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

Imaging of the Breast

Early detection of breast cancer combined with targeted therapy offers the best outcome for breast cancer patients. This volume deal with a wide range of new technical innovations for improving breast cancer detection, diagnosis and therapy. There is a special focus on improvements in mammographic image quality, image analysis, magnetic resonance imaging of the breast and molecular imaging. A chapter on targeted therapy explores the option of less radical postoperative therapy for women with early, screen-detected breast cancers

Sigma receptor ligands: novel applications in cancer imaging and treatment

Sigma receptoren (subtypes sigma-1 en sigma-2) zijn unieke bindingsplaatsen die een aanzienlijk hogere expressie vertonen in kanker dan in gezond weefsel. Hoewel de endogene agonisten niet met zekerheid geïdentificeerd werden, zijn vele kunstmatige liganden beschikbaar voor onderzoek van de normale en pathofysiologische functie van sigma receptoren. Van therapeutische doseringen van zulke verbindingen (met name sigma-1 antagonisten en sigma-2 agonisten) is bekend dat zij de proliferatie en overleving van kankercellen doen afnemen maar nauwelijks invloed hebben op normale cellen. Het onderzoek dat in dit proefschrift wordt beschreven was gericht op de verdere ontwikkeling van sigma liganden voor diagnostische beeldvorming en als chemotherapeutica in de oncologie. We presenteren gegevens die erop wijzen dat competitie door steroïdhormonen variabiliteit van de opname van sigma liganden tijdens PET-imaging kan veroorzaken. Met name progesteron competeert met 11C-SA4503 voor binding aan sigma receptoren in kankercellen. We tonen ook aan dat sigma-1 receptoren in spontane hypofysetumoren tot overexpressie komen en dat 11C-SA4503-PET een geschikte methode kan zijn om zulke laesies aan te tonen. We rapporteren dat het anti-kankereffect van sigma liganden wordt bepaald door de sigma-2 receptorbezetting in kankercellen. Cytotoxiciteit gaat gepaard met opvallende, vroege veranderingen van het metabolisme in zulke cellen. Meting van de sigma-2 receptor bezetting in menselijke tumoren d.m.v. PET kan wellicht worden gebruikt om de therapeutische dosis te voorspellen. Een combinatie van sigma liganden en cytokine-gebaseerde therapie werd getest en bleek robuste anti-kanker effecten te veroorzaken in melanoma cellijnen en in primair materiaal van ovariumcarcinoom afkomstig van kankerpatiënten. Sigma receptors (subtypes sigma-1 and sigma-2) are unique binding sites showing a considerably higher expression in cancerous compared to non-cancerous tissues. Although the endogenous agonists have not been identified with certainty, many artificial ligands are available to study the function of sigma receptors in health and disease. Therapeutic doses of such compounds (particularly sigma-1 antagonists and sigma-2 agonists) are known to decrease proliferation and survival of cancer cells, but minimally affect non-cancer cells. Research described in this thesis was aimed at further development of sigma ligands as diagnostic imaging agents and therapeutic drugs in oncology. We present evidence indicating that competition by steroid hormones accounts for variability of sigma ligand uptake during PET imaging. Specifically, progesterone competes with 11C-SA4503 for binding to sigma-1 receptors in cancer cells. We also show that sigma-1 receptors are overexpressed in spontaneous pituitary tumors and that 11C-SA4503-PET may be a suitable method for detection of such lesions. We report that sigma receptor occupancy in cancer cells determines the observed anti-cancer effect of sigma ligands. Cytotoxicity is accompanied by striking, early changes of metabolism in such cells. Assessment of sigma-2 receptor occupancy in human tumors with PET may be employed for prediction of the therapeutic dose. A combination of sigma ligands and cytokine-based therapy was tested and found to display robust anti-cancer effects in melanoma cell lines and in patient-derived primary samples of ovarian carcinoma.

Mitochondria and Brain Disorders

The mitochondrion is a unique and ubiquitous organelle that contains its own genome, encoding essential proteins that are major components of the respiratory chain and energy production system. Mitochondria play a dominant role in the life and function of eukaryotic cells including neurons and glia, as their survival and activity depend upon mitochondrial energy production and supply. Besides energy production, mitochondria also play a vital role in calcium homeostasis and may induce apoptosis by excitotoxicity. Mitochondrial dysfunction is related to common neurological diseases, such as Parkinson's disease, Alzheimer's disease, Friedreich's ataxia, Huntington's disease, and Multiple Sclerosis. An efficient treatment of mitochondrial dysfunction would open new horizons in the therapeutic perspectives of a substantial number of inflammatory and degenerative neurological disorders

Détection quantitative in vivo des récepteurs d'oestrogène par utilisation des traceurs 16a-[18F]fluoroestradiol et 4-fluoro-11b-méthoxy-16a-[18F] fluoroestradiol, et suivi d'hormonothérapie de tumeurs ER+ et ERaKD sur un modèle de souris par imagerie TEP

À partir des adénocarcinomes mammaires de souris MC7-L1 et MC4-L2, deux lignées exprimant le récepteur d'oestrogène a(ERa), de nouvelles lignées dont l'expression d'ERa est réprimée ont été créées (ERaKD). Ainsi, l'introduction d'une séquence shRNA ciblant ERa: dans ces cellules par infection lentivirale a réduit d'environ 60% l'expression d'ERa; tel que confirmé par diverses techniques in vitro. D'abord, un protocole d'imagerie TEP quantitative au FES a été validé en utilisant un modèle de souris porteuses de tumeurs ER+/ ERaKD. En effet, une baisse notable (et similaire à la diminution d'expression d'ERa) du pourcentage de dose injectée par gramme (%ID/g) de FES a été observée dans les tumeurs ERaKD. De plus, les %ID/g obtenus ex vivo pour les tumeurs ER+ et ERaKD sont très similaires aux %ID/g obtenus par TEP au FES, supportant la validité de la méthode d'imagerie. Ensuite, ces tumeurs ont été suivies pendant 14 jours par imagerie TEP quantitative au [18F]-fluorodésoxyglucose (FDG) ou à la [11C]-méthionine ([11C]-MET) sous traitement avec différentes hormonothérapies, soient le tamoxifène, le letrozole et le fulvestrant. Les tumeurs ER+ ont capté moins de FDG et de [11C]-MET que les tumeurs ERaKD après 7 et 14 jours de traitement. Les groupes traités ont une captation moindre des 2 traceurs par rapport au groupe non-traité pour leurs tumeurs ER+ après 7 et 14 jours de thérapie au fulvestrant et au letrozole, tandis que les tumeurs ERaKD ne sont pas affectées. Quant au traitement au tamoxifène, aucune différence de captation n'est observée par rapport au groupe non-traité. Ainsi, le protocole utilisé n'est pas assez sensible et à trop court terme pour voir l'effet connu à plus long terme du tamoxifène sur la croissance de ces tumeurs ER+. Enfin, la captation et le contraste du 4FMFES ont été comparés au FES par imagerie TEP sur le même modèle de souris porteuses de tumeurs. La captation et le contraste se sont avérés supérieurs en utilisant le 4FMFES, comparés au FES, pour les tumeurs ER+. Les données ex vivo ont confirmé les résultats d'imagerie. En conclusion, le modèle ER+/ERaKD a un grand potentiel pour l'évaluation de nouveaux traceurs des ER, ainsi que pour le suivi de thérapies ciblant les ER

Magnetic Resonance imaging of tumour biomarkers in ovarian cancer

This thesis explores the application of novel magnetic resonance imaging (MRI) techniques to the evaluation of ovarian cancer. Diffusion kurtosis imaging (DKI), sodium MRI, magnetization transfer (MT) imaging, hyperpolarized carbon-13 MRI and magnetic resonance fingerprinting (MRF) were employed to image ovarian tumours in human subjects. The results of the imaging were compared to semi-quantitative measurements of histology and immunohistochemistry staining of tissue samples. It was found that DKI may predict responders to cytotoxic drugs and that sodium MRI and MT measure cellularity. Effective techniques to perform hyperpolarized carbon-13 MRI and MRF were also shown in a clinical setting, where MRF may improve imaging speed and the reproducibility of proton imaging and hyperpolarized carbon-13 MRI could provide unique in vivo metabolic information that differs from FDG-PET.Gates Cambridge Trust Cancer Research UK Wellcome Trust Cambridge Experimental Cancer Medicine Centre The Medical Research Council (MRC), Addenbrooke’s Charitable Trus

Brain imaging studies in severe somatization

Somatization was described 4000 years ago but the pathophysiology of the, phenomenon is unknown. The aim of this investigation was to explore whether central nervous system (CNS) pathology is associated with severe somatization which was operationalized as somatization disorder (SD) and undifferentiated somatoform disorder. The study sample consisted of severely somatizing people who were included into the study after a multi-phase screening procedure in order to exclude psychiatric comorbidities and physical illnesses. Diagnosis of somatization disorder or undifferentiated sofatoform disorder were set according to Diagnostic and Statistical Manual of Mental Disorders 4th ed. (DSM-IV). The first study explored the regional cerebral metabolic rate of glucose (rCMRGlc) in severely somatizing females and found it to be reduced in several regions of the brain compared to healthy controls. The second study observed brain morphology with magnetic resonance imaging (MRI) based on the findings from the first study and showed enlarged caudate nuclei in somatizing women compared to healthy volunteers. The third study investigated temperament factors and brain metabolism, and their association with severe somatization. Low caudate and putamen metabolism, low novelty seeking as well as high harm avoidance were found to be associated with severe somatization in women, reduced caudate metabolism having the strongest association. The last study is a report of man with left-side gradient of multiple symptoms of unknown origin in the body. The examination revealed a hypermetabolic nucleus putamen on the contralateral side. All the main results reported in these four articles are original findings. The results suggest that CNS pathology is involved in the pathophysiology of severe somatization.Siirretty Doriast