CONSPECTUS Near-infrared (NIR) fluorescence light has been widely utilized in clinical imaging by providing surgeons highly specific images of target tissue. The “NIR window” from 650 to 900 nm is especially useful due to several special features such as minimal autofluorescence and absorption of biomolecules in tissue, as well as low light scattering. Compared with visible wavelengths, NIR fluorescence light is invisible, thus allowing highly sensitivity real-time image guidance in human surgery without changing the surgical field. The benefit of using NIR fluorescence light as a clinical imaging technology can be attributed to its molecular fluorescence as an exogenous contrast agent. Indeed, whole body preoperative imaging of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) remains important in diagnostic utility, but they lack the efficacy of innocuous and targeted NIR fluorophores to simultaneously facilitate the real-time delineation of diseased tissue while preserving vital tissues. Admittedly, NIR imaging technology has been slow to enter clinical use mostly due to the late-coming development of truly breakthrough contrast agents for use with current imaging systems. Therefore, clearly defining the physical margins of tumorous tissue remains of paramount importance in bioimaging and targeted therapy. An equally noteworthy yet less researched goal is the ability to outline healthy vital tissues that should be carefully navigated without transection during the intraoperative surgery. Both of these paths require optimizing a gauntlet of design considerations to obtain not only an effective imaging agent in the NIR window but also high molecular brightness, water solubility, biocompatibility, and tissue-specific targetability. The imaging community recognizes three strategic approaches which include (1) passive targeting via the EPR effect, (2) active targeting using the innate overall biodistribution of known molecules, and (3) activatable targeting through an internal stimulus, which turns on fluorescence from an off state. Recent advances in nanomedicine and bioimaging offer much needed promise toward fulfilling these stringent requirements as we develop a successful catalog of targeted contrast agents for illuminating both tumors and vital tissues in the same surgical space by employing spectrally distinct fluorophores in real time. These tissue-specific contrast agents can be versatile arsenals to physicians for real-time intraoperative navigation as well as image-guided targeted therapy. There is a versatile library of tissue-specific fluorophores available in the literature, with many discussed herein, which offers clinicians an array of possibilities that will undoubtedly improve intraoperative success and long-term postoperation prognosis.

The field of nuclear cardiology is witnessing growing interest in the use of cardiac PET for the evaluation of patients with coronary artery disease (CAD). The available evidence suggests that myocardial perfusion PET provides an accurate means for diagnosing obstructive CAD, which appears superior to SPECT especially in the obese and in those undergoing pharmacologic stress. The ability to record changes in left ventricular function from rest to peak stress and to quantify myocardial perfusion (in mL/min/g of tissue) provides an added advantage over SPECT for evaluating multivessel CAD. There is growing and consistent evidence that gated myocardial perfusion PET also provides clinically useful risk stratification. Although the introduction of hybrid PET/CT technology offers the exciting possibility of assessing the extent of anatomic CAD (CT coronary angiography) and its functional consequences (ischemic burden) in the same setting, there are technical challenges in the implementation of CT-based transmission imaging for attenuation correction. Nonetheless, this integrated platform for assessing anatomy and biology offers a great potential for translating advances in molecularly targeted imaging into humans. PET has contributed significantly to advance our understanding of heart physiology and pathophysiology for .25 y. Initially, it emerged as a powerful investigative tool that allowed in vivo quantification of physiologic processes, including myocardial perfusion and metabolism, neuronal and receptor function, and, more recently, molecularly targeted oncologic imaging. Despite its success in research applications, the limited availability of this technology, its increased cost, and the limited data supporting its use and reimbursement have all contributed to the relatively limited clinical acceptance of this imaging technology. Fortunately, there are now clear signs that change is under way. Indeed, the exponential growth in the number of PET/CT systemsattributable primarily to the technology's widely accepted role in clinical oncology-along with the Food and Drug Administration's approval of PET radiopharmaceuticals for cardiac imaging, changes in reimbursement, and the increasing documentation of PET's clinical efficacy have all contributed to help advance its clinical role in cardiovascular medicine.The emergence of integrated PET/CT technology as the dominant configuration of clinical scanners also holds great promise for cardiac imaging as it provides a potential opportunity to delineate the anatomic extent and physiologic severity of coronary atherosclerosis in a single setting. However, the recent rapid growth of PET/CT is now opening a considerable gap between the most sophisticated users of the technology and those with a more limited knowledge base and fewer training opportunities; this includes cardiologists, as well as nuclear medicine specialists, and radiologists, who frequently lack clinical experience in performing and interpreting these cardiovascular procedures. The objective of this review ...

82Rb cardiac PET allows the assessment of myocardial perfusion using a column generator in clinics that lack a cyclotron. We and others have previously shown that quantitation of myocardial blood flow (MBF) and coronary flow reserve (CFR) is feasible using dynamic 82Rb PET and factor and compartment analyses. The aim of the present work was to determine the intra- and inter-observer variability of MBF estimation using 82Rb PET as well as the reproducibility of our generalized factor + compartment analyses methodology to estimate MBF and assess its accuracy by comparing, in the same subjects, 82Rb estimates of MBF to those obtained using 13N-ammonia. Methods Twenty-two subjects were included in the reproducibility and twenty subjects in the validation study. Patients were injected with 60±5mCi of 82Rb and imaged dynamically for 6 minutes at rest and during dipyridamole stress Left and right ventricular (LV+RV) time-activity curves were estimated by GFADS and used as input to a 2-compartment kinetic analysis that estimates parametric maps of myocardial tissue extraction (K1) and egress (k2), as well as LV+RV contributions (fv,rv). Results Our results show excellent reproducibility of the quantitative dynamic approach itself with coefficients of repeatability of 1.7% for estimation of MBF at rest, 1.4% for MBF at peak stress and 2.8% for CFR estimation. The inter-observer reproducibility between the four observers that participated in this study was also very good with correlation coefficients greater than 0.87 between any two given observers when estimating coronary flow reserve. The reproducibility of MBF in repeated 82Rb studies was good at rest and excellent at peak stress (r2=0.835). Furthermore, the slope of the correlation line was very close to 1 when estimating stress MBF and CFR in repeated 82Rb studies. The correlation between myocardial flow estimates obtained at rest and during peak stress in 82Rb and 13N-ammonia studies was very good at rest (r2=0.843) and stress (r2=0.761). The Bland-Altman plots show no significant presence of proportional error at rest or stress, nor a dependence of the variations on the amplitude of the myocardial blood flow at rest or stress. A small systematic overestimation of 13N-ammonia MBF was observed with 82Rb at rest (0.129 ml/g/min) and the opposite, i.e., underestimation, at stress (0.22 ml/g/min). Conclusions Our results show that absolute quantitation of myocardial bloof flow is reproducible and accurate with 82Rb dynamic cardiac PET as compared to 13N-ammonia. The reproducibility of the quantitation approach itself was very good as well as inter-observer reproducibility.