Clinically feasible semi-automatic workflows for measuring metabolically active tumour volume in metastatic melanoma

PURPOSE: Metabolically active tumour volume (MATV) is a potential quantitative positron emission tomography (PET) imaging biomarker in melanoma. Accumulating data indicate that low MATV may predict increased chance of response to immunotherapy and overall survival. However, metastatic melanoma can present with numerous (small) tumour lesions, making manual tumour segmentation time-consuming. The aim of this study was to evaluate multiple semi-automatic segmentation workflows to determine reliability and reproducibility of MATV measurements in patients with metastatic melanoma. METHODS: An existing cohort of 64 adult patients with histologically proven metastatic melanoma was used in this study. 18F-FDG PET/CT diagnostic baseline images were acquired using a European Association of Nuclear Medicine (EANM) Research Limited-accredited Siemens Biograph mCT PET/CT system (Siemens Healthineers, Knoxville, USA). PET data were analysed using manual, gradient-based segmentation and five different semi-automatic methods: three direct PET image-derived delineations (41MAX, A50P and SUV40) and two based on a majority-vote approach (MV2 and MV3), without and with (suffix '+') manual lesion addition. Correlation between the different segmentation methods and their respective associations with overall survival was assessed. RESULTS: Correlation between the MATVs derived by the manual segmentation and semi-automated tumour segmentations ranged from R2 = 0.41 for A50P to R2 = 0.85 for SUV40+ and MV2+, respectively. Manual MATV segmentation did not differ significantly from the semi-automatic methods SUV40 (∆MATV mean ± SD 0.08 ± 0.60 mL, P = 0.303), SUV40+ (∆MATV - 0.10 ± 0.51 mL, P = 0.126), MV2+ (∆MATV - 0.09 ± 0.62 mL, P = 0.252) and MV3+ (∆MATV - 0.03 ± 0.55 mL, P = 0.615). Log-rank tests showed statistically significant overall survival differences between above and below median MATV patients for all segmentation methods with areas under the ROC curves of 0.806 for manual segmentation and between 0.756 [41MAX] and 0.807 [MV3+] for semi-automatic segmentations. CONCLUSIONS: Simple and fast semi-automated FDG PET segmentation workflows yield accurate and reproducible MATV measurements that correlate well with manual segmentation in metastatic melanoma. The most readily applicable and user-friendly SUV40 method allows feasible MATV measurement in prospective multicentre studies required for validation of this potential PET imaging biomarker for clinical use

Image Derived Input Functions: Effects of Motion on Tracer Kinetic Analyses

Purpose: To quantify the effects of motion affected image-derived input functions (IDIF) on the outcome of tracer kinetic analyses. Procedures: Two simulation studies, one based on high and the other on low cortical uptake, were performed. Different degrees of rotational and axial translational motion were added to the final frames of simulated dynamic positron emission tomography scans. Extracted IDIFs from motion affected simulated scans were compared to original IDIFs and to outcome of tracer kinetic analysis (volume of distribution, V T). Results: Differences in IDIF values of up to 239 % were found for the last frames. Patient motion of more than 6 ° or 5 mm resulted in at least 10 % higher or lower VT values for the high cortical tracer. Conclusion: The degrees of motion studied are commonly observed in clinical studies and hamper the extraction of accurate IDIFs. Therefore, it is essential to ensure that patient motion is minimal and corrected for

EANM/EARL harmonization strategies in PET quantification: from daily practice to multicentre oncological studies

Quantitative positron emission tomography/computed tomography (PET/CT) can be used as diagnostic or prognostic tools (i.e. single measurement) or for therapy monitoring (i.e. longitudinal studies) in multicentre studies. Use of quantitative parameters, such as standardized uptake values (SUVs), metabolic active tumor volumes (MATVs) or total lesion glycolysis (TLG), in a multicenter setting requires that these parameters be comparable among patients and sites, regardless of the PET/CT system used. This review describes the motivations and the methodologies for quantitative PET/ CT performance harmonization with emphasis on the EANM Research Ltd. (EARL) Fluorodeoxyglucose (FDG) PET/CT accreditation program, one of the international harmonization programs aiming at using FDG PET as a quantitative imaging biomarker. In addition, future accreditation initiatives will be discussed. The validation of the EARL accreditation program to harmonize SUVs and MATVs is described in a wide range of tumor types, with focus on therapy assessment using either the European Organization for Research and Treatment of Cancer (EORTC) criteria or PET Evaluation Response Criteria in Solid Tumors (PERCIST), as well as liver-based scales such as the Deauville score. Finally, also presented in this paper are the results from a survey across 51 EARL-accredited centers reporting how the program was implemented and its impact on daily routine and in clinical trials, harmonization of new metrics such as MATV and heterogeneity features

Feasibility of state of the art PET/CT systems performance harmonisation

Purpose The objective of this study was to explore the feasibility of harmonising performance for PET/CT systems equipped with time-of-flight (ToF) and resolution modelling/point spread function (PSF) technologies. A second aim was producing a working prototype of new harmonising criteria with higher contrast recoveries than current EARL standards using various SUV metrics. Methods Four PET/CT systems with both ToF and PSF capabilities from three major vendors were used to acquire and reconstruct images of the NEMA NU2-2007 body phantom filled conforming EANM EARL guidelines. A total of 15 reconstruction parameter sets of varying pixel size, post filtering and reconstruction type, with three different acquisition durations were used to compare the quantitative performance of the systems. A target range for recovery curves was established such that it would accommodate the highest matching recoveries from all investigated systems. These updated criteria were validated on 18 additional scanners from 16 sites in order to demonstrate the scanners' ability to meet the new target range. Results Each of the four systems was found to be capable of producing harmonising reconstructions with similar recovery curves. The five reconstruction parameter sets producing harmonising results significantly increased SUVmean (25%) and SUVmax (26%) contrast recoveries compared with current EARL specifications. Additional prospective validation performed on 18 scanners from 16 EARL accredited sites demonstrated the feasibility of updated harmonising specifications. SUVpeak was found to significantly reduce the variability in quantitative results while producing lower recoveries in smaller ( Conclusions Harmonising PET/CT systems with ToF and PSF technologies from different vendors was found to be feasible. The harmonisation of such systems would require an update to the current multicentre accreditation program EARL in order to accommodate higher recoveries. SUVpeak should be further investigated as a noise resistant alternative quantitative metric to SUVmax

Image Quality and Semiquantitative Measurements on the Biograph Vision PET/CT System:Initial Experiences and Comparison with the Biograph mCT

In May 2018, the Biograph Vision PET/CT system was installed at the University Medical Center Groningen. This study evaluated the initial experiences with this new PET/CT system in terms of perceived image quality and semiquantitative analysis in comparison to the Biograph mCT as a reference. Methods: In total, 20 oncologic patients were enrolled and received a single 3 MBq/kg injected dose of 18F-FDG followed by a dual-imaging PET scan. Ten patients were scanned on the Biograph mCT first, whereas the other 10 patients were scanned on the Biograph Vision first. The locally preferred clinically reconstructed images were blindly reviewed by 3 nuclear medicine physicians and scored (using a Likert scale of 1–5) on tumor lesion demarcation, overall image quality, and image noise. In addition, these clinically reconstructed images were used for semiquantitative analysis by measurement of SUVs in tumor lesions. Images acquired using reconstructions conform with the European Association of Nuclear Medicine Research Ltd. (EARL) specifications were also used for measurements of SUV in tumor lesions and healthy tissues for comparison between systems. Results: The 18F-FDG dose received by the 14 men and 6 women (age range, 36–84; mean ± SD, 61 ± 16 y) ranged from 145 to 405 MBq (mean ± SD, 268 ± 59.3). Images acquired on the Biograph Vision were scored significantly higher on tumor lesion demarcation, overall image quality, and image noise than images acquired on the Biograph mCT (P < 0.001). The overall interreader agreement showed a Fleiss κ of 0.61 (95% confidence interval, 0.53–0.70). Furthermore, the SUVs in tumor lesions and healthy tissues agreed well (within 95%) between PET/CT systems, particularly when EARL-compliant reconstructions were used on both systems. Conclusion: In this initial study, the Biograph Vision showed improved image quality compared with the Biograph mCT in terms of lesion demarcation, overall image quality, and visually assessed signal-to-noise ratio. The 2 systems are comparable in semiquantitatively assessed image biomarkers in both healthy tissues and tumor lesions. Improved quantitative performance may, however, be feasible using the clinically optimized reconstruction settings

EANM/EARL FDG-PET/CT accreditation - summary results from the first 200 accredited imaging systems

Purpose From 2010 until July 2016, the EANM Research Ltd. (EARL) FDG-PET/CT accreditation program has collected over 2500 phantom datasets from approximately 200 systems and 150 imaging sites worldwide. The objective of this study is to report the findings and impact of the accreditation program on the participating PET/CT systems. Methods To obtain and maintain EARL accredited status, sites were required to complete and submit two phantom scans - calibration quality control (CalQC), using a uniform cylindrical phantom and image quality control (IQQC), using a NEMA NU2-2007 body phantom. Average volumetric SUV bias and SUV recovery coefficients (RC) were calculated and the data evaluated on the basis of quality control (QC) type, approval status, PET/CT system manufacturer and submission order. Results SUV bias in 5% (n = 96) of all CalQC submissions (n = 1816) exceeded 10%. After corrective actions following EARL feedback, sites achieved 100% compliance within EARL specifications. 30% (n = 1381) of SUVmean and 23% (n = 1095) of SUVmax sphere recoveries from IQQC submissions failed to meet EARL accreditation criteria while after accreditation, failure rate decreased to 12% (n = 360) and 9% (n = 254), respectively. Most systems demonstrated longitudinal SUV bias reproducibility within +/- 5%, while RC values remained stable and generally within +/- 10% for the four largest and +/- 20% for the two smallest spheres. Conclusions Regardless of manufacturer or model, all investigated systems are able to comply with the EARL specifications. Within the EARL accreditation program, gross PET/CT calibration errors are successfully identified and longitudinal variability in PET/CT performances reduced. The program demonstrates that a harmonising accreditation procedure is feasible and achievable

Feasibility of state of the art PET/CT systems performance harmonisation

Purpose The objective of this study was to explore the feasibility of harmonising performance for PET/CT systems equipped with time-of-flight (ToF) and resolution modelling/point spread function (PSF) technologies. A second aim was producing a working prototype of new harmonising criteria with higher contrast recoveries than current EARL standards using various SUV metrics. Methods Four PET/CT systems with both ToF and PSF capabilities from three major vendors were used to acquire and reconstruct images of the NEMA NU2-2007 body phantom filled conforming EANM EARL guidelines. A total of 15 reconstruction parameter sets of varying pixel size, post filtering and reconstruction type, with three different acquisition durations were used to compare the quantitative performance of the systems. A target range for recovery curves was established such that it would accommodate the highest matching recoveries from all investigated systems. These updated criteria were validated on 18 additional scanners from 16 sites in order to demonstrate the scanners' ability to meet the new target range. Results Each of the four systems was found to be capable of producing harmonising reconstructions with similar recovery curves. The five reconstruction parameter sets producing harmonising results significantly increased SUVmean (25%) and SUVmax (26%) contrast recoveries compared with current EARL specifications. Additional prospective validation performed on 18 scanners from 16 EARL accredited sites demonstrated the feasibility of updated harmonising specifications. SUVpeak was found to significantly reduce the variability in quantitative results while producing lower recoveries in smaller (<= 17 mm diameter) sphere sizes. Conclusions Harmonising PET/CT systems with ToF and PSF technologies from different vendors was found to be feasible. The harmonisation of such systems would require an update to the current multicentre accreditation program EARL in order to accommodate higher recoveries. SUVpeak should be further investigated as a noise resistant alternative quantitative metric to SUVmax

Children's spatial analysis of simple and complex Hierarchical Patterns in a Drawing Task

BACKGROUND: Primary tumor volume is as an important and independent prognostic factor in Ewing sarcoma. However, the observer variability of magnetic resonance imaging (MRI)-based primary tumor volume measurements in newly diagnosed Ewing sarcoma has never been investigated. Furthermore, it is unclear how MRI-based volume measurements compare to (18)F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)-based volume measurements. This study aimed to determine the observer variability of simplified MRI-based primary tumor volume measurements in newly diagnosed treatment-naive Ewing sarcoma and to compare them to the actual primary tumor volume at MRI and the FDG-PET-based metabolically active tumor volume (MATV). MATERIAL AND METHODS: Twenty-nine newly diagnosed Ewing sarcoma patients with pretreatment MRI (of whom 11 also underwent FDG-PET) were included. Both exact and dichotomized (according to the proposed threshold of 200 mL) primary tumor volume measurements were analyzed. RESULTS: Mean inter- and intraobserver differences of MRI-based simplified tumor volume ± limits of agreement varied between 15-42 ± 155-204 mL and between 9-16 ± 64-250 mL, respectively. Inter- and intraobserver agreements of dichotomized MRI-based simplified tumor volume measurements was very good (κ = 0.827-1.000). Mean difference between simplified and actual tumor volumes at MRI ± limits of agreement was 60 ± 381 mL. Agreement between dichotomized simplified and actual tumor volumes at MRI was very good (κ = 0.839). Mean difference between MRI-based simplified tumor volume and MATV ± limits of agreement was 181 ± 549 mL and almost significantly different (p = .0581). Agreement between dichotomized MRI-based simplified tumor volume and MATV was moderate (κ = 0.560). CONCLUSIONS: Exact MRI-based simplified primary tumor volume measurements in Ewing sarcoma suffer from considerable observer variability, but observer agreement of dichotomized measurements (≤200 mL vs. >200 mL) is very good and generally matches MRI-based actual volume measurements. MRI-based primary tumor volume measurements poorly-moderately agree with and tend to be lower than the MATV

Dynamic PET image reconstruction utilizing intrinsic data-driven HYPR4D denoising kernel

Purpose: Reconstructed PET images are typically noisy, especially in dynamic imaging where the acquired data are divided into several short temporal frames. High noise in the reconstructed images translates to poor precision/reproducibility of image features. One important role of “denoising” is therefore to improve the precision of image features. However, typical denoising methods achieve noise reduction at the expense of accuracy. In this work, we present a novel four-dimensional (4D) denoised image reconstruction framework, which we validate using 4D simulations, experimental phantom, and clinical patient data, to achieve 4D noise reduction while preserving spatiotemporal patterns/minimizing error introduced by denoising. Methods: Our proposed 4D denoising operator/kernel is based on HighlY constrained backPRojection (HYPR), which is applied either after each update of OSEM reconstruction of dynamic 4D PET data or within the recently proposed kernelized reconstruction framework inspired by kernel methods in machine learning. Our HYPR4D kernel makes use of the spatiotemporal high frequency features extracted from a 4D composite, generated within the reconstruction, to preserve the spatiotemporal patterns and constrain the 4D noise increment of the image estimate. Results: Results from simulations, experimental phantom, and patient data showed that the HYPR4D kernel with our proposed 4D composite outperformed other denoising methods, such as the standard OSEM with spatial filter, OSEM with 4D filter, and HYPR kernel method with the conventional 3D composite in conjunction with recently proposed High Temporal Resolution kernel (HYPRC3D-HTR), in terms of 4D noise reduction while preserving the spatiotemporal patterns or 4D resolution within the 4D image estimate. Consequently, the error in outcome measures obtained from the HYPR4D method was less dependent on the region size, contrast, and uniformity/functional patterns within the target structures compared to the other methods. For outcome measures that depend on spatiotemporal tracer uptake patterns such as the nondisplaceable Binding Potential (BPND), the root mean squared error in regional mean of voxel BPND values was reduced from ~8% (OSEM with spatial or 4D filter) to ~3% using HYPRC3D-HTR and was further reduced to ~2% using our proposed HYPR4D method for relatively small target structures (~10 mm in diameter). At the voxel level, HYPR4D produced two to four times lower mean absolute error in BPND relative to HYPRC3D-HTR. Conclusion: As compared to conventional methods, our proposed HYPR4D method can produce more robust and accurate image features without requiring any prior information