Project Summary/Abstract Lung cancer is the leading cause of cancer death, accounting for over 1.6 million deaths worldwide. For initial detection of suspect peripheral tumors and central-chest lymph nodes, CT and PET imaging are used. For follow-on cancer diagnosis and staging, minimally invasive bronchoscopy and endobronchial ultrasound (EBUS) are used. A major paradigm shift, spurred by the ongoing roll-out of lung-cancer screening for early detection, is ushering in a new era focused on early-stage treatable disease. It also brings to light the major stumbling block posed by the lack of accurate, comprehensive tools for follow- on diagnosis and staging. The goal of this renewal project is to construct a multimodal image-guided bronchoscopy system for lung-cancer diagnosis and staging. As a step toward addressing this critical need, lung-cancer diagnosis has also seen a recent paradigm shift in that image-guided navigation systems have solved the task of bronchoscopic navigation. Navigation, however, is only part of the task. Upon reaching a tumor or lymph node, the physician must now perform a biopsy. Unfortunately, physician skill in using EBUS varies greatly, especially for physicians not at expert centers, resulting in poor biopsy yields. On a related note, comprehensive staging requires traversing many widely spaced nodal stations, a task rarely done because of the skill it demands. Thus, existing guidance systems suffer from two limitations: 1) they do not guide EBUS and the task of biopsy targeting; 2) they lack an efficient, systematic protocol for guiding comprehensive nodal staging, needed for reaching conclusive staging decisions. To appreciate how critical these limitations are, two national multi-center trials by the AQuIRE consortium studying state-of-the-art bronchoscopy tools for lung-cancer diagnosis and staging found a poor 47% diagnostic yield for peripheral tumor diagnosis and a 50% yield for central-chest nodal staging--- i.e., too many tumor biopsies were missed, resulting in too many uncertain diagnoses, and too few lymph- node stations were biopsied, resulting in too many uncertain staging decisions. Our objective now in this renewal is to create a new image-guided bronchoscopy/EBUS system that overcomes current limitations. To this end, the project has the following Specific Aims: Aim 1: Prototype an image-guided bronchoscopy system for lung-cancer disease diagnosis and staging. Aim 2: Perform animal (with PennVet), phantom, and human studies to optimize the system. Aim 3: Conduct prospective human studies to compare the optimized system to state-of-the-art practice. The final system is expected to enable accurate diagnosis/staging decisions in a single procedure, have fewer patient complications, and be easy to use independent of physician skill. In this way, inconclusive bronchoscopies decrease, ultimately leading to more timely patient treatment.