Development of methods, algorithms and applications for the robust and objective delineation of structures in diffusion weighted MR images

Diffusion weighted imaging (DWI) derived parameters like the apparent diffusion coefficient (ADC) are known to correlate inversely to tumour-proliferation in brain tumours. In high grade gliomas, the heterogeneity makes it difficult to delineate high and low proliferative areas. Furthermore, this separation is impeded by partial volume effects and blurred borders. In addition to that, necrosis and cerebrospinal fluid increase the uncertainty of a proper delineation. A second parameter derived by diffusion weighted imaging is the perfusion fraction f and can be used to differentiate pancreatic diseases like pancreatic carcinoma from healthy tissue and pancreatitis from pancreatic carcinoma, thanks to the hypoperfused nature of pancreatic carcinoma versus pancreatitis and healthy pancreatic tissue, respectively. In this thesis, we present algorithms and approaches for these two cases to objectively determine the derived parameters. In the glioma case, an approach is presented to automatically delineate the mentioned heterogeneous regions and to probabilistically quantify the tissue inhomogeneity. Two methods were tested to achieve this aim. Firstly, a Gaussian mixture model, solely consisting of Gaussians and a partial volume aware technique using an additional class. Next, an Expectation Maximization algorithm has been applied onto these two models to separate these regions. In the pancreatic case, we used linear rigid image registration, to spatially align the so called b value stack, representing the diffusion raw data, and tried to improve the reproducibility of the derived parameters and the plausibility of the anatomical structure. The results of the first study indicate that the Gaussian model excels the partial volume model in terms of reproducibility by using a systematic initialization routine automatically drawn onto the low and high-proliferative areas. In the second study, we could show that linear image registration significantly improves the plausibility of the spatially alignment of the b value stack and furthermore the reproducibility of the IVIM derived parameters such as f. In conclusion, we can say that the first study yields an automatic, rapid, reproducible and objective determination of regions of signal inhomogeneity in high grade gliomas by an automatic initialization whereas the second study results in a reduction of residual motion and artifacts ending up in a degradation of the standard deviation of the perfusion fraction f to better delineate between the pancreatic entities. This leads to a development of a pancreatic screening tool which could be eventually expanded onto the usage of other organs

Complexity Reduction in Image-Based Breast Cancer Care

The diversity of malignancies of the breast requires personalized diagnostic and therapeutic decision making in a complex situation. This thesis contributes in three clinical areas: (1) For clinical diagnostic image evaluation, computer-aided detection and diagnosis of mass and non-mass lesions in breast MRI is developed. 4D texture features characterize mass lesions. For non-mass lesions, a combined detection/characterisation method utilizes the bilateral symmetry of the breast s contrast agent uptake. (2) To improve clinical workflows, a breast MRI reading paradigm is proposed, exemplified by a breast MRI reading workstation prototype. Instead of mouse and keyboard, it is operated using multi-touch gestures. The concept is extended to mammography screening, introducing efficient navigation aids. (3) Contributions to finite element modeling of breast tissue deformations tackle two clinical problems: surgery planning and the prediction of the breast deformation in a MRI biopsy device

Quantification of tumour heterogenity in MRI

Cancer is the leading cause of death that touches us all, either directly or indirectly. It is estimated that the number of newly diagnosed cases in the Netherlands will increase to 123,000 by the year 2020. General Dutch statistics are similar to those in the UK, i.e. over the last ten years, the age-standardised incidence rate1 has stabilised at around 355 females and 415 males per 100,000. Figure 1 shows the cancer incidence per gender. In the UK, the rise in lifetime risk of cancer is more than one in three and depends on many factors, including age, lifestyle and genetic makeup

Strategies for intervertebral disc regeneration

Chronic low back pain (CLBP) affects a large population worldwide. Intervertebral disc (IVD) degeneration is a leading case of CLBP. To date, the clinical treatments are limited to pain relief strategies, and to date, no efficient therapy was developed aiming at IVD regeneration. This thesis aimed to understand the degenerative processes of IVD and propose potential therapeutic routes to halt degeneration and achieve regeneration. Blocking inflammation is considered a viable strategy to relieve pain and delay disc degeneration. Pro-inflammatory cytokine, TNF-α, is highly associated with inflammation and pain in IVD degeneration. Therefore, in Chapter 2, a TNF-α-induced ex vivo IVD degenerative model was established on the bovine whole caudal IVD culture system under mechanical loading. This model can be used to further elucidate the mechanisms of TNF-α-induced IVD degeneration, and importantly, can serve as a model for screening of bioactives targeting TNF-a inhibition. A previous study reported that bone morphogenetic protein- 4 (BMP-4) has potent effects on NP matrix regeneration, as shown in a co-culture of human NP cells and mesenchymal stem cells. In Chapter 3, the effects of BMP-4 on IVD regeneration were evaluated in vitro and in vivo sheep models. The regenerative effects of BMP-4 on NP and AF cells were shown by improved cell proliferation and ECM production. However, no regeneration in the NP nor AF was observed in vivo. These results suggest that direct intradiscal injection of BMP-4 may not be a suitable strategy for IVD regeneration. More factors should be considered before attempting translation BMP-4 for IVD regeneration, for instance, the delivery method. To restore the function of the IVD, keeping its structural integrity is essential. Although the AF is a crucial component of IVD, this structure is often overlooked in therapy development. In Chapter 4, AF analog scaffolds were explored and evaluated in vitro and ex vivo. Our findings demonstrate that the combination of cellular, biomaterial, and bioactive strategies has excellent potential for AF regeneration. In Chapter 5, we found that CD146 is essential for the contractility of AF cells. Furthermore, we partly elucidated the underlying signaling pathway of CD146 upregulation by TGF-β in AF cells and suggest that CD146 can potentially be used as a functional marker in AF repair strategies. Intradiscal administration has been proposed as a desirable strategy for drug delivery to increase local drug concentration, prolong drug retention, and reduce systemic side effects because of the isolated nature of IVD. In Chapter 6, this study provides evidence of drug release and retention profiles in the IVD by using different methods (nuclear magnetic resonance spectroscopy, near-infrared imaging) and models (ex vivo, and in vivo on sheep and rats). Results showed that drug retention in IVD can be affected by degeneration and that a proper drug release system could prolong drug retention in IVD, which theoretically may improve treatment outcomes