Rudolf A. Werner

Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG

18F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine (18F-LMI1195) is a new PET tracer designed for noninvasive assessment of sympathetic innervation of the heart. The 18F label facilitates the imaging advantages of PET over SPECT technology while allowing centralized manufacturing. Highly specific neural uptake of 18F-LMI1195 has previously been established, but the retention kinetics are not yet fully understood. Methods: Healthy New Zealand White rabbits were studied with 18F-LMI1195 using a small-animal PET system. Dynamic 40-min chest scans were started just before intravenous bolus injection of 18F-LMI1195. Imaging was performed under norepinephrine transport inhibition with desipramine pretreatment, a 1.5 mg/kg desipramine chase administered 10 min after tracer injection, and saline treatment of controls. As a reference, cardiac uptake of 11C-hydroxyephedrine and 123I-metaiodobenzylguanidine (123I-MIBG) was examined by PET and planar scintigraphy, respectively. Results: Cardiac uptake of all 3 tracers was inhibited by pretreatment with desipramine. Stable cardiac tracer retention was delineated by dynamic PET in control rabbits for 11C-hydroxyephedrine (washout rate, 0.42% ± 0.57%/min) and 18F-LMI1195 (washout rate, 0.058% ± 0.28%/min). A desipramine chase increased 11C-hydroxyephedrine washout from the heart (2.43% ± 0.15%/min, P < 0.001), whereas 18F-LMI1195 washout was not influenced (0.059% ± 0.11%/min, not statistically significant). Additionally, a desipramine chase did not change the cardiac 123I-MIBG uptake (delayed heart-to-mediastinum ratio, 1.99 ± 0.12 (desipramine chase) vs. 2.05 ± 0.16 (controls), not statistically significant). Conclusion: In vivo norepinephrine transporter (NET) blockade with desipramine confirmed specific neural uptake of 18F-LMI1195, 11C-hydroxyephedrine, and 123I-MIBG in rabbit hearts. 11C-hydroxyephedrine cardiac retention was sensitive to a NET inhibitor chase, indicating a cycle of continuous NET uptake and release at the nerve terminals. In contrast, 18F-LMI1195 and 123I-MIBG demonstrated stable storage at the nerve terminal with resistance to a NET inhibitor chase, mimicking physiologic norepinephrine turnover.

[68Ga]Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression After Myocardial Infarction

Due to the inability of myocytes to regenerate, acute and sustained ischemia usually results in irreversible myocardial damage and subsequent remodeling processes. Chemokine receptor 4 (CXCR4)/stromal cell-derived factor (SDF)-1α play a pivotal role in the recruitment and homing of stem and

Imaging of myocardial inflammation with somatostatin receptor based PET/CT — A comparison to cardiac MRI

BACKGROUND Acute myocarditis as well as post-ischemic myocardial inflammation are generally associated with a profound activation of the immune system. Current established imaging techniques such as cardiac MRI reliably demonstrate signs of acute myocardial injury. However, detection of mediating cells such as macrophages is currently limited to experimental settings. We aimed to investigate the feasibility of somatostatin receptor (SSTR) based positron emission tomography/computed tomography (PET/CT) for detecting inflammatory lesions in patients after acute myocardial infarction or acute peri-/myocarditis. METHODS 12 patients with active peri-/myocarditis (n=6) or sub-acute myocardial infarction (n=6) underwent SSTR-PET/CT and cardiac MRI within 3-10 days after onset of symptoms. The AHA 17-segment model of the left myocardium was used for visual localization of inflamed myocardium for both imaging modalities. Tracer uptake of infarcted/inflamed myocardium was assessed as mean and maximum standardized uptake value (SUVmean and SUVmax) and compared with both remote myocardium and left ventricular (LV) cavity. RESULTS SSTR-PET/CT revealed areas with increased cardiac tracer uptake in all patients. In the 17-segment model, PET/CT yielded 55 and MRI 47 positive segments. Overall, concordance of the 2 modalities was 85.3% (174/204 segments analyzed). In 9.3% (19/204), more positive segments were identified by PET/CT, whereas in 5.4% (11/204), MRI detected more positive segments. CONCLUSIONS The imaging patterns of SSTR-directed radiotracers and MRI in vivo show a close spatial relation of macrophage concentration and structural changes. This suggests the possibility of a new potential biomarker that predicts cardiac remodeling and, hence, progression towards heart failure. Prospective trials are warranted.

Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI.

Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR–PET/CT for detecting cardiac sarcoidosis in comparison to CMR. 15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUVmean) and maximum standardized uptake values (SUVmax) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity. SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET− subjects, one patient with minor involvement (<25% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET− patients displayed no adverse cardiac events during follow-up. In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% (245/255 segments analyzed). SUVmean and SUVmax in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUVmean and 2.0±0.3 and 1.7±0.3 for SUVmax, respectively. Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series.

68Gallium- and 90Yttrium-/177Lutetium: “theranostic twins” for diagnosis and treatment of NETs

Abundant expression of somatostatin receptors (SSTR) is frequently identified in differentiated neuroendocrine tumors and may serve as potential target for diagnostic imaging and treatment. This article discusses the “theranostic approach” of SSTR-targeting compounds including an overview of its role for diagnosis, staging and restaging, discussing its way to being established in clinical routine, and giving an outlook about further potentially relevant developments.

Detection of cardiac sarcoidosis by macrophage-directed somatostatin receptor 2-based positron emission tomography/computed tomography

A 54-year-old patient with suspected atypical myocarditis was referred. Coronary artery disease had been excluded by coronary angiography. Cardiac magnetic resonance imaging (CMR) revealed acute myocardial damage of the septal and anterior wall in T2 and contrast-enhanced images ( Panel A ). Macrophage-directed positron emission tomography/computed tomography (PET/CT) using a somatostatin receptor (SSTR) ligand …

Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach

C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [68Ga]Pentixafor in comparison to 68Ga-DOTA-D-Phe-Tyr3-octreotide ([68Ga]DOTATOC) and 18F-fluorodeoxyglucose ([18F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [68Ga]DOTATOC, [18F]FDG, and [68Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [68Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [18F]FDG revealed sites of disease in 10/12 and [68Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [68Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [68Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.

Prognostic Value of Serum Tumor Markers in Medullary Thyroid Cancer Patients Undergoing Vandetanib Treatment.

AbstractTyrosine kinase inhibitors (TKIs) such as vandetanib have shown clinical effectiveness in advanced medullary thyroid cancer (MTC). During TKI treatment, fluctuations in the tumor markers carcinoembryonic antigen (CEA) and calcitonin (CTN) are frequently observed. Their role for treatment monitoring and the decision-making process has not been fully elucidated yet.Twenty-one patients (male, 16, female, 5; mean age, 49 ± 13 years) with progressive MTC receiving vandetanib (300 mg orally per day) were considered. Tumor restaging was performed every 3 months including contrast-enhanced computed tomography (CT). Response was assessed according to recent criteria (Response Evaluation Criteria in Solid Tumors, RECIST 1.1). Additionally, CEA and CTN were measured at the day of CT imaging and alterations observed in tumor markers were compared to respective imaging findings (partial response, PR; stable disease, SD; progressive disease, PD).During long-term follow-up (510 ± 350 days [range, 97–1140 days]), CTN and CEA levels initially dropped in 71.4% and 61.9% of the patients followed by fluctuations in serum marker levels. A rise in CTN ≥39.5% between 2 subsequent measurements (defined by ROC analysis) had a sensitivity of 70.6% and a specificity of 83.2% in predicting PD with an accuracy of 82.0% (area under the curve (AUC), 0.76). Oscillations in CEA levels were not predictive for PD.Whereas tumor marker fluctuations in MTC patients undergoing TKI treatment are a frequent phenomenon, a significant rise in CTN ≥40% turns out to as an early indicator of tumor progression.

Dose Mapping After Endoradiotherapy with 177Lu-DOTATATE/DOTATOC by a Single Measurement After 4 Days

Dosimetry of organs and tumors helps to assess risks and benefit of treatment with 177Lu-DOTATATE/DOTATOC. However, it is often not performed in clinical routine because of additional efforts, the complexity of data collection and analysis, and the additional burden for the patients. Aiming at a simplification of dosimetry, we analyzed the accuracy of a theoretically substantiated approximation, which allows the calculation of absorbed doses from a single measurement of the abdominal activity distribution. Methods: Activity kinetics were retrospectively assessed from planar images in 29 patients with neuroendocrine tumors (NETs; n = 21) or meningioma (n = 8) after the administration of 177Lu-DOTATATE (n = 22) or 177Lu-DOTATOC (n = 7). Mono- or biexponential functions were fitted to measured data in 54 kidneys, 25 livers, 27 spleens, and 30 NET lesions. It was evaluated for each fit function how well the integral over time was represented by an approximation calculated as the product of the time tl of a single measurement, the expected reading at time tl, and the factor 2/ln(2). Tissue-specific deviations of the approximation from the time integral were calculated for time points tl of 24, 48, 72, 96, 120, and 144 h. Results: The correlation between time integral and approximation improved with increasing time tl. Pearson r exceeded 0.95 for a tl of 96 h or more in all tissues. The lowest maximum errors were observed at a tl of 96 h, with deviations of the approximation from the time integral of median +5% (range, −9% to +17%) for kidneys, +6% (range, −7% to +12%) for livers, +8% (range, +2% to +20%) for spleens, and +6% (range, −11% to +16%) for NET lesions. Accuracy was reduced for measurements after 72 or 120 h. For measurements after 24, 48, and 144 h, the approximation led to large deviations for some of the patients, in particular unacceptable underestimates of the absorbed dose to the kidneys. Conclusion: A single quantitative measurement of the abdominal activity concentration by SPECT/CT 4 d after the administration of 177Lu-DOTATATE/DOTATOC provides a 3-dimensional dose map and can be used to estimate the doses actually absorbed in the treatment cycle with minor additional resources and effort.

Localization of Parathyroid Adenoma With Real-Time Ultrasound: Freehand SPECT Fusion.

Preoperative localization of parathyroid adenoma in primary hyperparathyroidism gains in importance as there is a trend toward minimally invasive parathyroid surgery. Besides MRI, 4-dimensional CT, PET/CT, invasive-selective venous sampling, or angiography, both ultrasound and scintigraphy are standard of care for lesion localization. Here we report on a 53-year-old woman with suspicion of primary hyperparathyroidism using real-time fusion of scintigraphic (freehand SPECT) and ultrasound imaging for adenoma localization. Real-time fusion of ultrasound and freehand SPECT allowed noninvasive dedicated metabolic and anatomic adenoma localization and treatment planning.