Effects of Tracer Uptake Time in Non-Small Cell Lung Cancer 18F-FDG PET Radiomics.

PET radiomics applied to oncology allow the measurement of intratumoral heterogeneity. This quantification can be affected by image protocols; hence, there is an increased interest in understanding how radiomic expression on PET images is affected by different imaging conditions. To address that interest, this study explored how radiomic features are affected by changes in 18F-FDG uptake time, image reconstruction, lesion delineation, and radiomic binning settings. Methods: Ten non-small cell lung cancer patients underwent 18F-FDG PET on 2 consecutive days. On each day, scans were obtained at 60 and 90 min after injection and reconstructed following EARL version 1 and with point-spread-function resolution modeling (PSF-EARL2). Lesions were delineated with an SUV threshold of 4.0, with 40% of SUVmax, and with a contrast-based isocontour. PET image intensity was discretized with both a fixed bin width (FBW) and a fixed bin number before the calculation of the radiomic features. Repeatability of features was measured with the intraclass correlation coefficient, and the change in feature value over time was calculated as a function of its repeatability. Features were then classified into use-case scenarios based on their repeatability and susceptibility to tracer uptake time. Results: With PSF-EARL2 reconstruction, 40% of SUVmax lesion delineation, and FBW intensity discretization, most features (94%) were repeatable at both uptake times (intraclass correlation coefficient > 0.9), 35% being classified for dual-time-point use cases as being sensitive to changes in uptake time, 39% were classified for cross-sectional studies with an unclear dependency on time, 20% were classified for cross-sectional use while being robust to uptake time changes, and 6% were discarded for poor repeatability. EARL version 1 images had 1 fewer repeatable feature (neighborhood gray-level different matrix coarseness) than PSF-EARL2; the contrast-based delineation had the poorest repeatability of the delineation methods, with 45% of features being discarded; and fixed bin number resulted in lower repeatability than FBW (45% and 6% of features were discarded, respectively). Conclusion: Repeatability was maximized with PSF-EARL2 reconstruction, lesion delineation at 40% of SUVmax, and FBW intensity discretization. On the basis of their susceptibility to uptake time, radiomic features were classified into specific non-small cell lung cancer PET radiomics use cases.

Evaluation of FDG-PET/CT Use in Children with Suspected Infection or Inflammation.

[18F]-FDG-PET/CT ([18F]-fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT)) is increasingly used as a diagnostic tool in suspected infectious or inflammatory conditions. Studies on the value of FDG-PET/CT in children are scarce. This study assesses the role of FDG-PET/CT in suspected infection or inflammation in children. In this multicenter cohort study, 64 scans in 59 children with suspected infection or inflammation were selected from 452 pediatric FDG-PET/CT scans, performed in five hospitals between January 2016 and August 2017. Main outcomes were diagnostic information provided by FDG-PET/CT for diagnostic scans and impact on clinical management for follow-up scans. Of these 64 scans, 50 were performed for primary diagnosis and 14 to monitor disease activity. Of the positive diagnostic scans, 23/27 (85%) contributed to establishing a diagnosis. Of the negative diagnostic scans, 8/21 (38%) contributed to the final diagnosis by narrowing the differential or by providing information on the disease manifestation. In all follow-up scans, FDG-PET/CT results guided management decisions. CRP was significantly higher in positive scans than in negative scans (p = 0.004). In 6% of diagnostic scans, relevant incidental findings were identified. In conclusion, FDG-PET/CT performed in children with suspected infection or inflammation resulted in information that contributed to the final diagnosis or helped to guide management decisions in the majority of cases. Prospective studies assessing the impact of FDG-PET/CT results on diagnosis and patient management using a structured diagnostic protocol are feasible and necessary.

Repeatability of [18F]FDG PET/CT total metabolic active tumour volume and total tumour burden in NSCLC patients.

BACKGROUND: Total metabolic active tumour volume (TMATV) and total tumour burden (TTB) are increasingly studied as prognostic and predictive factors in non-small cell lung cancer (NSCLC) patients. In this study, we investigated the repeatability of TMATV and TTB as function of uptake interval, positron emission tomography/computed tomography (PET/CT) image reconstruction settings, and lesion delineation method. We used six lesion delineation methods, four direct PET image-derived delineations and two based on a majority vote approach, i.e. intersection between two or more delineations (MV2) and between three or more delineations (MV3). To evaluate the accuracy of those methods, they were compared with a reference delineation obtained from the consensus of the segmentations performed by three experienced observers. Ten NSCLC patients underwent two baseline whole-body [18F]2-Fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET/CT studies on separate days, within 3 days. Two scans were obtained on each day at 60 and 90 min post-injection to assess the influence of tracer uptake interval. PET/CT images were reconstructed following the European Association of Nuclear Medicine Research Ltd. (EARL) compliant settings and with point-spread-function (PSF) modelling. Repeatability between the measurements of each day was determined and the influence of uptake interval, reconstruction settings, and lesion delineation method was assessed using the generalized estimating equations model. RESULTS: Based on the Jaccard index with the reference delineation, the MV2 lesion delineation method was the most successful method for automated lesion segmentation. The best overall repeatability (lowest repeatability coefficient, RC) was found for TTB from 90 min of tracer uptake scans reconstructed with EARL compliant settings and delineated with 41% of lesion's maximum SUV method (RC = 11%). In most cases, TMATV and TTB repeatability were not significantly affected by changes in tracer uptake time or reconstruction settings. However, some lesion delineation methods had significantly different repeatability when applied to the same images. CONCLUSIONS: This study suggests that under some circumstances TMATV and TTB repeatability are significantly affected by the lesion delineation method used. Performing the delineation with a majority vote approach improves reliability and does not hamper repeatability, regardless of acquisition and reconstruction settings. It is therefore concluded that by using a majority vote based tumour segmentation approach, TMATV and TTB in NSCLC patients can be measured with high reliability and precision.

Variability and Repeatability of Quantitative Uptake Metrics in 18F-FDG PET/CT of Non-Small Cell Lung Cancer: Impact of Segmentation Method, Uptake Interval, and Reconstruction Protocol.

There is increased interest in various new quantitative uptake metrics beyond SUV in oncologic PET/CT studies. The purpose of this study was to investigate the variability and test-retest ratio (TRT) of metabolically active tumor volume (MATV) measurements and several other new quantitative metrics in non-small cell lung cancer using 18F-FDG PET/CT with different segmentation methods, user interactions, uptake intervals, and reconstruction protocols. Methods: Ten patients with advanced non-small cell lung cancer received 2 series of 2 whole-body 18F-FDG PET/CT scans at 60 min after injection and at 90 min after injection. PET data were reconstructed with 4 different protocols. Eight segmentation methods were applied to delineate lesions with and without a tumor mask. MATV, SUVmax, SUVmean, total lesion glycolysis, and intralesional heterogeneity features were derived. Variability and repeatability were evaluated using a generalized-estimating-equation statistical model with Bonferroni adjustment for multiple comparisons. The statistical model, including interaction between uptake interval and reconstruction protocol, was applied individually to the data obtained from each segmentation method. Results: Without masking, none of the segmentation methods could delineate all lesions correctly. MATV was affected by both uptake interval and reconstruction settings for most segmentation methods. Similar observations were obtained for the uptake metrics SUVmax, SUVmean, total lesion glycolysis, homogeneity, entropy, and zone percentage. No effect of uptake interval was observed on TRT metrics, whereas the reconstruction protocol affected the TRT of SUVmax Overall, segmentation methods showing poor quantitative performance in one condition showed better performance in other (combined) conditions. For some metrics, a clear statistical interaction was found between the segmentation method and both uptake interval and reconstruction protocol. Conclusion: All segmentation results need to be reviewed critically. MATV and other quantitative uptake metrics, as well as their TRT, depend on segmentation method, uptake interval, and reconstruction protocol. To obtain quantitative reliable metrics, with good TRT performance, the optimal segmentation method depends on local imaging procedure, the PET/CT system, or reconstruction protocol. Rigid harmonization of imaging procedure and PET/CT performance will be helpful in mitigating this variability.

3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Depicts Heterogeneous Proliferation Pathology in Idiopathic Pulmonary Arterial Hypertension Patient Lung.

BACKGROUND: Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodeling in pulmonary arterial hypertension. A noninvasive imaging biomarker is needed to track the pathology and assess the response to novel treatments targeted at resolving the structural changes. Here, we evaluated the application of radioligand 3'-deoxy-3'-[18F]-fluorothymidine (18FLT) using positron emission tomography. METHODS AND RESULTS: We performed dynamic 18FLT positron emission tomography in 8 patients with idiopathic pulmonary arterial hypertension (IPAH) and applied in-depth kinetic analysis with a reversible 2-compartment 4k model. Our results show significantly increased lung 18FLT phosphorylation (k3) in patients with IPAH compared with nonpulmonary arterial hypertension controls (0.086±0.034 versus 0.054±0.009 min-1; P<0.05). There was heterogeneity in the lung 18FLT signal both between patients with IPAH and within the lungs of each patient, compatible with histopathologic reports of lungs from patients with IPAH. Consistent with 18FLT positron emission tomographic data, TK1 (thymidine kinase 1) expression was evident in the remodeled vessels in IPAH patient lung. In addition, hyperproliferative pulmonary vascular fibroblasts isolated from patients with IPAH exhibited upregulated expression of TK1 and the thymidine transporter, ENT1 (equilibrative nucleoside transporter 1). In the monocrotaline and SuHx (Sugen hypoxia) rat pulmonary arterial hypertension models, increased lung 18FLT uptake was strongly associated with peripheral pulmonary vascular muscularization and the proliferation marker, Ki-67 score, together with prominent TK1 expression in remodeled vessels. Importantly, lung 18FLT uptake was attenuated by 2 antiproliferative treatments: dichloroacetate and the tyrosine kinase inhibitor, imatinib. CONCLUSIONS: Dynamic 18FLT positron emission tomography imaging can be used to report hyperproliferation in pulmonary hypertension and merits further study to evaluate response to treatment in patients with IPAH.

Parametric Method Performance for Dynamic 3'-Deoxy-3'-18F-Fluorothymidine PET/CT in Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Carcinoma Patients Before and During Therapy.

The objective of this study was to validate several parametric methods for quantification of 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET in advanced-stage non-small cell lung carcinoma (NSCLC) patients with an activating epidermal growth factor receptor mutation who were treated with gefitinib or erlotinib. Furthermore, we evaluated the impact of noise on accuracy and precision of the parametric analyses of dynamic 18F-FLT PET/CT to assess the robustness of these methods. Methods: Ten NSCLC patients underwent dynamic 18F-FLT PET/CT at baseline and 7 and 28 d after the start of treatment. Parametric images were generated using plasma input Logan graphic analysis and 2 basis functions-based methods: a 2-tissue-compartment basis function model (BFM) and spectral analysis (SA). Whole-tumor-averaged parametric pharmacokinetic parameters were compared with those obtained by nonlinear regression of the tumor time-activity curve using a reversible 2-tissue-compartment model with blood volume fraction. In addition, 2 statistically equivalent datasets were generated by countwise splitting the original list-mode data, each containing 50% of the total counts. Both new datasets were reconstructed, and parametric pharmacokinetic parameters were compared between the 2 replicates and the original data. Results: After the settings of each parametric method were optimized, distribution volumes (VT) obtained with Logan graphic analysis, BFM, and SA all correlated well with those derived using nonlinear regression at baseline and during therapy (R2 ≥ 0.94; intraclass correlation coefficient > 0.97). SA-based VT images were most robust to increased noise on a voxel-level (repeatability coefficient, 16% vs. >26%). Yet BFM generated the most accurate K1 values (R2 = 0.94; intraclass correlation coefficient, 0.96). Parametric K1 data showed a larger variability in general; however, no differences were found in robustness between methods (repeatability coefficient, 80%-84%). Conclusion: Both BFM and SA can generate quantitatively accurate parametric 18F-FLT VT images in NSCLC patients before and during therapy. SA was more robust to noise, yet BFM provided more accurate parametric K1 data. We therefore recommend BFM as the preferred parametric method for analysis of dynamic 18F-FLT PET/CT studies; however, SA can also be used.

Baseline and longitudinal variability of normal tissue uptake values of [18F]-fluorothymidine-PET images.

PURPOSE: [18F]-fluorothymidine ([18F]-FLT) is a PET-tracer enabling in-vivo visualization and quantification of tumor cell proliferation. For qualitative and quantitative analysis, adequate knowledge of normal tissue uptake is indispensable. This study aimed to quantitatively investigate baseline tracer uptake of blood pool, lung, liver and bone marrow and their precision, and to assess the longitudinal effect of systemic treatment on biodistribution. METHODS: 18F-FLT-PET(/CT) scans (dynamic or static) of 90 treatment-naïve oncological patients were retrospectively evaluated. Twenty-three patients received double baseline scans, and another 39 patients were also scanned early and late during systemic treatment with a tyrosine kinase inhibitor. Reproducible volume of interest were placed in blood pool, lung, liver, and bone marrow. For semi-quantitative analysis, SUVmean, SUVmax, and SUVpeak with several normalizations were derived. RESULTS: SUVs of basal lung, liver, and bone marrow were not significantly different between averaged dynamic and static images, in contrast with blood pool and apical lung. Highest repeatability was seen for liver and bone marrow, with repeatability coefficients of 18.6% and 20.4% when using SUVpeak. Systemic treatment with TKIs both increased and decreased normal tissue tracer uptake at early and late time points during treatment. CONCLUSION: Simultaneous evaluation of liver and bone marrow uptake in longitudinal response studies may be used to assess image quality, where changes in uptake outside repeatability limits should trigger investigators to perform additional quality control on individual PET images. ADVANCES IN KNOWLEDGE: For [18F]-FLT PET images, liver and bone marrow have low intra-patient variability when quantified with SUVpeak, but may be affected by systemic treatment. IMPLICATIONS FOR PATIENT CARE: In [18F]-FLT-PET response monitoring trials, liver and bone marrow uptake may be used for quality control of [18F]-FLT PET images.

Accuracy and Precision of Partial-Volume Correction in Oncological PET/CT Studies.

Accurate quantification of tracer uptake in small tumors using PET is hampered by the partial-volume effect as well as by the method of volume-of-interest (VOI) delineation. This study aimed to investigate the effect of partial-volume correction (PVC) combined with several VOI methods on the accuracy and precision of quantitative PET. METHODS: Four image-based PVC methods and resolution modeling (applied as PVC) were used in combination with several common VOI methods. Performance was evaluated using simulations, phantom experiments, and clinical repeatability studies. Simulations were based on a whole-body 18F-FDG PET scan in which differently sized spheres were placed in lung and mediastinum. A National Electrical Manufacturers Association NU2 quality phantom was used for the experiments. Repeatability data consisted of an 18F-FDG PET/CT study on 11 patients with advanced non-small cell lung cancer and an 18F-fluoromethylcholine PET/CT study on 12 patients with metastatic prostate cancer. RESULTS: Phantom data demonstrated that most PVC methods were strongly affected by the applied resolution kernel, with accuracy differing by about 20%-50% between full-width-at-half-maximum settings of 5.0 and 7.5 mm. For all PVC methods, large differences in accuracy were seen among all VOI methods. Additionally, the image-based PVC methods were observed to have variable sensitivity to the accuracy of the VOI methods. For most PVC methods, accuracy was strongly affected by more than a 2.5-mm misalignment of true (simulated) VOI. When the optimal VOI method for each PVC method was used, high accuracy could be achieved. For example, resolution modeling for mediastinal lesions and iterative deconvolution for lung lesions were 99% ± 1.5% and 99% ± 0.9% accurate, respectively, for spheres 15-40 mm in diameter. Precision worsened slightly for resolution modeling and to a larger extent for some image-based PVC methods. Uncertainties in delineation propagated into uncertainties in PVC performance, as confirmed by the clinical data. CONCLUSION: The accuracy and precision of the tested PVC methods depended strongly on VOI method, resolution settings, contrast, and spatial alignment of the VOI. PVC has the potential to substantially improve the accuracy of tracer uptake assessment, provided that robust and accurate VOI methods become available. Commonly used delineation methods may not be adequate for this purpose.

Repeatability of Quantitative Whole-Body 18F-FDG PET/CT Uptake Measures as Function of Uptake Interval and Lesion Selection in Non-Small Cell Lung Cancer Patients.

UNLABELLED: Change in (18)F-FDG uptake may predict response to anticancer treatment. The PERCIST suggest a threshold of 30% change in SUV to define partial response and progressive disease. Evidence underlying these thresholds consists of mixed stand-alone PET and PET/CT data with variable uptake intervals and no consensus on the number of lesions to be assessed. Additionally, there is increasing interest in alternative (18)F-FDG uptake measures such as metabolically active tumor volume and total lesion glycolysis (TLG). The aim of this study was to comprehensively investigate the repeatability of various quantitative whole-body (18)F-FDG metrics in non-small cell lung cancer (NSCLC) patients as a function of tracer uptake interval and lesion selection strategies. METHODS: Eleven NSCLC patients, with at least 1 intrathoracic lesion 3 cm or greater, underwent double baseline whole-body (18)F-FDG PET/CT scans at 60 and 90 min after injection within 3 d. All (18)F-FDG-avid tumors were delineated with an 50% threshold of SUVpeak adapted for local background. SUVmax, SUVmean, SUVpeak, TLG, metabolically active tumor volume, and tumor-to-blood and -liver ratios were evaluated, as well as the influence of lesion selection and 2 methods for correction of uptake time differences. RESULTS: The best repeatability was found using the SUV metrics of the averaged PERCIST target lesions (repeatability coefficients < 10%). The correlation between test and retest scans was strong for all uptake measures at either uptake interval (intraclass correlation coefficient > 0.97 and R(2) > 0.98). There were no significant differences in repeatability between data obtained 60 and 90 min after injection. When only PERCIST-defined target lesions were included (n = 34), repeatability improved for all uptake values. Normalization to liver or blood uptake or glucose correction did not improve repeatability. However, after correction for uptake time the correlation of SUV measures and TLG between the 60- and 90-min data significantly improved without affecting test-retest performance. CONCLUSION: This study suggests that a 15% change of SUVmean/SUVpeak at 60 min after injection can be used to assess response in advanced NSCLC patients if up to 5 PERCIST target lesions are assessed. Lower thresholds could be used in averaged PERCIST target lesions (<10%).

Repeatability of Radiomic Features in Non-Small-Cell Lung Cancer [(18)F]FDG-PET/CT Studies: Impact of Reconstruction and Delineation.

PURPOSE: To assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomorgraphy/computed tomography (PET/CT) studies. PROCEDURES: Eleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (n = 19) were delineated twice, once on PET and once on CT images. RESULTS: Sixty-three features showed an intraclass correlation coefficient ≥ 0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively). CONCLUSIONS: The majority of features in NSCLC [(18)F]FDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.

Metabolically active tumour volume segmentation from dynamic [(18)F]FLT PET studies in non-small cell lung cancer.

BACKGROUND: Positron emission tomography (PET) with (18)F-3'-deoxy-3'-fluorothymidine ([(18)F]FLT) can be used to assess tumour proliferation. A kinetic-filtering (KF) classification algorithm has been suggested for segmentation of tumours in dynamic [(18)F]FLT PET data. The aim of the present study was to evaluate KF segmentation and its test-retest performance in [(18)F]FLT PET in non-small cell lung cancer (NSCLC) patients. METHODS: Nine NSCLC patients underwent two 60-min dynamic [(18)F]FLT PET scans within 7 days prior to treatment. Dynamic scans were reconstructed with filtered back projection (FBP) as well as with ordered subsets expectation maximisation (OSEM). Twenty-eight lesions were identified by an experienced physician. Segmentation was performed using KF applied to the dynamic data set and a source-to-background corrected 50% threshold (A50%) was applied to the sum image of the last three frames (45- to 60-min p.i.). Furthermore, several adaptations of KF were tested. Both for KF and A50% test-retest (TRT) variability of metabolically active tumour volume and standard uptake value (SUV) were evaluated. RESULTS: KF performed better on OSEM- than on FBP-reconstructed PET images. The original KF implementation segmented 15 out of 28 lesions, whereas A50% segmented each lesion. Adapted KF versions, however, were able to segment 26 out of 28 lesions. In the best performing adapted versions, metabolically active tumour volume and SUV TRT variability was similar to those of A50%. KF misclassified certain tumour areas as vertebrae or liver tissue, which was shown to be related to heterogeneous [(18)F]FLT uptake areas within the tumour. CONCLUSIONS: For [(18)F]FLT PET studies in NSCLC patients, KF and A50% show comparable tumour volume segmentation performance. The KF method needs, however, a site-specific optimisation. The A50% is therefore a good alternative for tumour segmentation in NSCLC [(18)F]FLT PET studies in multicentre studies. Yet, it was observed that KF has the potential to subsegment lesions in high and low proliferative areas.

Assessment of simplified methods to measure 18F-FLT uptake changes in EGFR-mutated non-small cell lung cancer patients undergoing EGFR tyrosine kinase inhibitor treatment.

UNLABELLED: 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET/CT provides a noninvasive assessment of proliferation and, as such, could be a valuable imaging biomarker in oncology. The aim of the present study was to assess the validity of simplified quantitative parameters of (18)F-FLT uptake in non-small cell lung cancer (NSCLC) patients before and after the start of treatment with a tyrosine kinase inhibitor (TKI). METHODS: Ten patients with metastatic NSCLC harboring an activating epidermal growth factor receptor mutation were included in this prospective observational study. Patients underwent (15)O-H2O and (18)F-FLT PET/CT scanning on 3 separate occasions: within 7 d before treatment, and 7 and 28 d after the first therapeutic dose of a TKI (gefitinib or erlotinib). Dynamic scans were acquired and venous blood samples were collected during the (18)F-FLT scan to measure parent fraction and plasma and whole-blood radioactivity concentrations. Simplified measures (standardized uptake value [SUV] and tumor-to-blood ratio [TBR]) were correlated with fully quantitative measures derived from kinetic modeling. RESULTS: Twenty-nine of thirty (18)F-FLT PET/CT scans were evaluable. According to the Akaike criterion, a reversible 2-tissue model with 4 rate constants and blood volume parameter was preferred in 84% of cases. Relative therapy-induced changes in SUV and TBR correlated with those derived from kinetic analyses (r(2) = 0.83-0.97, P < 0.001, slope = 0.72-1.12). (18)F-FLT uptake significantly decreased at 7 and 28 d after the start of treatment compared with baseline (P < 0.01). Changes in (18)F-FLT uptake were not correlated with changes in perfusion, as measured using (15)O-H2O. CONCLUSION: SUV and TBR could both be used as surrogate simplified measures to assess changes in (18)F-FLT uptake in NSCLC patients treated with a TKI, at the cost of a small underestimation in uptake changes or the need for a blood sample and metabolite measurement, respectively.

Repeatability of metabolically active tumor volume measurements with FDG PET/CT in advanced gastrointestinal malignancies: a multicenter study.

PURPOSE: To evaluate the feasibility and repeatability of various metabolically active tumor volume ( MATV metabolically active tumor volume ) quantification methods in fluorine 18 fluorodeoxyglucose ( FDG fluorine 18 fluorodeoxyglucose ) positron emission tomography (PET)/computed tomography (CT) in a multicenter setting and propose the optimal MATV metabolically active tumor volume method together with the minimal threshold for future response evaluation studies. MATERIALS AND METHODS: The study was approved by the institutional review board of all four participating centers, and patients provided written informed consent. Thirty-four patients with advanced gastrointestinal malignancies underwent two FDG fluorine 18 fluorodeoxyglucose PET/CT examinations within 1 week. MATV metabolically active tumor volume s were defined semiautomatically with 27 variations of tumor delineation methods with different reference values. Feasibility was determined as the percentage of successful tumor segmentations per MATV metabolically active tumor volume method. Repeatability was determined with intraclass correlation coefficients, Bland-Altman plots, and limits of agreement ( LOA limit of agreement s) of the percentage difference between the test and repeat test measurements. In addition, LOA limit of agreement variability per center was investigated. RESULTS: In total, 136 lesions were identified. Feasibility of tumor segmentation ranged from 54% to 100% (74-136 of 136 lesions); repeatability was evaluated for 19 MATV metabolically active tumor volume methods with feasibility of greater than 95%. The median MATV metabolically active tumor volume derived with 50% threshold of mean standardized uptake value ( SUV standardized uptake value ) of a sphere of 12-mm diameter with highest local intensity ( SUVhp mean SUV of a sphere of 12-mm diameter with highest local intensity ), which may not include the voxel with highest SUV standardized uptake value corrected for local background, was 5.7 and 6.1 mL for test and retest scans, respectively, with a relative LOA limit of agreement of 36.1%. Comparable repeatability was found between centers. A difference in uptake time between scan 1 and 2 of 15 minutes or longer had a minor negative influence on repeatability. CONCLUSION: MATV metabolically active tumor volume measured with 50% of SUVhp mean SUV of a sphere of 12-mm diameter with highest local intensity corrected for local background is recommended in multicenter FDG fluorine 18 fluorodeoxyglucose PET/CT studies on the basis of a high feasibility (96%) and repeatability ( LOA limit of agreement of 36.1%).

Methodological considerations in quantification of 3'-deoxy-3'-[18F]fluorothymidine uptake measured with positron emission tomography in patients with non-small cell lung cancer.

PURPOSE: To investigate the effect of image-derived input functions (IDIF), input function corrections and volume of interest (VOI) size in quantification of [(18)F]FLT uptake in non-small cell lung cancer (NSCLC) patients. PROCEDURES: Twenty-three NSCLC patients were scanned on a HR+ scanner. IDIFs were defined over the aorta and left ventricle. Activity concentration and metabolite fraction were measured in venous blood samples. Venous blood samples at 30, 40 and 60 min after injection were used to calibrate the IDIF time-activity curves. Adaptive thresholds were used for VOI definition. Full kinetic analysis and simplified measures were performed. RESULTS: Non-linear regression analysis showed better fits for the irreversible model compared to the reversible model in the majority. Calibrated and metabolite corrected plus plasma-to-blood ratio corrected input function resulted in high correlations between SUV and Patlak K i (Pearson correlation coefficients 0.86-0.96, p value < 0.001). No significant differences in correlation between SUV and Patlak K i were observed with variation of IDIF structure or VOI size. CONCLUSIONS: Plasma-to-blood ratio correction, metabolite correction and calibration improved the correlation between SUV and Patlak K i significantly, indicating the need for these corrections when K i is used to validate semi-quantitative measures, such as SUV.

Pemetrexed induced thymidylate synthase inhibition in non-small cell lung cancer patients: a pilot study with 3'-deoxy-3'-[¹8F]fluorothymidine positron emission tomography.

OBJECTIVES: Pemetrexed is a thymidylate synthase (TS) inhibitor and is effective in non-small cell lung cancer (NSCLC). 3'-deoxy-3'-[¹8F]fluorothymidine (¹8F-FLT), a proliferation marker, could potentially identify tumor specific TS-inhibition. The aim of this study was to investigate the effect of pemetrexed-induced TS-inhibition on ¹8F-FLT uptake 4 hours after pemetrexed administration in metastatic NSCLC patients. METHODS: Fourteen NSCLC patients underwent dynamic ¹8F-FLT positron emission tomography (PET) scans at baseline and 4 hours after the first dose of pemetrexed. Volumes of interest were defined with a 41%, 50% and 70% threshold of the maximum pixel. Kinetic analysis and simplified measures were performed. At one, two, four and six hours after pemetrexed, plasma deoxyuridine was measured as systemic indicator of TS-inhibition. Tumor response measured with response evaluation criteria in solid tumors (RECIST), time to progression (TTP) and overall survival (OS) were determined. RESULTS: Eleven patients had evaluable ¹8F-FLT PET scans at baseline and 4 hours after pemetrexed. Two patients had increased ¹8F-FLT uptake of 35% and 31% after pemetrexed, whereas two other patients had decreased uptake of 31%. In the remaining seven patients ¹8F-FLT uptake did not change beyond test-retest borders. In all patients deoxyuridine levels raised after administration of pemetrexed, implicating pemetrexed-induced TS-inhibition. ¹8F-FLT uptake in bone marrow was significantly increased 4 hours after pemetrexed administration. Six weeks after the start of treatment 5 patients had partial response, 4 stable disease and 2 progressive disease. Median TTP was 4.2 months (range 3.0-7.4 months); median OS was 13.0 months (range 5.1-30.8 months). Changes in ¹8F-FLT uptake were not predictive for tumor response, TTP or OS. CONCLUSIONS: Measuring TS-inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in ¹8F-FLT uptake within the tumor. No significant association with tumor response, TTP or OS was observed.

Effects of image characteristics on performance of tumor delineation methods: a test-retest assessment.

UNLABELLED: PET can be used to monitor response during chemotherapy and assess biologic target volumes for radiotherapy. Previous simulation studies have shown that the performance of various automatic or semiautomatic tumor delineation methods depends on image characteristics. The purpose of this study was to assess test-retest variability of tumor delineation methods, with emphasis on the effects of several image characteristics (e.g., resolution and contrast). METHODS: Baseline test-retest data from 19 non-small cell lung cancer patients were obtained using (18)F-FDG (n = 10) and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) (n = 9). Images were reconstructed with varying spatial resolution and contrast. Six different types of tumor delineation methods, based on various thresholds or on a gradient, were applied to all datasets. Test-retest variability of metabolic volume and standardized uptake value (SUV) was determined. RESULTS: For both tracers, size of metabolic volume and test-retest variability of both metabolic volume and SUV were affected by the image characteristics and tumor delineation method used. The median volume test-retest variability ranged from 8.3% to 23% and from 7.4% to 29% for (18)F-FDG and (18)F-FLT, respectively. For all image characteristics studied, larger differences (≤10-fold higher) were seen in test-retest variability of metabolic volume than in SUV. CONCLUSION: Test-retest variability of both metabolic volume and SUV varied with tumor delineation method, radiotracer, and image characteristics. The results indicate that a careful optimization of imaging and delineation method parameters is needed when metabolic volume is used, for example, as a response assessment parameter.

Repeatability of metabolically active volume measurements with 18F-FDG and 18F-FLT PET in non-small cell lung cancer.

UNLABELLED: In addition to tumor size measurements with CT, there is a need for quantitative measurements of metabolic active volumes, possibly adding to tracer uptake measurements in oncologic response evaluation with PET. The aim of this study was to evaluate the metabolic volume test-retest variability in (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET studies for various commonly used volumes of interest (VOIs) and the dependence of that variability on lesion size and relative radiotracer uptake. METHODS: Twenty non-small cell lung cancer patients were scanned twice with (18)F-FDG (n = 11) or (18)F-FLT (n = 9). VOIs were defined on images reconstructed with normalization- and attenuation-weighted ordered-subset expectation maximization using 4 isocontours (A41%, A50%, and A70% thresholds, adapted for local background, and 50% threshold, uncorrected for background). Statistical analysis comprised intraclass correlation coefficients and Bland-Altman analysis. RESULTS: In the (18)F-FDG and (18)F-FLT groups, 34 and 20 lesions, respectively, were analyzed. Median volumes at the A50% threshold were 3.31 and 2.19 mL (interquartile range, 1.91-8.90 and 1.52-7.27 mL) for (18)F-FDG and (18)F-FLT, respectively. Intraclass correlation coefficients were greater than 0.9, with the exception of the A70%-based metabolic volumes for (18)F-FLT. For lesions greater than 4.2 mL, repeatability coefficients (RCs = 1.96 × SD) of the percentage difference ranged from 22% to 37% for (18)F-FDG and from 39% to 73% for (18)F-FLT, depending on the VOI method being used. Repeatability was better for larger tumors, but there was no dependence on absolute uptake (standardized uptake value). CONCLUSION: Results indicate that changes of greater than 37% for (18)F-FDG and greater than 73% for (18)F-FLT (1.96 × SD) for lesions with A50% metabolic volumes greater than 4.2 mL represent a biologic effect. For smaller lesions (A50% VOI < 4.2 mL), an absolute change of 1.0 and 0.9 mL for (18)F-FDG and (18)F-FLT, respectively, is biologically relevant. Considering the balance between the success rate of automatic tumor delineation and repeatability of metabolic volume, a 50% threshold with correction for local background activity (A50%) seems optimal among the VOI methods evaluated.