Compartmental analysis of dynamic nuclear medicine data: models and identifiability

Delbary, Fabrice; Garbarino, Sara; Vivaldi, Valentina

doi:10.1088/0266-5611/32/12/125010

Cited by 9 publications

(12 citation statements)

References 41 publications

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“…This analysis provided us with the method to convert the measured counting rates in time curves of activities and thus to estimate the rate constants of exchanges between the different pools, in analogy with the conventional analysis of time concentration curves 1,4,7–11 . In fact, the analysis reported in Supplementary Material S1 indicates that this approach provides a unique set of rate constants for each experiment 20 and thus ensures that the reconstructed numerical values of kinetic parameters are the only ones explaining the data 21,22 . We also observe that the estimated rate constants are comparable with the standard ones, with the only exception of FDG rate of entry into the cells ( k 1 ) that has to be converted into its counterpart () accounting for the ratio between intracellular ( V cyt ) and medium ( V i ) volume, according to the equation:…”

Section: Resultsmentioning

confidence: 99%

“…It may be shown that the vectors of parameters z 5 and z 4 can be uniquely determined by the given data (see 20 ). The uniqueness property ensures that the numerical values of kinetic parameters obtained by solving the compartmental inverse problem are the only values explaining the data 21,22 . We recall that the compartmental inverse problems of equation (22) and equation (23) were solved by means of a Newton-type iterative algorithm 37,38 , already used and validated in other works of our group 39–41 .…”

Section: Methodsmentioning

confidence: 99%

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G6Pase location in the endoplasmic reticulum: Implications on compartmental analysis of FDG uptake in cancer cells

Scussolini

Bauckneht

Cossu

et al. 2019

Sci Rep

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The favourable kinetics of 18 F-fluoro-2-deoxyglucose (FDG) permits to depict cancer glucose consumption by a single evaluation of late tracer uptake. This standard procedure relies on the slow radioactivity loss, usually attributed to the limited tumour expression of G6P-phosphatase (G6Pase). However, this classical interpretation intrinsically represents an approximation since, as in all tissues, cancer G6Pase activity is remarkable and is confined to the endoplasmic reticulum (ER), whose lumen must be reached by phosphorylated FDG to explain its hydrolysis and radioactivity release. The present study tested the impact of G6Pase sequestration on the mathematical description of FDG trafficking and handling in cultured cancer cells. Our data show that accounting for tracer access to the ER configures this compartment as the preferential site of FDG accumulation. This is confirmed by the reticular localization of fluorescent FDG analogues. Remarkably enough, reticular accumulation rate of FDG is dependent upon extracellular glucose availability, thus configuring the same ER as a significant determinant of cancer glucose metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

G6Pase location in the endoplasmic reticulum: Implications on compartmental analysis of FDG uptake in cancer cells

Scussolini

Bauckneht

Cossu

et al. 2019

Sci Rep

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“…However, that result does not account for the fact that in experiments relying on PET images, the only available measurements correspond to the sum of the tracer concentrations in the left ventricle and in the tumor, as illustrated in equation (10). Nevertheless, the standard techniques illustrated in (Scussolini et al, 2017; Delbary et al, 2016) and relying on the use of the Laplace transform straightforwardly leads to the following result: assume that the polynomials and are coprime; if is generic, then k is uniquely determined by C i and 𝒞 T , and the BC model of equations (1)–(10) is identifiable.…”

Section: Identifiability Issuesmentioning

confidence: 99%

The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

Scussolini

Cossu

Marini

et al. 2019

Preprint

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2A very recent result obtained by means of an in vitro experiment with cancer cultured cells 3 has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-4 deoxy-2-[ 18 F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is 5 made more significant by the fact that reticular accumulation rate of FDG is dependent upon 6 extracellular glucose availability. The objective of the present paper was to confirm this result 7 in vivo, using small animal models of CT26 cancer tissues. Specifically, assuming that the 8 endoplasmic reticulum plays a specific functional role in the framework of a three-compartment 9 model for FDG kinetics, we are able to explain positron emission tomography dynamic data in a 10 more reliable way than by means of a standard Sokoloff two-compartment system. This result is 11 made more solid from a computational viewpoint by means of some identifiability considerations 12 based on a mathematical analysis of the compartmental equations. 13 Keywords: cancer glucose metabolism, endoplasmic reticulum, in vivo models, FDG kinetics, compartmental analysis 14 1 INTRODUCTION 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) is widely used as a glucose analogue tracer to evaluate glucose 15 metabolism in living organisms. As glucose, FDG is first transported into cells, where it is phosphorylated 16to FDG-6-phosphate (FDG6P) by hexokinase (HK) and then accumulates intracellularly. The measured 17 amount of emitted radiation is considered an accurate marker of overall glucose uptake by cells and tissues 18 (Cherry et al., 2012). In addition, FDG consumption by cancer cells is increased by the Warburg effect for 19 glucose (Vander et al., 2009); consequently, FDG may be employed in cancer detection and staging, and to 20 determine the effectiveness of medical treatments (Cairns et al., 2011). 21A recent result concerning the characterization of FDG kinetics in cultured cancer cells (Scussolini et 22 al., 2019) showed that the endoplasmic reticulum (ER) is the preferential site of FDG accumulation and 23 that, even more importantly, FDG reticular accumulation rate is dependent upon extracellular glucose 24 availability. This result is coherent with recent progress in cell biochemistry, which clarified that the 25 glucose-6-phosphatase (G6Pase), responsible for the dephosphorylation, is compartmentalized within the 26 endoplasmic reticulum (ER) (Ghosh et al., 2002; Marini et al., 2016). 27 1 Scussolini et al. The role of the endoplasmic reticulum The investigation in (Scussolini et al., 2019) relied on two methodological tools, one experimental 28 and one computational. In fact, on the one hand, FDG kinetics in cells cultured over a Petri dish, was 29 evaluated using the dedicated Ligand Tracer device (Björke and Andersson, 2006), which is able to count 30 electron/positron events without contaminating the counting rate of the cultured cells. On the other hand, 31 the data analysis was performed within the framework of a novel compartmental model, which extend...

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“…The compartmental model describing the FDG metabolism of phosphorylation-dephosphorylation is the two-compartment catenary model shown in Figure 1 [9,39]. The two-compartment catenary model consists of:…”

Section: Two-compartment Catenary Systemmentioning

confidence: 99%

A physiology-based parametric imaging method for FDG–PET data

et al. 2017

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Parametric imaging is a compartmental approach that processes nuclear imaging data to estimate the spatial distribution of the kinetic parameters governing tracer flow. The present paper proposes a novel and efficient computational method for parametric imaging which is potentially applicable to several compartmental models of diverse complexity and which is effective in the determination of the parametric maps of all kinetic coefficients. We consider applications to [ 18 F]-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) data and analyze the two-compartment catenary model describing the standard FDG metabolization by an homogeneous tissue and the three-compartment non-catenary model representing the renal physiology. We show uniqueness theorems for both models. The proposed imaging method starts from the reconstructed FDG-PET images of tracer concentration and preliminarily applies image processing algorithms for noise reduction and image segmentation. The optimization procedure solves pixel-wise the non-linear inverse problem of determining the kinetic parameters from dynamic concentration data through a regularized Gauss-Newton iterative algorithm. The reliability of the method is validated against synthetic data, for the two-compartment system, and experimental real data of murine models, for the renal three-compartment system.

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Compartmental analysis of dynamic nuclear medicine data: models and identifiability

Cited by 9 publications

References 41 publications

G6Pase location in the endoplasmic reticulum: Implications on compartmental analysis of FDG uptake in cancer cells

G6Pase location in the endoplasmic reticulum: Implications on compartmental analysis of FDG uptake in cancer cells

The role of the endoplasmic reticulum in in vivo cancer FDG kinetics

A physiology-based parametric imaging method for FDG–PET data

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