The overall goal of this renewal application is to improve the effectiveness of single photon emission tomography (SPECT) imaging for the diagnosis and treatment of patients with cancer. More specifically, it focuses on the capabilities of modern SPECT systems that include X-ray computed tomography systems (CT) with a focus on the estimation of activity concentration. This proposed effort will include a systematic phantom exploration of two SPECT/CT systems (one with cone beam CT and one with 16 slice helical CT) with 16 different combinations of isotopes and collimators. The data will be collected in the current sinogram binned mode and, in parallel, in listmode (keeping all events above 50 keV). A 4 cm diameter 57Co cylinder with calibrated 57Co standards for the dose calibrator will be used to determine a conversion factor from counts/pixel to activity/volume. These data will be used to explore the feasibility of such a calibration measurement (one isotope, one collimator) and scaling factors to apply that calibration to all isotope/collimator combinations. As part of ths effort we will develop more accurate scatter and collimator response modeling using accelerated Monte Carlo simulation in the image reconstruction process. This new effort is an outgrowth of our previous work, under this grant funding, in exploring quantitation in PET, including isolating many sources of error, finding ways to minimize them, and exploring alternative scanner geometries. That work also included image reconstruction with modeling scanner non-stationary resolution response. As part of our previously funded research, a Simulation System for Emission Tomography (SimSET) has been developed. This Monte Carlo-based software package tracks photons through complex heterogeneous objects (patients) and models the effects of collimation and detection. The package has been essential to our efforts and has been adopted by more than 300 other investigators in their own work. Part of our effort will be to continue to improve SimSET with significance acceleration of SPECT collimator simulation tools. The SimSET software package is freely available via the Internet.