The optical properties of a receptor-targeted probe designed for dual-modality mapping of the sentinel lymph node (SLN) was optimized. Specific fluorescence brightness was used as the design criterion, which was defined as the fluorescence brightness per mole of the contrast agent. Adjusting the molar ratio of the coupling reactants, IRDye 800CW-NHS-ester and tilmanocept, enabled us to control the number of fluorescent molecules attached to each tilmanocept, which was quantified by H 1 nuclear magnetic resonance spectroscopy. Quantum yields and molar absorptivities were measured for unconjugated IRDye 800CW and IRDye 800CW-tilmanocept (800CW-tilmanocept) preparations at 0.7, 1.5, 2.3, 2.9, and 3.8 dyes per tilmanocept. Specific fluorescence brightness was calculated by multiplication of the quantum yield by the molar absorptivity and the number of dyes per tilmanocept. It predicted that the preparation with 2.3 dyes per tilmanocept would exhibit the brightest signal, which was confirmed by fluorescence intensity measurements using three optical imaging systems. When radiolabeled with Ga 68 and injected into the footpads of mice, the probe identified SLNs by both fluorescence and positron emission tomography (PET) while maintaining high percent extraction by the SLN. These studies demonstrated the feasibility of 800CW-tilmanocept for multimodal SLN mapping via fluorescence and PET–computed tomography imaging.
Early detection is important for many solid cancers but the images provided by ultrasound, magnetic resonance imaging (MRI), and computed tomography applied alone or together, are often not sufficient for decisive early screening/diagnosis. We demonstrate that MRI augmented with fluorescence intensity (FI) substantially improves detection. Early stage murine pancreatic tumors that could not be identified by blinded, skilled observers using MRI alone, were easily identified with MRI along with FI images acquired with photomultiplier tube detection and offset laser scanning. Moreover, we show that fluorescence lifetime (FLT) imaging enables positive identification of the labeling fluorophore and discriminates it from surrounding tissue autofluorescence. Our data suggest combined-modality imaging with MRI, FI, and FLT can be used to screen and diagnose early tumors.
PET imaging can quantify metabolic processes in-vivo; this requires the measurement of an input function which is invasive and labor intensive. A non-invasive, semi-automated, image based method of input function generation would be efficient, patient friendly, and allow quantitative PET to be applied routinely. A fully automated procedure would be ideal for studies across institutions. Factor analysis (FA) was applied as processing tool for definition of temporally changing structures in the field of view. FA has been proposed earlier, but the perceived mathematical difficulty has prevented widespread use. FA was utilized to delineate structures and extract blood and tissue time-activity-curves (TACs). These TACs were used as input and output functions for tracer kinetic modeling, the results of which were compared with those from an input function obtained with serial blood sampling. Dynamic image data of myocardial perfusion studies with N-13 ammonia, O-15 water, or Rb-82, cancer studies with F-18 FDG, and skeletal studies with F-18 fluoride were evaluated. Correlation coefficients of kinetic parameters obtained with factor and plasma input functions were high. Linear regression usually furnished a slope near unity. Processing time was 7 min/patient on an UltraSPARC. Conclusion: FA can non-invasively generate input functions from image data eliminating the need for blood sampling. Output (tissue) functions can be simultaneously generated. The method is simple, requires no sophisticated operator interaction and has little inter-operator variability. FA is well suited for studies across institutions and standardized evaluations.
To study the effects of RMP7, an bradykinin analog, on BBB permeability changes in brain tumor patients, Ga-68 EDTA PET was used for quantitative determination of tumor tissue permeability, two dynamic Ga-68 EDTA PET scans (with and without RMP7) were performed for each patient. Changes between the results of the two scans were used to assess the effect of the drug. MRI was also performed to provide the anatomical information. Patient movement during the dynamic PET studies were corrected by frame-to-frame PET image registration. Due to different orientation among PET and MRI images, all PET images were co-registered to the MRI images of the corresponding patient. All frames of a dynamic scan were summed before registering to the MRI images. The main features for registration were boundaries of skull and tumor. After registration, region of interest (ROI) was defined on MRI images and was copied to registered PET dynamic images. The whole tumor radioactivity was calculated based on each plane's tumor ROI. The transport constant from plasma to tissue (Ki) that is related to BBB permeability was estimated by a two-compartmental model. The PET-MRI registration method developed by Lin et al was found to work well for Ga-68 PET-MRI image registration. Estimated whole tumor Ki was 0.0002 +/- 0.0019 (s.d.)ml/min/g for the baseline study and was increased by 46 +/- 42 (s.d.)% with RMP7.
In this study, we applied factor analysis of dynamic structures (FADS) techniques in dynamic PET images to (1) extract the arterial time activity curve (TAC) from human adult or small monkey dynamic FDG PET; and (2) investigate the use of FADS generated factor images and factor curves to detect large subject movements during dynamic GA-68 EDTA scans of brain tumor patients. The results showed that a blood sample constraint improved the accuracy of FADS technique in extracting the `pure' blood pool TAC from dynamic PET studies that have large spillover problems. The studies of GA-68 EDTA brain PET studies showed that three major factors were extracted from images using FADS. For studies with little patient movement, a standard pattern of three factor curves and three factor images were obtained. However, large patient movement changed the outcomes of FADS results. We conclude that (1) FADS technique with a blood sample allows the extraction of the `pure' blood pool TAC directly from quantitative PET images without requiring multiple blood samples, region-of- interest drawing or spillover correction; and (2) FADS technique provides a sensitive way to detect large patient movements in dynamic PET studies.
Carl Hoh, Randall Hawkins, John Glaspy, Magnus Dahlbom, Nielson Tse, Edward Hoffman, Christiaan Schiepers, Yong Choi, Sheila Rege, Egbert Nitzsche, Jamshid Maddahi, Michael Phelps
Until recently, positron emission tomography (PET) has been acquired and displayed in a standard transaxial image format. The development of whole body PET has allowed biochemical and physiologic imaging of the entire body, expanding the limited axial field of view of the conventional PET scanner. In this study, the application of whole body PET studies with 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) for tumor imaging was evaluated. Whole body PET studies were positive (presence of focal FDG uptake relative to surrounding tissue activity) in 61 of 70 patients (87%) with biopsy confirmed malignant tumors. PET images failed to reveal focal hypermetabolism in 9 of the 70 patients. Of the 17 patients with benign biopsies lesions, 13 patients had whole body PET studies without focal areas of FDG uptake. Because of the high glycolytic rate of malignant tissue, the whole body PET FDG technique has promise in the detection of a wide variety of both primary and metastatic malignancies. The presence of FDG uptake in benign inflammatory conditions may limit the specificity of the technique. The true positive rates for the characterization of known lesions was 87% in this series, and the PET FDG method is promising both in determining both the nature of a localized lesion, and in defining the systemic extent of malignant disease.
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