Simultaneous estimation of tracer kinetic model parameters using analytical and inverse approaches with a hybrid method

The inverse problem approach to Tracer Kinetic Modelling (TKM) using dynamic positron-emission tomography (PET) images is important in identifying the kinetic parameters and then quantifying the tracer concentrations in the region of interest. In parameter estimation, knowledge of good initial approximations to the parameters is essential. The aim of this paper is to extend existing work on an inverse method for tracer kinetics by proposing an improved hybrid method integrated with an analytic solution in a multi-objective formulation of the inverse method. The analytical solution is derived through the use of the Laplace transformation technique. This integrated approach will be compared against other parameter estimation techniques in terms of computational efficiency and accuracy

Advanced perfusion quantification methods for dynamic PET and MRI data modelling

The functionality of tissues is guaranteed by the capillaries, which supply the microvascular network providing a considerable surface area for exchanges between blood and tissues. Microcirculation is affected by any pathological condition and any change in the blood supply can be used as a biomarker for the diagnosis of lesions and the optimization of the treatment. Nowadays, a number of techniques for the study of perfusion in vivo and in vitro are available. Among the several imaging modalities developed for the study of microcirculation, the analysis of the tissue kinetics of intravenously injected contrast agents or tracers is the most widely used technique. Tissue kinetics can be studied using different modalities: the positive enhancement of the signal in the computed tomography and in the ultrasound dynamic contrast enhancement imaging; T1-weighted MRI or the negative enhancement of T2* weighted MRI signal for the dynamic susceptibility contrast imaging or, finally, the uptake of radiolabelled tracers in dynamic PET imaging. Here we will focus on the perfusion quantification of dynamic PET and MRI data. The kinetics of the contrast agent (or the tracer) can be analysed visually, to define qualitative criteria but, traditionally, quantitative physiological parameters are extracted with the implementation of mathematical models. Serial measurements of the concentration of the tracer (or of the contrast agent) in the tissue of interest, together with the knowledge of an arterial input function, are necessary for the calculation of blood flow or perfusion rates from the wash-in and/or wash-out kinetic rate constants. The results depend on the acquisition conditions (type of imaging device, imaging mode, frequency and total duration of the acquisition), the type of contrast agent or tracer used, the data pre-processing (motion correction, attenuation correction, correction of the signal into concentration) and the data analysis method. As for the MRI, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a non-invasive imaging technique that can be used to measure properties of tissue microvasculature. It is sensitive to differences in blood volume and vascular permeability that can be associated with tumour angiogenesis. DCE-MRI has been investigated for a range of clinical oncologic applications (breast, prostate, cervix, liver, lung, and rectum) including cancer detection, diagnosis, staging, and assessment of treatment response. Tumour microvascular measurements by DCE-MRI have been found to correlate with prognostic factors (such as tumour grade, microvessel density, and vascular endothelial growth factor expression) and with recurrence and survival outcomes. Furthermore, DCE-MRI changes measured during treatment have been shown to correlate with outcome, suggesting a role as a predictive marker. The accuracy of DCE-MRI relies on the ability to model the pharmacokinetics of an injected contrast agent using the signal intensity changes on sequential magnetic resonance images. DCE-MRI data are usually quantified with the application of the pharmacokinetic two-compartment Tofts model (also known as the standard model), which represents the system with the plasma and tissue (extravascular extracellular space) compartments and with the contrast reagent exchange rates between them. This model assumes a negligible contribution from the vascular space and considers the system in, what-is-known as, the fast exchange limit, assuming infinitely fast transcytolemmal water exchange kinetics. In general, the number, as well as any assumption about the compartments, depends on the properties of the contrast agent used (mainly gadolinium) together with the tissue physiology or pathology studied. For this reason, the choice of the model is crucial in the analysis of DCE-MRI data. The value of PET in clinical oncology has been demonstrated with studies in a variety of cancers including colorectal carcinomas, lung tumours, head and neck tumours, primary and metastatic brain tumours, breast carcinoma, lymphoma, melanoma, bone cancers, and other soft-tissue cancers. PET studies of tumours can be performed for several reasons including the quantification of tumour perfusion, the evaluation of tumour metabolism, the tracing of radiolabelled cytostatic agents. In particular, the kinetic analysis of PET imaging has showed, in the past few years, an increasing value in tumour diagnosis, as well as in tumour therapy, through providing additional indicative parameters. Many authors have showed the benefit of kinetic analysis of anticancer drugs after labelling with radionuclide in measuring the specific therapeutic effect bringing to light the feasibility of applying the kinetic analysis to the dynamic acquisition. Quantification methods can involve visual analysis together with compartmental modelling and can be applied to a wide range of different tracers. The increased glycolysis in the most malignancies makes 18F-FDG-PET the most common diagnostic method used in tumour imaging. But, PET metabolic alteration in the target tissue can depend by many other factors. For example, most types of cancer are characterized by increased choline transport and by the overexpression of choline kinase in highly proliferating cells in response to enhanced demand of phosphatidylcholine (prostate, breast, lung, ovarian and colon cancers). This effect can be diagnosed with choline-based tracers as the 18Ffluoromethylcholine (18F-FCH), or the even more stable 18F-D4-Choline. Cellular proliferation is also imaged with 18F-fluorothymidine (FLT), which is trapped within the cytosol after being mono phosphorylated by thymidine kinase-1 (TK1), a principal enzyme in the salvage pathway of DNA synthesis. 18F-FLT has been found to be useful for noninvasive assessment of the proliferation rate of several types of cancer and showed high reproducibility and accuracy in breast and lung cancer tumours. The aim of this thesis is the perfusion quantification of dynamic PET and MRI data of patients with lung, brain, liver, prostate and breast lesions with the application of advanced models. This study covers a wide range of imaging methods and applications, presenting a novel combination of MRI-based perfusion measures with PET kinetic modelling parameters in oncology. It assesses the applicability and stability of perfusion quantification methods, which are not currently used in the routine clinical practice. The main achievements of this work include: 1) the assessment of the stability of perfusion quantification of D4-Choline and 18F-FLT dynamic PET data in lung and liver lesions, respectively (first applications in the literature); 2) the development of a model selection in the analysis of DCE-MRI data of primary brain tumours (first application of the extended shutter speed model); 3) the multiparametric analysis of PET and MRI derived perfusion measurements of primary brain tumour and breast cancer together with the integration of immuohistochemical markers in the prediction of breast cancer subtype (analysis of data acquired on the hybrid PET/MRI scanner). The thesis is structured as follows: - Chapter 1 is an introductive chapter on cancer biology. Basic concepts, including the causes of cancer, cancer hallmarks, available cancer treatments, are described in this first chapter. Furthermore, there are basic concepts of brain, breast, prostate and lung cancers (which are the lesions that have been analysed in this work). - Chapter 2 is about Positron Emission Tomography. After a brief introduction on the basics of PET imaging, together with data acquisition and reconstruction methods, the chapter focuses on PET in the clinical settings. In particular, it shows the quantification techniques of static and dynamic PET data and my results of the application of graphical methods, spectral analysis and compartmental models on dynamic 18F-FDG, 18F-FLT and 18F-D4- Choline PET data of patients with breast, lung cancer and hepatocellular carcinoma. - Chapter 3 is about Magnetic Resonance Imaging. After a brief introduction on the basics of MRI, the chapter focuses on the quantification of perfusion weighted MRI data. In particular, it shows the pharmacokinetic models for the quantification of dynamic contrast enhanced MRI data and my results of the application of the Tofts, the extended Tofts, the shutter speed and the extended shutter speed models on a dataset of patients with brain glioma. - Chapter 4 introduces the multiparametric imaging techniques, in particular the combined PET/CT and the hybrid PET/MRI systems. The last part of the chapter shows the applications of perfusion quantification techniques on a multiparametric study of breast tumour patients, who simultaneously underwent DCE-MRI and 18F-FDG PET on a hybrid PET/MRI scanner. Then the results of a predictive study on the same dataset of breast tumour patients integrated with immunohistochemical markers. Furthermore, the results of a multiparametric study on DCE-MRI and 18F-FCM brain data acquired both on a PET/CT scanner and on an MR scanner, separately. Finally, it will show the application of kinetic analysis in a radiomic study of patients with prostate cancer

Parametric Images in Assessing Bone Grafts Using Dynamic 18F-Fluoride PET

The early identification of graft failure would improve patient management. 18F-fluoride is a suitable tracer for quantifying bone metabolism. Performance of parametric images constructed by Patlak graphical analysis (PGA) with various time periods was evaluated in the analysis of dynamic 18F-fluoride PET studies of eight patients with fibula bone grafts after limb salvage surgery. The PGA parametric image approach tended to underestimate influx rate. The linear portion of PGA analysis was found to be from 10 to 50 min. It shows promise in providing a quantitative assessment of the viability of bone grafts

Methodological considerations in quantification of oncological FDG PET studies

Contains fulltext : 87741.pdf (publisher's version ) (Closed access) Contains fulltext : 87741-1.pdf (postprint version ) (Open Access)PURPOSE: This review aims to provide insight into the factors that influence quantification of glucose metabolism by FDG PET images in oncology as well as their influence on repeated measures studies (i.e. treatment response assessment), offering improved understanding both for clinical practice and research. METHODS: Structural PubMed searches have been performed for the many factors affecting quantification of glucose metabolism by FDG PET. Review articles and references lists have been used to supplement the search findings. RESULTS: Biological factors such as fasting blood glucose level, FDG uptake period, FDG distribution and clearance, patient motion (breathing) and patient discomfort (stress) all influence quantification. Acquisition parameters should be adjusted to maximize the signal to noise ratio without exposing the patient to a higher than strictly necessary radiation dose. This is especially challenging in pharmacokinetic analysis, where the temporal resolution is of significant importance. The literature is reviewed on the influence of attenuation correction on parameters for glucose metabolism, the effect of motion, metal artefacts and contrast agents on quantification of CT attenuation-corrected images. Reconstruction settings (analytical versus iterative reconstruction, post-reconstruction filtering and image matrix size) all potentially influence quantification due to artefacts, noise levels and lesion size dependency. Many region of interest definitions are available, but increased complexity does not necessarily result in improved performance. Different methods for the quantification of the tissue of interest can introduce systematic and random inaccuracy. CONCLUSIONS: This review provides an up-to-date overview of the many factors that influence quantification of glucose metabolism by FDG PET.01 juli 201

Evaluation of image quality and reconstruction parameters in recent PET-CT and PET-MR systems

In this PhD dissertation, we propose to evaluate the impact of using different PET isotopes for the National Electrical Manufacturers Association (NEMA) tests performance evaluation of the GE Signa integrated PET/MR. The methods were divided into three closely related categories: NEMA performance measurements, system modelling and evaluation of the image quality of the state-of-the-art of clinical PET scanners. NEMA performance measurements for characterizing spatial resolution, sensitivity, image quality, the accuracy of attenuation and scatter corrections, and noise equivalent count rate (NECR) were performed using clinically relevant and commercially available radioisotopes. Then we modelled the GE Signa integrated PET/MR system using a realistic GATE Monte Carlo simulation and validated it with the result of the NEMA measurements (sensitivity and NECR). Next, the effect of the 3T MR field on the positron range was evaluated for F-18, C-11, O-15, N-13, Ga-68 and Rb-82. Finally, to evaluate the image quality of the state-of-the-art clinical PET scanners, a noise reduction study was performed using a Bayesian Penalized-Likelihood reconstruction algorithm on a time-of-flight PET/CT scanner to investigate whether and to what extent noise can be reduced. The outcome of this thesis will allow clinicians to reduce the PET dose which is especially relevant for young patients. Besides, the Monte Carlo simulation platform for PET/MR developed for this thesis will allow physicists and engineers to better understand and design integrated PET/MR systems

Improving Quantification in Lung PET/CT for the Evaluation of Disease Progression and Treatment Effectiveness

Positron Emission Tomography (PET) allows imaging of functional processes in vivo by measuring the distribution of an administered radiotracer. Whilst one of its main uses is directed towards lung cancer, there is an increased interest in diffuse lung diseases, for which the incidences rise every year, mainly due to environmental reasons and population ageing. However, PET acquisitions in the lung are particularly challenging due to several effects, including the inevitable cardiac and respiratory motion and the loss of spatial resolution due to low density, causing increased positron range. This thesis will focus on Idiopathic Pulmonary Fibrosis (IPF), a disease whose aetiology is poorly understood while patient survival is limited to a few years only. Contrary to lung tumours, this diffuse lung disease modifies the lung architecture more globally. The changes result in small structures with varying densities. Previous work has developed data analysis techniques addressing some of the challenges of imaging patients with IPF. However, robust reconstruction techniques are still necessary to obtain quantitative measures for such data, where it should be beneficial to exploit recent advances in PET scanner hardware such as Time of Flight (TOF) and respiratory motion monitoring. Firstly, positron range in the lung will be discussed, evaluating its effect in density-varying media, such as fibrotic lung. Secondly, the general effect of using incorrect attenuation data in lung PET reconstructions will be assessed. The study will compare TOF and non-TOF reconstructions and quantify the local and global artefacts created by data inconsistencies and respiratory motion. Then, motion compensation will be addressed by proposing a method which takes into account the changes of density and activity in the lungs during the respiration, via the estimation of the volume changes using the deformation fields. The method is evaluated on late time frame PET acquisitions using ¹⁸F-FDG where the radiotracer distribution has stabilised. It is then used as the basis for a method for motion compensation of the early time frames (starting with the administration of the radiotracer), leading to a technique that could be used for motion compensation of kinetic measures. Preliminary results are provided for kinetic parameters extracted from short dynamic data using ¹⁸F-FDG

Long-axial field-of-view PET/CT: perspectives and review of a revolutionary development in nuclear medicine based on clinical experience in over 7000 patients.

Recently introduced long-axial field-of-view (LAFOV) PET/CT systems represent one of the most significant advancements in nuclear medicine since the advent of multi-modality PET/CT imaging. The higher sensitivity exhibited by such systems allow for reductions in applied activity and short duration scans. However, we consider this to be just one small part of the story: Instead, the ability to image the body in its entirety in a single FOV affords insights which standard FOV systems cannot provide. For example, we now have the ability to capture a wider dynamic range of a tracer by imaging it over multiple half-lives without detrimental image noise, to leverage lower radiopharmaceutical doses by using dual-tracer techniques and with improved quantification. The potential for quantitative dynamic whole-body imaging using abbreviated protocols potentially makes these techniques viable for routine clinical use, transforming PET-reporting from a subjective analysis of semi-quantitative maps of radiopharmaceutical uptake at a single time-point to an accurate and quantitative, non-invasive tool to determine human function and physiology and to explore organ interactions and to perform whole-body systems analysis. This article will share the insights obtained from 2 years' of clinical operation of the first Biograph Vision Quadra (Siemens Healthineers) LAFOV system. It will also survey the current state-of-the-art in PET technology. Several technologies are poised to furnish systems with even greater sensitivity and resolution than current systems, potentially with orders of magnitude higher sensitivity. Current barriers which remain to be surmounted, such as data pipelines, patient throughput and the hindrances to implementing kinetic analysis for routine patient care will also be discussed