Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for VPAC1. The transgenic MMTVneu mice spontaneously develop BC and metastatic lesions that overexpress cyclin D1 and VPAC1 biomarkers. The MMTVneu mouse, therefore, provides an excellent animal model that mimics the pathogenesis of human BC. The objective of this investigation was to determine the ability of 1 of the peptide analogs, 64 Cu-TP3805, to detect BC in MMTVneu mice using 18 F-FDG as a gold standard. Methods: The transgenic MMTVneu mouse colony was maintained. Offspring were screened for transgenic status by reverse transcriptase polymerase chain reaction (RT-PCR). Nine mice with visible, palpable, or unknown metastatic lesions were entered into the protocol. 18 F-FDG (6,475 6 1,628 kBq [175 6 44 mCi]) PET served as a control, followed by a CT scan and 24-48 h later by PET with 64 Cu-TP3805 (4,588 6 962 kBq [124 6 26 mCi]). RT-PCR on excised tumors determined VPAC1 expression, and histology ascertained the pathology. Results: Ten tumors were detected by PET. Four tumors were detected both by 18 F-FDG and by 64 Cu-TP3805. Additionally, 4 tumors were imaged with 64 Cu-TP3805 only. These 8 tumors overexpressed VPAC1 receptors and were malignant by histology. The 2 remaining tumors were visualized with 18 F-FDG only. These tumors did not express the VPAC1 oncogene product and had benign histology. The standard uptake value ranged from 3.1 to 18.3 for 64 Cu-TP3805 and 0.9 to 1.4 for 18 F-FDG. Conclusion: 64 Cu-TP3805 identified all malignant lesions unequivocally that overexpressed the VPAC1 oncogene surface product. The 2 benign tumors that did not express the VPAC1 receptor were not imaged. 64 Cu-TP3805 promises to have the potential for the early and accurate imaging of primary and metastatic BC.

Purpose Infection is ubiquitous and a major cause of morbidity and mortality. The most reliable method for localizing infection requires radiolabeling autologous white blood cells ex vivo. A compound that can be injected directly into a patient and can selectively image infectious foci will eliminate the drawbacks. The resolution of infection is associated with neutrophil apoptosis and necrosis presenting phosphatidylserine (PS) on the neutrophil outer leaflet. Targeting PS with intravenous administration of a PS-specific, near-infrared (NIR) fluorophore will permit localization of infectious foci by optical imaging. Methods Bacterial infection and sterile inflammation were induced in separate groups (n=5) of mice. PS was targeted with a NIR fluorophore, PSVue®794 (2.7 pmol). Imaging was performed (ex=730 nm, em=830 nm) using Kodak Multispectral FX-Pro system. The contralateral normal thigh served as an individualized control. Confocal microscopy of normal and apoptotic neutrophils and bacteria confirmed PS specificity. Results Lesions, with a 10-s image acquisition, were unequivocally visible at 5 min post-injection. At 3 h post-injection, the lesion to background intensity ratios in the foci of infection (6.6±0.2) were greater than those in inflammation (3.2±0.5). Image fusions confirmed anatomical locations of the lesions. Confocal microscopy determined the fluorophore specificity for PS. Conclusions Targeting PS presented on the outer leaflet of apoptotic or necrotic neutrophils as well as gram-positive microorganism with PS-specific NIR fluorophore provides a sensitive means of imaging infection. Literature indicates that NIR fluorophores can be detected 7-14 cm deep in tissue. This observation together with the excellent results and the continued development of versatile imaging devices could make optical imaging a simple, specific, and rapid modality for imaging infection.

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In this study we have attempted to optimize a PET based adaptive threshold segmentation method for delineating small tumors, particularly in a background of high tracer activity. The metabolic nature of pituitary adenomas and the constraints of MRI imaging in the postoperative setting to delineate these tumors during radiosurgical procedures motivated us to develop this method. Phantom experiments were done to establish a relationship between the threshold required for segmenting the PET images and the target size and the activity concentration within the target in relation to its background. The threshold was developed from multiple linear regression of the experimental data optimized for tumor sizes less than 4 cm3. We validated our method against the phantom target volumes with measured target to background ratios ranging from 1.6 to 14.58. The method was tested on ten retrospective patients with residual growth hormone‐secreting pituitary adenomas that underwent radiosurgery and compared against the volumes delineated by manual method. The predicted volumes against the true volume of the phantom inserts gave a correlation coefficient of 99% (p<0.01). In the ten retrospective patients, the automatically segmented tumor volumes against volumes manually delineated by the clinicians had a correlation of 94% (p<0.01). This adaptive threshold segmentation showed promising results in delineating tumor volumes in pituitary adenomas planned for stereotactic radiosurgery, particularly in the postoperative setting where MR and CT images may be associated with artifacts, provided optimization experiment is carried out.PACS number: 87.57.nm, 87.57.uk

Abstract. This paper presents an improved GrowCut (IGC), a positron emission tomography-based segmentation algorithm, and tests its clinical applicability. Contrary to the traditional method that requires the user to provide the initial seeds, the IGC algorithm starts with a threshold-based estimate of the tumor and a threedimensional morphologically grown shell around the tumor as the foreground and background seeds, respectively. The repeatability of IGC from the same observer at multiple time points was compared with the traditional GrowCut algorithm. The algorithm was tested in 11 nonsmall cell lung cancer lesions and validated against the clinician-defined manual contour and compared against the clinically used 25% of the maximum standardized uptake value [SUV-(max)], 40% SUV max , and adaptive threshold methods. The time to edit IGC-defined functional volume to arrive at the gross tumor volume (GTV) was compared with that of manual contouring. The repeatability of the IGC algorithm was very high compared with the traditional GrowCut (p ¼ 0.003) and demonstrated higher agreement with the manual contour with respect to threshold-based methods. Compared with manual contouring, editing the IGC achieved the GTV in significantly less time (p ¼ 0.11). The IGC algorithm offers a highly repeatable functional volume and serves as an effective initial guess that can well minimize the time spent on labor-intensive manual contouring.

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REPORT DOCUMENTATION PAGEForm Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) 29- 07-2009 -28-07-2011 REPORT DATE (DD-MM-YYYY) 28-08-2011 REPORT TYPE Final DATES COVERED SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)Medical Research and Materiel USAMRMC Materiel Command TATRC Telemedicine & Advanced Fort Detrick SPONSOR/MONITOR'S REPORTTechnology Research Center Maryland 21702-5012 NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACTWe hypothesized in Aim 1 that docking of three-dimensional (3D) projections of potential target binding agents with 3D projections of macromolecular disease targets visualized on a computer with touch and feel feedback will enable identification of optimal agent designs, and culling of suboptimal agent designs, prior to synthesis. We found that direct measurements of cellular uptake of two different EGF fragments, EGF20-31 and EGF32-48, agreed with the computer predictions of no uptake by EGF20-31, and significant uptake by EGF32-48. This observation is consistent with our first hypothesis. We hypothesized in Aim 2 that 3D FDG PET images of patients superimposed on 3D anatomical images of patients visualized on a large computer display would enable improved preoperative planning, because the FDG PET images revealed specific sites of active disease. We found that a set of 6 experienced surgeons found that the final 3D version was accurate, useful, and worth applying in practice. This observation is consistent with our second hypothesis. SUBJECT TERMScancer, computerized tomography, haptic, hybridization, imaging, molecular dynamics, nuclear medicine, oncogene, pancreatic, positron emission tomography, receptors, surgery, volumetric A. INTRODUCTIONWe hypothesized that our fusion of genetic, visual, and tactile information would improve surgeons' understanding of the extent of disease and will ultimately permit surgeons to better plan operations and to prepare for the actual pathology found. We proposed to combine current medical imaging technologies with genetic imaging to leverage our ability to pr...

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