Thomas Opfermann

In vivo molecular imaging of experimental joint inflammation by combined 18F-FDG positron emission tomography and computed tomography

IntroductionThe purpose of this work was to establish and validate combined small animal positron emission tomography - computed tomography (PET/CT) as a new in vivo imaging method for visualisation and quantification of joint inflammation.MethodsSignalling of radioisotope 18F labelled Fluorodeoxyglucose (18F-FDG) injected in mice with glucose-6-phosphate isomerase (G6PI)-induced arthritis was analysed by PET/CT. Accumulation of 18F-FDG in tissue was quantified by PET measurement, whereas high definition CT delivered anatomical information. The fusion of both images revealed in detail spatial and temporal distribution and metabolism of 18F-FDG.ResultsA distinct 18F-FDG signal could be measured by PET in carpal and tarsal joints, from mice with early or established arthritis. In contrast, no accumulation of 18F-FDG was detectable before arthritis onset. Comparison of 18F-FDG joint uptake with histopathological evaluation revealed a significant correlation of both methods.ConclusionsSmall animal PET/CT using 18F-FDG is a feasible method for monitoring and, more importantly, quantitative assessment of inflammation in G6PI-arthritis. Since it is possible to perform repeated non-invasive measurements in vivo, not only numbers of animals in preclinical studies can markedly be reduced by this method, but also longitudinal studies come into reach, e. g. for individual flare-up reactions or monitoring therapy response in progressive arthritis.

Implementation of 89Zr production and in vivo imaging of B-cells in mice with 89Zr-labeled anti-B-cell antibodies by small animal PET/CT.

We examined the production, separation, and characterization of (89)Zr, including supplementation of a commercial Cyclone(®) 18/9 with a self-made Solid Target System (STS). Obtained [(89)Zr]Zr-oxalate was used for the labeling of anti-B cell antibodies with desferrioxamine-p-SCN as a bifunctional chelator. (89)Zr-labeled antibodies were injected in DBA/1 mice to examine usability for detection of B cells in vivo. PET measurements showed binding of (89)Zr-labeled anti-B cell antibodies in tissues with high frequencies of B cells, i.e. in spleen and lymph nodes.

Early Dynamic 18F-FDG PET to Detect Hyperperfusion in Hepatocellular Carcinoma Liver Lesions

In addition to angiographic data on vascularity and vascular access, demonstration of hepatocellular carcinoma (HCC) liver nodule hypervascularization is a prerequisite for certain intrahepatic antitumor therapies. Early dynamic (ED) 18F-FDG PET/CT could serve this purpose when the current standard method, contrast-enhanced (CE) CT, or other CE morphologic imaging modalities are unsuitable. A recent study showed ED 18F-FDG PET/CT efficacy in this setting but applied a larger-than-standard 18F-FDG activity and an elaborate protocol likely to hinder routine use. We developed a simplified protocol using standard activities and easily generated visual and descriptive or quantitative endpoints. This pilot study assessed the ability of these endpoints to detect HCC hyperperfusion and, thereby, evaluated the suitability in of the protocol everyday practice. Methods: Twenty-seven patients with 34 HCCs (diameter ≥ 1.5 cm) with hypervascularization on 3-phase CE CT underwent liver ED 18F-FDG PET for 240 s, starting with 18F-FDG (250-MBq bolus injection). Four frames at 15-s intervals, followed by 3 frames at 60-s intervals were reconstructed. Endpoints included focal tracer accumulation in the first 4 frames (60 s), subsequent focal washout, and visual and quantitative differences between tumor and liver regions of interest in maximum and mean ED standardized uptake value (ED SUVmax and ED SUVmean, respectively) 240-s time–activity curves. Results: All 34 lesions were identified by early focal 18F-FDG accumulation and faster time-to-peak ED SUVmax or ED SUVmean than in nontumor tissue. Tumor peak ED SUVmax and ED SUVmean exceeded liver levels in 85% and 53%, respectively, of lesions. Nadir tumor signal showed no consistent pattern relative to nontumor signal. HCC had a significantly shorter time to peak and significantly faster rate to peak for both ED SUVmax and ED SUVmean curves and a significantly higher peak ED SUVmax but not peak ED SUVmean than the liver. Conclusion: This pilot study provided proof of principle that our simplified ED 18F-FDG PET/CT protocol includes endpoints that effectively detect HCC hypervascularization; this finding suggests that the protocol can be used routinely.

Hybrid Integration of Real-time US and Freehand SPECT: Proof of Concept in Patients with Thyroid Diseases

PURPOSE To report an initial experience regarding the feasibility and applicability of quasi-integrated freehand single photon emission computed tomography (SPECT)/ultrasonography (US) fusion imaging in patients with thyroid disease. MATERIALS AND METHODS Local ethics committee approval was obtained, and 34 patients were examined after giving written informed consent. After intravenous application of 75 MBq of technetium 99m pertechnetate, freehand three-dimensional SPECT was performed. Data were reconstructed and transferred to a US system. The combination of two independent positioning systems enabled real-time fusion of metabolic and morphologic information during US examination. Quality of automatic coregistration was evaluated visually, and deviation was determined by measuring the distance between the center of tracer distribution and the center of the US correlate. RESULTS All examinations were technically successful. For 18 of 34 examinations, the automatic coregistration and image fusion exhibited very good agreement, with no deviation. Only minor limitations in fusion offset occurred in 16 patients (mean offset ± standard deviation, 0.67 cm ± 0.3; range, 0.2-1.0 cm). SPECT artifacts occurred even in situations of clear thyroid findings (eg, unifocal autonomy). CONCLUSION The freehand SPECT/US fusion concept proved feasible and applicable; however, technical improvements are necessary.

18 F-Fluoride positron emission tomography/computed tomography for noninvasive in vivo quantification of pathophysiological bone metabolism in experimental murine arthritis

IntroductionEvaluation of disease severity in experimental models of rheumatoid arthritis is inevitably associated with assessment of structural bone damage. A noninvasive imaging technology allowing objective quantification of pathophysiological alterations of bone structure in rodents could substantially extend the methods used to date in preclinical arthritis research for staging of autoimmune disease severity or efficacy of therapeutical intervention. Sodium 18 F-fluoride (18 F-NaF) is a bone-seeking tracer well-suited for molecular imaging. Therefore, we systematically examined the use of 18 F-NaF positron emission tomography/computed tomography (PET/CT) in mice with glucose-6-phosphate isomerase (G6PI)–induced arthritis for quantification of pathological bone metabolism.MethodsF-fluoride was injected into mice before disease onset and at various time points of progressing experimental arthritis. Radioisotope accumulation in joints in the fore- and hindpaws was analyzed by PET measurements. For validation of bone metabolism quantified by 18 F-fluoride PET, bone surface parameters of high-resolution μCT measurements were used.ResultsBefore clinical arthritis onset, no distinct accumulation of 18 F-fluoride was detectable in the fore- and hindlimbs of mice immunized with G6PI. In the course of experimental autoimmune disease, 18 F-fluoride bone uptake was increased at sites of enhanced bone metabolism caused by pathophysiological processes of autoimmune disease. Moreover, 18 F-fluoride signaling at different stages of G6PI-induced arthritis was significantly correlated with the degree of bone destruction. CT enabled identification of exact localization of 18 F-fluoride signaling in bone and soft tissue.ConclusionsThe results of this study suggest that small-animal PET/CT using 18 F-fluoride as a tracer is a feasible method for quantitative assessment of pathophysiological bone metabolism in experimental arthritis. Furthermore, the possibility to perform repeated noninvasive measurements in vivo allows longitudinal study of therapeutical intervention monitoring.

Low-activity 124I-PET/low-dose CT versus 99mTc-pertechnetate planar scintigraphy or 99mTc-pertechnetate single-photon emission computed tomography of the thyroid: a pilot comparison.

Purpose of the ReportThe standard thyroid functional imaging method, 99mTc-pertechnetate (99mTc-PT) planar scintigraphy, has technical drawbacks decreasing its sensitivity in detecting nodules or anatomical pathology. 124I-PET, lacking these disadvantages and allowing simultaneous CT, may have greater sensitivity for these purposes. We performed a blinded pilot comparison of 124I-PET(/CT) versus 99mTc-PT planar scintigraphy or its cross-sectional enhancement, 99mTc-PT single-photon emission CT (SPECT), in characterizing the thyroid gland with benign disease. Patients and MethodsTwenty-one consecutive adults with goiter underwent low-activity (1 MBq/0.027 mCi) 124I-PET/low-dose (30 mAs) CT, 99mTc-PT planar scintigraphy, and 99mTc-PT-SPECT. Endpoints included the numbers of “hot spots” with/without central photopenia and “cold spots” detected, the proportion of these lesions with morphological correlates, the mean volume and diameter of visualized nodules, and the number of cases of lobus pyramidalis or retrosternal thyroid tissue identified. Results124I-PET detected significantly more “hot spots” with/without central photopenia (P < 0.001), significantly more nodules (P < 0.001), and more “cold spots” than did 99mTc-PT planar scintigraphy or 99mTc-PT-SPECT, including all lesions seen on the 99mTc-PT modalities. Ultrasonographic correlates were found for all nodules visualized on all 3 modalities and 92.5% of nodules seen only on 124I-PET. Nodules discernible only on 124I-PET had significantly smaller mean volume or diameter (P < 0.001) than did those visualized on 99mTc-PT planar scintigraphy or 99mTc-PT-SPECT. 124I-PET(/CT) identified significantly more patients with a lobus pyramidalis (P < 0.001) or retrosternal thyroid tissue (P < 0.05). Conclusions124I-PET(/CT) may provide superior imaging of benign thyroid disease compared to planar or cross-sectional 99mTc-PT scintigraphy.

Motion-artifact-free in vivo imaging utilizing narcotized avian embryos in ovo.

PurposeThe chick embryo in ovo is a well-accessible and economical in vivo model, but its use in molecular imaging has been limited because of motion artifacts on resulting images. The purpose of this study was to develop a method using narcotics to inhibit motility and to perform motion-artifact-free imaging of living chick embryos in ovo.ProceduresChick embryos in ovo were narcotized using three different narcotics: isoflurane, 2,2,2-tribromoethanol, and urethane/α-chloralose. Narcotized embryos were imaged using micro-computed tomography (microCT) at days 10–18 of incubation, and the resulting images were analyzed for reduction of motion artifacts.ResultsAll three anesthetics could be used for anesthetizing living chick embryos in ovo thus allowing the acquisition of motion-artifact-free images.ConclusionsOur experiments revealed that isoflurane is the best-suited narcotic for single and repeated applications to image living chick embryos in ovo.

Insights into Bone Metabolism of Avian Embryos In Ovo Via 3D and 4D 18F-fluoride Positron Emission Tomography

PurposeThe chick embryo is a well-known economical in vivo model system and is widely applied in preclinical research, e.g., bone development studies. It is therefore surprising that no studies concerning the application of 18F-fluoride microPET to bone metabolism have been reported so far. This may be due to motion artifacts or the lack of convenient tracer injection sites.MethodsWe resolved the above problems using a combination of sample preparation, anesthesia, microPET imaging, and computational processing, and describe a convenient way of visualizing three- and four- dimensional features of bone metabolism in living chick embryos.ResultsThe application of 18F-fluoride microPET facilitates repeat measurements, highly reproducible and motion-artifact-free skeletal imaging, and provides quantitative measurements of in ovo metabolic activities in the bones of developing chick. During microPET measurement, radio tracer was injected intravascularly using a custom-made catheter system, allowing us to additionally investigate early time points in tracer kinetics and uptake.ConclusionsOur results show that bone metabolism in living chick embryos can be reproducibly studied and quantified in ovo, even for multiple tracer injections over a longer time period. The use of dynamic 18F-fluoride microPET imaging made it possible to visualize and analyze even small bone structures with excellent quality. Moreover, as our data are comparable to data from corresponding rodent experiments, the use of embryonated chicken eggs is a convenient and economical alternative to other animal models.

Diagnosis of de quervain's subacute thyroiditis via sensor-navigated 124Iodine PET/ultrasound (124I-PET/US) fusion.

The role of 124Iodine-PET/US Fusion technique is demonstrated in a 52-year-old woman with De Quervains subacute thyroiditis. A small and adversely located lesion not detected by thyroid scintigraphy could be unambiguously matched with a hypofunctional PET finding. The presented case supports the clinical potential of PET/US Fusion technique in thyroid disease especially in small and uncertain findings.

The use of ostrich eggs for in ovo research - Making preclinical imaging research affordable and available

In ovo studies are a valuable option in preclinical research, but imaging studies are severely limited by the costs of dedicated equipment needed for small-sized eggs. We sought to verify the feasibility of using larger, ostrich, eggs (Struthio camelus) for imaging on the PET/CT scanners used for routine clinical investigations. Methods: Ostrich eggs were incubated until shortly before hatching, prepared for intravitelline venous injection of contrast medium or radiotracer, and imaged using native CT, contrast-enhanced CT, and PET/CT. Any technical adaptations that were needed to improve the outcome were noted. Results: Of the 34 eggs initially incubated, 12 became fully available for imaging of embryonal development. In ovo imaging with conventional PET/CT not only was feasible but also provided images of good quality, including on dynamic PET imaging. Conclusion: In ovo imaging with ostrich eggs and routine clinical scanners may allow broader application of this field of preclinical research, obviating costly dedicated equipment and reducing the number of animals needed for classic animal research. Further experiments are warranted to refine this novel approach, especially to reduce motion artifacts and improve monitoring of viability.