Insertion of synthetic lesions on patient data: a method for evaluating clinical performance differences between PET systems.

BACKGROUND: Performance assessment of positron emission tomography (PET) scanners is crucial to guide clinical practice with efficiency. We have already introduced and experimentally evaluated a simulation method allowing the creation of a controlled ground truth for system performance assessment. In the current study, the goal was to validate the method using patient data and demonstrate its relevance to assess PET performances accuracy in clinical conditions. METHODS: Twenty-four patients were recruited and sorted into two groups according to their body mass index (BMI). They were administered with a single dose of 2 MBq/kg 18F-FDG and scanned using clinical protocols consecutively on two PET systems: the Discovery-IQ (DIQ) and the Discovery-MI (DMI). For each BMI group, sixty synthetic lesions were dispatched in three subgroups and inserted at relevant anatomical locations. Insertion of synthetic lesions (ISL) was performed at the same location into the two consecutive exams. Two nuclear medicine physicians evaluated individually and blindly the images by qualitatively and semi-quantitatively reporting each detected lesion and agreed on a consensus. We assessed the inter-system detection rates of synthetic lesions and compared it to an initial estimate of at least 1.7 more targets detected on the DMI and the detection rates of natural lesions. We determined the inter-reader variability, evaluated according to the inter-observer agreement (IOA). Adequate inter-reader variability was found for IOA above 80%. Differences in standardized uptake value (SUV) metrics were also studied. RESULTS: In the BMI ≤ 25 group, the relative true positive rate (RTPR) for synthetic and natural lesions was 1.79 and 1.83, respectively. In the BMI > 25 group, the RTPR for synthetic and natural lesions was 2.03 and 2.27, respectively. For each BMI group, the detection rate using ISL was consistent to our estimate and with the detection rate measured on natural lesions. IOA above 80% was verified for any scenario. SUV metrics showed a good agreement between synthetic and natural lesions. CONCLUSIONS: ISL proved relevant to evaluate performance differences between PET scanners. Using these synthetically modified clinical images, we can produce a controlled ground truth in a realistic anatomical model and exploit the potential of PET scanner for clinical purposes.

An extended bore length solid-state digital-BGO PET/CT system: design, preliminary experience, and performance characteristics.

PURPOSE: A solid-state PET/CT system uses bismuth germanium oxide (BGO) scintillating crystals coupled to silicon photomultipliers over an extended 32 cm axial field-of-view (FOV) to provide high spatial resolution and very high sensitivity. Performance characteristics were determined for this digital-BGO system, including NEMA and EARL standards. METHODS: Spatial resolution, scatter fraction (SF), noise equivalent count rate (NECR), sensitivity, count rate accuracy, and image quality (IQ) were evaluated for the digital-BGO system as per NEMA NU 2-2018, at 2 sites of first clinical install. System energy resolution was measured. Bayesian penalized-likelihood reconstruction (BPL) was used for IQ. EARL Standards 2 studies were reconstructed by BPL combined with a contrast-enhancing deep learning algorithm. An Esser PET phantom was evaluated. Three patient examples were obtained with low-dose radiotracer activity: 2 MBq/kg of [18F]FDG ([18F]-2-fluoro-2-deoxy-D-glucose), 2.3 MBq/kg [68Ga]Ga-DOTA-TATE ([dodecane tetra-acetic acid,Tyr3]-octreotate), and 14.5 MBq/kg [82Rb]RbCl ([82Rb]-rubidium-chloride). Total scan times were ≤ 8 min. RESULTS: NEMA sensitivity was 47.6 cps/kBq at the axial center. Spatial resolution at 1 cm from the center axis was ≤4.5 mm (filtered back projection) and ≤3.8 mm (ordered subset expectation maximization). SF was 35.6%, count rate accuracy was 2.16%, and peak NECR was 485.2 kcps at 16.9 kBq/mL. Contrast for IQ was 61.1 to 90.7% (smallest to largest sphere) with background variations from 7.6 to 2.1%, and a "lung" error of 4.7%. The average detector energy resolution was 9.67%. Image quality for patient scans was good. EARL Standards 2 criteria were robustly met and Esser phantom features ≥4.8 mm were resolved at 2 min per bed position. CONCLUSION: A solid-state 32 cm axial FOV digital-BGO PET/CT system provides good spatial and energy resolution, high count rates, and superior NEMA sensitivity in its class, enabling fast clinical acquisitions with low-dose radiotracer activity.

Evaluation of a method based on synthetic data inserted into raw data prior to reconstruction for the assessment of PET scanners.

BACKGROUND: Performance assessment of positron emission tomography (PET) scanners is crucial to guide clinical practice with efficiency. Even though clinical data are the final target, their use to characterize systems response is constrained by the lack of ground truth. Phantom tests overcome this limitation by controlling the object of study, but remain simple and are not representative of patient complexity. The objective of this study is to evaluate the accuracy of a simulation method using synthetic spheres inserted into acquired raw data prior to reconstruction, simulating multiple scenarios in comparison with equivalent physical experiments. METHODS: We defined our experimental framework using the National Electrical Manufacturers Association NU-2 2018 Image Quality standard, but replaced the standard sphere set with more appropriate sizes (4, 5, 6, 8, 10 and 13 mm) better suited to current PET scanner performance. Four experiments, with different spheres-to-background ratios (2:1, 4:1, 6:1 and 8:1), were performed. An additional dataset was acquired with a radioactive background but no activity within the spheres (water only) to establish a baseline. Then, we artificially simulated radioactive spheres to reproduce other experiments using synthetic data inserted into the original sinogram. Images were reconstructed following standard guidelines using ordered subset expectation maximization algorithm along with a Bayesian penalized likelihood algorithm. We first visually compared experimental and simulated images. Afterward, we measured the activity concentration values into the spheres to calculate the mean and maximum recovery coefficients (RCmean and RCmax) which we used in a quantitative analysis. RESULTS: No significant visual differences were identified between experimental and simulated series. Mann-Whitney U tests comparing simulated and experimental distributions showed no statistical differences for both RCmean (P value = 0.611) and RCmax (P value = 0.720). Spearman tests revealed high correlation for RCmean (ρ = 0.974, P value < 0.001) and RCmax (ρ = 0.974, P value < 0.001) between both datasets. From Bland-Altman plots, we highlighted slight shifts in RCmean and RCmax of, respectively, 2.1 ± 16.9% and 3.3 ± 22.3%. CONCLUSIONS: We evaluated the efficiency of our hybrid method in faithfully mimicking practical situations producing satisfactory results compared to equivalent experimental data.

Evaluation of PET quantitation accuracy among multiple discovery IQ PET/CT systems via NEMA image quality test.

INTRODUCTION: Quantitative imaging biomarkers are becoming usual in oncology for assessing therapy response. The harmonization of image quantitation reporting has become of utmost importance due to the multi-center trials increase. The NEMA image quality test is often considered for the evaluation of quantitation and is more accurate with a radioactive solid phantom that reduces variability. The goal of this project is to determine the level of variability among imaging centers if acquisition and imaging protocol parameters are left to the center's preference while all other parameters are fixed including the scanner type. METHODS: A NEMA-IQ phantom filled with radioactive 68Ge solid resin was imaged in five clinical sites throughout Europe. Sites reconstructed data with OSEM and BSREM algorithms applying the sites' clinical parameters. Images were analyzed according with the NEMA-NU2-2012 standard using the manufacturer-provided NEMA tools to calculate contrast recovery (CR) and background variability (BV) for each sphere and the lung error (LE) estimation. In addition, a 18F-filled NEMA-IQ phantom was also evaluated to obtain a gauge for variability among centers when the sites were provided with identical specific instructions for acquisition and reconstruction protocol (the aggregate of data from 12 additional sites is presented). RESULTS: The data using the 68Ge solid phantom showed no statistical differences among different sites, proving a very good reproducibility among the PET center models even if dispersion of data is higher with OSEM compared to BSREM. Furthermore, BSREM shows better CR and comparable BV, while LE is slightly reduced. Two centers exhibit significant differences in CR and BV values for the 18F NEMA NU2-2012 experiments; these outlier results are explained. CONCLUSION: The same PET system type from the various sites produced similar quantitative results, despite allowing each site to choose their clinical protocols with no restriction on data acquisition and reconstruction parameters. BSREM leads to lower dispersion of quantitative data among different sites. A solid radioactive phantom may be recommended to qualify the sites to perform quantitative imaging.

Gated 18F-FDG PET/CT of the Lung Using a Respiratory Spirometric Gating Device: A Feasibility Study.

Spirometric gating devices (SGDs) can measure the respiratory signal with high temporal resolution and accuracy. The primary objective of this study was to assess the feasibility and tolerance of a gated lung PET/CT acquisition using an SGD. The secondary objective was to compare the technical quality, accuracy, and interoperability of the SGD with that of a standard respiratory gating device, Real-Time Position Management (RPM), based on measurement of vertical thoracoabdominal displacement. Methods: A prospective phase I monocentric clinical study was performed on patients undergoing 18F-FDG PET/CT for assessment of a solitary lung nodule, staging of lung malignancy, or planning of radiotherapy. After whole-body PET/CT, a centered gated acquisition of both PET and CT was simultaneously obtained with the SGD and RPM during normal breathing. Results: Of the 46 patients who were included, 6 were prematurely excluded (1 because of hyperglycemia and 5 because of distant metastases revealed by whole-body PET/CT, leading to an unjustified extra gated acquisition). No serious adverse events were observed. Of the 40 remaining patients, the gated acquisition was prematurely stopped in 1 patient because of mask discomfort (2.5%; confidence interval [CI], 0.1%-13.2%). This event was considered patient tolerance failure. The SGD generated accurately gated PET/CT images, with more than 95% of the breathing cycle detected and high temporal resolution, in 34 of the 39 patients (87.2%; 95% CI, 60.0%-100.0%) and failed to generate a biologic tumor volume in 1 of 21 patients with increased 18F-FDG uptake (4.8%; 95% CI, 0.1%-26.5%). The quality and accuracy of respiratory signal detection and synchronization were significantly better than those obtained with RPM (P < 0.05). Conclusion: This trial supports the use of an SGD for gated lung PET/CT because of its high patient tolerance and accuracy. Although this technique seems to technically outperform RPM for gated PET/CT, further assessment of its superiority and the clinical benefit is warranted. We believe that this technique could be used as a gold standard to develop innovative approaches to eliminate respiration-induced blurring artifacts.

Evaluation of 2 diuretic 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography imaging protocols for intrapelvic cancer.

BACKGROUND: 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) plays an important part in the oncological evaluation of the abdomen and pelvis, but the interpretation and quantification is often hampered by intense physiological urinary activity. We evaluate 2 different diuretic imaging protocols by comparing intensity of urinary activity and we look at the impact of multiple variables on the final urinary activity. METHODS: Comparative analysis of 102 patients (median age: 64) having intrapelvic carcinoma. After full body acquisition, 58 patients were administered 20 mg of furosemide 90 min post injection of FDG (P90). For 44 patients, 20 mg of furosemide was administered 30 min post injection of FDG (P30). Comparisons between groups were performed using the Mann-Whitney Test and χ2. The BMI, creatinine, clearance, age, injected activity, diuretic protocol, gender and glycemia were evaluated with multivariate analysis for their impact on the final urinary activity. RESULTS: Concerning the comparison of the urinary activity we observe a significant difference (P=0.0029) between P90 and P30 for the SUVmax (median 4.3 [range 1.6: 17.7] vs. 6.0 [range 2.9: 15.1]), and for the SUVmean (P<0.001) (median 2.4 [range 1.1; 9.9] vs. 3.8 [range 2.0; 10.1]). For 2 patients of P30, the acquisition was interrupted because the patient needed to void. Multivariate analysis shows that creatinine and creatinine clearance do not have a significant independent impact on the final bladder activity. CONCLUSIONS: By comparing the 2 diuretic imaging protocols, we found a significant lower urinary activity for the P90 protocol and the regression decision tree shows that the P90 protocol is mostly superior. The P30 protocol, which seems to be less well tolerated, is adequate in the group of patients with an injected activity of less than 240 MBq and older than 65 years, if P90 is not feasible. For most patients with injected activity ≥240 MBq or BMI of ≥25 and a glycemia >120 mg/dL, a significant amount of residual urinary activity remains for both protocols.

Fluorine-18-fluorocholine PET/CT parameters predictive for hematological toxicity to radium-223 therapy in castrate-resistant prostate cancer patients with bone metastases: a pilot study.

PURPOSE: This study aims to predict hematological toxicity induced by Ra therapy. We investigated the value of metabolically active bone tumor volume (MBTV) and total bone lesion activity (TLA) calculated on pretreatment fluorine-18-fluorocholine (F-FCH) PET/CT in castrate-resistant prostate cancer (CRPC) patients with bone metastases treated with Ra radionuclide therapy. PATIENTS AND METHODS: F-FCH PET/CT imaging was performed in 15 patients with CRPC before treatment with Ra. Bone metastatic disease was quantified on the basis of the maximum standardized uptake value (SUV), total lesion activity (TLA=MBTV×SUVmean), or MBTV/height (MBTV/H) and TLA/H. F-FCH PET/CT bone tumor burden and activity were analyzed to identify which parameters could predict hematological toxicity [on hemoglobin (Hb), platelets (PLTs), and lymphocytes] while on Ra therapy. Pearson's correlation was used to identify the correlations between age, prostate-specific antigen, and F-FCH PET parameters. RESULTS: MBTV ranged from 75 to 1259 cm (median: 392 cm). TLA ranged from 342 to 7198 cm (median: 1853 cm). Patients benefited from two to six cycles of Ra (n=56 cycles in total). At the end of Ra therapy, five of the 15 (33%) patients presented grade 2/3 toxicity on Hb and lymphocytes, whereas three of the 15 (20%) patients presented grade 2/3 PLT toxicity.Age was correlated negatively with both MBTV (r=-0.612, P=0.015) and TLA (r=-0.596, P=0.018). TLA, TLA/H, and MBTV/H predicted hematological toxicity on Hb, whereas TLA/H and MBTV/H predicted toxicity on PLTs at the end of Ra cycles. Receiver operating characteristic curve analysis allowed to define the cutoffs for MBTV (915 cm) and TLA (4198 cm) predictive for PLT toxicity, with an accuracy of 0.92 and 0.99. CONCLUSION: Tumor bone burden calculation is feasible with F-FCH PET/CT with freely available open-source software. In this pilot study, baseline F-FCH PET/CT markers (TLA, MBTV) have shown abilities to predict Hb and PLT toxicity after Ra therapy and could be explored for patient selection and treatment optimization.

A clinical evaluation of the impact of the Bayesian penalized likelihood reconstruction algorithm on PET FDG metrics.

PURPOSE: The aim of this study was to evaluate the impact of using the Bayesian penalized likelihood (BPL) algorithm on a bismuth germanium oxide positron emission tomography (PET)/computed tomography (CT) system for F-FDG PET/CT exams in case of low injected activity and scan duration. MATERIALS AND METHODS: F-FDG respiratory gated PET/CT performed on 102 cancer patients, injected with ∼2 MBq/kg of F-FDG, were reconstructed using two algorithms: ordered subset expectation maximization (OSEM) and BPL. The signal-to-noise ratio (SNR) was calculated as the ratio of mean standard uptake value (SUV) over the standard deviation in a reference volume defined automatically in the liver. The peak SUV and volumes were also measured in lesions larger than 2 cm thanks to the automated segmentation method. RESULTS: On 85 respiratory gated patients, the median SNR was significantly higher with BPL (P<0.0001) and it is even better when the BMI of the patient increases (odds ratio=1.26).For the 55 lesions, BPL significantly increased the SUVpeak [difference: (-0.5; 1.4), median=0.4, P<0.0001] compared with OSEM in 83.6% of the cases. With BPL, the volume was lower in 61.8% of the cases compared with OSEM, but this was not statistically significant. CONCLUSION: The BPL algorithm improves the image quality and lesion contrast and appears to be particularly appropriate for patients with a high BMI as it improves the SNR. However, it will be important for patient follow-up or multicenter studies to use the same algorithm and preferably BPL.

Clinical outcomes 1 year after empiric 131I therapy for hyperthyroid disorders: real life experience and predictive factors of functional response.

Radioiodine is a therapeutic option in Europe for Graves' disease (GD) and toxic multinodular goiter (MNG). PURPOSE: To compare empiric and calculated I activities using 2013 EANM recommendations. To look for predictive factors of therapeutic response to an empiric activity of I. To assess clinical situations favoring calculated treatment modalities. PATIENTS AND METHODS: Prospective monocentric study of clinical outcomes at 1 year follow-up in 86 patients with GD and MNG who received empiric I therapeutic activities (348-939 MBq). Differences between empiric and calculated activities were confronted to clinical outcomes. Physicians were not aware of the calculated activity at the time of prescription. RESULTS: One year after treatment, 9% (5/57) of GD patients and 7% (2/29) of MNG patients were still in a hyperthyroid state. Thyroid volume was reduced by 67% for GD and by 50% for MNG. In GD, empiric I activities were higher than calculated ones (564±131 vs. 316±319 MBq, P<0.001) in 93% (53/57) of patients. Pretherapeutic thyroid volume (>26 ml for GD; >40 ml for MNG) was associated with persistent hyperthyroidism. CONCLUSION: Empirically administered I for GD and MNG was associated with very high efficacy in thyroid function control and no side effects. Thyroid volume reduction did not preclude treatment efficacy. Activity calculation could be a useful method for treating patients with GD and thyroid volumes higher than 26 ml or patients with MNG and thyroid volumes higher than 40 ml. A selective approach based on pretherapeutic thyroid volume and radioiodine biokinetics might improve treatment success.

Comparison of an alternative and existing binning methods to reduce the acquisition duration of 4D PET/CT.

PURPOSE: Respiratory motion is a source of artifacts that reduce image quality in PET. Four dimensional (4D) PET/CT is one approach to overcome this problem. Existing techniques to limiting the effects of respiratory motions are based on prospective phase binning which requires a long acquisition duration (15-25 min). This time is uncomfortable for the patients and limits the clinical exploitation of 4D PET/CT. In this work, the authors evaluated an existing method and an alternative retrospective binning method to reduce the acquisition duration of 4D PET/CT. METHODS: The authors studied an existing mixed-amplitude binning (MAB) method and an alternative binning method by mixed-phases (MPhB). Before implementing MPhB, they analyzed the regularity of the breathing patterns in patients. They studied the breathing signal drift and missing CT slices that could be challenging for implementing MAB. They compared the performance of MAB and MPhB with current binning methods to measure the maximum uptake, internal volume, and maximal range of tumor motion. RESULTS: MPhB can be implemented depending on an optimal phase (in average, the exhalation peak phase -4.1% of the entire breathing cycle duration). Signal drift of patients was in average 35% relative to the breathing amplitude. Even after correcting this drift, MAB was feasible in 4D CT for only 64% of patients. No significant differences appeared between the different binning methods to measure the maximum uptake, internal volume, and maximal range of tumor motion. The authors also determined the inaccuracies of MAB and MPhB to measure the maximum amplitude of tumor motion with three bins (less than 3 mm for movement inferior to 12 mm, up to 6.4 mm for a 21 mm movement). CONCLUSIONS: The authors proposed an alternative binning method by mixed-phase binning that halves the acquisition duration of 4D PET/CT. Mixed-amplitude binning was challenging because of signal drift and missing CT slices. They showed that more than three bins were necessary for a more accurate measurement of the maximum amplitude of the tumor motion. However, the current 4D-CT technology limits the increase of the number of bins in 4D PET/CT because of missing CT slices. One can reconstruct 4D PET images with more bins but without attenuation/scatter correction.

A new respiratory gating device to improve 4D PET/CT.

PURPOSE: Respiratory motion creates artifacts in positon emission tomography with computed tomography (PET/CT) images especially for lung tumors, and can alter diagnosis. To account for motion effects, respiratory gating techniques have been developed. However, the lack of measures strongly correlated with tumor motion limits their accuracy. The authors developed a real-time pneumotachograph device (SPI) allowing to sort PET and CT images depending on lung volumes. METHODS: The performance of this innovative respiratory tracking system was characterized and compared to a standard system. Our experimental setup consisted in a movable platform and a thorax phantom with six fillable spheres simulating lung tumors. The accuracy of SPI to detect inhalation peaks was also determined on volunteers. A comparison with the real-time position management (RPM) device, that relies on abdominal height measurement, was then investigated. RESULTS: Experiments showed a high accuracy of the measured signal compared to the input signal (R = 0.88 to 0.99), and of the detection of the inhalation peaks (error of 0.1 +/- 5.8 ms) necessary for prospective binning mode. Activity recovery coefficient was improved (until +39%) and the smearing effect was reduced (until 2.74 times lower) with SPI compared to ungated PET/CT acquisition. The spatial distribution of activity in spheres was similar for 4D PET gated with SPI and RPM. Significant improvement of the binning stability and matching between PET and CT were highlighted for irregular breathing patterns with SPI. CONCLUSIONS: SPI is an innovative device that provides better binning performance than the current gating device on phantom experiments. Future works will focus on patients where the authors expect a significant improvement of specificity and sensitivity of PET/CT examinations.

Preclinical and clinical evidence that Deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography is a reliable tool for the detection of early molecular responses to erlotinib in head and neck cancer.

PURPOSE: There is a clinical need to identify predictive markers of the responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography with computed tomography ((18)FDG-PET/CT) could be a tool of choice for monitoring the early effects of this class of agent on tumor activity. EXPERIMENTAL DESIGN: Using models of human head and neck carcinoma (CAL33 and CAL166 cell lines), we first tested in vitro and in vivo whether the in vivo changes in (18)FDG-PET/CT uptake were associated with the molecular and cellular effects of the EGFR-TKI erlotinib. Then, the pathologic and morphologic changes and the (18)FDG-PET/CT uptake before and after erlotinib exposure in patients were analyzed. RESULTS: Erlotinib strongly inhibited extracellular signal-regulated kinase-1/2 (ERK-1/2) phosphorylation both in the preclinical models and in patients. Western blotting, immunofluorescence, and immunohistochemistry showed that erlotinib did not modify Glut-1 expression at the protein level either in cell line models or in tumor tissue from mouse xenografts or in patients. Phospho-ERK-1/2 inhibition was associated with a reduction in (18)FDG uptake in animal and human tumors. The biological volume was more accurate than the standardized uptake value for the evaluation of the molecular responses. CONCLUSION: These results show that the (18)FDG-PET/CT response is a reliable surrogate marker of the effects of erlotinib in head and neck carcinoma.