Visualization and Localization of Interventional Devices with MRI by Susceptibility Mapping

Recently, interventional procedures can be performed with the visual assistance of MRI. However, the devices used in these procedures, such as brachytherapy seeds, biopsy needles, markers, and stents, have a large magnetic susceptibility that leads to severe signal loss and distortion in the MRI images and degrades the accuracy of the localization. Right now, there is no effective way to correctly identify, localize and visualize these interventional devices in MRI images. In this dissertation, we proposed a method to improve the accuracy of localization and visualization by generating positive contrast of the interventional devices using a regularized L1 minimization algorithm. Specifically, the spin-echo sequence with a shifted 180-degree pulse is used to acquire high SNR data. A short shift time is used to avoid severe phase wrap. A phase unwrapping method based on Markov Random Field using Highest-Confidence-First algorithm is proposed to unwrap the phase image. Then the phase images with different shifted time are used to calculate the field map. Next, L1 regularized deconvolution is performed to calculate the susceptibility map. With much higher susceptibility of the interventional devices than the background tissue, the interventional devices show positive-contrast in the susceptibility image. Computer simulations were performed to study the effect of the signal-to-noise ratio, resolution, orientation and size of the interventional devices on the accuracy of the results. Experiments were performed using gelatin and tissue phantom with brachytherapy seeds, gelatin phantoms with platinum wires, and water phantom with titanium needles. The results show that the proposed method provide positive contrast images of these interventional devices, differentiate them from other structures in the MRI images, and improves the visualization and localization of the devices

Encapsulated Contrast Agent Markers for MRI-based Post-implant Dosimetry

Low-dose-rate prostate brachytherapy involves the implantation of tiny radioactive seeds into the prostate to treat prostate cancer. The current standard post-implant imaging modality is computed tomography (CT). On CT images, the radioactive seeds can be distinctively localized but delineation of the prostate and surrounding soft tissue is poor. Magnetic resonance imaging (MRI) provides better prostate and soft tissue delineation, but seed localization is difficult. To aid with seed localization, MRI markers with encapsulated contrast agent that provide positive-contrast on MRI images (Sirius MRI markers; C4 Imaging, Houston, TX) have been proposed to be placed adjacent to the negative-contrast seeds. This dissertation describes the development of the Sirius MRI markers for prostate post-implant dosimetry. First, I compared the dose-volume histogram and other dosimetry parameters generated by MIM Symphony (a brachytherapy treatment planning system that allow the use of MRI images for treatment planning; MIM Software Inc., Cleveland, OH) and VariSeed (a widely used brachytherapy treatment planning system; Varian Medical Systems, Inc., Palo Alto, CA), and found the dosimetry between both brachytherapy treatment planning systems to be comparable. To gain more insight into the MRI contrast characteristics of the Sirius MRI markers, I measured the Sirius MRI marker contrast agent\u27s spin-lattice and spin-spin relaxivities, and studied the relaxation characteristics\u27 dependence on MRI field strength, temperature, and orientation. From the Sirius MRI marker\u27s contrast agent relaxation characteristics, I systematically studied the effect of varying MRI scan parameters such as flip angle, number of excitations, bandwidth, field of view, slice thickness, and encoding steps, on the Sirius MRI markers\u27 signal and contrast, as well as image noise, artifact and scan time. On patients implanted with Sirius MRI markers, I evaluated the visibility of the Sirius MRI markers and image artifacts. Lastly, I semi-automated the localization of markers and seeds to more enable the efficient incorporation of Sirius MRI markers as part of the clinical post-implant workflow. Ultimately, the Sirius MRI markers may change the paradigm from CT-based to MRI-based post-implant dosimetry, for a more accurate understanding of dose-response relationships in patients undergoing low dose rate prostate brachytherapy

MRI Susceptibility Mapping of Brachytherapy Seeds with Deep Learning

Contrast is an essential element of magnetic resonance imaging. Good contrast in an MR image is necessary to correctly differentiate between different tissue structures and make accurate diagnoses. However, objects with high magnetic susceptibility, like metallic objects, cause severe artifacts that interfere with operations and routine evaluations. In this work, we present a deep learning-based method to undo these effects, with a focus on brachytherapy seeds. We train the network on synthetic data to generate positive contrast images from magnetic field maps for localizing the seeds from their surroundings. We evaluate the model on other synthetic data, then show that the proposed model exhibits generalization to real MRI data and outputs a result quickly. We compare its performance with another positive contrast algorithm for brachytherapy seeds to demonstrate the potential of the deep learning implementation

Development and evaluation of low-dose rate radioactive gold nanoparticles for application in nanobrachytherapy

Depuis les dix dernières années, l’innovation des traitements d’oncologie a fait une utilisation croissante de la nanotechnologie. De nouveaux traitements à base de nanoparticules (NPs) sont notamment rendus au stade de l’essai clinique. Possédant des caractéristiques physico-chimiques particulières, les NPs peuvent être utilisées afin de bonifier l’effet thérapeutique des traitements actuels. Par exemple, l’amélioration de la curiethérapie (c.-à-d. radiothérapie interne) nécessite le développement de nouvelles procédures permettant de diminuer la taille des implants, et ce, tout en augmentant l’homogénéité de la dose déposée dans les tumeurs. Des études théoriques et expérimentales ont démontré que l’injection de NPs d’or à proximité des implants traditionnels de curiethérapie de faible débit de dose (par ex. 125I, 103Pd) permettrait d’augmenter significativement leur efficacité thérapeutique. L'interaction entre l’or et les photons émis par les implants de curiethérapie (c.-à-d. l’effet de radiosensibilisation) génère des rayonnements divers (photoélectrons, électrons Auger, rayons X caractéristiques) qui augmentent significativement la dose administrée. Dans le cadre de cette thèse, l’approche proposée était de développer des NPs d’or radioactives comme nouveau traitement de curiethérapie contre le cancer de la prostate. L’aspect novateur et unique était de synthétiser une particule coeurcoquille (Pd@Au) en utilisant l’isotope actuellement employé en curiethérapie de la prostate: le palladium-103 (103Pd, 20 keV). Dans ce cas-ci, la présence d’atomes d’or permet de produire l’effet de radiosensibilisation et d’augmenter la dose déposée. La preuve de concept a été démontrée par la synthèse et la caractérisation des NPs 103Pd@Au-PEG NPs. Ensuite, une étude longitudinale in vivo impliquant l’injection des NPs dans un modèle xénogreffe de tumeurs de la prostate chez la souris a été effectuée. L’efficacité thérapeutique induite par les NPs a été démontrée par le retard de la croissance tumorale des souris injectées par rapport aux souris non injectées (contrôles). Enfin, une étude de cartographie de la dose générée par les NPs à l’échelle cellulaire et tumorale a permis de comprendre davantage les mécanismes thérapeutiques liés aux NPs radioactives. En résumé, l’ensemble des travaux présentés dans cette thèse font office de précurseurs relativement au domaine de la nanocuriethérapie, et pourraient ouvrir la voie à une nouvelle génération de NPs pour la radiothérapie.The last decade saw the emergence of new innovative oncology treatments based on nanotechnology. New treatments using nanoparticles (NPs) are now translated to clinical trials. NPs possess unique physical and chemical properties that can be advantageously used to improve the therapeutic effect of current treatments. For instance, therapeutic efficiency enhancement related to internal radiotherapy (i.e., brachytherapy), requires the development of new procedures leading to a decrease of the implant size, while increasing the dose homogeneity and distribution in tumors. Several theoretical and experimental studies based on low-dose brachytherapy seeds (e.g., 125I and 103Pd) combined with gold nanoparticles (Au NPs) showed very promising results in terms of dose enhancement. Gold is a radiosensitizer that enhances the efficiency of radiotherapy by increasing the energy deposition in the surrounding tissues. Dose enhancement is caused by the photoelectric products (photoelectrons, Auger electrons, characteristic X-rays) that are generated after the irradiation of Au NPs. In this thesis, the proposed approach was to develop radioactive Au NPs as a new brachytherapy treatment for prostate cancer. The unique and innovative aspect of this strategy was to synthesize core-shell NPs based on the radioisotope palladium-103 (103Pd, 20 keV), which is currently used in low-dose rate prostate cancer brachytherapy. In this concept, the administrated dose is increased via the radiosensitization effect that is generated through the interactions of low-energy photons with the gold atoms. The proof-ofconcept of this approach was first demonstrated by the synthesis and characterization of the core-shell NPs (103Pd@Au-PEG NPs). Then, a longitudinal in vivo study following the injection of NPs in a prostate cancer xenograft murine model was performed. The therapeutic efficiency was confirmed by the tumor growth delay of the treated group as compared to the control group (untreated). Finally, a mapping study of the dose distribution generated by the NPs at the cellular and tumor levels provided new insights about the therapeutic mechanisms related to radioactive NPs. In summary, the studies presented in this thesis are precursors works in the field of nanobrachytherapy, and could pave the way for a new generation of NPs for radiotherapy

Quantitative PET-CT Perfusion Imaging of Prostate Cancer

Functional imaging of 18F-Fluorocholine PET holds promise in the detection of dominant prostatic lesions. Quantitative parameters from PET-CT Perfusion may be capable of measuring choline kinase activity, which could assist in identification of the dominant prostatic lesion for more accurate targeting of biopsies and radiation dose escalation. The objectives of this thesis are: 1) investigate the feasibility of using venous TACs in quantitative graphical analysis, and 2) develop and test a quantitative PET-CT Perfusion imaging technique that shows promise for identifying dominant prostatic lesions. Chapter 2 describes the effect of venous dispersion on distribution volume measurements with the Logan Plot. The dispersion of venous PET curves was simulated based on the arterio-venous transit time spectrum measured in a perfusion CT study of the human forearm. The analysis showed good agreement between distribution volume measurements produced by the arterial and venous TACs. Chapter 3 details the mathematical implementation of a linearized solution of the 3-Compartment kinetic model for hybrid PET-CT Perfusion imaging. A noise simulation determined the effect of incorporating CT perfusion parameters into the PET model on the accuracy and variability of measurements of the choline kinase activity. Results indicated that inclusion of CT perfusion parameters known a priori can significantly improve the accuracy and variability of imaging parameters measured with PET. Chapter 4 presents the implementation of PET-CT Perfusion imaging in a xenograft mouse model of human prostate cancer. Image-derived arterial TACs from the left ventricle were corrected for partial volume and spillover effects and validated by comparing to blood sampled curves. The PET-CT Perfusion imaging technique produced parametric maps of the choline kinase activity, k3. The results showed that the partial volume and spillover corrected arterial TACs agreed well with the blood sampled curves, and that k3max was significantly correlated with tumor volume, while SUV was not. In summary, this thesis establishes a solid foundation for future clinical research into 18F-fluorocholine PET imaging for the identification of dominant prostatic lesions. Quantitative PET-CT Perfusion imaging shows promise for assisting targeting of biopsy and radiation dose escalation of prostate cancer

Convolutional Neural Network Optimization and Parallel Compressive Sensing Algorithms for Accelerated MRI Reconstruction

Magnetic resonance imaging (MRI) is a noninvasive imaging modality that produces high-quality images. One of the biggest challenges in MRI is the lengthy scan procedure which could lead to motion artifact and patient discomfort. Due to the physical and physiological limits, undersampling the signals in the k-space signals has been used to shorten the scan time. However, the undersampling of k-space data results in undersampling artifacts that require advanced reconstruction algorithms to compensate for the missed signals. Many reconstruction algorithms have been proposed to address this problem. Linear interpolations in parallel imaging (PI) techniques usually suffer from high noise-like interpolation artifacts, and compressive sensing (CS) reconstructions are usually blurred in high-order undersampling factors. In this study, we first introduce a hybrid CS-PI algorithm and show it outperforms CS or PI individually in image reconstructions using actual data from MR-guided radiotherapy. Nevertheless, PI, CS, and hybrid CS-PI highly depend on the number of ACS in the center of the k-space and require a particular sampling strategy. Deep learning models can solve these problems with lower scan and reconstruction time with fewer interpolation artifacts and blurriness. In deep learning-based MRI reconstruction methods, the network’s architecture plays a crucial role in the quality of the reconstructed image. According to the large number of architectures that can be considered for these models, manually designing architectures and testing all the possible solutions are not practical. We introduce a new evolutionary-based search strategy to design a deep network for MR reconstruction automatically. We use different numerical metrics to compare the results of the optimized model with the ad-hoc model and three different published methods. The results showed that the proposed algorithm could automatically design a network that is not limited to only one particular sampling strategy and outperforms three related published models

Multi-parametric MRI to guide salvage treatment of recurrent prostate cancer

Prostate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial treatment. Patients with localised recurrent PCa are candidates for curative (i.e. salvage) treatment. To overcome the toxicity associated with whole-gland approaches, focal salvage treatments target the index lesion while sparing the surrounding tissue. The studies described in this thesis elaborate on the use of quantitative multi-parametric MRI (mp-MRI) for the detection and localisation of locally recurrent PCa after radiotherapy. Pre-treatment radiomic imaging features were found to have potential to improve recurrence-risk prediction models for high-risk PCa patients treated with radiotherapy. In this thesis, the mp-MRI properties of irradiated benign tissue and recurrent tumour were characterised, with access to pathological samples. These findings can be used as a foundation to establish guidelines (which are currently absent) on how to assess and score MRI scans after radiotherapy. Improving radiological knowledge in the recurrent setting can lead to improved staging and result in better patient selection for salvage treatments. Lastly, this thesis provides evidence on how best to define the region to target, leading to a refinement of focal salvage strategies.KWF KankerbestrijdingLUMC / Geneeskund

Gold and Iron Loaded Micelles: A Multifunctional Approach for Combined Imaging and Therapy, With Improved Pharmacokinetics

Radiation therapy is an important component in the treatment and management of cancer patients. Despite current advances in imaging technologies and treatment planning strategies, a major limitation persists in accurately delineating tumor from normal tissue resulting in radiation–induced damage to healthy structures. Therefore, the frequency and dose of radiation exposure is limited by the generated toxicity in healthy tissues. The use of nanoparticles for contrast–enhanced imaging could improve the accuracy of therapeutic delivery and guide radiation treatments to maximize delivery to disease target tissues while sparing adjacent normal structures. Further, advancements in radiation therapy focus on the use of radiosensitizers that are intended to enhance tumor cell killing while minimizing effects on normal tissue. We have developed multifunctional nanoplatforms, containing sub–nanometer gold and iron nanoparticles that can provide contrast enhancement using computed tomography and magnetic resonance imaging, while also serving as radiosensitizers for X–ray therapy. The effectiveness of these nanoparticles was evaluated in vivo demonstrating an improvement in both tumor margin visualization for image-guided radiation therapy and overall survival in tumor bearing mice. Importantly, we found that measurements of contrast enhancement in imaging correlated strongly with tumor response after radiation therapy. Furthermore, we have found that by encapsulating sub–nanometer gold particles within micelles we are able achieve improved excretion profiles compared to larger gold particles, with gold detected in both urine and feces suggesting that particles within this size range are more efficiently removed by the kidneys and liver. Finally, the use of an actively targeted nanoplatform can achieve higher tumor retention, facilitate nanoparticle internalization, and improve tumor specificity. To facilitate the introduction of targeting molecules onto micelle formulations, a naturally occurring surfactant protein oleosin was used to stabilize superparamagnetic iron oxide clusters. Functionalization with targeting ligands (e.g. Her2/neu affibody) was achieved by fusing the biologically relevant motifs to oleosin using standard cloning techniques, and cell specific targeting was confirmed using magnetic relaxation techniques. In the future, we envision that strategies like this will minimize the off–target effects of radiation, reduce tumor burden, provide information on the likelihood of tumor regression in response to therapy and reduce long–term nanoparticle retention