BackgroundData-driven gating (DDG) can improve PET quantitation and alleviate many issues with patient motion. However, misregistration between DDG-PET and CT may occur due to the distinct temporal resolutions of PET and CT and can be mitigated by DDG-CT. Here, the effects of misregistration and respiratory motion on PET quantitation and lesion segmentation were assessed with a new DDG-PET/CT method.MethodsA low-dose cine-CT was acquired in misregistered regions to enable both average CT (ACT) and DDG-CT. The following were compared: (1) baseline PET/CT, (2) PET/ACT (attenuation correction, AC = ACT), (3) DDG-PET (AC = helical CT), and (4) DDG-PET/CT (AC = DDG-CT). For DDG-PET, end-expiration (EE) data were derived from 50% of the total PET data at 30% from end-inspiration. For DDG-CT, EE phase CT data were extracted from cine-CT data by lung Hounsfield unit (HU) value and body contour. A total of 91 lesions from 16 consecutive patients were assessed for changes in standard uptake value (SUV), lesion glycolysis (LG), lesion volume, centroid-to-centroid distance (CCD), and DICE coefficients.ResultsRelative to baseline PET/CT, median changes in SUVmax ± σ for all 91 lesions were 20 ± 43%, 26 ± 23%, and 66 ± 66%, respectively, for PET/ACT, DDG-PET, and DDG-PET/CT. Median changes in lesion volume were 0 ± 58%, − 36 ± 26%, and − 26 ± 40%. LG for individual lesions increased for PET/ACT and decreased for DDG-PET, but was not different for DDG-PET/CT. Changes in mean HU from baseline PET/CT were dramatic for most lesions in both PET/ACT and DDG-PET/CT, especially for lesions with mean HU < 0 at baseline. CCD and DICE were both affected more by motion correction with DDG-PET than improved registration with ACT or DDG-CT.ConclusionAs misregistration becomes more prominent, the impact of motion correction with DDG-PET is diminished. The potential benefits of DDG-PET toward accurate lesion segmentation and quantitation could only be fully realized when combined with DDG-CT. These results impress upon the necessity of ensuring both misregistration and motion correction are accounted for together to optimize the clinical utility of PET/CT.