99mTc­labeled single-domain antibody for SPECT/CT assessment of HER2 expression in diverse cancer types.

The expression status of human epidermal growth factor receptor 2 (HER2) in cancer predicts response to HER2-targeted therapy. Therefore, its accurate determination is of utmost importance. In recent years, there has been an increase in research on noninvasive techniques for molecular imaging, as this method offers the advantages of a more accurate determination of HER2 status without the need for multiple biopsies. The technetium-labeled single-domain antibody RAD201, previously known as 99mTc-NM-02, has been shown to be safe for use in breast cancer imaging with reasonable radiation doses, favorable biodistribution, and imaging characteristics. METHODS: A total of six HER2-positive, heavily pretreated patients with different cancer types aged between 42 and 69 years (5 women and 1 man; the median age of 55.5) have been examined. In six of seven scans, the patients were administered 500 ml of Gelofusine® solution (40 mg/ml) for radiation protection before the tracer injection (434 ± 42 MBq). Planar scans were acquired with the patient supine at 10 min, 60 min, 160 min, 20 h, and 24 h after injection. A CT scan was acquired at 95 min, followed by local tomographic SPECT imaging. RESULTS: One patient was scanned twice with RAD201, 3 months apart, resulting in a total of seven scans for six patients. Here, we show that the use of RAD201 in our patient group shows the same favorable biodistribution as in a previous study with RAD201 (NCT04040686) and that the radiation dose to the critical organ kidney can be reduced by the application of the plasma expander Gelofusine® by almost 50%. CONCLUSION: RAD201 appears safe for use in humans and is a promising noninvasive tool for discriminating HER2 status in metastatic (breast) cancer, regardless of ongoing HER2-targeted antibody treatment.

Increasing striatal dopamine release through repeated bouts of theta burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. A 18F-desmethoxyfallypride positron emission tomography study.

Introduction: Transcranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) - a Dopamine receptor-antagonist - the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured. Methods: 23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen). Results: Verum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session. Conclusion: Results suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression.

Sodium [18F]Fluoride PET Can Efficiently Monitor In Vivo Atherosclerotic Plaque Calcification Progression and Treatment.

Given the high sensitivity and specificity of sodium [18F]Fluoride (Na[18F]F) for vascular calcifications and positive emerging data of vitamin K on vascular health, the aim of this study is to assess the ability of Na[18F]F to monitor therapy and disease progression in a unitary atherosclerotic mouse model. ApoE-/- mice were placed on a Western-type diet for 12-weeks and then split into four groups. The early stage atherosclerosis group received a chow diet for an additional 12-weeks, while the advanced atherosclerosis group continued the Western-type diet. The Menaquinone-7 (MK-7) and Warfarin groups received MK-7 or Warfarin supplementation during the additional 12-weeks, respectively. Control wild type mice were fed a chow diet for 24-weeks. All of the mice were scanned with Na[18F]F using a small animal positron emission tomography (PET)/computed tomography (CT). The Warfarin group presented spotty calcifications on the CT in the proximal aorta. All of the spots corresponded to dense mineralisations on the von Kossa staining. After the control, the MK-7 group had the lowest Na[18F]F uptake. The advanced and Warfarin groups presented the highest uptake in the aortic arch and left ventricle. The advanced stage group did not develop spotty calcifications, however Na[18F]F uptake was still observed, suggesting the presence of micro-calcifications. In a newly applied mouse model, developing spotty calcifications on CT exclusively in the proximal aorta, Na[18F]F seems to efficiently monitor plaque progression and the beneficial effects of vitamin K on cardiovascular disease.

Evaluation of a Pretargeting Strategy for Molecular Imaging of the Prostate Stem Cell Antigen with a Single Chain Antibody.

In pretargeted radio-immunotherapy, the gradual administration of a non-radioactive tumor antigen-addressing antibody-construct and the subsequent application of a radioactive labeled, low molecular weight substance enable a highly effective and selective targeting of tumor tissue. We evaluated this concept in prostate stem cell antigen (PSCA)-positive cancers using the antigen-specific, biotinylated single chain antibody scFv(AM1)-P-BAP conjugated with tetrameric neutravidin. To visualize the systemic biodistribution, a radiolabeled biotin was injected to interact with scFv(AM1)-P-BAP/neutravidin conjugate. Biotin derivatives conjugated with different chelators for complexation of radioactive metal ions and a polyethylene glycol linker (n = 45) were successfully synthesized and evaluated in vitro and in a mouse xenograft model. In vivo, the scFv(AM1)-P-BAP showed highly PSCA-specific tumor retention with a PSCA+ tumor/PSCA- tumor accumulation ratio of ten. PEGylation of radiolabeled biotin resulted in lower liver uptake improving the tumor to background ratio.

Impact of Glutathione Modulation on Stability and Pharmacokinetic Profile of Redox-Sensitive Nanogels.

Nanoparticles degradable upon external stimuli combine pharmacokinetic features of both small molecules as well as large nanoparticles. However, despite promising preclinical results, several redox responsive disulphide-linked nanoparticles failed in clinical translation, mainly due to their unexpected in vivo behavior. Glutathione (GSH) is one of the most evaluated antioxidants responsible for disulfide degradation. Herein, the impact of GSH on the in vivo behavior of redox-sensitive nanogels under physiological and modulated conditions is investigated. Labelling of nanogels with a DNA-intercalating dye and a radioisotope allows visualization of the redox responsiveness at the cellular and the systemic levels, respectively. In vitro, efficient cleavage of disulphide bonds of nanogels is achieved by manipulation of intracellular GSH concentration. While in vivo, the redox-sensitive nanogels undergo, to a certain extent, premature degradation in circulation leading to rapid renal elimination. This instability is modulated by transient inhibition of GSH synthesis with buthioninsulfoximin. Altered GSH concentration significantly changes the in vivo pharmacokinetics. Lower GSH results in higher elimination half-life and altered biodistribution of the nanogels with a different metabolite profile. These data provide strong evidence that decreased nanogel degradation in blood circulation can limit the risk of premature drug release and enhance circulation half-life of the nanogel.

Multistage Passive and Active Delivery of Radiolabeled Nanogels for Superior Tumor Penetration Efficiency.

Development of nanosized drug delivery systems in cancer therapy is directed toward improving tumor selectivity and minimizing damages of healthy tissue. We introduce a delivery system with synergistic optimization and combination of passive and active targeting strategies. The approach is based on radiopeptide labeled redox sensitive hydrophilic nanogels, which exploit passive targeting by the enhanced permeability and retention effect while avoiding elimination by the mononuclear phagocyte system and fast hepatic and renal clearance. The targeting peptide promotes endocytotic uptake of the nanogels by cancer cells. Specific to this delivery system, tumor-specific degradation by the antioxidant glutathione enhances penetration and retention within the tumor tissue. Using in vivo molecular imaging we demonstrate the superiority of combined passive and active targeting with down-sizable nanogels over exclusive passive targeting. Furthermore, the homogeneous tumor distribution of functionalized nanogels compared to the clinically used mere radiopeptide supports the potentially high impact of our targeting concept.

The reconstruction algorithm used for [68Ga]PSMA-HBED-CC PET/CT reconstruction significantly influences the number of detected lymph node metastases and coeliac ganglia.

PURPOSE: To investigate whether the numbers of lymph node metastases and coeliac ganglia delineated on [68Ga]PSMA-HBED-CC PET/CT scans differ among datasets generated using different reconstruction algorithms. METHODS: Data were constructed using the BLOB-OS-TF, BLOB-OS and 3D-RAMLA algorithms. All reconstructions were assessed by two nuclear medicine physicians for the number of pelvic/paraaortal lymph node metastases as well the number of coeliac ganglia. Standardized uptake values (SUV) were also calculated in different regions. RESULTS: At least one [68Ga]PSMA-HBED-CC PET/CT-positive pelvic or paraaortal lymph node metastasis was found in 49 and 35 patients using the BLOB-OS-TF algorithm, in 42 and 33 patients using the BLOB-OS algorithm, and in 41 and 31 patients using the 3D-RAMLA algorithm, respectively, and a positive ganglion was found in 92, 59 and 24 of 100 patients using the three algorithms, respectively. Quantitatively, the SUVmean and SUVmax were significantly higher with the BLOB-OS algorithm than with either the BLOB-OS-TF or the 3D-RAMLA algorithm in all measured regions (p < 0.001 for all comparisons). The differences between the SUVs with the BLOB-OS-TF- and 3D-RAMLA algorithms were not significant in the aorta (SUVmean, p = 0.93; SUVmax, p = 0.97) but were significant in all other regions (p < 0.001 in all cases). The SUVmean ganglion/gluteus ratio was significantly higher with the BLOB-OS-TF algorithm than with either the BLOB-OS or the 3D-RAMLA algorithm and was significantly higher with the BLOB-OS than with the 3D-RAMLA algorithm (p < 0.001 in all cases). CONCLUSION: The results of [68Ga]PSMA-HBED-CC PET/CT are affected by the reconstruction algorithm used. The highest number of lesions and physiological structures will be visualized using a modern algorithm employing time-of-flight information.

Metabolic tumour volume of anal carcinoma on (18)FDG PET/CT before combined radiochemotherapy is the only independant determinant of recurrence free survival.

AIM: to determine whether [(18)F]2-fluoro-2-deoxyglucose (FDG) positron emission tomography and X-ray computed tomography (PET/CT) findings and metabolic parameters before combined chemo- and radiotherapy (CRT) have a prognostic value in patients with anal carcinoma. MATERIALS AND METHODS: 45 patients with anal cancer who underwent pre-treatment FDG-PET/CT were included. Metabolic parameters, recurrence and anal carcinoma specific survival were analyzed. RESULTS: SUV max and metabolic volume of the primary tumour were significantly higher in patients with lymph node or distant metastases than in those with locally confined disease (p=0.020 and p=0.015, respectively). The extent of disease (local tumour only, lymph node or distant metastases) was highly predictive of both for recurrence free and disease specific survival (p=0.010 and p<0.001, respectively). Recurrence free (p=0.010) and anal carcinoma specific survival (p=0.006) differed significantly between patients with a metabolic volume ≤45ml and >45ml. Multivariate analysis revealed that a metabolic volume >45ml was the only significant independent determinant (p=0.19) for recurrence free survival whereas for anal carcinoma specific survival the extent of disease was identified as the only significant independent determinant (p=0.002). CONCLUSIONS: the extent of disease on FDG PET/CT before combined radio-chemotherapy is strongly predictive of prognosis in anal cancer. Furthermore, patients with a large metabolic volume of the primary tumour (>45ml) are at significantly higher risk of recurrence.

Comparison of automatic versus manual procedures for the quantification of dopamine D2 receptor availability using I-123-IBZM-SPECT.

INTRODUCTION: I-123-IBZM-SPECT is often used to differentiate between idiopathic Parkinson's syndrome and atypical parkinsonian syndromes. The aim of this study was to compare three different procedures to quantify the receptor availability of striatal dopamine D2 receptors. (a) Manual quantification performed using individually adjusted volume of interests sets (mVoi). (b) Automatic quantification applying the commercially available Hermes BRASS software (BRASS). (c) Automatic quantification applying the open-source software IBZM Toolbox (TBX). MATERIALS AND METHODS: Using the three methods, we analyzed 100 scans. For the mVOI methods, three different investigators (two experienced, one inexperienced) carried out the analysis. We compared the different methods with each other and with the reference standard established by clinical follow-up. The diagnostic performance was assessed by calculating receiver-operating characteristic (ROC) curves. RESULTS: Correlation analyses resulted in the following: mVOI versus BRASS (r=0.694) (P<0.005), mVOI versus TBX (r=0.557) (P<0.005); BRASS versus TBX (r=0.466) (P<0.005). We found a fair agreement for mVOI versus BRASS; slight agreement for mVOI versus TBX; and fair agreement for BRASS versus TBX. Moreover, we found a substantial agreement between the experienced investigators, but not with the inexperienced investigator in the case of mVOI. The ROC analysis shows the largest area under the ROC curve (Az=0.7295) for mVOI, followed by BRASS (Az=0.709) and TBX (Az=0.627). CONCLUSION: In direct comparison, the manual quantification used by experienced observers shows the best results, although it does not differ significantly from the commercial Hermes BRASS software. Both are superior to TBX.

Simulation-based partial volume correction for dopaminergic PET imaging: Impact of segmentation accuracy.

AIM: Partial volume correction (PVC) is an essential step for quantitative positron emission tomography (PET). In the present study, PVELab, a freely available software, is evaluated for PVC in (18)F-FDOPA brain-PET, with a special focus on the accuracy degradation introduced by various MR-based segmentation approaches. METHODS: Four PVC algorithms (M-PVC; MG-PVC; mMG-PVC; and R-PVC) were analyzed on simulated (18)F-FDOPA brain-PET images. MR image segmentation was carried out using FSL (FMRIB Software Library) and SPM (Statistical Parametric Mapping) packages, including additional adaptation for subcortical regions (SPML). Different PVC and segmentation combinations were compared with respect to deviations in regional activity values and time-activity curves (TACs) of the occipital cortex (OCC), caudate nucleus (CN), and putamen (PUT). Additionally, the PVC impact on the determination of the influx constant (Ki) was assessed. RESULTS: Main differences between tissue-maps returned by three segmentation algorithms were found in the subcortical region, especially at PUT. Average misclassification errors in combination with volume reduction was found to be lowest for SPML (PUT < 30%) and highest for FSL (PUT > 70%). Accurate recovery of activity data at OCC is achieved by M-PVC (apparent recovery coefficient varies between 0.99 and 1.10). The other three evaluated PVC algorithms have demonstrated to be more suitable for subcortical regions with MG-PVC and mMG-PVC being less prone to the largest tissue misclassification error simulated in this study. Except for M-PVC, quantification accuracy of Ki for CN and PUT was clearly improved by PVC. CONCLUSIONS: The regional activity value of PUT was appreciably overcorrected by most of the PVC approaches employing FSL or SPM segmentation, revealing the importance of accurate MR image segmentation for the presented PVC framework. The selection of a PVC approach should be adapted to the anatomical structure of interest. Caution is recommended in subsequent interpretation of Ki values. The possible different change of activity concentrations due to PVC in both target and reference regions tends to alter the corresponding TACs, introducing bias to Ki determination. The accuracy of quantitative analysis was improved by PVC but at the expense of precision reduction, indicating the potential impropriety of applying the presented framework for group comparison studies.

123I-iodobenzamide SPECT is not an independent predictor of dopaminergic responsiveness in patients with suspected atypical parkinsonian syndromes.

UNLABELLED: The prediction of dopaminergic responsiveness in patients with parkinsonism is desirable for effective treatment strategies. We investigated whether striatal dopamine D2/D3 receptor (D2R) binding assessed by (123)I-iodobenzamide SPECT is an independent predictor of dopaminergic responsiveness in patients with parkinsonism. METHODS: Seventy-eight patients with clinically suspected atypical parkinsonian syndrome (APS) were prospectively recruited for imaging. To quantify striatal D2R binding, (123)I-iodobenzamide SPECT datasets were subjected to an observer-independent, regions-of-interest analysis. A final clinical diagnosis of Lewy-body disease (LBD) or APS was made after a mean follow-up of 12 mo. On the basis of follow-up data, dopaminergic responsiveness was classified as 0 (none), 1 (transient), 2 (sustained mild), or 3 (sustained strong). Uni- and multivariate analyses of the relationship between treatment response, D2R binding, and confounding variables were conducted. RESULTS: Sixty patients with clinically verified LBD (n = 28; 22/28 with Parkinson disease) or APS (n = 32), in whom dopaminergic responsiveness could be assessed (n = 19/13/15/13 in categories 0/1/2/3; 18 were excluded because of insufficient dosing), were included in the statistical analysis. Univariate analyses revealed that a sustained treatment response was significantly associated with higher D2R binding, clinical diagnosis of LBD, lower Hoehn and Yahr scores, and younger age. After multivariate correction of D2R binding for diagnosis, age, symptom duration, Hoehn and Yahr score, and dopaminergic pretreatment, no association was found between D2R binding and treatment response, either in the pooled group or in LBD or APS subgroups. CONCLUSION: Striatal D2R binding assessed by (123)I-iodobenzamide SPECT does not provide additional predictive information about treatment response beyond other clinical variables, most notably the clinical diagnosis.

Quantitative myocardial perfusion-SPECT: algorithm-specific influence of reorientation on calculation of summed stress score.

PURPOSE: Myocardial perfusion SPECT (MPS) with software-assisted determination of summed stress score (SSS) is of established importance for diagnosis/therapy planning in coronary artery disease. Differences in contour finding suggest algorithm-specific influence on quantification if heart axes are chosen incorrectly. Thus, this study quantified the influence of heart-axis tilt on SSS calculation using Quantitative Perfusion SPECT and 4D-MSPECT. PATIENTS AND METHODS: Stress MPS of 50 men acquired on a triple-head gamma camera were correctly reoriented by experienced technologists (R0) and then tilted by 5 degrees/10 degrees/15 degrees/20 degrees/30 degrees/45 degrees along both long axes (R5-R45). SPECT images were quantified for SSS using QPS and 4D-MSPECT. SSS values for R0 and R5-R45 were analyzed using correlation analysis. Weighted kappa values (κ) were calculated to measure agreement regarding perfusion abnormality severity (4-step SSS rating: 0-3, 4-8, 9-13, and ≥14). RESULTS: For QPS SSS correlation, R0 vs. tilted datasets remained very high (R > 0.97) up to 20 degrees, but degraded for higher tilts (R = 0.895/0.780 for 30 degrees/45 degrees). 4D-MSPECT showed comparable SSS correlation only up to 10 degrees (R > 0.95) and strong deterioration thereafter (R = 0.863-0.347 for 15-45 degrees). Deviation in severity class from R0 increased from 6/50 (R5; κ = 0.914) to 25/50 (R45; κ = 0.252) using QPS and from 7/50 (R5; κ = 0.899) to 33/50 (R45; κ = 0.065) using 4D-MSPECT. CONCLUSION: For tilted MPS datasets, considerable differences in SSS calculation emerge using QPS and 4D-MSPECT. QPS showed more stable results than 4D-MSPECT.

Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET.

UNLABELLED: Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. (18)F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ((18)F-CPFPX) has been established as a highly selective and affine PET ligand for the A(1) adenosine receptor (A(1)AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A(1)AR by caffeine using (18)F-CPFPX and PET. METHODS: Fifteen subjects (age range, 24-68 y) underwent a 140-min bolus-plus-constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (V(T)) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5-4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy V(T) of the A(1)AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. RESULTS: Caffeine displaced 5%-44% of (18)F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Half-maximal displacement was achieved at a plasma caffeine concentration of 67 µM, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. CONCLUSION: Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A(1)AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that (18)F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.

[¹8F]FDG-PET is superior to [¹²³I]IBZM-SPECT for the differential diagnosis of parkinsonism.

OBJECTIVE: Imaging of regional cerebral glucose metabolism with PET and striatal dopamine D2/D3 receptors (D2R) with SPECT improves the differential diagnosis of parkinsonism. We prospectively investigated 1) the diagnostic merits of these approaches in differentiating between Lewy body diseases (LBD; majority Parkinson disease [PD]) and atypical parkinsonian syndromes (APS); 2) the diagnostic value of [¹8F]fluorodeoxyglucose (FDG)-PET to differentiate among APS subgroups. METHODS: Ninety-five of 107 consecutive patients with clinically suspected APS referred for imaging were recruited. [¹8F]FDG-PET scans were analyzed by visual assessment (including individual voxel-based statistical maps). Based on a priori defined disease-specific patterns, patients with putative APS were differentiated from LBD (first level) and allocated to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD) (second level). [¹²³I] iodobenzamide (IBZM)-SPECT datasets were subjected to an observer-independent regions-of-interest analysis to assess striatal D2R availability. Movement disorder specialists made final clinical diagnoses after a median follow-up time of 12 months. RESULTS: Seventy-eight patients with clinically verified APS (n = 44) or LBD (n = 34) were included in the statistical analysis. The area under the receiver operating characteristic curve for discrimination between APS and LBD was significantly larger for [¹8F]FDG-PET (0.94) than for [¹²³I]IBZM-SPECT (0.74; p = 0.0006). Sensitivity/specificity of [¹8F]FDG-PET for diagnosing APS was 86%/91%, respectively. Sensitivity/specificity of [¹8F]FDG-PET in identifying APS subgroups was 77%/97% for MSA, 74%/95% for PSP, and 75%/92% for CBD. CONCLUSIONS: The diagnostic accuracy of [¹8F]FDG-PET for discriminating LBD from APS is considerably higher than for [¹²³I]IBZM-SPECT. [¹8F]FDG-PET reliably differentiates APS subgroups.

Image quality and data quantification in dopamine transporter SPECT: advantage of 3-dimensional OSEM reconstruction?

PURPOSE: Reconstruction of striatal dopamine transporter (DAT) SPECT is commonly done by filtered back projection (FBP). We investigated if image reconstruction by 3-dimensional ordered-subset expectation maximization (3D-OSEM) with resolution recovery, which has recently become available for clinical routine, provides a relevant improvement. METHODS: I-FP-CIT SPECT studies of 18 patients with normal to severely decreased DAT binding were reconstructed by FBP, 2D-OSEM (without resolution recovery), and 3D-OSEM, each with 2 different filter settings, yielding 3 data set pairs of relatively low and high resolution and noise: FBP with seventh-order Butterworth filter [cutoff frequency, 0.36 Nyquist (FBPlow) and 0.45 Nyquist (FBPhigh)] and OSEM with 8 iterations and 8 subsets (2D-/3D-OSEMlow) and 6 iterations and 16 subsets (2D-/3D-OSEMhigh), each with 8-mm Gaussian filtering. Mean regional counts, variability of counts (coefficient of variation), and binding potential (BPND) were assessed by volume-of-interest analyses of the caudate nucleus, the putamen, and the occipital cortex (reference region). RESULTS: On visual inspection, both 2D- and 3D-OSEM-reconstructed images showed an optimal delineation of striatal structures, whereas variability (noise) of nonspecific cortical I-FP-CIT uptake was lowest (most homogenous) with FBPlow, slightly higher with 2D-/3D-OSEMlow, and notably higher for the other methods. Volume-of-interest analyses revealed no significant differences of counts in the occipital reference region in comparison to FBPlow (reference method). In caudate nucleus, counts and, consequently, BPND values increased significantly with FBPhigh (mean BPND change, +5.2%), 2D-OSEMlow/high (+3.7%/+6.2%), and, most notably, 3D-OSEMlow/high (+11.1%/+14.0%). In the putamen, this effect was less pronounced for FBPhigh (+1.8%) and 3D-OSEMlow/high (+5.6%/+6.8%) and failed to reach statistical significance for 2D-OSEMlow/high (-0.2%/+0.8%). Regression analyses indicated excellent correlations of BPND between FBPlow and all other methods (R > 0.97), with the highest regression slopes for 3D-OSEM (1.12-1.16) followed by FBPhigh (1.04-1.06) and then 2D-OSEM (1.01-1.04). The order of the variability of counts in the occipital cortex was as follows: FBPlow (12.5%), 2D-OSEMlow (13.9%), 3D-OSEMlow (14.2%), FBPhigh (15.1%), 2D-OSEMhigh (17.0%), and 3D-OSEMhigh (17.6%). CONCLUSIONS: Three-dimensional OSEM considerably improves DAT SPECT reconstruction by offering an optimal combination of high-resolution delineation of striatal structures, superior recovery of signal and BPND, and sufficiently homogeneous nonspecific tracer uptake of the reference region.

A phantom assessment of portable imaging and radio-guided surgery systems with technetium-99m and fluorine-18.

AIM: To perform a detailed analysis of the performance of mobile intraoperative imaging systems and gamma probes in a phantom set-up, and compare this with a conventional gamma camera. METHODS: Two separate experiments were performed. In the first, a modified Jaszczak phantom equipped with five (99m)Tc-filled hot spheres (0.5-20 ml) was analyzed using Sentinella, declipseSPECT and a conventional gamma camera under three conditions: no background, spheres on the surface of the background activity, and totally immersed spheres (contrast level in both 1: 8). In the second experiment, two phantom spheres (0.5 and 2 ml) filled with (99m)Tc and (18)F (infinite contrast, 1: 4 and 1: 8) were measured using the hand-held probes Navigator and GammaLocator DXI. Data analysis consisted of signal-to-background ratios and determination of the full-width at half-maximum (FWHM). A visual scoring was performed by three nuclear medicine physicians. RESULTS: At infinite contrast, (99m)Tc-filled spheres with volumes of at least 2 ml could be detected adequately with all systems (e.g. 2 ml sphere, FWHM: ECAM 11 mm, declipseSPECT 9 mm, Navigator 13 mm, GammaLocator 12 mm). Under decreased contrast conditions, the results for all systems were impaired and the 0.5 ml phantom sphere filled with either (99m)Tc or (18)F was only detected accurately by the GammaLocator (FWHM range: 13-17 mm). CONCLUSION: All systems are suitable for intraoperative sentinel node detection with nearly infinite signal-to-background contrast. At a lower contrast, the GammaLocator performed best for the detection of small volumes at low-contrast ratios regardless of the radionuclide.

Dose-escalation using intensity-modulated radiotherapy for prostate cancer - evaluation of quality of life with and without (18)F-choline PET-CT detected simultaneous integrated boost.

BACKGROUND: In comparison to the conventional whole-prostate dose escalation, an integrated boost to the macroscopic malignant lesion might potentially improve tumor control rates without increasing toxicity. Quality of life after radiotherapy (RT) with vs. without (18)F-choline PET-CT detected simultaneous integrated boost (SIB) was prospectively evaluated in this study. METHODS: Whole body image acquisition in supine patient position followed 1 h after injection of 178-355MBq (18)F-choline. SIB was defined by a tumor-to-background uptake value ratio > 2 (GTV(PET)). A dose of 76Gy was prescribed to the prostate (PTV(prostate)) in 2Gy fractions, with or without SIB up to 80Gy. Patients treated with (n = 46) vs. without (n = 21) SIB were surveyed prospectively before (A), at the last day of RT (B) and a median time of two (C) and 19 month (D) after RT to compare QoL changes applying a validated questionnaire (EPIC - expanded prostate cancer index composite). RESULTS: With a median cut-off standard uptake value (SUV) of 3, a median GTV(PET) of 4.0 cm(3) and PTV(boost) (GTV(PET) with margins) of 17.3 cm(3) was defined. No significant differences were found for patients treated with vs. without SIB regarding urinary and bowel QoL changes at times B, C and D (mean differences ≤3 points for all comparisons). Significantly decreasing acute urinary and bowel score changes (mean changes > 5 points in comparison to baseline level at time A) were found for patients with and without SIB. However, long-term urinary and bowel QoL (time D) did not differ relative to baseline levels - with mean urinary and bowel function score changes < 3 points in both groups (median changes = 0 points). Only sexual function scores decreased significantly (> 5 points) at time D. CONCLUSIONS: Treatment planning with (18)F-choline PET-CT allows a dose escalation to a macroscopic intraprostatic lesion without significantly increasing toxicity.

Quantification of left ventricular volumes and ejection fraction from gated 99mTc-MIBI SPECT: MRI validation of the EXINI heart software package.

UNLABELLED: The aim of the study was to validate the accuracy of the EXINI heart software (EXINI) package in assessing left ventricular end-diastolic/systolic volumes (EDV, ESV) and ejection fraction (LVEF) from gated (99m)Tc-MIBI single-photon emission tomography (SPECT). Cardiac magnetic resonance imaging (cMRI) was used as reference. Furthermore, effects of perfusion defects and image quality in SPECT on correlation between gated SPECT and magnetic resonance imaging were investigated. METHODS: Seventy patients were examined using gated SPECT (rest study, eight gates per cardiac cycle). EDV, ESV and LVEF were calculated from gated SPECT using EXINI. Directly before or after SPECT, cMRI (20 gates cardiac per cycle) was performed. EDV, ESV and LVEF were calculated using Simpson's rule. Perfusion defects were quantified using the summed-rest-score (SRS). Total number of myocardial counts were used to rate image quality. RESULTS: Correlation between results of gated SPECT and cMRI was high for EDV (R = 0.89) and ESV (R = 0.94) and good for LVEF (R = 0.78). ESV (EXINI 54 +/- 31 ml versus cMRI 57 +/- 34 ml) and LVEF (EXINI 62.9 +/- 11.7% versus cMRI 60.6 +/- 13.9%) did not differ significantly whereas EXINI overestimated EDV significantly compared with cMRI (EXINI 144 +/- 41 ml versus cMRI 137 +/- 36 ml; P<0.005). No correlation was found between absolute differences of the results given by gated SPECT and cMRI and SRS or total myocardial counts (R < 0.18). CONCLUSION: End-diastolic volume, ESV and LVEF calculated from gated SPECT using EXINI agree with cMRI over a wide range of values. Correlation between both the methods was good for EDV and ESV, and acceptable for LVEF. No relevant influence of image quality or SRS on the accuracy of EXINI results was found.

Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release.

The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [(11)C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [(11)C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.

Gated myocardial perfusion SPECT: algorithm-specific influence of reorientation on calculation of left ventricular volumes and ejection fraction.

UNLABELLED: Gated myocardial perfusion SPECT allows calculation of end-diastolic and end-systolic volumes (EDV and ESV, respectively) and left ventricular ejection fraction (LVEF). The quantification algorithms QGS (quantitative gated SPECT), 4D-MSPECT, and CARE heart show a good correlation with cardiac MRI. Nevertheless, differences in contour finding suggest algorithm-specific effects if heart axes vary. The effect of tilting heart axes on gated SPECT was quantified as a possible source of error. METHODS: Sixty men underwent gated SPECT (450 MBq of (99m)Tc-tetrofosmin or sestamibi, 8 gates/cycle). After correct reorientation (R(0)), datasets were tilted by 5 degrees , 10 degrees , 15 degrees , 20 degrees , 30 degrees , and 45 degrees along both long axes (R(5), R(10), R(15), R(20), R(30), and R(45), respectively). EDV, ESV, and LVEF were calculated using QGS, 4D-MSPECT, and CARE heart. Because a 15 degrees tilt could be a maximum possible misreorientation in routine, R(0) and R(15) results were analyzed in detail. Absolute-difference values between results of tilted and correctly reoriented datasets were calculated for all tilts and algorithms. RESULTS: QGS and CARE heart succeeded for R(0) and R(15) in all cases, whereas 4D-MSPECT failed to find the basal plane in 1 case (patient B). R(2) values between paired R(15)/R(0) results were 0.992 (QGS), 0.796 (4D-MSPECT; R(2) = 0.919 in n = 59 after exclusion of the failed case), and 0.916 (CARE heart) for EDV; 0.994 (QGS), 0.852 (4D-MSPECT; R(2) = 0.906 in n = 59), and 0.899 (CARE heart) for ESV; and 0.988 (QGS), 0.814 (4D-MSPECT; R(2) = 0.810 in n = 59), and 0.746 (CARE heart) for LVEF. Concerning all levels of misreorientation, 1 patient was excluded for all algorithms because of multiple problems in contour finding; additionally for 4D-MSPECT patient B was excluded. In the 45 degrees group, QGS succeeded in 58 of 59 cases, 4D-MSPECT in 58 of 58, and CARE heart in 33 of 59. Mean absolute differences for EDV ranged from 5.1 +/- 4.1 to 12.8 +/- 10.5 mL for QGS, from 6.7 +/- 6.3 to 34.2 +/- 20.7 mL for 4D-MSPECT, and from 5.4 +/- 5.6 to 25.2 +/- 16.1 mL for CARE heart (tilts between 5 degrees and 45 degrees ). Mean absolute differences for ESV ranged from 4.1 +/- 3.7 to 8.0 +/- 9.4 mL for QGS, from 5.6 +/- 8.0 to 10.0 +/- 10.5 mL for 4D-MSPECT, and from 5.4 +/- 5.6 to 25.5 +/- 16.1 mL for CARE heart. Mean absolute differences for LVEF ranged from 1.1% +/- 1.0% to 2.2% +/- 1.8% for QGS, from 4.0% +/- 3.5% to 8.0% +/- 7.1% for 4D-MSPECT, and from 3.4% +/- 2.9% to 9.2% +/- 6.0% for CARE heart. CONCLUSION: Despite tilted heart axes, QGS showed stable results even when using tilts up to 45 degrees . 4D-MSPECT and CARE heart results varied with reorientation of the heart axis, implying that published validation results apply to correctly reoriented data only.