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Background: Drugs targeting angiogenic pathway remain the mainstay of treatment for metastatic renal cell carcinoma (mRCC). Tyrosine Kinase Inhibitors (TKI) as Sunitinib, Pazopanib as single agents and humanised monoclonal antibody bevacizumab (Bev) in combination with Interferon- α2a (IFN) have established as the first-line therapy for mRCC. Despite improvements in treatment, there are multiple questions which remain unanswered. In the combination of Bev and IFN, the respective role of each drug and whether any additional anti-angiogenic activity is gained by adding IFN to Bev remains unknown. As the clinical benefit obtained with these cytostatic agents does not always correlate with the conventional response assessment techniques as RECIST, it is necessary to reconsider the methods by which we assess benefit from these therapies. In this thesis, I report three studies aiming to answer these questions. Methods: With the clinical trial reported here, I explore whether Bev induced changes in vascular parameters measured by Dynamic Contrast Enhanced MRI (DCE-MRI) is significantly enhanced by the addition of IFN. In a phase II, randomised, open labelled, multicentre trial, treatment naïve mRCC patients were randomised to receive Bev on its own or in combination with a low dose (3MU) or standard dose (9MU) IFN. DCE-MRI was used to assess the changes in vascularity with the primary endpoint being, changes in transfer coefficient (Ktrans) after six weeks of treatment. I also report two retrospective imaging-based studies, using contrast-enhanced CT scans, performed to improve the methodology of response assessment for these antiangiogenic therapeutics. Here I explore the use of a) combining changes in size and arterial phase contrast enhancement measured using CT scan and b) changes in CT texture as methods of therapeutic response assessment in mRCC patients treated with TKI. Results: With the phase 2 clinical trial, we faced significant difficulty in recruitment as a result of restrictions in access to treatment in NHS, other competing studies and restrictions proposed by the DCE-MRI inclusion criteria. With slow recruitment, an unplanned analysis was performed after 21 patients were recruited. Analysis of primary endpoint showed no trend in the difference between arms with no correlation found between change in Ktrans and addition of IFN to bevacizumab. Effect size analysis performed due to the small numbers recruited failed to show any significance in the observed difference in Ktrans. Change in Ktrans and Kep may identify a group of patients likely to have PFS > 6 months, but this observation needs to evaluation in a larger sample size. Measuring size and change in arterial phase enhancement retrospectively using CT, a new criterion "modified" Choi, which prerequisite a combination of a decrease in arterial phase density by 15% and a decrease in size by 10% for response was proposed. Response assessment was measured with RECIST, Choi and modified Choi individually in 20 evaluable patients retrospectively and clinical benefit compared with Kaplan-Meier statistics and Log-Rank test. Response assessment as defined by the modified Choi criteria successfully identified patients who received clinical benefit from the treatment. Time to progression (TTP) was 448 days for the partial response and 89 days for stable disease as per the new criteria which were statistically significant with a p-value of 0.002. The second retrospective analysis explored the textural changes in enhanced CT scan. Performed in collaboration with researchers from Brighton University who developed the software algorithm used to assess changes in entropy and uniformity, 87 metastases from 39 patients with mRCC were analysed at baseline and after two cycles of TKI treatment. Textural parameters and response assessment criteria were correlated with TTP. After two cycles of TKI, the decrease in tumour entropy was 3%-45%, and increase in uniformity was 5%-21%. At a threshold change of -2% with uniformity, on a coarse scale of 2.5, the textural change was able to separate responders from non-responders. With Kaplan-Meier analysis comparing all four criteria, the percentage change in uniformity was statistically more significant than for RECIST, Choi, and Modified Choi criteria. Cox regression analysis showed that texture uniformity was an independent predictor of time to progression. Discussion: With the studies reported here, I was able to demonstrate the importance of improving the methodology in assessment of therapeutic response to targeted anti-angiogenic therapy in metastatic renal cell carcinoma. Even though the clinical trial, terminated early due to slow recruitment, did not reach its primary endpoint, changes in other vascular parameters as Kep combined with changes Ktrans showed tendency towards identifying a group of patients who derived clinical benefit of >6months with these therapies. This is particularly exciting as given the vascular stabilisation effect proposed for bevacizumab, the effusion parameter Kep may be a better tool in assessing response rather than Ktrans and warrants further assessment in a larger cohort. Modified choi criterion and textural analysis are two important methodological improvements in response assessment of cytostatic anti-angiogenic therapy. In the analyses reported here, both techniques have shown superiority over RECIST in response assessment and differentiating mRCC patients who is likely to gain clinical benefit by TKI therapy. Validation of these criteria on a larger patient cohort is important. As these criterions are assessed on standard enhanced CT scans, incorporating these criteria, especially modified choi criterion, as part of standard CT assessment could be performed and will provide a real world validation. Retrospective assessment using larger cohort of patients from previous phase 3 trials or inclusion of these parameters prospectively in phase 3 trials would also help us in evaluating these modalities further.

La séquence d’IRM de perfusion pondérée T1 après injection de Gadolinium (Gd), appelée dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) fait partie du protocole d’IRM multiparamétrique (IRM-mp) réalisée pour le bilan d’extension du cancer prostatique (CaP). Le rationnel pour l’utilisation de cette séquence est d’une part le rôle capital de la néoangiogénèse dans le développement et la dissémination du CaP et d’autre part la possibilité d’imager l’angiogénèse in vivo et de façon non invasive. L’analyse quantitative nécessite un post-traitement multi-étapes complexe, dont le principe repose sur la modélisation pharmacocinétique (PC) de la biodistrubtion du Gd. Elle permet de calculer des paramètres PC reflétant la perméabilité capillaire et/ou la perfusion. Dans le CaP, ces paramètres PC ont montré leur potentiel pour évaluer l’agressivité tumorale, le pronostic, l’efficacité d’un traitement et/ou pour déterminer la dose efficace d’une nouvelle molécule anti-angiogéniques ou antivasculaires en cours de développement. Néanmoins, ils manquent de reproductibilité, notamment du fait des différentes techniques de quantifications utilisées par les logiciels de post-traitement.Nous avons développé au sein du laboratoire un outil de quantification capable de calculer une cartographie T1(0) à partir de la méthode des angles de bascule variables, nécessaire pour convertir les courbes du signal en courbe de concentration du Gd (Ct); de déterminer la fonction d’entrée artérielle (AIF – arterial input function) dans l’artère fémorale (Indivuduelle – Ind) ou lorsque cela n’était pas possible, d’utiliser une AIF issue de la littérature, telle que celle de Weinmann (W) ou de Fritz-Hansen (FH) ; et d’utiliser deux modèles PC, celui de Tofts et celui de Tofts modifié. Le logiciel a été validé sur des données simulées et sur une petite série clinique.Nous avons ensuite étudié l’impact du choix de la fonction d’entrée artériel sur les paramètres PC et notamment sur leur capacité à distinguer le CaP du tissu sain. 38 patients avec un CaP (>0,5cc) de la zone périphérique (ZP) ont été rétrospectivement inclus. Chaque patient avait bénéficié d’une IRM-mp sur laquelle deux régions d’intérêt (RI) : une tumorale et une bénigne ont été sélectionnées en utilisant une corrélation avec des cartes histo-morphométriques obtenues après prostatectomie radicale. En utilisant trois logiciels d’analyse quantitative différents, les valeurs moyennes de Ktrans (constante de transfert), ve (fraction du volume interstitiel) and vp (fraction du volume plasmatique) dans les RI ont été calculées avec trois AIF différentes (AIF Ind, AIF de W et AIF de FH). Ktrans était le paramètre PC qui permettait de mieux distinguer le CaP du tissu sain et ses valeurs étaient significativement supérieures dans le CaP, quelque soit l’AIF ou le logiciel. L’AIF de W donnait des aires sous les courbes ROC (Receiver Operating Characteristic) significativement plus grandes que l’AIF de FH (0.002≤p≤0.045) et plus grandes ou égales à l’AIF Ind (0.014≤p≤0.9). L’AIF Ind et de FH avaient des aires sous les courbes ROC comparables (0.34≤p≤0.81). Nous avons donc montré que les valeurs de Ktrans et sa capacité à distinguer CaP du tissu sain variaient significativement avec le choix de l’AIF et que les meilleures performances étaient obtenues avec l’AIF de W. / Dynamic contrast enhanced (DCE)-MRI is a T1 weighted sequence performed before, during and after a bolus injection of a contrast agent (CA). It is included in the multi-parametric prostate MRI (mp-MRI) protocol using to assess the extent of prostate cancer (PCa). The rationale for using DCE-MRI in PCa is that on one hand angiogenesis has been shown to play a central role in the PCa development and metastasis and on the other hand that DCE-MRI is a non invasive method able to depict this angiogenesis in vivo. The quantitative analysis of DCE-MRI data is a complex and multi-step process. The principle is to use a pharmacokinetic (PK) model reflecting the theoretical distribution of the CA in a tissue to extract PK parameters that describe the perfusion and capillary permeability. These parameters are of growing interest, especially in the field of oncology, for their use in assessing the aggressiveness, the prognosis and the efficacy of anti-angiogenic or anti-vascular treatments. The potential utility of these parameters is significant; however, the parameters often lack reproducibility, particularly between different quantitative analysis software programs.Firstly, we developed a quantitative analysis software solution using the variable flip angle method to estimate the T1 mapping which is needed to convert the signal-time curves to CA concentration-time curves; using three different arterial input functions (AIF): an individual AIF (Ind) measured manually in a large artery, and two literature population average AIFs of Weinmann (W) and of Fritz-Hansen (FH); and using two PK models (Tofts and modified Tofts). The robustness of the software programs was assessed on synthetic DCE-MRI data set and on a clinical DCE-MRI data set. Secondly, we assessed the impact of the AIF selection on the PK parameters to distinguish PCa from benign tissue. 38 patients with clinically important peripheral PCa (≥0.5cc) were retrospectively included. These patients underwent 1.5T multiparametric prostate MR with PCa and benign regions of interest (ROI) selected using a visual registration with morphometric reconstruction obtained from radical prostatectomy. Using three pharmacokinetic (PK) analysis software programs, the mean Ktrans, ve and vp of ROIs were computed using three AIFs: Ind-AIF, W-AIF and FH-AIF. The Ktrans provided higher area under the receiver operating characteristic curves (AUROCC) than ve and vp. The Ktrans was significantly higher in the PCa ROIs than in the benign ROIs. AUROCCs obtained with W-AIF were significantly higher than FH-AIF (0.002≤p≤0.045) and similar to or higher than Ind-AIF (0.014≤p≤0.9). Ind-AIF and FH-AIF provided similar AUROCC (0.34≤p≤0.81).We have then demonstrated that the selection of AIF can modify the capacity of the PK parameter Ktrans to distinguish PCa from benign tissue and that W-AIF yielded a similar or higher performance than Ind-AIF and a higher performance than FH-AIF.

Evolution of vulnerable carotid plaques are crucial reason for cerebral ischemic strokes and identifying them in the early stage can become very important in avoiding the risk of stroke. In order to improve the identification and quantification accuracy of infancy plaques better visualization techniques are needed. Improving the visualization and quantification of neovascularization in carotid plaque using contrast enhanced ultrasound imaging still remains a challenging task. In this thesis work, three optimization techniques are proposed, which showed an improvement in the sensitivity of contrast agents when compared to the conventional clinical settings and insonation strategies. They are as follows:1) Insonation at harmonic specific (2nd harmonic) resonance frequency instead of resonance frequency based on maximum energy absorption provides enhanced nonlinear contribution.2) At high frequency ultrasound imaging, shorter pulse length will provide improved harmonic signal content when compared to longer pulse lengths. Applying this concept to multi- pulse sequencing (Pulse Inversion and Cadence contrast pulse sequencing) resulted in increased magnitude of the remaining harmonic signal after pulse summations.3) Peak negative pressure optimization of Pulse Inversion and Cadence contrast pulse sequencing was showed to further enhance the nonlinear content of the backscattered signal from contrast microbubbles without increasing the safety limits, defined by the mechanical index.The results presented in this thesis are based on computational modeling (Bubblesim software) and as a future continuation we plan to verify the simulation results with vitro studies.

Magnetic resonance imaging (MRI) is the preferred imaging modality for visualization of intracranial soft tissues. Surgical planning, and increasingly surgical navigation, use high resolution 3-D patient-specific structural maps of the brain. However, the process of MRI is a multi-parameter tomographic technique where high resolution imagery competes against high contrast and reasonable acquisition times. Resolution enhancement techniques based on super-resolution are particularly well suited in solving the problems of resolution when high contrast with reasonable times for MRI acquisitions are needed. Super-resolution is the concept of reconstructing a high resolution image from a set of low-resolution images taken at dierent viewpoints or foci. The MRI encoding techniques that produce high resolution imagery are often sub-optimal for the desired contrast needed for visualization of some structures in the brain. A novel super-resolution reconstruction framework for MRI is proposed in this thesis. Its purpose is to produce images of both high resolution and high contrast desirable for image-guided minimally invasive brain surgery. The input data are multiple 2-D multi-slice Inversion Recovery MRI scans acquired at orientations with regular angular spacing rotated around a common axis. Inspired by the computed tomography domain, the reconstruction is a 3-D volume of isotropic high resolution, where the inversion process resembles a projection reconstruction problem. Iterative algorithms for reconstruction are based on the projection onto convex sets formalism. Results demonstrate resolution enhancement in simulated phantom studies, and in ex- and in-vivo human brain scans, carried out on clinical scanners. In addition, a novel motion correction method is applied to volume registration using an iterative technique in which super-resolution reconstruction is estimated in a given iteration following motion correction in the preceding iteration. A comparison study of our method with previously published methods in super-resolution shows favorable characteristics of the proposed approach.

Židininiai kepenų pakitimai (ŽKP) – vieni dažnesnių patologinių radinių tiriant pacientus dėl įvairių virškinimo ar kitų organizmo sistemų ligų. Įvairių spindulinės diagnostikos metodų dėka nustačius patologinius židinius kepenyse ypač svarbi jų klinikinė diferencinės diagnostikos reikšmė. ŽKP diferencinės diagnostikos esmė yra kiek įmanoma tikslesnis židinio kepenyse kraujotakos nustatymas ir aprašymas. Šios problemos sprendime naujų galimybių įgyja santykinai nauja ir Lietuvoje niekur kitur dar neatliekama UG tyrimo su i/v kontrastavimu metodika, kurios metu gaunami rezultatai lyginami su dominuojančių įprastų KT ir MRT kontrastinių tyrimų rezultatais. Tikslas: nustatyti radiologinių tyrimų vertę diagnozuojant židininius kepenų pakitimus (ŽKP) Uždaviniai: 1. Nustatyti įprastinio UG, UG su i/v kontrastavimu ir KT su i/v kontrastavimu diagnostikos metodų tikslumo rodiklius nepiktybiniams ir piktybiniams ŽKP. 2. Nustatyti UG ir KT su i/v kontrastavimu vertingiausius diagnostikos kriterijus vertinant židininių kepenų pokyčių prigimtį. 3. Palyginti tarpusavyje UG ir KT su i/v kontrastavimu nustatytų židininių kepenų pakitimų diagnostikos metodų tikslumo rodiklius nepiktybiniams ir piktybiniams ŽKP. 4. Įvertinti kepenų hemangiomų radiologinių diagnostikos metodų tikslumo vertę. / Focal hepatic lesions (FHL) are one of the most common pathological findings in patients who are examined for gastrointestinal or other diseases. The rigorous description of blood circulation in the hepatic focus is essential in differential diagnosis of FHL. US with i/v contrast enhancement is a new imaging method enabling definition of nature of FHL, follow-up, treatment efficacy and monitoring for possible relapse of the process. This study is conducted solely in the Radiology Department of Kaunas University of Medicine Hospital. Aim of the study To evaluate and compare the value of ‘bolus’ contrast-enhanced CT and contrast-enhanced US in diagnostics of focal hepatic lesions. Tasks of the study 1. To determine rates of diagnostic accuracy of conventional US, US with i/v contrast enhancement and ‘bolus’ contrast-enhanced CT in diagnosis of benign and malingnant FHL. 2. To establish the main and most effective diagnostic criteria of US and CT with i/v contrast enhancement for the assessment of nature of focal hepatic lesions. 3. To compare rates of diagnostic accuracy of US with i/v contrast enhancement and ‘bolus’ contrast-enhanced CT in diagnosis of benign and malingnant FHL. 4. To assess the reliability of radiological diagnostics of hemangioma, comparing the results of US, CT, and MRI.

Since its introduction, contrast-enhanced ultrasonography (CEUS) has significantly extended the value of ultrasonography (US). CEUS can be used to more accurately determine pancreatic lesions compared to conventional US or to characterize lesions already detectable by US. Thus, CEUS can aid in the differential diagnosis of pancreatic tumors. Using US contrast media, it is possible to visually detect microvessels in the majority of pancreatic ductal adenocarcinomas. Thus, the use of quantitatively evaluated transabdominal CEUS can help in the differentiation of patients with mass-forming pancreatitis from patients with pancreatic adenocarcinomas. In neuroendocrine pancreatic tumors, different enhancement patterns can be observed in relation to the tumor mass: larger ones show a rapid early enhancement sometimes combined with necrotic central structures, and smaller ones disclose a capillary-blush enhancement. Pseudocysts, the most widespread cystic lesions of the pancreas, are not vascularized. They do not show any signal in CEUS and remain entirely anechoic in all phases, while true cystic pancreatic tumors usually have vascularized septa and parietal nodules. In summary, CEUS is effective for differentiating solid pancreatic tumors in most cases. CEUS is safe and cost effective and can better discriminate solid from cystic pancreatic lesions, thereby directing further imaging modalities. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The aim of this project is the application of Dual Energy technique in breast phantoms using Complimentary-Metal-Oxide-Semiconductor (CMOS)Active-Pixel-Sensor (APS). This includes both, lab experimentation on developed breast phantoms, as well as simulations validating the results. Initially, phantoms were carefully prepared simulating the properties of real breast tissue and were imaged using X-ray unit. The next step in this project involved image processing and data representation. Using the dual energy technique, different concentrations of contrast agent (Iodine) were measured to relate clinical to medium kinetic measurements. With respect to this projects‟ clinical application, the implementation of this technique can be used to evaluate the iodine projected thickness (mg/cm2) using Contrast Enhanced Digital Mammography (CEDM) based on Dual Energy technique for the breast cancer detection. / Ο στόχος του εργασίας αυτής είναι η εφαρμογή της τεχνικής Διπλής Ενέργειας σε ομοιώματα μαστού χρησιμοποιώντας Complimentary-Metal-Oxide-Semiconductor (CMOS) Active-Pixel-Sensor (APS). Αυτό περιλαμβάνει, τον πειραματισμό σε αναπτυγμένα ομοιώματα μαστού, καθώς και προσομοιώσεις για την επικύρωση των αποτελεσμάτων. Αρχικά, κατασκευάστηκαν προσεκτικά τα ομοιώματα μαστού όπου προσομοιώνουν τις πραγματικές ιδιότητες των ιστών του μαστού και στη συνέχεια απεικονίστηκαν με χρήση μονάδων ακτίνων-Χ . Το επόμενο βήμα σε αυτό την εργασία ήταν η επεξεργασία εικόνας και παρουσίαση δεδομένων. Χρησιμοποιώντας την τεχνική της διπλής ενέργειας, διαφορετικές συγκεντρώσεις σκιαγραφικού (ιώδιο) μετρήθηκαν ώστε να σχετίζουν κλινικά την μέτρηση της αγγειογένεσης εν συναρτήση του χρόνου. Η εφαρμογή αυτής της τεχνικής μπορεί να χρησιμοποιηθεί για να αξιολογήσει το προβλεπόμενο πάχος του ιωδίου (mg/cm^2) χρησιμοποιώντας Ενίσχυση Αντίθεσης στην Ψηφιακή Μαστογραφία βασίσμένη στην τεχνική της διπλής ενέργειας για την ανίχνευση του καρκίνου του μαστού.

<b>Background:</b> Systemic chemotherapy and radiotherapy play an important role in the treatment of colorectal cancer. Tumour perfusion and oxygenation is known to influence radiosensitivity and chemosensitivity. In this thesis, I propose that the evaluation of changes in tumour perfusion using perfusion CT (pCT) and dynamic contrast-enhanced (Dce) MRI can guide the rational sequencing of drugs and radiation. <b>Methods:</b> Dce-MRI and pCT scans were incorporated into a clinical trial of hypofractionated pelvic radiotherapy and nelfinavir in 10 patients with rectal cancer. Toxicity and tissue biomarkers (tumour cell density, microvessel density, CAIX, HIF1-alpha, phospho-Akt and phospho-PRAS40) were evaluated. pCT liver scans were incorporated into an imaging study in patients with colorectal liver metastases randomised to receive either oxaliplatin/ 5FU chemotherapy or oxaliplatin/ 5FU chemotherapy plus selective internal radiotherapy. <b>Results:</b> After 7 days of nelfinavir concurrent with hypo-fractionated pelvic radiotherapy, there was a mean 42&percnt; increase in median K^trans (P=0.03, paired t test) on Dce-MRI and a median 30&percnt; increase in mean blood flow on pCT (P=0.028, Wilcoxon Rank Sum), although no statistically significant changes in perfusion parameters were demonstrated after 7 days of nelfinavir prior to radiotherapy. The feasibility of evaluating tumour cell density in rectal biopsies before and after radiotherapy and a radiosensitising drug as an early endpoint of response was demonstrated. In patients with colorectal liver metastases who received oxaliplatin and modified de Gramont chemotherapy alone, after 4 cycles of chemotherapy, a 28&percnt; decrease in the mean hepatic arterial fraction was observed (P=0.018, paired t test). Between pCT scans 2 days before SIRT and 39-47 days following SIRT and continued 2-weekly chemotherapy, there was a mean 62&percnt; (P=0.009) reduction in Blood Flow and 61&percnt; (P=0.006) reduction in Blood Volume (paired t test). <b>Conclusions</b> This research does not support the hypothesis that nelfinavir before radiotherapy improves blood flow to human rectal cancer. Increases in rectal tumour perfusion during radiotherapy and concurrent nelfinavir are likely to be primarily explained by the acute biological effects of radiation. Four or more cycles of oxaliplatin and modified de Gramont chemotherapy may result in changes in tumour perfusion of colorectal liver metastases which would be detrimental to subsequent radiotherapy. Selective internal radiotherapy resulted in substantial reductions in tumour perfusion 39-47 days after the treatment. Perfusion imaging can be used to detect changes in tumour perfusion in response to radiotherapy and systemic therapy which have implications for the sequencing of therapies.