Background: VSV-IFNβ-NIS (Voyager V1; VV1) is a VSV-derived OV with low human seroprevalence. In addition to its tumor-selective and immune-stimulatory properties, VV1 encodes the human thyroidal sodium iodide symporter NIS to allow imaging of virus-infected tumors with IV 99mTc pertechnetate. Preclinical studies show increasing 99mTc uptake correlates with virus dose and allows spatial and temporal tracking of virus. Methods: Single-photon emission computerized tomography (SPECT/CT) is used to assess virus replication and spread. In a phase 1 study, VV1 is given intratumorally into 1 target lesion on Day 1 (D1). SPECT/CT imaging is performed 45 minutes after 20 mCi IV 99mTc at baseline and D3. If there is uptake in injected tumor on D3, SPECT/CTs are also done D8 and D15. Imaging requirements include: gamma camera, low energy high resolution collimators with standard acquisition protocols and iterative image reconstruction. All images are read locally and centrally. Results: SPECT/CT has been performed on 12 patients at 4 VV1 dose levels (DL). 99mTc uptake was not detected at the first 2 DLs but was seen in injected lesions of 2/4 pts at DL 3 (3e7 TCID50) in pts with metastatic colorectal and pancreas cancer, and 1/2 to date at DL 4. PD analysis revealed SPECT/CT-positive pts had peak uptake in injected lesions between D3 and D8. Tumor biopsy samples are being analyzed to correlate SPECT/CT with viral RNA. Spread to uninjected lesions was not yet visualized, but viral RNA was recovered in cystic fluid from the lesion with the strongest signal in a pancreas cancer pt. Conclusions: This novel therapeutic and diagnostic approach allows PD visualization of the investigational oncolytic virotherapy, VV1, replicating within the injected lesion. Positive images at dose levels 3-4 indicate we have reached a viral dose that allows sufficient viral replication for potential clinical activity. Further objectives include correlation of SPECT/CT positivity with clinical response, viremia, immune infiltrates, and genetic markers of susceptibility to OV therapy. Clinical trial identification: NCT02923466. Legal entity responsible for the study: Vyriad. Funding: Vyriad. Disclosure: R.M. Diaz: Paid consultant running the trial: Vyriad. S.J. Russell: CEO and own equity: Vyriad. A.S. Bexon: Paid consultant and CMO: Vyriad. K.W. Peng: CTO and own equity: Vyriad. All other authors have declared no conflicts of interest.

Introduction: Some patients with upper gastrointestinal disorders have rapid gastric emptying. In patients who have not had prior surgery, the etiology of rapid gastric emptying is unclear. Patients with rapid GE may have rapid GE at one and/or two hours; whether these patterns represent different phenotypes, which are underpinned by different pathophysiological mechanisms is also unknown. Hence, our aims were to assess differences in the demographic and clinical features between patients with normal and rapid GE and separately among subtypes, defined by GE values, in patients with rapid gastric emptying.1212 Figure 1. Demographics and clinical featuresMethods: We reviewed the medical records of 6500 patients, aged 18 years or older in whom gastric emptying was evaluated with scintigraphy (296 kcal, regular fat meal) at Mayo Clinic, Rochester, and who authorized use of their medical records for research. Using sex—appropriate normal values, GE was classified as rapid if it was more than 5% above the upper limit of normal. Patients with rapid GE were categorized into 3 groups: rapid GE at 1 hour only, 2 hours only, or both. Results: After excluding 2660 patients who had major gastrointestinal operations (fundoplication, major intestinal and colonic resection), there were 3840 patients who had normal (2838), rapid GE at 1h only (464), 2h only (55) and or 1 and 2 h (483). Approximately 75% of patients in all groups were women and 40% were overweight or obese; the distribution of age, sex and BMI was not significantly different among groups. In addition to nausea and/or vomiting and diarrhea, between 48 and 67% of patients with rapid GE had constipation, which was more common (p<0.05) in patients with rapid GE at 2h than in the other 2 categories (Table 1). Between 42 and 47% patients had delayed colonic transit. Of various symptoms, anxiety and/or depression were more common (p<0.05) in rapid GE at 2hr, than in the other two categories. Conclusion: Approximately 26% of 3840 consecutive patients undergoing scintigraphy had rapid GE. The primary gastrointestinal symptoms were nausea and/or vomiting, dyspepsia, abdominal pain, heartburn, constipation and diarrhea. A substantial proportion of patients with rapid GE had constipation, not diarrhea, which is counterintuitive, but may be explained, at least partly, by activation of the ileal brake via rapid GE.

Aim/Background: The purpose of this study is to test the feasibility and safety of in situ gene therapy using non-replicating adenovirus (Ad5)-mediated expression of the sodium-iodide symporter (NIS) gene injected directly into the prostate in patients with locally recurrent prostate cancer following external radiotherapy (EBRT) or permanent prostate brachytherapy (PPB). Methods: Approval for human investigation by the Federal Drug Administration (FDA) and Institutional Review Board (IRB) was obtained for this study. The procedure includes injection of the adenovirus directly into the prostate via a template-guided transperineal route similar to a PPB approach using fluoroscopy and trans-rectal ultrasound image guidance. Viral particles are injected in 5 mL of solution subdivided into equivalent aliquots to 50 separate intraprostatic injection sites. Three days following injection, patients undergo 123I tracer dose imaging with subsequent planned 131I therapy subject to the condition that a prostate dose from 5-20 Gy can be delivered. Results: In preclinical animal studies, SPECT/CT imaging demonstrated distinct images of the NIS-transduced prostates. In the first eight human subjects treated to the 109 to 1012 viral particle levels, no Grade 2 or greater toxicity has been observed with median 2.1 years (range:0.1 to 6.5 years) of follow up. Dose levels of 109 to 1011 viral particles did not demonstrate 123I tracer uptake sufficient to deliver a therapeutic dose of 131I, whereas 3 of 5 patients receiving 1012 viral particles demonstrated sufficient uptake and received 131I. Conclusions: Direct injection of non-replicating adenovirus into the prostate in pre-clinical animal and clinical studies has been without significant adverse events. Adequate uptake by the transfected cells expressing the NIS gene has been demonstrated in vivo and meaningful doses of radiation delivered to the prostate in patients receiving 1012 injected viral particles. Patient accrual continues in order to fully evaluate the safety and efficacy of this novel approach in the management of localized radiorecurrent prostate cancer. Source of Funding: National Cancer Institute grant P50 91956. Disclosure: All authors have declared no conflicts of interest.

Heart failure is a leading cause of morbidity and mortality, and cardiac gene delivery has the potential to provide novel therapeutic approaches. Adeno-associated virus serotype 9 (AAV9) transduces the rodent heart efficiently, but cardiotropism, immune tolerance, and optimal delivery strategies in large animals are unclear. In this study, an AAV9 vector encoding canine sodium iodide symporter (NIS) was administered to adult immunocompetent dogs via epicardial injection, coronary infusion without and with cardiac recirculation, or endocardial injection via a novel catheter with curved needle and both end- and side-holes. As NIS mediates cellular uptake of clinical radioisotopes, expression was tracked by single-photon emission computerized tomography (SPECT) imaging in addition to Western blot and immunohistochemistry. Direct epicardial or endocardial injection resulted in strong cardiac expression, whereas expression after intracoronary infusion or cardiac recirculation was undetectable. A threshold myocardial injection dose that provides robust nonimmunogenic expression was identified. The extent of transmural myocardial expression was greater with the novel catheter versus straight end-hole needle delivery. Furthermore, the authors demonstrate that cardiac NIS reporter gene expression and duration can be quantified using serial noninvasive SPECT imaging up to 1 year after vector administration. These data are relevant to efforts to develop cardiac gene delivery as heart failure therapy.

Purpose: To evaluate the performance characteristics of a novel dedicated breast PET system (Mammi-PET, Oncovision). The system has 2 detector rings giving axial/transaxial field of view of 8/17 cm. Each ring consists of 12 monolithic LYSO modules coupled to PSPMTs. Methods: Uniformity, sensitivity, energy and spatial resolution were measured according to NEMA standards. Count rate performance was investigated using a source of F-18 (1384uCi) decayed over 5 half-lives. A prototype PET phantom was imaged for 20 min to evaluate image quality, recovery coefficients and partial volume effects. Under an IRB-approved protocol, 11 patients who just underwent whole body PET/CT exams were imaged prone with the breast pendulant at 5–10 minutes/breast. Image quality was assessed with and without scatter/attenuation correction and using different reconstruction algorithms. Results: Integral/differential uniformity were 9.8%/6.0% respectively. System sensitivity was 2.3% on axis, 2.2% and 2.8% at 3.8 cm and 7.8 cm off-axis. Mean energy resolution of all modules was 23.3%. Spatial resolution (FWHM) was 1.82 mm and 2.90 mm on axis and 5.8 cm off axis. Three cylinders (14 mm diameter) in the PET phantom were filled with activity concentration ratios of 4:1, 3:1, and 2:1 relative to the background. Measured cylinder to background ratios were 2.6, 1.8 and 1.5 (without corrections) and 3.6, 2.3 and 1.5 (with attenuation/scatter correction). Five cylinders (14, 10, 6, 4 and 2 mm diameter) each with an activity ratio of 4:1 were measured and showed recovery coefficients of 1, 0.66, 0.45, 0.18 and 0.18 (without corrections), and 1, 0.53, 0.30, 0.13 and 0 (with attenuation/scatter correction). Optimal phantom image quality was obtained with 3D MLEM algorithm, >20 iterations and without attenuation/scatter correction. Conclusion: The MAMMI system demonstrated good performance characteristics. Further work is needed to determine the optimal reconstruction parameters for qualitative and quantitative applications.

Approaches to imaging the breast with nuclear medicine and/or molecular imaging methods have been under investigation since the early 1990s. Nuclear medicine procedures, which detect the preferential uptake of a radiotracer in breast lesions, have the potential to offer valuable functional information that complements conventional anatomical imaging techniques such as mammography and ultrasound. Despite initial enthusiasm for scintimammography, nuclear medicine techniques in general have struggled to gain mainstream acceptance by the breast imaging community. In the last 5-10 years, older-generation scintillating gamma systems, such breast-specific gamma imaging systems, have been replaced by a new generation of dual detector cadmium zinc telluride [CZT] detectors that perform direct conversion [DC] of gamma ray energy to signal and yield improved spatial and energy resolution. Using CZT-based detectors, DC-Molecular breast Imaging [DC-MBI] has demonstrated the ability to reliably detect breast tumors in a variety of diagnostic and screening settings. Recent improvements in both the detector technology and patient preparation have enabled the associated radiation dose from DC-MBI to be reduced to less than 1.5 mSv. The most robust evidence for the clinical use of DC-MBI is in the screening of women with dense breast tissue. In two large screening studies, the addition of DC-MBI to mammography was significantly more sensitive than mammography alone in detecting cancer (91

Over the last 2 years, there has been considerable attention focused on the potential cancer risks from medical imaging procedures, particularly with the widespread use of multislice CT. Almost all studies rely upon the BEIR VII report (Biological Effects of Ionizing Radiation panel formed under the auspices of the National Academy of Sciences) to generate an estimate of the risk of cancer from a given procedure. In doing so, most studies treat the BEIR VII report as a solid basis of scientific evidence for estimation of cancer risk. In reality, a close reading of this report shows that there are a large number of assumptions inherent in all aspects of the estimates of cancer risk - a fact that is often and clearly stated in the report. This presentation will review some of the assumptions used by the BEIR panel to calculate cancer risk, including the impact of different models (excess absolute risk vs. excess relative risk), the dose and dose rate effectiveness factor (DDREF) and relative biological effectiveness (RBE), on cancer estimates. Often lost in the discussion on medical exposure is a reference level by which exposure levels can be compared to something that unavoidable and impacts everyone on earth - background radiation. This presentation will review the consequences of applying the BEIR model to background radiation and known variations in levels of background radiation throughout the U.S., and how the cancer rate from background compares with that from medical imaging.LEARNING OBJECTIVES:1. Understand the assumptions underlying the BEIR VII report 2. Be able to compare the relative risks of medical imaging procedures to that from background radiation.