Publisher Correction: In vitro imaging of bacteria using 18F-fluorodeoxyglucose micro positron emission tomography.

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RaCaT: An open source and easy to use radiomics calculator tool.

PURPOSE: The widely known field 'Radiomics' aims to provide an extensive image based phenotyping of e.g. tumors using a wide variety of feature values extracted from medical images. Therefore, it is of utmost importance that feature values calculated by different institutes follow the same feature definitions. For this purpose, the imaging biomarker standardization initiative (IBSI) provides detailed mathematical feature descriptions, as well as (mathematical) test phantoms and corresponding reference feature values. We present here an easy to use radiomic feature calculator, RaCaT, which provides the calculation of a large number of radiomic features for all kind of medical images which are in compliance with the standard. METHODS: The calculator is implemented in C++ and comes as a standalone executable. Therefore, it can be easily integrated in any programming language, but can also be called from the command line. No programming skills are required to use the calculator. The software architecture is highly modularized so that it is easily extendible. The user can also download the source code, adapt it if needed and build the calculator from source. The calculated feature values are compliant with the ones provided by the IBSI standard. Source code, example files for the software configuration, and documentation can be found online on GitHub (https://github.com/ellipfaehlerUMCG/RaCat). RESULTS: The comparison with the standard values shows that all calculated features as well as image preprocessing steps, comply with the IBSI standard. The performance is also demonstrated on clinical examples. CONCLUSIONS: The authors successfully implemented an easy to use Radiomics calculator that can be called from any programming language or from the command line. Image preprocessing and feature settings and calculations can be adjusted by the user.

Repeatability of 18 F-FDG PET radiomic features: A phantom study to explore sensitivity to image reconstruction settings, noise, and delineation method.

BACKGROUND: 18 F-fluoro-2-deoxy-D-Glucose positron emission tomography (18 F-FDG PET) radiomics has the potential to guide the clinical decision making in cancer patients, but validation is required before radiomics can be implemented in the clinical setting. The aim of this study was to explore how feature space reduction and repeatability of 18 F-FDG PET radiomic features are affected by various sources of variation such as underlying data (e.g., object size and uptake), image reconstruction methods and settings, noise, discretization method, and delineation method. METHODS: The NEMA image quality phantom was scanned with various sphere-to-background ratios (SBR), simulating different activity uptakes, including spheres with low uptake, that is, SBR smaller than 1. Furthermore, images of a phantom containing 3D printed inserts reflecting realistic heterogeneity uptake patterns were acquired. Data were reconstructed using various matrix sizes, reconstruction algorithms, and scan durations (noise). For every specific reconstruction and noise level, ten statistically equal replicates were generated. The phantom inserts were delineated using CT and PET-based segmentation methods. A total of 246 radiomic features was extracted from each image dataset. Images were discretized with a fixed number of 64 bins (FBN) and a fixed bin width (FBW) of 0.25 for the high and a FBW of 0.05 for the low uptake data. In terms of feature reduction, we determined the impact of these factors on the composition of feature clusters, which were defined on the basis of Spearman's correlation matrices. To assess feature repeatability, the intraclass correlation coefficient was calculated over the ten replicates. RESULTS: In general, larger spheres with high uptake resulted in better repeatability compared to smaller low uptake spheres. In terms of repeatability, features extracted from heterogeneous phantom inserts were comparable to features extracted from bigger high uptake spheres. For example, for an EARL-compliant reconstruction, larger and smaller high uptake spheres yielded good repeatability for 32% and 30% of the features, while the heterogeneous inserts resulted in 34% repeatable features. For the low uptake spheres, this was the case for 22% and 20% of the features for bigger and smaller spheres, respectively. Images reconstructed with point-spread-function (PSF) resulted in the highest repeatability when compared with OSEM or time-of-flight, for example, 53%, 30%, and 32% of repeatable features, respectively (for unsmoothed data, discretized with FBN, 300 s scan duration). Reducing image noise (increasing scan duration and smoothing) and using CT-based segmentation for the low uptake spheres yielded improved repeatability. FBW discretization resulted in higher repeatability than FBN discretization, for example, 89% and 35% of the features, respectively (for the EARL-compliant reconstruction and larger high uptake spheres). CONCLUSION: Feature space reduction and repeatability of 18 F-FDG PET radiomic features depended on all studied factors. The high sensitivity of PET radiomic features to image quality suggests that a high level of image acquisition and preprocessing standardization is required to be used as clinical imaging biomarker.

SMART (SiMulAtion and ReconsTruction) PET: an efficient PET simulation-reconstruction tool.

BACKGROUND: Positron-emission tomography (PET) simulators are frequently used for development and performance evaluation of segmentation methods or quantitative uptake metrics. To date, most PET simulation tools are based on Monte Carlo simulations, which are computationally demanding. Other analytical simulation tools lack the implementation of time of flight (TOF) or resolution modelling (RM). In this study, a fast and easy-to-use PET simulation-reconstruction package, SiMulAtion and ReconsTruction (SMART)-PET, is developed and validated, which includes both TOF and RM. SMART-PET, its documentation and instructions to calibrate the tool to a specific PET/CT system are available on Zenodo. SMART-PET allows the fast generation of 3D PET images. As input, it requires one image representing the activity distribution and one representing the corresponding CT image/attenuation map. It allows the user to adjust different parameters, such as reconstruction settings (TOF/RM), noise level or scan duration. Furthermore, a random spatial shift can be included, representing patient repositioning. To evaluate the tool, simulated images were compared with real scan data of the NEMA NU 2 image quality phantom. The scan was acquired as a 60-min list-mode scan and reconstructed with and without TOF and/or RM. For every reconstruction setting, ten statistically equivalent images, representing 30, 60, 120 and 300 s scan duration, were generated. Simulated and real-scan data were compared regarding coefficient of variation in the phantom background and activity recovery coefficients (RCs) of the spheres. Furthermore, standard deviation images of each of the ten statistically equivalent images were compared. RESULTS: SMART-PET produces images comparable to actual phantom data. The image characteristics of simulated and real PET images varied in similar ways as function of reconstruction protocols and noise levels. The change in image noise with variation of simulated TOF settings followed the theoretically expected behaviour. RC as function of sphere size agreed within 0.3-11% between simulated and actual phantom data. CONCLUSIONS: SMART-PET allows for rapid and easy simulation of PET data. The user can change various acquisition and reconstruction settings (including RM and TOF) and noise levels. The images obtained show similar image characteristics as those seen in actual phantom data.

Comparative biodistribution analysis across four different 89Zr-monoclonal antibody tracers-The first step towards an imaging warehouse.

Rationale: Knowledge on monoclonal antibody biodistribution in healthy tissues in humans can support clinical drug development. Molecular imaging with positron emission tomography (PET) can yield information in this setting. However, recent imaging studies have analyzed the behavior of single antibodies only, neglecting comparison across different antibodies. Methods: We compared the distribution of four 89Zr-labeled antibodies in healthy tissue in a retrospective analysis based on the recently published harmonization protocol for 89Zr-tracers and our delineation protocol. Results: The biodistribution patterns of 89Zr-lumretuzumab, 89Zr-MMOT0530A, 89Zr-bevacizumab and 89Zr-trastuzumab on day 4 after tracer injection were largely similar. The highest tracer concentration was seen in healthy liver, spleen, kidney and intestines. About one-third of the injected tracer dose was found in the circulation, up to 15% in the liver and only 4% in the spleen and kidney. Lower tracer concentration was seen in bone marrow, lung, compact bone, muscle, fat and the brain. Despite low tracer accumulation per gram of tissue, large-volume tissues, especially fat, can influence overall distribution: On average, 5-7% of the injected tracer dose accumulated in fat, with a peak of 19% in a patient with morbid obesity. Conclusion: The similar biodistribution of the four antibodies is probably based on their similar molecular structure, binding characteristics and similar metabolic pathways. These data provide a basis for a prospectively growing, online accessible warehouse of molecular imaging data, which enables researchers to increase and exchange knowledge on whole body drug distribution and potentially supports drug development decisions.

In vitro imaging of bacteria using 18F-fluorodeoxyglucose micro positron emission tomography.

Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (18F-FDG) can be applied to detect infection and inflammation. However, it was so far not known to what extent bacterial pathogens may contribute to the PET signal. Therefore, we investigated whether clinical isolates of frequently encountered bacterial pathogens take up 18F-FDG in vitro, and whether FDG inhibits bacterial growth as previously shown for 2-deoxy-glucose. 22 isolates of Gram-positive and Gram-negative bacterial pathogens implicated in fever and inflammation were incubated with 18F-FDG and uptake of 18F-FDG was assessed by gamma-counting and µPET imaging. Possible growth inhibition by FDG was assayed with Staphylococcus aureus and the Gram-positive model bacterium Bacillus subtilis. The results show that all tested isolates accumulated 18F-FDG actively. Further, 18F-FDG uptake was hampered in B. subtilis pts mutants impaired in glucose uptake. FDG inhibited growth of S. aureus and B. subtilis only to minor extents, and this effect was abrogated by pts mutations in B. subtilis. These observations imply that bacteria may contribute to the signals observed in FDG-PET infection imaging in vivo. Active bacterial FDG uptake is corroborated by the fact that the B. subtilis phosphotransferase system is needed for 18F-FDG uptake, while pts mutations protect against growth inhibition by FDG.

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors.

Purpose: We evaluated biodistribution and tumor targeting of 89Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received 89Zr-lumretuzumab and underwent positron emission tomography (PET). In part A, 89Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results: Optimal PET conditions were found to be 4 and 7 days after administration of 89Zr-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5), and 24.6% (±20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab.Conclusions: PET imaging showed biodistribution and tumor-specific 89Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. Clin Cancer Res; 23(20); 6128-37. ©2017 AACR.

In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey.

11C-preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aimed to evaluate the suitability of 11C-preladenant PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. Methods:11C-preladenant was intravenously injected into conscious monkeys (n = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (VT) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BPND) in A2AR-rich regions. BPND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BPND and DVR-1 were investigated. VT and BPND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A2AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A2AR occupancy was studied with caffeine blockade. Results: Regional uptake of 11C-preladenant was consistent with the distribution of A2ARs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on k4 to stabilize fits. The highest VT was observed in A2AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3). BPND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in A2AR-rich regions). Preladenant preinjection decreased the tracer uptake in A2AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. Conclusion:11C-preladenant PET is suitable for noninvasive quantification of A2ARs and assessment of A2AR occupancy in A2AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A2AR quantification.

In vivo evaluation of [11C]preladenant positron emission tomography for quantification of adenosine A2A receptors in the rat brain.

[11C]Preladenant was developed as a novel adenosine A2A receptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [11C]preladenant positron emission tomography for the quantification of striatal A2A receptor density and the assessment of striatal A2A receptor occupancy by KW-6002. Sixty- or ninety-minute dynamic positron emission tomography imaging was performed on rats. Tracer kinetics was quantified by the two-tissue compartment model, Logan graphical analysis and several reference tissue-based models. Test-retest reproducibility was assessed by repeated imaging on two consecutive days. Two-tissue compartment model and Logan plot estimated comparable distribution volume ( VT) values of ∼10 in the A2A receptor-rich striatum and substantially lower values in all extra-striatal regions (∼1.5-2.5). The simplified reference tissue model with midbrain or occipital cortex as the reference region proved to be the best non-invasive model for quantification of A2A receptor, showing a striatal binding potential ( BPND) value of ∼5.5, and a test-retest variability of ∼5.5%. The brain metabolite analysis showed that at 60-min post injection, 17% of the radioactivity in the brain was due to radioactive metabolites. The ED50 of KW-6002 in rat striatum for i.p. injection was 0.044-0.062 mg/kg. The study demonstrates that [11C]preladenant is a suitable tracer to quantify striatal A2A receptor density and assess A2A receptor occupancy by A2A receptor-targeting molecules.

Radiation Dosimetry of a Novel Adenosine A2A Receptor Radioligand [11C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats.

PURPOSE: [11C]Preladenant was developed as a novel adenosine A2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [11C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats. PROCEDURES: Male Wistar rats (n = 35) were i.v. injected with [11C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty volumes of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical reference. The dynamic time-activity curves were used to calculate organ residence times (RTs). Human radiation dosimetry estimates, derived from rat data, were calculated with OLINDA/EXM 1.1. RESULTS: PET-imaging and organ-harvesting estimated comparable organ RTs, with differences of 6-27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, respectively. The critical organ was the small intestine with a dose of 25 µSv/MBq. The effective doses (EDs) calculated from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 µSv/MBq, respectively, using the International Commission on Radiological Protection 60 tissue weighting factors. CONCLUSIONS: The ED of [11C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estimation of the radiation dosimetry of [11C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the number of laboratory animals required.

Effects of Radioiodine Treatment on Salivary Gland Function in Patients with Differentiated Thyroid Carcinoma: A Prospective Study.

Complaints of a dry mouth (xerostomia) and sialoadenitis are frequent side effects of radioiodine treatment in differentiated thyroid cancer (DTC) patients. However, detailed prospective data on alterations in salivary gland functioning after radioiodine treatment (131I) are scarce. Therefore, the primary aim of this study was to prospectively assess the effect of high-activity radioiodine treatment on stimulated whole saliva flow rate. Secondary aims were to study unstimulated whole and stimulated glandular (i.e., parotid and submandibular) saliva flow rate and composition alterations, development of xerostomia, characteristics of patients at risk for salivary gland dysfunction, and whether radioiodine uptake in salivary glands on diagnostic scans correlates to flow rate alterations. METHODS: In a multicenter prospective study, whole and glandular saliva were collected both before and 5 mo after radioiodine treatment. Furthermore, patients completed the validated xerostomia inventory. Alterations in salivary flow rate, composition, and xerostomia inventory score were analyzed. Salivary gland radioiodine uptake on diagnostic scans was correlated with saliva flow rate changes after radioiodine treatment. RESULTS: Sixty-seven patients (mean age ± SD, 48 ± 17 y; 63% women, 84% underwent ablation therapy) completed both study visits. Stimulated whole saliva flow rate decreased after ablation therapy (from 0.92 [interquartile range, 0.74-1.25] to 0.80 [interquartile range, 0.58-1.18] mL/min, P = 0.003), as well as unstimulated whole- and stimulated glandular flow rates (P < 0.05). The concentration of salivary electrolytes was similar at both study visits, whereas the output of proteins, especially amylase (P < 0.05), was decreased. The subjective feeling of dry mouth increased (P = 0.001). Alterations in saliva flow rate were not associated with semiquantitatively assessed radioiodine uptake in salivary glands on diagnostic scans. For the small cohort of patients undergoing repeated radioiodine therapy, we could not demonstrate alterations in salivary parameters. CONCLUSION: We prospectively showed that salivary gland function is affected after high-activity radioiodine ablation therapy in patients with DTC. Therefore, more emphasis should be placed on salivary gland dysfunction during follow-up for DTC patients receiving high-activity radioiodine treatment.

89Zr-Bevacizumab PET Visualizes Disease Manifestations in Patients with von Hippel-Lindau Disease.

UNLABELLED: Patients with von Hippel-Lindau disease (VHL) are at risk to develop multiple tumors. The growth of lesions is unpredictable, and regular surveillance is critical for early treatment to control local damage. Vascular endothelial growth factor A (VEGF-A) produced locally is supposed to play an important role in development of disease manifestations and is a target for antiangiogenic therapy with the monoclonal antibody bevacizumab. We aimed to assess whether VHL manifestations can be visualized with (89)Zr-bevacizumab PET and to explore whether (89)Zr-bevacizumab PET can differentiate progressive from nonprogressive lesions. METHODS: VHL patients with at least 1 measurable hemangioblastoma were eligible. (89)Zr-bevacizumab (37 MBq) was administered intravenously 4 d before the scan. Maximum standardized uptake values were calculated. PET scans were fused with routine MRI of the central nervous system and abdominal MRI or CT. Progressive lesions were defined as new lesions, lesions that became symptomatic, and lesions ≥ 10 mm that increased ≥ 10% and ≥ 4 mm on repeated anatomic imaging within 12 mo. RESULTS: Twenty-two patients were enrolled. At baseline, anatomic imaging showed 311 lesions. (89)Zr-bevacizumab PET visualized 59 VHL manifestations, 0-17 per patient. The median of maximum standardized uptake values was 8.5 (range, 1.3-35.8). The detection rate for lesions ≥ 10 mm was 30.8%. Seven additional hotspots without substrate on baseline anatomic imaging were found; 2 were also detected with anatomic imaging during follow-up. Nine of 25 progressive lesions were visible on PET and 27 of 175 nonprogressive lesions, corresponding to a positive predictive value of 25% and a negative predictive value of 90%. SUVmax was similar in progressive and nonprogressive lesions (median, 4.8; range, 0.9-8.9 vs. median, 6.7; range, 1.3-35.8, P = 0.14). CONCLUSION: VHL manifestations can be visualized with (89)Zr-bevacizumab PET with a striking heterogeneity in tracer accumulation. (89)Zr-bevacizumab uptake does not predict progression within 12 mo. In one third of the lesions, the drug target VEGF is available and accessible. (89)Zr-bevacizumab PET might offer a tool to select VHL patients for anti-VEGF therapy.

ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody-Drug Conjugate Treatment.

PURPOSE: Mesothelin (MSLN) is frequently overexpressed in pancreatic and ovarian cancers, making it a potential drug target. We performed an (89)Zr-PET imaging study with MMOT0530A, a MSLN antibody, in conjunction with a phase I study with the antibody-drug conjugate DMOT4039A, containing MMOT0530A bound to MMAE. The aim was to study antibody tumor uptake, whole-body distribution, and relation between uptake, response to treatment, and MSLN expression. EXPERIMENTAL DESIGN: Before DMOT4039A treatment, patients received 37 MBq (89)Zr-MMOT0530A followed by PET/CT imaging 2, 4, and 7 days postinjection. Tracer uptake was expressed as standardized uptake value (SUV). MSLN expression was determined with immunohistochemistry (IHC) on archival tumor tissue. RESULTS: Eleven patients were included, 7 with pancreatic and 4 with ovarian cancer. IHC MSLN expression varied from absent to strong. Suitable tracer antibody dose was 10 mg MMOT0530A and optimal imaging time was 4 and 7 days postinjection. Tumor tracer uptake occurred in 37 lesions with mean SUVmax of 13.1 (±7.5) on PET 4 days postinjection, with 11.5 (±7.5) in (N= 17) pancreatic and 14.5 (±8.7) in (N= 20) ovarian cancer lesions. Within patients, a mean 2.4-fold (±1.10) difference in uptake between tumor lesions existed. Uptake in blood, liver, kidneys, spleen, and intestine reflected normal antibody distribution. Tracer tumor uptake was correlated to IHC. Best response to DMOT4039A was partial response in one patient. CONCLUSIONS: With (89)Zr-MMOT0530A-PET, pancreatic and ovarian cancer lesions as well as antibody biodistribution could be visualized. This technique can potentially guide individualized antibody-based treatment.

89Zr-bevacizumab PET visualizes heterogeneous tracer accumulation in tumor lesions of renal cell carcinoma patients and differential effects of antiangiogenic treatment.

UNLABELLED: No validated predictive biomarkers for antiangiogenic treatment of metastatic renal cell carcinoma (mRCC) exist. Tumor vascular endothelial growth factor A (VEGF-A) level may be useful. We determined tumor uptake of (89)Zr-bevacizumab, a VEGF-A-binding PET tracer, in mRCC patients before and during antiangiogenic treatment in a pilot study. METHODS: Patients underwent (89)Zr-bevacizumab PET scans at baseline and 2 and 6 wk after initiating either bevacizumab (10 mg/kg every 2 wk) with interferon-α (3-9 million IU 3 times/wk) (n = 11) or sunitinib (50 mg daily, 4 of every 6 wk) (n = 11). Standardized uptake values were compared with plasma VEGF-A and time to disease progression. RESULTS: (89)Zr-bevacizumab PET scans visualized 125 evaluable tumor lesions in 22 patients, with a median SUV(max) (maximum standardized uptake value) of 6.9 (range, 2.3-46.9). Bevacizumab/interferon-α induced a mean change in tumor SUV(max) of -47.0% (range, -84.7 to +20.0%; P < 0.0001) at 2 wk and an additional -9.7% (range, -44.8 to +38.9%; P = 0.015) at 6 wk. In the sunitinib group, the mean change in tumor SUV(max) was -14.3% at 2 wk (range, -80.4 to +269.9; P = 0.006), but at 6 wk the mean change in tumor SUV(max) was +72.6% (range, -46.4 to +236%; P < 0.0001) above baseline. SUV(max) was not related to plasma VEGF-A at all scan moments. A baseline mean tumor SUV(max) greater than 10.0 in the 3 most intense lesions corresponded with longer time to disease progression (89.7 vs. 23.0 wk; hazard ratio, 0.22; 95% confidence interval, 0.05-1.00). CONCLUSION: Tumor uptake of (89)Zr-bevacizumab is high in mRCC, with remarkable interpatient and intrapatient heterogeneity. Bevacizumab/interferon-α strongly decreases tumor uptake whereas sunitinib results in a modest reduction with an overshoot after 2 drug-free weeks. High baseline tumor SUV(max) was associated with longer time to progression.

Influence of respiratory gating, image filtering, and animal positioning on high-resolution electrocardiography-gated murine cardiac single-photon emission computed tomography.

Cardiac parameters obtained from single-photon emission computed tomographic (SPECT) images can be affected by respiratory motion, image filtering, and animal positioning. We investigated the influence of these factors on ultra-high-resolution murine myocardial perfusion SPECT. Five mice were injected with 99m technetium (99mTc)-tetrofosmin, and each was scanned in supine and prone positions in a U-SPECT-II scanner with respiratory and electrocardiographic (ECG) gating. ECG-gated SPECT images were created without applying respiratory motion correction or with two different respiratory motion correction strategies. The images were filtered with a range of three-dimensional gaussian kernels, after which end-diastolic volumes (EDVs), end-systolic volumes (ESVs), and left ventricular ejection fractions were calculated. No significant differences in the measured cardiac parameters were detected when any strategy to reduce or correct for respiratory motion was applied, whereas big differences (> 5%) in EDV and ESV were found with regard to different positioning of animals. A linear relationship (p < .001) was found between the EDV or ESV and the kernel size of the gaussian filter. In short, respiratory gating did not significantly affect the cardiac parameters of mice obtained with ultra-high-resolution SPECT, whereas the position of the animals and the image filters should be the same in a comparative study with multiple scans to avoid systematic differences in measured cardiac parameters.

(111)In-trastuzumab scintigraphy in HER2-positive metastatic breast cancer patients remains feasible during trastuzumab treatment.

Human epidermal growth factor receptor (HER)2 imaging with radiolabeled trastuzumab might support HER2-targeted therapy. It is, however, frequently questioned whether HER2 imaging is also possible during trastuzumab treatment as the receptor might be saturated. We studied the effect of trastuzumab treatment on 111In-trastuzumab uptake. Patients received trastuzumab weekly and paclitaxel once every 3 weeks. 111In-trastuzumab was injected on day 1 of cycle 1 and day 15 of cycle 4. Whole-body planar scintigraphy was acquired at different time points postinjection. Tumor uptake and organ distribution between the first and repeated scan series were calculated via residence times. Twenty-five tumor lesions in 12 patients were visualized on both scintigraphy series. Tumor uptake decreased (19.6%; p  =  .03). The residence times of normal organs remained similar except for the cardiac blood pool (+ 16.3%; p  =  .014). Trastuzumab treatment decreases tumor 111In-trastuzumab uptake around 20%. HER2 imaging is feasible during trastuzumab treatment.

Everolimus Reduces (89)Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors.

UNLABELLED: Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients. METHODS: Patients with advanced progressive well-differentiated NETs underwent (89)Zr-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. (89)Zr-bevacizumab uptake was quantified by the maximum standardized uptake value (SUVmax). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly). RESULTS: In 4 of the 14 patients entered, no tumor lesions were visualized with (89)Zr-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUVmax decreased during everolimus treatment, with a median of -7% at 2 wk (P = 0.09) and a median of -35% at 12 wk (P < 0.001). The difference in SUVmax at 2 and 12 wk with respect to SUVmax at baseline correlated with percentage change on CT at 6 mo (r(2) = 0.51, P < 0.05, and r(2) = 0.61, P < 0.01, respectively). CONCLUSION: This study demonstrates variable (89)Zr-bevacizumab PET tumor uptake in NET patients. (89)Zr-bevacizumab tumor uptake diminished during everolimus treatment. Serial (89)Zr-bevacizumab PET might be useful as an early predictive biomarker of anti-VEGF-directed treatment in NET patients.

Multicenter harmonization of 89Zr PET/CT performance.

UNLABELLED: This study investigated the feasibility of quantitative accuracy and harmonized image quality in (89)Zr-PET/CT multicenter studies. METHODS: Five PET/CT scanners from 3 vendors were included. (89)Zr activity was measured in a central dose calibrator before delivery. Local activity assays were based on volume as well as on the local dose calibrator. Accuracy and image noise were determined from a cross calibration experiment. Image quality was assessed from recovery coefficients derived from different volume-of-interest (VOI) methods (VOI A 50%, based on a 3-dimensional isocontour at 50% of the maximum voxel value with local background correction; VOI Max, based on the voxel with the highest uptake; and VOI 3Dpeak, based on a spheric VOI of 1.2-cm diameter positioned so as to maximize the enclosed average). PET images were analyzed before and after postreconstruction smoothing, applied to match image noise. RESULTS: PET/CT accuracy and image noise ranged from -3% to 10% and from 13% to 22%, respectively. VOI 3Dpeak produced the most reproducible recovery coefficients. After calibration of the local dose calibrator to the central dose calibrator, differences between the local activity assays were within 6%. CONCLUSION: This study showed that quantitative accuracy and harmonized image quality can be reached in (89)Zr PET/CT multicenter studies.

In vivo responses of human A375M melanoma to a σ ligand: 18F-FDG PET imaging.

UNLABELLED: σ-ligands can kill tumor cells. Previously we have shown that a short in vitro incubation of C6 tumor cells with σ-ligands (24 h) results in a dose-dependent increase of cellular (18)F-FDG uptake and that the magnitude of this increase is predictive of subsequent cell death. Here, we aimed to assess whether the σ-ligand rimcazole inhibits growth of A375M melanoma xenografts in nude mice and whether rimcazole treatment changes (18)F-FDG uptake in vivo. METHODS: Athymic mice were inoculated with A375M melanoma cells. After 2 wk, tumors had reached a size of 41 ± 6 mm(3). We then started a 14-d treatment schedule with daily drug dosing. Control animals were injected with water and treated animals with rimcazole (26 mg/kg) in water. Three small-animal PET scans with (18)F-FDG were obtained: on days 0, 7, and 14 of treatment. After the last scan, animals were terminated, and a biodistribution study was performed. RESULTS: Rimcazole treatment resulted in a greater than 4-fold reduction of tumor weight in comparison to controls at day 14 (100 ± 26 vs. 436 ± 117 mg, respectively, P < 0.03). Treatment did not affect the levels of (nonradioactive) glucose in blood, σ-1 and σ-2 receptor expression in the tumor, animal weight, behavior, or appearance. Antitumor activity of rimcazole was accompanied by a transient increase of the tumor uptake of (18)F-FDG (measured at day 7). Significant increases of (18)F-FDG uptake at day 14 were observed in the liver and pancreas. CONCLUSION: Rimcazole strongly inhibited the growth of A375M melanoma xenografts. This growth inhibition is accompanied by an early increase of (18)F-FDG uptake in the tumor.

89Zr-bevacizumab PET imaging in primary breast cancer.

UNLABELLED: Vascular endothelial growth factor (VEGF)-A is overexpressed in most malignant and premalignant breast lesions. VEGF-A can be visualized noninvasively with PET imaging and using the tracer (89)Zr-labeled bevacizumab. In this clinical feasibility study, we assessed whether VEGF-A in primary breast cancer can be visualized by (89)Zr-bevacizumab PET. METHODS: Before surgery, breast cancer patients underwent a PET/CT scan of the breasts and axillary regions 4 d after intravenous administration of 37 MBq of (89)Zr-bevacizumab per 5 mg. PET images were compared with standard imaging modalities. (89)Zr-bevacizumab uptake was quantified as the maximum standardized uptake value (SUV max). VEGF-A levels in tumor and normal breast tissues were assessed with enzyme-linked immunosorbent assay. Data are presented as mean ± SD. RESULTS: Twenty-five of 26 breast tumors (mean size ± SD, 25.1 ± 19.8 mm; range, 4-80 mm) in 23 patients were visualized. SUV max was higher in tumors (1.85 ± 1.22; range, 0.52-5.64) than in normal breasts (0.59 ± 0.37; range, 0.27-1.69; P < 0.001). The only tumor not detected on PET was 10 mm in diameter. Lymph node metastases were present in 10 axillary regions; 4 could be detected with PET (SUV max, 2.66 ± 2.03; range, 1.32-5.68). VEGF-A levels in the 17 assessable tumors were higher than in normal breast tissue in all cases (VEGF-A/mg protein, 184 ± 169 pg vs. 10 ± 21 pg; P = 0.001), whereas (89)Zr-bevacizumab tumor uptake correlated with VEGF-A tumor levels (r = 0.49). CONCLUSION: VEGF-A in primary breast cancer can be visualized by means of (89)Zr-bevacizumab PET.