a sufficient time window for future clinical protocols with tracer injection remote from the scanner, such as in a stress testing laboratory or chest pain unit.

Unlabelled: The accuracy of myocardial perfusion SPECT improves with attenuation correction. Algorithms for attenuation correction in hybrid SPECT/CT systems have the potential for misregistration of emission and transmission scans because CT and SPECT are obtained sequentially. Misregistration will influence regional tracer distribution and may reduce diagnostic accuracy. This study focused on the role of misregistration in cardiac SPECT/CT and the performance of a software-based approach for reregistration., Methods: We included 105 consecutive patients who underwent clinical myocardial perfusion imaging on a SPECT/CT system. Images were quantitatively assessed for misregistration using fusion software. Results were recorded in millimeters in the x-, y-, and z-axes. Regional tracer uptake in 6 segments (anterior, septal, inferior, lateral, anteroapical, and inferoapical) for noncorrected and attenuation-corrected images before and after reregistration was obtained from polar maps. To determine the relative influence of misregistration, we correlated individual differences between noncorrected and attenuation-corrected images, as well as between attenuation-corrected images before and after reregistration, with the degree of misregistration in a multivariate analysis including additional clinical variables such as sex and body weight., Results: The difference in regional radiotracer uptake was significant between noncorrected and attenuation-corrected images in all 6 segments and was most pronounced in the inferior wall. On multivariate analysis, misregistration contributed significantly to changes in radiotracer distribution in the anterior (P = 0.038), septal (P = 0.011), and inferior (P = 0.006) segments. The mean misregistration was 8.6 +/- 3.8 mm (1.25 +/- 0.55 pixel). Misregistration of one or more pixels was observed in 64% of studies. Reregistration of misalignment significantly affected regional radiotracer distribution in the segments shown to be influenced by misregistration., Conclusion: Misregistration occurs with SPECT/CT systems and influences regional tracer distribution on attenuation-corrected myocardial images. Reregistration of misaligned studies may be a useful tool for correction. The impact of this strategy on the diagnostic and prognostic accuracy of cardiac hybrid imaging needs to be determined.

Introduction: Balance of the autonomic nervous system is essential for adequate cardiac performance, and alterations seem to play a key role in the development and progression of various cardiac diseases., Pet as an Imaging Tool: PET imaging of the cardiac autonomic nervous system has advanced extensively in recent years, and multiple pre- and postsynaptic tracers have been introduced. The high spatial and temporal resolution of PET enables noninvasive quantification of neurophysiologic processes at the tissue level. Ligands for catecholamine receptors, along with radiolabeled catecholamines and catecholamine analogs, have been applied to determine involvement of sympathetic dysinnervation at different stages of heart diseases such as ischemia, heart failure, and arrhythmia., Review: This review summarizes the recent findings in neurocardiological PET imaging. Experimental studies with several radioligands and clinical findings in cardiac dysautonomias are discussed.

On the basis of clinical observations that acute coronary events often result from rupture of atherosclerotic plaques at sites with no or minor luminal narrowing, the search for techniques by which to identify vulnerable, rupture-prone lesions has developed into a quest for the holy grail of cardiovascular medicine. Vulnerable plaques may show characteristic morphologic features, but they may still differ in their biology and their activity, which ultimately leads to rupture. As a consequence, considerable efforts have been undertaken to identify biologic mechanisms of atherosclerotic lesions by use of molecular-targeted radiolabeled probes. A variety of approaches aiming at plaque inflammation, apoptosis, smooth muscle cell proliferation, extracellular matrix activation, or platelet binding have been introduced. Nevertheless, molecular imaging of atherosclerosis is still a work in progress. Challenges related to the best targeting approach, to translation of animal model results to the clinical setting, to adequate imaging methodology for visualization of coronary artery biology, and to a suitable target patient population will need to be overcome. But the field is steadily moving ahead and getting closer to the ultimate goal of an improved clinical risk assessment through in vivo assessment of vascular biology.

Cardiac sympathetic activity plays a key role in supporting cardiac function in both health and disease conditions, and nuclear cardiac imaging has always represented the only way for the non-invasive evaluation of the functional integrity of cardiac sympathetic terminals, mainly through the use of radiopharmaceuticals that are analogues of norepinephrine and, in particular, with the use of 123I- m IBG imaging. This technique demonstrates the presence of cardiac sympathetic dysfunction in different cardiac pathologies, linking the severity of sympathetic nervous system impairment to adverse patient's prognosis. This article will outline the state-of-the-art of cardiac 123I- m IBG imaging and define the value and clinical applications in the different fields of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response. [ABSTRACT FROM AUTHOR]

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: Urinary radiotracer excretion of 68Ga-Labelled prostate-specific membrane antigen (PSMA) ligands may complicate the assessment of the prostate region and differentiation of lymph nodes from ureteral activity. The aim of this study was to assess the value of delayed imaging after forced diuresis.Materials and Methods: Sixty-six patients underwent 68Ga-PSMA I&T PET/CT for evaluation of prostate cancer at 60 min post-injection. In subgroups of patients, this was amended by delayed imaging after 180 min post-injection, preceded by furosemide and oral hydration early, at the time of tracer injection, or delayed, at 100 min post-injection. Urinary tracer activity within the bladder and focal ureteral activity was analyzed.Results: After forced diuresis, linear and focal visualization of ureters was significantly reduced. After delayed furosemide, mean and peak bladder activity decreased (p < 0.001), and image quality of the prostate region improved on delayed images (p < 0.001). Early furosemide co-injection with tracer resulted in increased mean and peak bladder activity (p < 0.001) and in deteriorated image quality of the prostate region on delayed images (p = 0.008).Conclusion: Ga-PSMA I&T PET/CT delayed imaging after forced diuresis can improve the assessment of prostate region and pelvic lymph nodes by removing excreted tracer from the lower urinary tract.Key Points: • Forced diuresis can improve image quality in 68 Ga-PSMA I&T. • After forced diuresis, linear and focal visualization of ureters was reduced. • Timing of diuresis relative to 68 Ga-PSMA I&T injection is important. • Early furosemide co-injection with tracer resulted in deteriorated image quality on delayed images. • After delayed furosemide, image quality improved on delayed images. [ABSTRACT FROM AUTHOR]

A bicyclononyne-based prosthetic group has been developed for 18F-labeling of anti-microRNA-21, an oligonucleotide, in a near-stoichiometric manner. [ABSTRACT FROM AUTHOR]

Simple Summary: Assessment of the radiation-induced alterations in peripheral blood lymphocytes is a validated strategy for biological dosimetry and assessment of individual radiosensitivity. However, its clinical significance as a liquid biopsy for predicting hematotoxicity and treatment response when targeting tumor cells with ionizing radiation from a systemically administered radioligand is unexplored. The results from this study revealed that the analysis of radiation-induced foci in peripheral blood lymphocytes may hold potential for predicting both individual subclinical hematotoxicity and tumor response to somatostatin-receptor targeted radioligand therapy in patients with advanced gastroenteropancreatic neuroendocrine tumors. These preliminary data provide the rationale for further studies evaluating analyses-guided treatment intensification in patients at high risk of early progression. Background: We aimed to characterize γ-H2AX and 53BP1 foci formation in patients receiving somatostatin receptor-targeted radioligand therapy, and explored its role for predicting treatment-related hematotoxicity, and treatment response. Methods: A prospective analysis of double-strand break (DSB) markers was performed in 21 patients with advanced gastroenteropancreatic neuroendocrine tumors. γ-H2AX and 53BP1 foci formation were evaluated in peripheral blood lymphocytes (PBLs) at baseline, +1 h and +24 h after administration of 7.4 GBq (177Lu)Lu-DOTA-TATE. Hematotoxicity was evaluated using standard hematology. Therapy response was assessed using (68Ga)Ga-DOTA-TATE PET/CT before enrollment and after 2 cycles of PRRT according to the volumetric modification of RECIST 1.1. Results: DSB marker kinetics were heterogeneous among patients. Subclinical hematotoxicity was associated with γ-H2AX and 53BP1 foci formation (e.g., change in platelet count vs change in γ-H2AX+ cells between baseline and +1 h (r = −0.6080; p = 0.0045). Patients showing early development of new metastases had less γ-H2AX (p = 0.0125) and less 53BP1 foci per cell at +1 h (p = 0.0289), and demonstrated a distinct kinetic pattern with an absence of DSB marker decrease at +24 h (γ-H2AX: p = 0.0025; 53BP1: p = 0.0008). Conclusions: Assessment of γ-H2AX and 53BP1 foci formation in PBLs of patients receiving radioligand therapy may hold promise for predicting subclinical hematotoxicity and early treatment response. [ABSTRACT FROM AUTHOR]

The article reports on endomyocardial biopsy, a molecular imaging for the detection of cardiac involvement in systemic disease. It states that radiotracer techniques are employed for molecular mechanisms in systemic disease condition and nuclear imaging with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used for detection of disease. It mentions that diseases such as amyloidosis use diphosphonate (DPD) imaging.