Repeatability of quantitative18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis

INTRODUCTION: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative18F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of18F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. METHODS: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five18F-FLT repeatability cohorts in solid tumors.18F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUVmax, SUVmean, SUVpeak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. RESULTS: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all18F-FLT uptake metrics (R2 ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUVpeak(RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUVmax ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repeatability of SUV metrics. CONCLUSIONS: In multi-center studies, differences ≥ 25% in18F-FLT SUV metrics likely represent a true change in tumor uptake. Larger differences are required for FLT metrics comprising volume estimates when no lesion selection criteria are applied

SMART (SiMulAtion and ReconsTruction) PET:an efficient PET simulation-reconstruction tool

Background: Positron-emission tomography (PET) simulators are frequently used for development and performance evaluation of segmentation methods or quantitative uptake metrics. To date, most PET simulation tools are based on Monte Carlo simulations, which are computationally demanding. Other analytical simulation tools lack the implementation of time of flight (TOF) or resolution modelling (RM). In this study, a fast and easy-to-use PET simulation-reconstruction package, SiMulAtion and ReconsTruction (SMART)-PET, is developed and validated, which includes both TOF and RM. SMART-PET, its documentation and instructions to calibrate the tool to a specific PET/CT system are available on Zenodo.SMART-PET allows the fast generation of 3D PET images. As input, it requires one image representing the activity distribution and one representing the corresponding CT image/attenuation map. It allows the user to adjust different parameters, such as reconstruction settings (TOF/RM), noise level or scan duration. Furthermore, a random spatial shift can be included, representing patient repositioning. To evaluate the tool, simulated images were compared with real scan data of the NEMA NU 2 image quality phantom. The scan was acquired as a 60-min list-mode scan and reconstructed with and without TOF and/or RM. For every reconstruction setting, ten statistically equivalent images, representing 30, 60, 120 and 300 s scan duration, were generated. Simulated and real-scan data were compared regarding coefficient of variation in the phantom background and activity recovery coefficients (RCs) of the spheres. Furthermore, standard deviation images of each of the ten statistically equivalent images were compared.Results: SMART-PET produces images comparable to actual phantom data. The image characteristics of simulated and real PET images varied in similar ways as function of reconstruction protocols and noise levels. The change in image noise with variation of simulated TOF settings followed the theoretically expected behaviour. RC as function of sphere size agreed within 0.3-11% between simulated and actual phantom data.Conclusions: SMART-PET allows for rapid and easy simulation of PET data. The user can change various acquisition and reconstruction settings (including RM and TOF) and noise levels. The images obtained show similar image characteristics as those seen in actual phantom data.</p

Design of the NL-ENIGMA study: Exploring the effect of Souvenaid on cerebral glucose metabolism in early Alzheimer's disease

Alzheimer's disease is associated with early synaptic loss. Specific nutrients are known to be rate limiting for synapse formation. Studies have shown that administering specific nutrients may improve memory function, possibly by increasing synapse formation. This Dutch study explores the Effect of a specific Nutritional Intervention on cerebral Glucose Metabolism in early Alzheimer's disease (NL-ENIGMA, Dutch Trial Register NTR4718, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4718). The NL-ENIGMA study is designed to test whether the specific multinutrient combination Fortasyn Connect present in the medical food Souvenaid influences cerebral glucose metabolism as a marker for improved synapse function. Methods This study is a double-blind, randomized controlled parallel-group single-center trial. Forty drug-naive patients with mild cognitive impairment or mild dementia with evidence of amyloid deposition are 1:1 randomized to receive either the multinutrient combination or placebo once daily. Main exploratory outcome parameters include absolute quantitative positron emission tomography with 18F-fluorodeoxyglucose (including arterial sampling) and standard uptake value ratios normalized for the cerebellum or pons after 24 weeks. Discussion We expect the NL-ENIGMA study to provide further insight in the potential of this multinutrient combination to improve synapse function

Day-to-Day Test–Retest Variability of CBF, CMRO2, and OEF Measurements Using Dynamic 15O PET Studies

Contains fulltext : 169592.pdf (publisher's version ) (Open Access)PURPOSE: We assessed test-retest variability of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) measurements derived from dynamic (15)O positron emission tomography (PET) scans. PROCEDURES: In seven healthy volunteers, complete test-retest (15)O PET studies were obtained; test-retest variability and left-to-right ratios of CBF, CBV, OEF, and CMRO(2) in arterial flow territories were calculated. RESULTS: Whole-brain test-retest coefficients of variation for CBF, CBV, CMRO(2), and OEF were 8.8%, 13.8%, 5.3%, and 9.3%, respectively. Test-retest variability of CBV left-to-right ratios was <7.4% across all territories. Corresponding values for CBF, CMRO(2), and OEF were better, i.e., <4.5%, <4.0%, and <1.4%, respectively. CONCLUSIONS: The test-retest variability of CMRO(2) measurements derived from dynamic (15)O PET scans is comparable to within-session test-retest variability derived from steady-state (15)O PET scans. Excellent regional test-retest variability was observed for CBF, CMRO(2), and OEF. Variability of absolute CBF and OEF measurements is probably affected by physiological day-to-day variability of CBF

Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology

BACKGROUND: Positron emission tomography (PET) may be useful for defining the gross tumour volume for radiation treatment planning and for response monitoring of non-small cell lung cancer (NSCLC) patients. The purpose of this study was to compare tumour sizes obtained from CT- and various more commonly available PET-based tumour delineation methods to pathology findings. METHODS: Retrospective non-respiratory gated whole body [(18)F]-fluoro-2-deoxy-D-glucose PET/CT studies from 19 NSCLC patients were used. Several (semi-)automatic PET-based tumour delineation methods and manual CT-based delineation were used to assess the maximum tumour diameter. RESULTS: 50%, adaptive 41% threshold-based and contrast-oriented delineation methods showed good agreement with pathology after removing two outliers (R(2)=0.82). An absolute SUV threshold of 2.5 also showed a good agreement with pathology after the removal of 5 outliers (R(2): 0.79), but showed a significant overestimation in the maximum diameter (19.8 mm, p<0.05). Adaptive 50%, relative threshold level and gradient-based methods did not show any outliers, provided only small, non-significant differences in maximum tumour diameter (<4.7 mm, p>0.10), and showed fair correlation (R(2)>0.62) with pathology. Although adaptive 70% threshold-based methods showed underestimation compared to pathology (36%), it provided the best precision (SD: 14%) together with good correlation (R(2)=0.81). Good correlation between CT delineation and pathology was observed (R(2)=0.77). However, CT delineation showed a significant overestimation compared with pathology (3.8 mm, p<0.05). CONCLUSIONS: PET-based tumour delineation methods provided tumour sizes in agreement with pathology and may therefore be useful to define the (metabolically most) active part of the tumour for radiotherapy and response monitoring purposes

Neurophysiological effects of sleep deprivation in healthy adults, a pilot study

Total sleep deprivation (TSD) may induce fatigue, neurocognitive slowing and mood changes, which are partly compensated by stress regulating brain systems, resulting in altered dopamine and cortisol levels in order to stay awake if needed. These systems, however, have never been studied in concert. At baseline, after a regular night of sleep, and the next morning after TSD, 12 healthy subjects performed a semantic affective classification functional magnetic resonance imaging (fMRI) task, followed by a [11C]raclopride positron emission tomography (PET) scan. Saliva cortisol levels were acquired at 7 time points during both days. Affective symptoms were measured using Beck Depression Inventory (BDI), Spielberger State Trait Anxiety Index (STAI) and visual analogue scales. After TSD, perceived energy levels, concentration, and speed of thought decreased significantly, whereas mood did not. During fMRI, response speed decreased for neutral words and positive targets, and accuracy decreased trendwise for neutral words and for positive targets with a negative distracter. Following TSD, processing of positive words was associated with increased left dorsolateral prefrontal activation. Processing of emotional words in general was associated with increased insular activity, whereas contrasting positive vs. negative words showed subthreshold increased activation in the (para)hippocampal area. Cortisol secretion was significantly lower after TSD. Decreased voxel-by-voxel [11 C]raclopride binding potential (BPND) was observed in left caudate. TSD induces widespread cognitive, neurophysiologic and endocrine changes in healthy adults, characterized by reduced cognitive functioning, despite increased regional brain activity

Reproducibility of quantitative F-18-3'-deoxy-3'-fluorothymidine measurements using positron emission tomography

Positron emission tomography (PET) using F-18-3'-deoxy-3'-fluorothymidine ([F-18]FLT) allows noninvasive monitoring of tumour proliferation. For serial imaging in individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative [F-18]FLT measurements. Nine patients with non-small-cell lung cancer (NSCLC) and six with head-and-neck cancer (HNC) underwent [F-18]FLT PET twice within 7 days prior to therapy. The maximum pixel value (SUVmax) and a threshold defined volume (SUV41%) were defined for all delineated lesions. The plasma to tumour transfer constant (K-i) was estimated using both Patlak graphical analysis and nonlinear regression (NLR). NLR was also used to estimate k(3), which, at least in theory, selectively reflects thymidine kinase 1 activity. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. All primary tumours and > 90% of clinically suspected locoregional metastases could be delineated. In total, 24 lesions were defined. NLR-derived K-i, Patlak-derived K-i, SUV41% and SUVmax showed excellent reproducibility with ICCs of 0.92, 0.95, 0.98 and 0.93, and SDs of 16%, 12%, 7% and 11%, respectively. Reproducibility was poor for k(3) with an ICC of 0.43 and SD of 38%. Quantitative [F-18]FLT measurements are reproducible in both NSCLC and HNC patients. When monitoring response in individual patients, changes of more than 15% in SUV41%, 20-25% in SUVmax and Patlak-derived K-i, and 32% in NLR3k-derived K-i are likely to represent treatment effect