This thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section... Show moreThis thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section II, various studies are described which lay the groundwork for further investigation into response monitoring and prediction in rectal cancer using various imaging modalities. Show less
The aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of... Show moreThe aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of vulvar and HPV-driven diseases.Firstly, this thesis focuses on the recognition and validation of imaging-based biomarkers for recognition of diseases of the skin and external genitalia. Clinical studies were performed using 3D photography, dermatoscopy optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) on vulvar HSIL, lichen sclerosus, cutaneous warts and anogenital warts. These techniques were subsequently implemented in a clinical trial in which a novel small molecule was tested for safety and exploratory efficacy for the treatment of cutaneous warts.Furthermore, this thesis explores sequencing-based biomarkers for vulvar disease, facilitating insight into the aetiology of vulvar diseases and identifying potential new therapeutic targets. The currently available literature on the vulvar microbiome composition was investigated and expanded in an observational study characterising the vulvar microbiome composition of healthy volunteers, vulvar HSIL patients and lichen sclerosus patients. Lastly, a perspective on recent developments in the field of premalignant vulvar disease is provided, with recommendations for future applications of the biomarkers studied in this thesis. Show less
The general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were... Show moreThe general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were MTI, tCBF and WSS measurements. The new markers we studied were cerebral microbleeds and iron accumulation in the basal ganglia. In chapter 2 we investigated whether MTI changes could be detected in the GM, WM or both in patients suffering from MCI or AD. Using MTI we found evidence for structural brain changes in both GM and WM of patients with MCI and AD. Furthermore, these MTI changes were related to cognitive impairment as expressed by the mini mental state examination (MMSE) score. These findings imply that cerebral changes can be detected in both GM and WM even before patients are clinically demented. The finding of MTI changes in the GM might relate to classical AD type pathology, whereas WM MTI changes could indicate concomitant vascular pathology. The findings in chapter 2 raised the question of how the MTI changes found in this study are distributed over the GM and WM. This was investigated in chapter 3. In this study we showed that brain damage, as detected by MTI, is widespread over the lobes in both AD and MCI patients whereas GM damage is more focally present in the temporal and frontal lobe of MCI patients. These findings are compatible with the knowledge that GM damage originates from the temporal lobe in AD. This interpretation is further supported by the observed independent association between temporal GM peak height and cognitive decline. MTI changes were found in all four lobes of the MCI patients investigated in this study and show the involvement of a diffuse process affecting the WM even before patients are clinically demented, a finding potentially explained by the presence of diffuse vascular pathology. Chapter 4 shows that the tCBF is strongly associated with parenchymal volume rather than age and, although much weaker, with the severity of WMHs. Although the association between tCBF and parenchyma volume seems straightforward, this finding has important implications for future studies. Volume flow measurements should be corrected for parenchymal volume ratherthan age in all future studies in which flow measurements are being used as a diagnostic tool. In addition, studies including elderly patients or patients with a pathological increase of WMHs, such as diabetic type II subjects, should also correct their tCBF measurements for WMH volumes. Chapter 5 shows that hemodynamic conditions of the carotid and basilar arteries, as expressed in lower WSS parameters, are worse in both MCI and AD compared to controls. In addition, the WSS parameters were found to correlate strongly with cognition. Again, this study is additional evidence for an important role of vascular pathology in the development of AD. In chapter 6, we found a high prevalence of microbleeds in a population of patients suffering from vascular disease or at high risk of developing this condition. Age, hypertension and WMH were the most important risk factors for microbleeds, especially when located in the cortico-subcortical junction and basal ganglia. Regarding the associations between the presence and location of microbleeds on the one hand and parameters of cognitive functioning on the other, chapter 7 shows that microbleeds located infratentorially are associated with impaired cognitive functioning in the aging population with increased vascular risk factors. This suggests that in elderly individuals microbleeds in the posterior fossa should be considered a sign of small vessel disease with potential functional consequences. The semi-quantative scale for scoring basal ganglia hypo-intensity on T2*- weighted imaging presented in chapter 8 was associated with markers of neurodegeneration. This study showed that low signal intensity of the caudate nucleus T2*-weighted MR is a frequent finding which is associated with more cerebral atrophy, a higher load of WMH and a higher load of invisible changes in both cortical GM and NAWM non-demented elderly. Furthermore, hypo- intensity limited to the globus pallidus and putamen was not associated with any of these parameters of neurodegeneration. In chapter 9 we present a method for automated detection and classification of hypo-intense regions on T2-weighted MR images of the basal ganglia. In this chapter we not only show an association between basal ganglia hypo-intensity and cardiovascular risk factors but also with measures of cognitive functioning. From this we conclude that hypo-intensity of the basal ganglia on T2-weighted MR is not only a radiological finding accompanying cerebral aging but also an independent marker of neurodegeneration. Show less
The general introduction of this thesis gives an overview of the epidemiology of ST-segment elevation myocardial infarction (STEMI) and the current focus of the guidelines concerning the management... Show moreThe general introduction of this thesis gives an overview of the epidemiology of ST-segment elevation myocardial infarction (STEMI) and the current focus of the guidelines concerning the management of these patients. In the past decades changes in the treatment and outcome of STEMI patients have influenced the risk stratification of this population and the focus has been shifted to the evaluation of infarct size. Furthermore, the role of echocardiography in the risk stratification after STEMI is addressed including the evolving echocardiographic techniques. The aim of the current thesis was to evaluate the clinical characteristics of this contemporary population of STEMI patients and to assess the value of echocardiography for the improvement of the risk stratification of these patients. First, the current population of STEMI patients treated with primary percutaneous coronary intervention is described in Part I, where clinical parameters are being evaluated in relation to short- and long-term outcome. In Part II, the role of conventional and novel echocardiographic techniques is being evaluated for the assessment of left ventricular (LV) systolic function and the importance of LV diastolic function is addressed in Part III. Finally, the role of echocardiography in patients with chronic ischemic heart disease is studied in Part IV. Show less
In this research heavy chain antibody fragments (VHHs) are developed as potential tools for non-invasive in vivo imaging of Alzheimer__s disease (AD) and Cerebral Amyloid Angiopathy (CAA). First... Show moreIn this research heavy chain antibody fragments (VHHs) are developed as potential tools for non-invasive in vivo imaging of Alzheimer__s disease (AD) and Cerebral Amyloid Angiopathy (CAA). First the generation of antibody fragments, directed against A_ is described. VHHs that were selected from different libraries showed differential affinity for different A_ epitopes when used for immunohistochemistry. These observations indicate that the VHHs are the first immunologic probes with the capacity to differentiate between parenchymal and vascular beta amyloid aggregates. Next, in chapter three the VHH are assessed on their ability to cross the blood-brain barrier using an established in vitro blood brain barrier co-culture system. VHH ni3A showed the highest transmigration efficiency of all tested VHHs. This transport is, in part, facilitated by a 3 amino acid substitution in its N-terminal domain. Additional studies indicated that the mechanism of transcellular passage of ni3A is by active transport. The data described in chapter four provides preliminary proof that these VHHs have the capacity to target A_ depositions in vivo. Consequently, the VHHs are promising tools for further development as imaging agents for the differential diagnosis of A_-related neurodegenerative diseases like CAA and AD. Show less
