Noninvasive quantification of F-18-FLT human brain PET for the assessment of tumour proliferation in patients with high-grade glioma

Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch-Laboratories, Gleueler Str 50, 50931 Cologne, Germany.
European Journal of Nuclear Medicine (Impact Factor: 5.38). 09/2009; 36(12):1960-7. DOI: 10.1007/s00259-009-1244-4
Source: PubMed


Compartmental modelling of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples.
Based on the analysis of 11 patients with glioma (WHO grade II-IV) a procedure for the automated extraction of an input function from 18F-FLT brain PET data was derived. The time-activity curve of the volume of interest with the maximum difference in 18F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K1 (transport across the blood-brain barrier) and Ki (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation.
The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K1,img and K1,sample, r = 0.95, p < 10(-5); Ki,img and Ki,sample, r = 0.86, p < 0.001). A paired t-test showed no significant differences in the parameters derived with the two methods (K1,img and K1,sample, p = 0.20; Ki,img and Ki,sample, p = 0.92). Furthermore, a significant correlation between Ki,img and the percentage of Ki-67-positive cells was observed (r = 0.73, p = 0.01).
Kinetic modelling of 18F-FLT brain PET data using image-derived input functions extracted from human brain PET data with the practical procedure described here provides information about the proliferative activity of brain tumours which might have clinical relevance especially for monitoring of therapy response in future clinical trials.

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    • "Some methods used to extract input functions from PET images attempt to explicitly correct the PVE using anatomical information taken from computed tomography (CT) or magnetic resonance scans [10-12]. Other approaches, most commonly used in brain imaging, assume that the activity measured in a region represents a mixture of blood and surrounding tissue activities and implicitly correct the PVE by modelling the relative contributions of blood and tissue to the total imaged regional activity [13-16]. "
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    ABSTRACT: We present a method for extracting arterial input functions from dynamic [18F]FLT PET images of the head and neck, directly accounting for the partial volume effect. The method uses two blood samples, for which the optimum collection times are assessed. Six datasets comprising dynamic PET images, co-registered computed tomography (CT) scans and blood-sampled input functions were collected from four patients with head and neck tumours. In each PET image set, a region was identified that comprised the carotid artery (outlined on CT images) and surrounding tissue within the voxels containing the artery. The time course of activity in the region was modelled as the sum of the blood-sampled input function and a compartmental model of tracer uptake in the surrounding tissue. The time course of arterial activity was described by a mathematical function with seven parameters. The parameters of the function and the compartmental model were simultaneously estimated, aiming to achieve the best match between the modelled and imaged time course of regional activity and the best match of the estimated blood activity to between 0 and 3 samples. The normalised root-mean-square (RMSnorm) differences and errors in areas under the curves (AUCs) between the measured and estimated input functions were assessed. A one-compartment model of tracer movement to and from the artery best described uptake in the tissue surrounding the artery, so the final model of the input function and tissue kinetics has nine parameters to be estimated. The estimated and blood-sampled input functions agreed well when two blood samples, obtained at times between 2 and 8 min and between 8 and 60 min, were used in the estimation process (RMSnorm values of 1.1 ± 0.5 and AUC errors for the peak and tail region of the curves of 15% ± 9% and 10% ± 8%, respectively). A third blood sample did not significantly improve the accuracy of the estimated input functions. Input functions for FLT-PET studies of the head and neck can be estimated well using a one-compartment model of tracer movement and TWO blood samples obtained after the peak in arterial activity.
    Full-text · Article · Dec 2013 · EJNMMI Research
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    • "To date, relatively few limited sampling methodologies (four to eight samples for blood radioactivity concentration and at least one sample for metabolite analysis) have been proposed for FLT-PET [14,19-22], and FLT kinetics has been recently estimated using image-derived input function in colorectal cancer [21], non-small-cell lung cancer [22] and high grade gliomas [23]. In this study, we investigated the consequences of using a population input approach and highly reduced sampling protocols to estimate FLT kinetics in oncology PET studies without continuous arterial sampling. "
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    ABSTRACT: Quantification of kinetic parameters of positron emission tomography (PET) imaging agents normally requires collecting arterial blood samples which is inconvenient for patients and difficult to implement in routine clinical practice. The aim of this study was to investigate whether a population-based input function (POP-IF) reliant on only a few individual discrete samples allows accurate estimates of tumour proliferation using [18F]fluorothymidine (FLT). Thirty-six historical FLT-PET data with concurrent arterial sampling were available for this study. A population average of baseline scans blood data was constructed using leave-one-out cross-validation for each scan and used in conjunction with individual blood samples. Three limited sampling protocols were investigated including, respectively, only seven (POP-IF7), five (POP-IF5) and three (POP-IF3) discrete samples of the historical dataset. Additionally, using the three-point protocol, we derived a POP-IF3M, the only input function which was not corrected for the fraction of radiolabelled metabolites present in blood. The kinetic parameter for net FLT retention at steady state, Ki, was derived using the modified Patlak plot and compared with the original full arterial set for validation. Small percentage differences in the area under the curve between all the POP-IFs and full arterial sampling IF was found over 60 min (4.2%-5.7%), while there were, as expected, larger differences in the peak position and peak height.A high correlation between Ki values calculated using the original arterial input function and all the population-derived IFs was observed (R2 = 0.85-0.98). The population-based input showed good intra-subject reproducibility of Ki values (R2 = 0.81-0.94) and good correlation (R2 = 0.60-0.85) with Ki-67. Input functions generated using these simplified protocols over scan duration of 60 min estimate net PET-FLT retention with reasonable accuracy.
    Full-text · Article · Mar 2012 · EJNMMI Research
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    • "In summary, venous samples can be substituted for arterial samples only for a limited time-window of variable length that must be assessed individually for each tracer. The most straightforward way to overcome this problem would be arterialization of venous blood through heating, which has been successfully employed for different tracers (Backes et al, 2009; Moriwaki et al, 1993; Phelps et al, 1979; Wahl et al, 1999; Wong et al, 1997). Alternatively, sampling from a different vein may allow investigators to obtain blood concentrations that are closer to those in arterial blood. "
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    ABSTRACT: Quantitative positron emission tomography (PET) brain studies often require that the input function be measured, typically via arterial cannulation. Image-derived input function (IDIF) is an elegant and attractive noninvasive alternative to arterial sampling. However, IDIF is also a very challenging technique associated with several problems that must be overcome before it can be successfully implemented in clinical practice. As a result, IDIF is rarely used as a tool to reduce invasiveness in patients. The aim of the present review was to identify the methodological problems that hinder widespread use of IDIF in PET brain studies. We conclude that IDIF can be successfully implemented only with a minority of PET tracers. Even in those cases, it only rarely translates into a less-invasive procedure for the patient. Finally, we discuss some possible alternative methods for obtaining less-invasive input function.
    Full-text · Article · Aug 2011 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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