18F-fluorodeoxyglucose (FDG) PET or 18F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study.

PURPOSE: This study evaluated the ability of 18F-Fluorodeoxyglucose (FDG) and 18F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors. METHODS: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery. RESULTS: FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range -45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range -77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range < 1 to 41%)]. Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery. CONCLUSIONS: A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.

Technical Note: A digital reference object representing Hoffman's 3D brain phantom for PET scanner simulations.

PURPOSE: Physical and digital phantoms play a key role in the development and testing of nuclear medicine instrumentation and processing algorithms for clinical and research applications, including neuroimaging using positron emission tomography (PET). We have developed and tested a digital reference object (DRO) version of the original segmented magnetic resonance imaging (MRI) data used for the three-dimensional (3D) PET brain phantom developed by Hoffman et al., which is used as the basis of a commercially available physical test phantom. METHODS: The DRO was constructed by subdividing the MRI image planes the original phantom was based on to create equal-thickness slices and re-labeling voxels. The digital data was then embedded in a PET Digital Imaging and Communications in Medicine format and tested for compliance. RESULTS: We then tested the DRO by comparing it to computed tomography (CT) images of the physical phantom summed to form composite slices with axial extent similar to the DRO, but with a factor of two better in-slice resolution. For composite slices, 91% of voxels were labeled in full agreement, 5% of the voxels were 50-75% accurate, and the remaining 4% of voxels had 25% or less agreement. CONCLUSIONS: This DRO can be used as an input for PET scanner simulation studies or for comparing simulations to measured Hoffman phantom images.

PET/CT-guided biopsy with respiratory motion correction.

PURPOSE: Given the ability of positron emission tomography (PET) imaging to localize malignancies in heterogeneous tumors and tumors that lack an X-ray computed tomography (CT) correlate, combined PET/CT-guided biopsy may improve the diagnostic yield of biopsies. However, PET and CT images are naturally susceptible to problems due to respiratory motion, leading to imprecise tumor localization and shape distortion. To facilitate PET/CT-guided needle biopsy, we developed and investigated the feasibility of a workflow that allows to bring PET image guidance into interventional CT suite while accounting for respiratory motion. METHODS: The performance of PET/CT respiratory motion correction using registered and summed phases method was evaluated through computer simulations using the mathematical 4D extended cardiac-torso phantom, with motion simulated from real respiratory traces. The performance of PET/CT-guided biopsy procedure was evaluated through operation on a physical anthropomorphic phantom. Vials containing radiolabeled 18F-fluorodeoxyglucose were placed within the physical phantom thorax as biopsy targets. We measured the average distance between target center and the simulated biopsy location among multiple trials to evaluate the biopsy localization accuracy. RESULTS: The computer simulation results showed that the RASP method generated PET images with a significantly reduced noise of 0.10 ± 0.01 standardized uptake value (SUV) as compared to an end-of-expiration image noise of 0.34 ± 0.04 SUV. The respiratory motion increased the apparent liver lesion size from 5.4 ± 1.1 to 35.3 ± 3.0 cc. The RASP algorithm reduced this to 15.7 ± 3.7 cc. The distances between the centroids for the static image lesion and two moving lesions in the liver and lung, when reconstructed with the RASP algorithm, were 0.83 ± 0.72 mm and 0.42 ± 0.72 mm. For the ungated imaging, these values increased to 3.48 ± 1.45 mm and 2.5 ± 0.12 mm, respectively. For the ungated imaging, this increased to 1.99 ± 1.72 mm. In addition, the lesion activity estimation (e.g., SUV) was accurate and constant for images reconstructed using the RASP algorithm, whereas large activity bias and variations (± 50%) were observed for lesions in the ungated images. The physical phantom studies demonstrated a biopsy needle localization error of 2.9 ± 0.9 mm from CT. Combined with the localization errors due to respiration for the PET images from simulations, the overall estimated lesion localization error would be 3.08 mm for PET-guided biopsies images using RASP and 3.64 mm when using ungated PET images. In other words, RASP reduced the localization error by approximately 0.6 mm. The combined error analysis showed that replacing the standard end-of-expiration images with the proposed RASP method in PET/CT-guided biopsy workflow yields comparable lesion localization accuracy and reduced image noise. CONCLUSION: The RASP method can produce PET images with reduced noise, attenuation artifacts and respiratory motion, resulting in more accurate lesion localization. Testing the PET/CT-guided biopsy workflow using computer simulation and physical phantoms with respiratory motion, we demonstrated that guided biopsy procedure with the RASP method can benefit from improved PET image quality due to noise reduction, without compromising the accuracy of lesion localization.

Bias in PET Images of Solid Phantoms Due to CT-Based Attenuation Correction.

The use of computed tomography (CT) images to correct for photon attenuation in positron emission tomography (PET) produces unbiased patient images, but it is not optimal for synthetic materials. For test objects made from epoxy, image bias and artifacts have been observed in well-calibrated PET/CT scanners. An epoxy used in commercially available sources was infused with long-lived 68Ge/68Ga nuclide and measured on several PET/CT scanners as well as on older PET scanners that measured attenuation with 511-keV photons. Bias in attenuation maps and PET images of phantoms was measured as imaging parameters and methods varied. Changes were made to the PET reconstruction to show the influence of CT-based attenuation correction. Additional attenuation measurements were made with a new epoxy intended for use in radiology and radiation treatment whose photonic properties mimic water. PET images of solid phantoms were biased by between 3% and 24% across variations in CT X-ray energy and scanner manufacturer. Modification of the reconstruction software reduced bias, but object-dependent changes were required to generate accurate attenuation maps. The water-mimicking epoxy formulation showed behavior similar to water in limited testing. For some solid phantoms, transformation of CT data to attenuation maps is a major source of PET image bias. The transformation can be modified to accommodate synthetic materials, but our data suggest that the problem may also be addressed by using epoxy formulations that are more compatible with PET/CT imaging.

Test-Retest Reproducibility of 18F-FDG PET/CT Uptake in Cancer Patients Within a Qualified and Calibrated Local Network.

Calibration and reproducibility of quantitative 18F-FDG PET measures are essential for adopting integral 18F-FDG PET/CT biomarkers and response measures in multicenter clinical trials. We implemented a multicenter qualification process using National Institute of Standards and Technology-traceable reference sources for scanners and dose calibrators, and similar patient and imaging protocols. We then assessed SUV in patient test-retest studies. Methods: Five 18F-FDG PET/CT scanners from 4 institutions (2 in a National Cancer Institute-designated Comprehensive Cancer Center, 3 in a community-based network) were qualified for study use. Patients were scanned twice within 15 d, on the same scanner (n = 10); different but same model scanners within an institution (n = 2); or different model scanners at different institutions (n = 11). SUVmax was recorded for lesions, and SUVmean for normal liver uptake. Linear mixed models with random intercept were fitted to evaluate test-retest differences in multiple lesions per patient and to estimate the concordance correlation coefficient. Bland-Altman plots and repeatability coefficients were also produced. Results: In total, 162 lesions (82 bone, 80 soft tissue) were assessed in patients with breast cancer (n = 17) or other cancers (n = 6). Repeat scans within the same institution, using the same scanner or 2 scanners of the same model, had an average difference in SUVmax of 8% (95% confidence interval, 6%-10%). For test-retest on different scanners at different sites, the average difference in lesion SUVmax was 18% (95% confidence interval, 13%-24%). Normal liver uptake (SUVmean) showed an average difference of 5% (95% confidence interval, 3%-10%) for the same scanner model or institution and 6% (95% confidence interval, 3%-11%) for different scanners from different institutions. Protocol adherence was good; the median difference in injection-to-acquisition time was 2 min (range, 0-11 min). Test-retest SUVmax variability was not explained by available information on protocol deviations or patient or lesion characteristics. Conclusion:18F-FDG PET/CT scanner qualification and calibration can yield highly reproducible test-retest tumor SUV measurements. Our data support use of different qualified scanners of the same model for serial studies. Test-retest differences from different scanner models were greater; more resolution-dependent harmonization of scanner protocols and reconstruction algorithms may be capable of reducing these differences to values closer to same-scanner results.

Calibration Software for Quantitative PET/CT Imaging Using Pocket Phantoms.

Multicenter clinical trials that use positron emission tomography (PET) imaging frequently rely on stable bias in imaging biomarkers to assess drug effectiveness. Many well-documented factors cause variability in PET intensity values. Two of the largest scanner-dependent errors are scanner calibration and reconstructed image resolution variations. For clinical trials, an increase in measurement error significantly increases the number of patient scans needed. We aim to provide a robust quality assurance system using portable PET/computed tomography "pocket" phantoms and automated image analysis algorithms with the goal of reducing PET measurement variability. A set of the "pocket" phantoms was scanned with patients, affixed to the underside of a patient bed. Our software analyzed the obtained images and estimated the image parameters. The analysis consisted of 2 steps, automated phantom detection and estimation of PET image resolution and global bias. Performance of the algorithm was tested under variations in image bias, resolution, noise, and errors in the expected sphere size. A web-based application was implemented to deploy the image analysis pipeline in a cloud-based infrastructure to support multicenter data acquisition, under Software-as-a-Service (SaaS) model. The automated detection algorithm localized the phantom reliably. Simulation results showed stable behavior when image properties and input parameters were varied. The PET "pocket" phantom has the potential to reduce and/or check for standardized uptake value measurement errors.

Simultaneous Estimation of Bias and Resolution in PET Images With a Long-Lived "Pocket" Phantom System.

A challenge in multicenter trials that use quantitative positron emission tomography (PET) imaging is the often unknown variability in PET image values, typically measured as standardized uptake values, introduced by intersite differences in global and resolution-dependent biases. We present a method for the simultaneous monitoring of scanner calibration and reconstructed image resolution on a per-scan basis using a PET/computed tomography (CT) "pocket" phantom. We use simulation and phantom studies to optimize the design and construction of the PET/CT pocket phantom (120 × 30 × 30 mm). We then evaluate the performance of the PET/CT pocket phantom and accompanying software used alongside an anthropomorphic phantom when known variations in global bias (±20%, ±40%) and resolution (3-, 6-, and 12-mm postreconstruction filters) are introduced. The resulting prototype PET/CT pocket phantom design uses 3 long-lived sources (15-mm diameter) containing germanium-68 and a CT contrast agent in an epoxy matrix. Activity concentrations varied from 30 to 190 kBq/mL. The pocket phantom software can accurately estimate global bias and can detect changes in resolution in measured phantom images. The pocket phantom is small enough to be scanned with patients and can potentially be used on a per-scan basis for quality assurance for clinical trials and quantitative PET imaging in general. Further studies are being performed to evaluate its performance under variations in clinical conditions that occur in practice.

An algorithm for automated ROI definition in water or epoxy-filled NEMA NU-2 image quality phantoms.

Drawing regions of interest (ROIs) in positron emission tomography/computed tomography (PET/CT) scans of the National Electrical Manufacturers Association (NEMA) NU-2 Image Quality (IQ) phantom is a time-consuming process that allows for interuser variability in the measurements. In order to reduce operator effort and allow batch processing of IQ phantom images, we propose a fast, robust, automated algorithm for performing IQ phantom sphere localization and analysis. The algorithm is easily altered to accommodate different configurations of the IQ phantom. The proposed algorithm uses information from both the PET and CT image volumes in order to overcome the challenges of detecting the smallest spheres in the PET volume. This algorithm has been released as an open-source plug-in to the Osirix medical image viewing software package. We test the algorithm under various noise conditions, positions within the scanner, air bubbles in the phantom spheres, and scanner misalignment conditions. The proposed algorithm shows run-times between 3 and 4 min and has proven to be robust under all tested conditions, with expected sphere localization deviations of less than 0.2 mm and variations of PET ROI mean and maximum values on the order of 0.5% and 2%, respectively, over multiple PET acquisitions. We conclude that the proposed algorithm is stable when challenged with a variety of physical and imaging anomalies, and that the algorithm can be a valuable tool for those who use the NEMA NU-2 IQ phantom for PET/CT scanner acceptance testing and QA/QC.

Evaluation of Cross-Calibrated 68Ge/68Ga Phantoms for Assessing PET/CT Measurement Bias in Oncology Imaging for Single- and Multicenter Trials.

Quantitative PET imaging is an important tool for clinical trials evaluating the response of cancers to investigational therapies. The standardized uptake value, used as a quantitative imaging biomarker, is dependent on multiple parameters that may contribute bias and variability. The use of long-lived, sealed PET calibration phantoms offers the advantages of known radioactivity activity concentration and simpler use than aqueous phantoms. We evaluated scanner and dose calibrator sources from two batches of commercially available kits, together at a single site and distributed across a local multicenter PET imaging network. We found that radioactivity concentration was uniform within the phantoms. Within the regions of interest drawn in the phantom images, coefficients of variation of voxel values were less than 2%. Across phantoms, coefficients of variation for mean signal were close to 1%. Biases of the standardized uptake value estimated with the kits varied by site and were seen to change in time by approximately ±5%. We conclude that these biases cannot be assumed constant over time. The kits provide a robust method to monitor PET scanner and dose calibrator biases, and resulting biases in standardized uptake values.