Energy-based scatter estimation in clinical PET.

BACKGROUND: Scatter correction (SC) is essential in PET for accurate quantitative imaging. The state-of-the-art SC method is single-scatter simulation (SSS). Although this method is usually robust and accurate, it can fail in some situations, for example when there is motion between the CT and PET scans in PET/CT. Therefore, it is of interest to consider other SC methods. PURPOSE: In this work, an energy-based scatter estimation (EBS) method is described in detail, tested in phantoms and patients, and compared to SSS. METHODS: This version of EBS was developed for list-mode data from Biograph Vision-600 PET/CT scanner. EBS is based on digitized 2D energy histograms in each bin of a coarsely sampled PET sinogram, either with or without time of flight (TOF). The histograms are modeled as a noisy realization of a linear combination of nine basis functions whose parameters were derived from a measurement of the 511-keV photopeak spectrum as well as Monte-Carlo simulations of the scattering process. EBS uses an iterative expectation maximization approach to determine the coefficients in the linear combination, and from this estimates the scatter. The investigation was restricted to 18 F-based PET data in which the acquired number of counts was similar to the levels seen in oncological whole-body PET/CT scans. To evaluate the performance, phantom scans were used that involved the NEMA NU2-2018 protocol, a slab phantom, an NU 2-1994 phantom, a cardiac phantom in an anthropomorphic chest phantom, and a uniformly-filled torso phantom with a bladder phantom slightly outside the axial field of view. Contrast recovery (CR) and other parameters were evaluated in images reconstructed with SSS and EBS. Furthermore, FDG PET scans of seven lung cancer patients were used in the evaluation. Standardized uptake values (SUV) based on SSS and EBS were compared in 27 lesions. RESULTS: EBS and SSS images were visually similar in all cases except the torso + bladder phantom, where the EBS was much closer to the expected uniform image. The NU2-2018 analysis indicated a 2% scatter residual in EBS images compared to 3% with SSS, and 10% higher background variability, which is a surrogate for image noise. The cardiac phantom scan showed that CR was 98.2% with EBS and 99.6% with SSS, and that the SSS sinogram had values greater than the net-true emission sinogram, indicating a slight overcorrection in the case of SSS. In the lesion SUV comparison in patient scans, EBS correlated strongly (R2  = 0.9973) with SSS, and SUV based on EBS were systematically 0.1 SUV lower. In the case of the torso + bladder phantom portion, the SSS image of the torso + bladder phantom was 299% times hotter than expected in one area, due to scatter estimation error, compared to 16% colder with EBS. CONCLUSIONS: In evaluating clinically relevant parameters such as SUV in focal lesions, EBS and SSS give almost the same results. In phantoms, some scatter figures of merit were slightly improved by use of EBS, though an image variability figure of merit was slightly degraded. In typical oncological whole-body PET/CT, EBS may be a suitable replacement for SSS, especially when SSS fails due to technical problems during the scan.

Abbreviated scan protocols to capture 18F-FDG kinetics for long axial FOV PET scanners.

PURPOSE: Kinetic parameters from dynamic 18F-fluorodeoxyglucose (FDG) imaging offer complementary insights to the study of disease compared to static clinical imaging. However, dynamic imaging protocols are cumbersome due to the long acquisition time. Long axial field-of-view (LAFOV) PET scanners (> 70 cm) have two advantages for dynamic imaging over clinical PET scanners with a standard axial field-of-view (SAFOV; 16-30 cm). The large axial coverage enables multi-organ dynamic imaging in a single bed position, and the high sensitivity may enable clinically routine abbreviated dynamic imaging protocols. METHODS: In this work, we studied two abbreviated protocols using data from a 65-min dynamic 18F-FDG scan: (A) dynamic imaging immediately post-injection (p.i.) for variable durations, and (B) dynamic imaging immediately p.i. for variable durations plus a 1-h p.i. (5-min-long) datapoint. Nine cancer patients were imaged on the Biograph Vision Quadra (Siemens Healthineers). Time-activity curves over the lesions (N = 39) were fitted using the Patlak graphical analysis and a 2-tissue-compartment (2C, k4 = 0) model for variable scan durations (5-60 min). Kinetic parameters from the complete dataset served as the reference. Lesions from all cancers were grouped into low, medium, and high flux groups, and bias and precision of Ki (Patlak) and Ki, K1, k2, and k3 (2C) were calculated for each group. RESULTS: Using only early dynamic data with the 2C (or Patlak) model, accurate quantification of Ki required at least 50 (or 55) min of dynamic data for low flux lesions, at least 30 (or 40) min for medium flux lesions, and at least 15 (or 20) min for high flux lesions to achieve both 10% bias and precision. The addition of the final (5-min) datapoint allowed for accurate quantification of Ki with a bias and precision of 10% using only 10-15 min of early dynamic data for either model. CONCLUSION: Dynamic imaging for 10-15 min immediately p.i. followed by a 5-min scan at 1-h p.i can accurately and precisely quantify 18F-FDG on a long axial FOV scanner, potentially allowing for more widespread use of dynamic 18F-FDG imaging.

Preliminary Evaluation of 68Ga-P16-093, a PET Radiotracer Targeting Prostate-Specific Membrane Antigen in Prostate Cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising molecular target for imaging of prostate adenocarcinoma. 68Ga-P16-093, a small molecule PSMA ligand, previously showed equivalent diagnostic performance compared to 68Ga-PSMA-11 PET/CT in a pilot study of prostate cancer patients with biochemical recurrence (BCR). We performed a pilot study for further characterization of 68Ga-P16-093 including comparison to conventional imaging. PROCEDURES: Patients were enrolled into two cohorts. The biodistribution cohort included 8 treated prostate cancer patients without recurrence, who underwent 6 whole body PET/CT scans with urine sampling for dosimetry using OLINDA/EXM. The dynamic cohort included 15 patients with BCR and 2 patients with primary prostate cancer. Two patients with renal cell carcinoma were also enrolled for exploratory use. A dynamic PET/CT was followed by 2 whole body scans for imaging protocol optimization based on bootstrapped replicates. 68Ga-P16-093 PET/CT was compared for diagnostic performance against available 18F-fluciclovine PET/CT, 99mTc-MDP scintigraphy, diagnostic CT, and MRI. RESULTS: 68Ga-P16-093 deposited similar effective dose (0.024 mSv/MBq) and lower urinary bladder dose (0.064 mSv/MBq) compared to 68Ga-PSMA-11. The kidneys were the critical organ (0.290 mSv/MBq). While higher injected activities were preferable, lower injected activities at 74-111 MBq (2-3 mCi) yielded 80% retention in signal-to-noise ratio. The optimal injection-to-scan interval was 60 min, with acceptable delay up to 90 min. 68Ga-P16-093 PET/CT showed superior diagnostic performance over conventional imaging with overall patient-level lesion detection rate of 71%, leading to a change in management in 42% of the patients. CONCLUSIONS: Based on its favorable imaging characteristics and diagnostic performance in prostate cancer, 68Ga-P16-093 PET/CT merits further investigation in larger clinical studies.

A proof-of-concept study of an in-situ partial-ring time-of-flight PET scanner for proton beam verification.

Development of a PET system capable of in-situ imaging requires a design that can accommodate the proton treatment beam nozzle. Among the several PET instrumentation approaches developed thus far, the dual-panel PET scanner is often used as it is simpler to develop and integrate within the proton therapy gantry. Partial-angle coverage of these systems can however lead to limited-angle artefacts in the reconstructed PET image. We have previously demonstrated via simulations that time-of-flight (TOF) reconstruction reduces the artifacts accompanying limited-angle data, and permits proton range measurement with 1-2 mm accuracy and precision. In this work we show measured results from a small proof-of-concept dual-panel PET system that uses TOF information to reconstruct PET data acquired after proton irradiation. The PET scanner comprises of two detector modules, each comprised of an array of 4×4×30 mm3 lanthanum bromide scintillator. Measurements are performed with an oxygen-rich gel-water, an adipose tissue equivalent material, and in vitro tissue phantoms. For each phantom measurement, 2 Gy dose was deposited using 54 - 100 MeV proton beams. For each phantom, a Monte Carlo simulation generating the expected distribution of PET isotope from the corresponding proton irradiation was also performed. Proton range was calculated by drawing multiple depth-profiles over a central region encompassing the proton dose deposition. For each profile, proton range was calculated using two techniques (a) 50% pick-off from the distal edge of the profile, and (b) comparing the measured and Monte Carlo profile to minimize the absolute sum of differences over the entire profile. A 10 min PET acquisition acquired with minimal delay post proton-irradiation is compared with a 10 min PET scan acquired after a 20 min delay. Measurements show that PET acquisition with minimal delay is necessary to collect 15O signal, and maximize 11C signal collection with a short PET acquisition. In comparison with the 50% pick-off technique, the shift technique is more robust and offers better precision in measuring the proton range for the different phantoms. Range measurements from PET images acquired with minimal delay, and the shift technique demonstrate the ability to achieve <1.5 mm accuracy and precision in estimating proton range.

Quantitative PET in the 2020s: a roadmap.

Positron emission tomography (PET) plays an increasingly important role in research and clinical applications, catalysed by remarkable technical advances and a growing appreciation of the need for reliable, sensitive biomarkers of human function in health and disease. Over the last 30 years, a large amount of the physics and engineering effort in PET has been motivated by the dominant clinical application during that period, oncology. This has led to important developments such as PET/CT, whole-body PET, 3D PET, accelerated statistical image reconstruction, and time-of-flight PET. Despite impressive improvements in image quality as a result of these advances, the emphasis on static, semi-quantitative 'hot spot' imaging for oncologic applications has meant that the capability of PET to quantify biologically relevant parameters based on tracer kinetics has not been fully exploited. More recent advances, such as PET/MR and total-body PET, have opened up the ability to address a vast range of new research questions, from which a future expansion of applications and radiotracers appears highly likely. Many of these new applications and tracers will, at least initially, require quantitative analyses that more fully exploit the exquisite sensitivity of PET and the tracer principle on which it is based. It is also expected that they will require more sophisticated quantitative analysis methods than those that are currently available. At the same time, artificial intelligence is revolutionizing data analysis and impacting the relationship between the statistical quality of the acquired data and the information we can extract from the data. In this roadmap, leaders of the key sub-disciplines of the field identify the challenges and opportunities to be addressed over the next ten years that will enable PET to realise its full quantitative potential, initially in research laboratories and, ultimately, in clinical practice.

Quantifying bias and precision of kinetic parameter estimation on the PennPET Explorer, a long axial field-of-view scanner.

Long axial field-of-view (AFOV) PET scanners allow for full-body dynamic imaging in a single bed-position at very high sensitivity. However, the benefits for kinetic parameter estimation have yet to be studied. This work uses (1) a dynamic GATE simulation of [18F]-fluorothymidine (FLT) in a modified NEMA IQ phantom and (2) a lesion embedding study of spheres in a dynamic [18F]-fluorodeoxyglucose (FDG) human subject imaged on the PennPET Explorer. Both studies were designed using published kinetic data of lung and liver cancers and modeled using two tissue compartments. Data were reconstructed at various emulated doses. Sphere time-activity curves (TACs) were measured on resulting dynamic images, and TACs were fit using a two-tissue-compartment model (k4 ≠ 0) for the FLT study and both a two-tissue-compartment model (k4 = 0) and Patlak graphical analysis for the FDG study to estimate flux (Ki) and delivery (K1) parameters. Quantification of flux and K1 shows lower bias and better precision for both radiotracers on the long AFOV scanner, especially at low doses. Dynamic imaging on a long AFOV system can be achieved for a greater range of injected doses, as low as 0.5-2 mCi depending on the sphere size and flux, compared to a standard AFOV scanner, while maintaining good kinetic parameter estimation.

Evaluating attenuation correction strategies in a dedicated, single-gantry breast PET-tomosynthesis scanner.

We are developing a dedicated, combined breast positron emission tomography (PET)-tomosynthesis scanner. Both the PET and digital breast tomosynthesis (DBT) scanners are integrated in a single gantry to provide spatially co-registered 3D PET-tomosynthesis images. The DBT image will be used to identify the breast boundary and breast density to improve the quantitative accuracy of the PET image. This paper explores PET attenuation correction (AC) strategies that can be performed with the combined breast PET-DBT scanner to obtain more accurate, quantitative high-resolution 3D PET images. The PET detector is comprised of a 32 × 32 array of 1.5 × 1.5 × 15 mm3 LYSO crystals. The PET scanner utilizes two detector heads separated by either 9 or 11 cm, with each detector head having a 4 × 2 arrangement of PET detectors. GEANT4 Application for Tomographic Emission simulations were performed using an anthropomorphic breast phantom with heterogeneous attenuation under clinical DBT-compression. FDG-avid lesions, each 5 mm in diameter with 8:1 uptake, were simulated at four locations within the breast. Simulations were performed with a scan time of 2 min. PET AC was performed using the actual breast simulation model as well as DBT reconstructed volumetric images to derive the breast outline. In addition to using the known breast density as defined by the breast model, we also modeled it as uniform patient-independent soft-tissue, and as a uniform patient-specific material derived from breast tissue composition. Measured absolute lesion uptake was used to evaluate the quantitative accuracy of performing AC using the various strategies. This study demonstrates that AC is necessary to obtain a closer estimate of the true lesion uptake and background activity in the breast. The DBT image dataset assists in measuring lesion uptake with low bias by facilitating accurate breast delineation as well as providing accurate information related to the breast tissue composition. While both the uniform soft-tissue and patient-specific material approaches provides a close estimate to the ground truth, <5% bias can be achieved by using a uniform patient-specific material to define the attenuation map.

Biodistribution, dosimetry, and temporal signal-to-noise ratio analyses of normal and cancer uptake of [68Ga]Ga-P15-041, a gallium-68 labeled bisphosphonate, from first-in-human studies.

INTRODUCTION: [68Ga]Ga-P15-041 ([68Ga]Ga-HBED-CC-BP) is a novel bone-seeking PET radiotracer that can be generator-produced. We undertook a Phase 0/I clinical trial to assess its potential for imaging bone metastases in prostate cancer including assessment of radiotracer biodistribution and dosimetry. METHODS: Subjects with prostate cancer and known or suspected osseous metastatic disease were enrolled into one of two arms: dosimetry or dynamic. Dosimetry was performed with 6 whole body PET acquisitions and urine collection spanning 3 h; normal organ dosimetry was calculated using OLINDA/EXM. Dynamic imaging included a 60 min acquisition over a site of known or suspected disease followed by two whole body scans. Bootstrapping and subsampling of the acquired list-mode data were conducted to recommend image acquisition parameters for future clinical trials. RESULTS: Up to 233 MBq (6.3 mCi) of [68Ga]Ga-P15-041 was injected into 12 enrolled volunteers, 8 in dosimetry and 4 in dynamic cohorts. Radiotracer accumulated in known bone lesions and cleared rapidly from blood and soft tissue. The highest individual organ dose was 0.135 mSv/MBq in the urinary bladder wall. The average effective dose was 0.0173 ± 0.0036 mSv/MBq. An average injected activity of 166.5 MBq (4.5 mCi) resulted in absorbed dose estimates of 22.5 mSv to the urinary bladder wall, 8.2 mSv to the kidneys, and an effective dose of 2.9 mSv. Lesion signal to noise ratios on images generated from subsampled data were significantly higher for injected activities above 74 MBq (2 mCi) and were also significantly higher for imaging at 90 min than at 180 min post-injection. CONCLUSIONS: Dosimetry estimates are acceptable and [68Ga]Ga-P15-041 uptake characteristics in patients with confirmed bone metastases support its continued development. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Use of [68Ga]Ga-P15-041 would not require cyclotron infrastructure for manufacturing and distribution, allowing for improved patient access to a promising PET bone imaging agent.

State of the art in total body PET.

The idea of a very sensitive positron emission tomography (PET) system covering a large portion of the body of a patient already dates back to the early 1990s. In the period 2000-2010, only some prototypes with long axial field of view (FOV) have been built, which never resulted in systems used for clinical research. One of the reasons was the limitations in the available detector technology, which did not yet have sufficient energy resolution, timing resolution or countrate capabilities for fully exploiting the benefits of a long axial FOV design. PET was also not yet as widespread as it is today: the growth in oncology, which has become the major application of PET, appeared only after the introduction of PET-CT (early 2000).The detector technology used in most clinical PET systems today has a combination of good energy and timing resolution with higher countrate capabilities and has now been used since more than a decade to build time-of-flight (TOF) PET systems with fully 3D acquisitions. Based on this technology, one can construct total body PET systems and the remaining challenges (data handling, fast image reconstruction, detector cooling) are mostly related to engineering. The direct benefits of long axial FOV systems are mostly related to the higher sensitivity. For single organ imaging, the gain is close to the point source sensitivity which increases linearly with the axial length until it is limited by solid angle and attenuation of the body. The gains for single organ (compared to a fully 3D PET 20-cm axial FOV) are limited to a factor 3-4. But for long objects (like body scans), it increases quadratically with scanner length and factors of 10-40 × higher sensitivity are predicted for the long axial FOV scanner. This application of PET has seen a major increase (mostly in oncology) during the last 2 decades and is now the main type of study in a PET centre. As the technology is available and the full body concept also seems to match with existing applications, the old concept of a total body PET scanner is seeing a clear revival. Several research groups are working on this concept and after showing the potential via extensive simulations; construction of these systems has started about 2 years ago. In the first phase, two PET systems with long axial FOV suitable for large animal imaging were constructed to explore the potential in more experimental settings. Recently, the first completed total body PET systems for human use, a 70-cm-long system, called PennPET Explorer, and a 2-m-long system, called uExplorer, have become reality and first clinical studies have been shown. These results illustrate the large potential of this concept with regard to low-dose imaging, faster scanning, whole-body dynamic imaging and follow-up of tracers over longer periods. This large range of possible technical improvements seems to have the potential to change the current clinical routine and to expand the number of clinical applications of molecular imaging. The J-PET prototype is a prototype system with a long axial FOV built from axially arranged plastic scintillator strips.This paper gives an overview of the recent technical developments with regard to PET scanners with a long axial FOV covering at least the majority of the body (so called total body PET systems). After explaining the benefits and challenges of total body PET systems, the different total body PET system designs proposed for large animal and clinical imaging are described in detail. The axial length is one of the major factors determining the total cost of the system, but there are also other options in detector technology, design and processing for reducing the cost these systems. The limitations and advantages of different designs for research and clinical use are discussed taking into account potential applications and the increased cost of these systems.

Benefit of Improved Performance with State-of-the Art Digital PET/CT for Lesion Detection in Oncology.

The latest digital whole-body PET scanners provide a combination of higher sensitivity and improved spatial and timing resolution. We performed a lesion detectability study on two generations of Biograph PET/CT scanners, the mCT Flow and the Vision, to study the impact of improved physical performance on clinical performance. Our hypothesis was that the improved performance of the Vision would result in improved lesion detectability, allowing shorter imaging times or, equivalently, a lower injected dose. Methods: Data were acquired with the Society of Nuclear Medicine and Molecular Imaging Clinical Trials Network torso phantom combined with a 20-cm-diameter cylindrical phantom. Spherical lesions were emulated by acquiring sphere-in-air data and combining them with the phantom data to generate combined datasets with embedded lesions of known contrast. Two sphere sizes and uptakes were used: 9.89-mm-diameter spheres with 6:1 (lung) and 3:1 (cylinder) local activity concentration uptakes and 4.95-mm-diameter spheres with 9.6:1 (lung) and 4.5:1 (cylinder) local activity concentration uptakes. Standard image reconstruction was performed: an ordinary Poisson ordered-subsets expectation maximization algorithm with point-spread function and time-of-flight modeling and postreconstruction smoothing with a 5-mm gaussian filter. The Vision images were also generated without any postreconstruction smoothing. Generalized scan statistics methodology was used to estimate the area under the localized receiver-operating-characteristic curve (ALROC). Results: The higher sensitivity and improved time-of-flight performance of the Vision leads to reduced contrast in the background noise nodule distribution. Measured lesion contrast is also higher on the Vision because of its improved spatial resolution. Hence, the ALROC is noticeably higher for the Vision than for the mCT Flow. Conclusion: Improved overall performance of the Vision provides a factor of 4-6 reduction in imaging time (or injected dose) over the mCT Flow when using the ALROC metric for lesions at least 9.89 mm in diameter. Smaller lesions are barely detected in the mCT Flow, leading to even higher ALROC gains with the Vision. The improved spatial resolution of the Vision also leads to a higher measured contrast that is closer to the real uptake, implying improved quantification. Postreconstruction smoothing, however, reduces this improvement in measured contrast, thereby reducing the ALROC for small, high-uptake lesions.

Numerical observer study of lesion detectability for a long axial field-of-view whole-body PET imager using the PennPET Explorer.

This work uses lesion detectability to characterize the performance of long axial field of view (AFOV) PET scanners which have increased sensitivity compared to clinical scanners. Studies were performed using the PennPET Explorer, a 70 cm long AFOV scanner built at the University of Pennsylvania, for small lesions distributed in a uniform water-filled cylinder (simulations and measurements), an anthropomorphic torso phantom (measurement), and a human subject (measurement). The lesion localization and detection task was quantified numerically using a generalized scan statistics methodology. Detectability was studied as a function of background activity distribution, scan duration for a single bed position, and axial location of the lesions. For the cylindrical phantom, the areas under the localization receiver operating curve (ALROCs) of lesions placed at various axial locations in the scanner were greater than 0.8-a value considered to be clinically acceptable (i.e. 80% probability of detecting lesion)-for scan times of 60 s or longer for standard-of-care (SoC) clinical dose levels. 10 mm diameter lesions placed in the anthropomorphic phantom and human subject resulted in ALROCs of 0.8 or greater for scan times longer than 30 s in the lung region and 60 s in the liver region, also for SoC doses. ALROC results from all three activity distributions show similar trends as a function of counts detected per axial location. These results will be used to guide decisions on imaging parameters, such as scan time and patient dose, when imaging patients in a single bed position on long AFOV systems and can also be applied to clinical scanners with consideration of the sensitivity differences.

Spatially-variant image-based modeling of PSF deformations with application to a limited angle geometry from a dual-panel breast-PET imager.

Dual-panel PET system configuration can lead to spatially variable point-spread functions (PSF) of considerable deformations due to depth-of-interaction effects and limited angular coverage. If not modelled properly, these effects result in decreased and inconsistent recovery of lesion activity across the field-of-view (FOV), as well as mispositioning of lesions in the reconstructed image caused by strong PSF asymmetries. We implemented and evaluated models of such PSF deformations with spatially-variant image-based resolution modeling (IRM) within reconstruction (varRM) using the Direct Image REConstruction for Time-of-flight (DIRECT) method and within post-reconstruction deconvolution methods. In addition, DIRECT reconstruction was performed with a spatially-invariant IRM (invRM) and without resolution modeling (noRM) for comparison. The methods were evaluated using simulated data for a realistic breast model with a set of 5 mm lesions located throughout the FOV of a dual-panel Breast-PET scanner. We simulated high-count data to focus on the ability of each method to correctly recover the PSF deformations, and a clinically realistic count level to assess the impact of low count data on the quantitative performance of the evaluated techniques. Performance of the methods evaluated herein was assessed by comparing lesion activity recovery (%BIAS), consistency (%SD) across the FOV, overall error (%RMSE), and recovery of each lesion location. As expected, all techniques using IRM provide considerable improvement over the noRM reconstruction. For the high-count cases, the overall quantitative performance of all IRM techniques, whether within reconstruction or within post-reconstruction, is similar if the lesion location misplacements are ignored. However, invRM provides less consistent performance on activity across lesions and is not able to recover accurate lesion locations. For a clinically realistic count level, varRM reconstruction consistently outperforms all compared approaches, while the post-reconstruction IRM approaches exhibit higher %SD and %RMSE values due to being more affected by the data noise than the within-reconstruction IRM approaches.

Advances in PET Diagnostics for Guiding Targeted Cancer Therapy and Studying In Vivo Cancer Biology.

Purpose of the Review: We present an overview of recent advances in positron emission tomography (PET) diagnostics as applied to the study of cancer, specifically as a tool to study in vivo cancer biology and to direct targeted cancer therapy. The review is directed to translational and clinical cancer investigators who may not be familiar with these applications of PET cancer diagnostics, but whose research might benefit from these advancing tools. Recent Findings: We highlight recent advances in 3 areas: (1) the translation of PET imaging cancer biomarkers to clinical trials; (2) methods for measuring cancer metabolism in vivo in patients; and (3) advances in PET instrumentation, including total-body PET, that enable new methodologies. We emphasize approaches that have been translated to human studies. Summary: PET imaging methodology enables unique in vivo cancer diagnostics that go beyond cancer detection and staging, providing an improved ability to guide cancer treatment and an increased understanding of in vivo human cancer biology.

Validation of phantom-based harmonization for patient harmonization.

PURPOSE: To improve the precision of multicenter clinical trials, several efforts are underway to determine scanner-specific parameters for harmonization using standardized phantom measurements. The goal of this study was to test the correspondence between quantification in phantom and patient images and validate the use of phantoms for harmonization of patient images. METHODS: The National Electrical Manufacturers' Association image quality phantom with hot spheres was scanned on two time-of-flight PET scanners. Whole-body [18 F]-fluorodeoxyglucose (FDG)-PET scans were acquired of subjects on the same systems. List-mode events from spheres (diam.: 10-28 mm) measured in air on each scanner were embedded into the phantom and subject list-mode data from each scanner to create lesions with known uptake with respect to the local background in the phantom and each subject's liver and lung regions, as a proxy to characterize true lesion quantification. Images were analyzed using the contrast recovery coefficient (CRC) typically used in phantom studies and serving as a surrogate for the standardized uptake value used clinically. Postreconstruction filtering (resolution recovery and Gaussian smoothing) was applied to determine if the effect on the phantom images translates equivalently to subject images. Three postfiltering strategies were selected to harmonize the CRCmean or CRCmax values between the two scanners based on the phantom measurements and then applied to the subject images. RESULTS: Both the average CRCmean and CRCmax values for lesions embedded in the lung and liver in four subjects (BMI range 25-38) agreed to within 5% with the CRC values for lesions embedded in the phantom for all lesion sizes. In addition, the relative changes in CRCmean and CRCmax resulting from the application of the postfilters on the subject and phantom images were consistent within measurement uncertainty. Further, the root mean squared percent difference (RMSpd ) between CRC values on the two scanners calculated over the three sphere sizes was significantly reduced in the subjects using postfiltering strategies chosen to harmonize CRCmean or CRCmax based on phantom measurements: RMSpd of the CRCmean values in subjects was reduced from 36% to < 8% after harmonizing CRCmean , while RMSpd for CRCmax was reduced from ~33% to < 6% after harmonizing CRCmax with a different strategy. However, with this strategy designed to harmonize CRCmax , the RMSpd for CRCmean only improved to ~14% in subjects. CONCLUSIONS: The consistency of the CRC measurements between the phantom and subject data demonstrates that harmonization strategies defined with phantom studies track well to patient images. However, quantitative agreement between different scanners as represented by the RMSpd depends on the metric chosen for harmonization.

Qualification of National Cancer Institute-Designated Cancer Centers for Quantitative PET/CT Imaging in Clinical Trials.

The National Cancer Institute developed the Centers for Quantitative Imaging Excellence (CQIE) initiative in 2010 to prequalify imaging facilities at all of the National Cancer Institute-designated comprehensive and clinical cancer centers for oncology trials using advanced imaging techniques, including PET. Here we review the CQIE PET/CT scanner qualification process and results in detail. Methods: Over a period of approximately 5 y, sites were requested to submit a variety of phantoms, including uniform and American College of Radiology-approved phantoms, PET/CT images, and examples of clinical images. Submissions were divided into 3 distinct time periods: initial submission (T0) and 2 requalification submissions (T1 and T2). Images were analyzed using standardized procedures, and scanners received a pass or fail designation. Sites had the opportunity to submit new data for scanners that failed. Quantitative results were compared across scanners within a given time period and across time periods for a given scanner. Results: Data from 65 unique PET/CT scanners across 56 sites were submitted for CQIE T0 qualification; 64 scanners passed the qualification. Data from 44 (68%) of those 65 scanners were submitted for T2. From T0 to T2, the percentage of scanners passing the CQIE qualification on the first attempt rose from 38% for T1 to 67% for T2. The most common reasons for failure were SUV outside specifications, incomplete submission, and uniformity issues. Uniform phantom and American College of Radiology-approved phantom results between scanner manufacturers were similar. Conclusion: The results of the CQIE process showed that periodic requalification may decrease the frequency of deficient data submissions. The CQIE project also highlighted the concern within imaging facilities about the burden of maintaining different qualifications and accreditations. Finally, for quantitative imaging-based trials, further evaluation of the relationships between the level of the qualification (e.g., bias or precision) and the quality of the image data, accrual rates, and study power is needed.

Advances in time-of-flight PET.

This paper provides a review and an update on time-of-flight PET imaging with a focus on PET instrumentation, ranging from hardware design to software algorithms. We first present a short introduction to PET, followed by a description of TOF PET imaging and its history from the early days. Next, we introduce the current state-of-art in TOF PET technology and briefly summarize the benefits of TOF PET imaging. This is followed by a discussion of the various technological advancements in hardware (scintillators, photo-sensors, electronics) and software (image reconstruction) that have led to the current widespread use of TOF PET technology, and future developments that have the potential for further improvements in the TOF imaging performance. We conclude with a discussion of some new research areas that have opened up in PET imaging as a result of having good system timing resolution, ranging from new algorithms for attenuation correction, through efficient system calibration techniques, to potential for new PET system designs.

Repeatability of 18F-FDG PET/CT in Advanced Non-Small Cell Lung Cancer: Prospective Assessment in 2 Multicenter Trials.

UNLABELLED: PET/CT with the glucose analog (18)F-FDG has several potential applications for monitoring tumor response to therapy in patients with non-small cell lung cancer (NSCLC). A prerequisite for many of these applications is detailed knowledge of the repeatability of quantitative parameters derived from (18)F-FDG PET/CT studies. METHODS: The repeatability of the (18)F-FDG signal was evaluated in 2 prospective multicenter trials. Patients with advanced NSCLC (tumor stage III-IV) underwent two (18)F-FDG PET/CT studies while not receiving therapy. Tumor (18)F-FDG uptake was quantified by measurement of the maximum standardized uptake value within a lesion (SUVmax) and the average SUV within a small volume of interest around the site of maximum uptake (SUVpeak). Analysis was performed for the lesion in the chest with the highest (18)F-FDG uptake and a size of at least 2 cm (target lesion) as well as for up to 6 additional lesions per patient. Repeatability was assessed by Bland-Altman plots and calculation of 95% repeatability coefficients (RCs) of the log-transformed SUV differences. RESULTS: Test-retest repeatability was assessed in 74 patients (34 from the ACRIN 6678 trial and 40 from the Merck MK-0646-008 trial). SUVpeak was 11.57 ± 7.89 g/mL for the ACRIN trial and 6.89 ± 3.02 for the Merck trial. The lower and upper RCs were -28% (95% confidence interval [CI], -35% to -23%) and +39% (95% CI, 31% to 54%) in the ACRIN trial, indicating that a decrease of SUVpeak by more than 28% or an increase by more than 39% has a probability of less than 2.5%. The corresponding RCs from the Merck trial were -35% (95% CI, -42% to -29%) and +53% (95% CI, 41% to 72%). Repeatability was similar for SUVmax of the target lesion, averaged SUVmax, and averaged SUVpeak of up to 6 lesions per patient. CONCLUSION: The variability of repeated measurements of tumor (18)F-FDG uptake in patients with NSCLC is somewhat larger than previously reported in smaller single-center studies but comparable to that of gastrointestinal malignancies in a previous multicenter trial. The variability of measurements supports the definitions of tumor response according to PET Response Criteria in Solid Tumors.

Oncogene pathway activation in mammary tumors dictates FDG-PET uptake.

Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography of the labeled glucose analogue 2[(18)F]fluoro-2-deoxy-D-glucose (FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake--and that underlie the heterogeneity observed across cancers-remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC, HER2/neu, Wnt1, or H-Ras oncogenes in genetically engineered mice, correlating it to tumor growth, cell proliferation, and expression levels of gene involved in key steps of glycolytic metabolism. We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and hypoxia-inducible factor-1α (HIF1α) and associated negatively with PFK-2b expression and p-AMPK. The correlation between HK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/neu. Together, these results demonstrate that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes, and provide a framework to interpret effects on this key parameter in clinical imaging.

A Dedicated Breast Positron Emission Tomography Scanner: Proof of Concept.

PURPOSE: This study developed and tested a novel scanner constructed for dedicated positron emission tomography (PET) of the breast. The breast PET (B-PET) scanner is designed with two opposing detectors using curve plate NaI(Tl) detectors to achieve a combination of high spatial resolution and energy resolution. METHODS: Phantom and clinical studies (n = 20) with 18F-fluorodeoxyglucose were carried out on the whole-body Philips Allegro scanner and the B-PET scanner. Images were subjectively assessed by an expert panel. RESULTS: Phantom studies indicated improved contrast for B-PET over conventional PET. Of the 20 clinical studies with breast cancer demonstrated on whole-body fluorodeoxyglucose PET, 10 B-PET scans showed agreement. Of the remaining 10 studies, three had breasts that were too small to be imaged, four had lesions that were too deep to be captured in the field of view, and three were excluded due to technical errors. CONCLUSIONS: Compared with conventional PET, B-PET images provided greater detail in breast lesions suggesting that the low-cost and relatively simple design of B-PET may potentially be an important adjunct to traditional mammography in helping determine the nature of a lesion.

Design Study of a Whole-Body PET Scanner with Improved Spatial and Timing Resolution.

Current state-of-art whole-body PET scanners achieve a system spatial resolution of 4-5 mm with limited sensitivity. Since the reconstructed spatial resolution and image quality are limited by the count statistics, there has not been a significant push for developing higher resolution whole-body PET scanners. Our goal in this study is to investigate the impact of improved spatial resolution together with time-of-flight (TOF) capability on lesion uptake estimation and lesion detectability, two important tasks in whole-body oncologic studies. The broader goal of this project is the development of a new state-of-art TOF PET scanner operating within an MRI while pushing the technology in PET system design. We performed Monte Carlo simulations to test the effects of crystal size (4 mm and 2.6 mm wide crystals), TOF timing resolution (300ps and 600ps), and 2-level depth-of-interaction (DOI) capability. Spatial resolution was calculated by simulating point sources in air at multiple positions. Results show that smaller crystals produced improved resolution, while degradation of resolution due to parallax error could be reduced with a 2-level DOI detector. Lesion phantoms were simulated to measure the contrast recovery coefficient (CRC) and area under the LROC curve (ALROC) for 0.5 cm diameter lesions with 6:1 activity uptake relative to the background. Smaller crystals produce higher CRC, leading to increased ALROC values or a reduction in scan time. Improved timing resolution provides faster CRC convergence and once again leads to an increase in ALROC value or reduced scan time. Based on our choice of timing resolution and crystal size, improved timing resolution (300ps) with larger crystals (4 mm wide) has similar ALROC as smaller crystals (2.6 mm wide) with 600ps timing resolution. A 2-level DOI measurement provides some CRC and ALROC improvement for lesions further away from the center, leading to a more uniform performance within the imaging field-of-view (FOV). Given a choice between having either an improved spatial resolution, improved timing resolution, or DOI capability, improved spatial or timing resolution provide an overall higher ALROC relative to a 2-level DOI detector.