There is tremendous inherent value of the Radiologist investigators as a core resource for the mission of the Intramural Research Program. The strength of the Radiologist investogators lies in its deep and robust roots and networks to the research of the Institutes, as the Diagnostic Radiology Department (DRD) provides major radiology, imaging, and image guided interventional support for the work of the Institutes. The DRD provides clinical services to the ICs and CC, but also has a modest research agenda and mandate, as well as a small research training program. Thus, DRD research is most often synergistic with the projects and missions of the ? The core facilities have helped support translation of Computer-aided detection algorithms to the clinic for the detection of colonic polyps as well as new ways to translate navigation technologies to clinic using the multimodality operating room of the future, of which the CC is home to a worlds first suite of its kind. ? The Clinical Center became a place for the delivery mechanical or thermal energy to the soft tissues via needle electrodes or high intensity focused ultrasound combined with thermally deployed vectors containing chemotherapy agents or contrast for various liver tumors. This latter concept was taken from bench to bedside here at the Clinical Center. Novel ways to improve the technique of thermal ablation have been pioneered here, including the use of RFA for liver abscesses in the immunocompromised, and the use of RFA for nephron sparing kidney tumor ablation in hereditary renal cell carcinoma in patients without other effective means of treatment. Core resources support the study of the natural history, safety, and efficacy of this new technology for novel clinical applications like adrenocortical carcinoma, liver abscess in the immunocompromised host, and for hormonally-active tumors like pheochromocytoma. ? NIH Clinical Center became the home to one of the first drug + device combination phase 1 clinical trials in heat deployed drug delivery, the result of many years of bench to bedside translation, and is now in 40 centers and 5 countries for Phase 3 trials. The Clinical Center also helped develop a navigation system that uses tiny electromagnetic sensors inside of medical devices that converts the device into a GPS-like localization system, with the device being the car, and the magnetic box field generator sitting nearby being the satellite. The first clinical trial in humans using this technology for tumor ablations was performed here. The multimodality multiparametric navigation system may help clarify the significance of specific tissue phenotyping, proteomics, genomics, or in prescribing the appropriate therapeutic cocktail for the cancer patient. Such targeted sequential biopsies are becoming a routine research tool for many NCI investigators. High intensity focused ultrasound (HIFU) activating thermally sensitive contrast agents or drugs is a relatively new phase of study, with phase 1 dose escalation trials planned. The NIH will also be the home of North Americas first MRI guided Spiral HIFU, and will help direct a multicenter trial at transcatheter fibroid embolization versus MRI-guided HIFU fibroid ablation. NIH has long been the site for the CT-based multimodality procedural suite of the future.? The Molecular Imaging Lab became more translational in FY 08, and less based upon mechanistic work, exploratory studies, and basic science. Avb3 integrin antagonist was patented, investigated, as applied to atherosclerosis and tumor imaging and possibly therapeutic delivery with collaborators from NIBIB and NCI. Conceptually, imaging can be used to facilitate target identification, localize the relevant molecular targets in vivo in a spatially and/or temporally resolved fashion, and ultimately personalized treatment regimens can be developed based on a combination of imaging and image guided tissue analysis. In the past few years, molecular imaging has become a popular term. The core efforts support translational goals and first-in-human clinical applications, rather than the primary discovery of specific imaging and therapeutic probes. Molecular imaging may seem like a linear process of building chemical or biologic probes specific to molecular targets identified by molecular biology, pathology and immunology (using techniques such as functional genomics, proteomics, immuno-histochemistry or fluorescence-activated cell sorting (FACS)). These chemical or biologic probes are designed to be detected in vivo by various imaging techniques. Using these probes various biologic processes such as gene expression, molecular receptor up-regulation and metabolic activities can be monitored in vivo (a powerful research tool). Such developments of molecular probes requires the collaboration of scientists from multiple disciplines such as chemistry, computer modeling, biochemistry, molecular biology and drug delivery. Typically, chemical probes can be designed either by a rational approach, sometimes using computer modeling, or drug + device paradigms. The potentially useful chemical probes are then subjected to in vitro biochemical assays followed by in vivo studies. In vivo drug delivery has many hidden barriers on the way to clinical trials in patients. Understanding physiologic barriers and pharmacokinetics is critical issues for translation. For example, the experience from years of immuno-scintigraphy research suggests that even in the ideal case only 0.001 to 0.01% of monoclonal antibodies injected intravenously will reach and bind to target tissues in humans despite high selectivity, affinity and avidity in vitro. Since many of the molecular targets exist only in low concentrations in the target tissues, signal amplification by chemical or physical means may be required (such as image guided HIFU). In order to prove that an imaging probe is effective, image guided tissue biopsies from the animals undergoing the imaging experiments need to be carried out. These tissue samples are studied with techniques such as immuno-histochemistry, histopathology, c-DNA analysis etc. to confirm that the imaging test results correspond to the in vitro tissue analysis results. Once we have an imaging test that can be used for tracking a molecular event in vivo, new opportunities are available. One can imagine using this imaging test to select tissues with a certain molecular characteristics and then use these images for guiding procurement of tissue samples. These tissue samples can then be analyzed using various techniques. This type of approach will allow the study and interactions between different molecular pathways which could result in identifications of molecular targets relationships. New molecular imaging probes developed for the new molecular targets in a highly iterative process. ? ? Prior projects assisted by Molecular Imaging Lab staff have included Integrin antagonists for the detection of cancer, vulnerable atherosclerotic plaque, optical probes for beta amyloid, optical biufunctional compounds, targeted contrast agents, polymerized liposomes, peptidomimetic integrin antagonists, serum proteomic screening in acute coronary syndromes, to name a few.
