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
First the VG-RVPO as a monitoring for PAH in SSc patients was evaluated, here serial measurements of the VG-RVPO, can be used as a follow-up instrument to detect early changes in RV pressure over... Show moreFirst the VG-RVPO as a monitoring for PAH in SSc patients was evaluated, here serial measurements of the VG-RVPO, can be used as a follow-up instrument to detect early changes in RV pressure over time. Then we investigated the role of the VG-RVPO in improving the efficiency of the YEARS algorithm. Neither as a stand-alone diagnostic test nor when combined with the YEARS algorithm, it had any diagnostic value. Then the role of VG-RVPO in estimating the presence of PH, and the prognostic value of an abnormal VG-RVPO in PE patients was evaluated. There was an association between VG-RVPO and RV overload as measured by CTPA. In Chapter 5, the outcome of AAOCA patients is described and linked to pre-and postoperative symptoms. Overall, surgical correction significantly reduces symptoms. The CTOA on pre-and post-operative CTAs of patients with AAOCA was compared and related to anatomy and post-operative outcome. It suggests that CTA can be used to look at the anatomy of AAOCA patients before and after surgery. The last study re-evaluates the late clinical outcome and hemodynamics in patients with TOF. The findings shows, after 17.1 years there was a stabilization of RV function and an impressive durability of the homograft. Show less
This thesis focuses on health inequity in Spondyloarthritis (SpA) and potential drivers for this. The general lack of evidence on the role of socioeconomic factors, mainly at the level of the... Show moreThis thesis focuses on health inequity in Spondyloarthritis (SpA) and potential drivers for this. The general lack of evidence on the role of socioeconomic factors, mainly at the level of the individual, but also at the wider societal level, on disease outcomes in SpA, stimulated the undertaking of the individual studies described in the thesis. The possibility to study socioeconomic factors give a unique dimension to the analyses presented and provide more insights that complement the existing body of evidence. The studies presented also highlight much unmet need in our understanding of disease and in particular the intricate relationships between biological and non-biological factors that drive adverse outcomes in SpA. Many of these relationships are naturally complex and the observed effects on outcomes, multifactorial in origin. The thesis has three overarching aims, all pertaining to better understanding the role of socioeconomic factors in SpA, from different angles, both at the individual as well as the country-level and the impact on outcomes, namely imaging and work outcomes. Show less
This thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research... Show moreThis thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research was performed with the ultimate goal to clarify whether autoantibody-negative and autoantibody-positive RA are distinct diseases that require different diagnoses and treatment. Show less
Near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) is a promising imaging technique for the assessment of tissue perfusion. This thesis describes the quest for valid and reliable... Show moreNear-infrared (NIR) fluorescence imaging with indocyanine green (ICG) is a promising imaging technique for the assessment of tissue perfusion. This thesis describes the quest for valid and reliable quantitative assessment of tissue perfusion using this technique, predominantly in patients with lower extremity arterial disease. Two systematic reviews were performed, describing the experience with ICG NIR fluorescence imaging within various surgical fields. In three original studies, perfusion patterns were described in various groups, including lower extremity arterial disease, healthy controls and in patients undergoing free flap reconstructive breast surgery. By applying normalization to the quantitative assessment, an increased validity and reliability was seen. To describe potential clinical applications, the use of ICG NIR fluorescence imaging was described for two indications. In patients undergoing unilateral revascularization, quantitative assessment showed an increase of inflow parameters, whilst parameters in the untreated side remained unchanged. In a cohort of patients undergoing amputation surgery, ICG NIR fluorescence imaging was able to predict postoperative skin necrosis in all four cases. Future use of ICG NIR fluorescence imaging should focus on improving validity and reliability of quantitative perfusion assessment. Show less
Venous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of... Show moreVenous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of upper extremity, abdomen and cerebrum. As symptoms of VTE are nonspecific, the diagnosis of VTE is based on diagnostic tests, including clinical decision rules (CDR), D-dimer tests and imaging. Although the diagnostic management of VTE has greatly advanced in recent years with the introduction of novel CDRs and high-sensitive D-dimer tests, the diagnosis may still be challenging in certain settings. The latter is mainly caused by the indirect way of thrombus visualisation by current imaging tests, such as by showing incompressibility with compression ultrasonography (CUS) or a filling defect on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI).This thesis focuses on challenging settings for diagnosing VTE, including suspected recurrent ipsilateral DVT, upper extremity DVT, cerebral vein thrombosis and portal vein thrombosis. We studied a novel imaging technique called Magnetic Resonance Non-Contrast Thrombus Imaging (MR-NCTI) and its application in these different VTE settings. Show less
In this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying... Show moreIn this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying it independently of the rheumatologist’s opinion. Our findings likely add knowledge to what axSpA really is. Future studies will learn us how much of these insights will translate into a better recognition of the disease in clinical practice and in better classifying them for research purposes. Since SpA is a slowly progressing disease, several years are needed to see meaningful changes in imaging abnormalities of the axial skeleton, which poses methodological challenges. We have shown that thoughtful analytical approaches, that make best use of imaging data, are helpful in better estimating progression, in unravelling its determinants and in clarify which outcomes are best to monitor disease. Efforts are made to further improve outcome measurement in axSpA, including the development of new imaging techniques, which can benefit from our proposed solutions to long-term imaging scoring. Show less
With tomography it is possible to reconstruct the interior of an object without destroying. It is an important technique for many applications in, e.g., science, industry, and medicine. The runtime... Show moreWith tomography it is possible to reconstruct the interior of an object without destroying. It is an important technique for many applications in, e.g., science, industry, and medicine. The runtime of conventional reconstruction algorithms is typically much longer than the time it takes to perform the tomographic experiment, and this prohibits the real-time reconstruction and visualization of the imaged object. The research in this dissertation introduces various techniques such as new parallelization schemes, data partitioning methods, and a quasi-3D reconstruction framework, that significantly reduce the time it takes to run conventional tomographic reconstruction algorithms without affecting image quality. The resulting methods and software implementations put reconstruction times in the same ballpark as the time it takes to do a tomographic scan, so that we can speak of real-time tomographic reconstruction. Show less
Despite the available treatment options and sophisticated imaging technologies for monitoring lesion development, the morbidity and mortality from acute cardiovascular events remain unacceptably... Show moreDespite the available treatment options and sophisticated imaging technologies for monitoring lesion development, the morbidity and mortality from acute cardiovascular events remain unacceptably high.While cholesterol-lowering, anti-inflammatory and anti-platelet therapies benefits can increase survival as a primary or secondary prevention, they are not sufficient for plaque rupture prevention. Moreover, the most advance imaging technologies to detect high-risk atherosclerotic patients fail to visualize and explore cellular events in small preclinical models. Therefore, there is a clear need for the development of new therapies and the application of high-resolution imaging modalities.In the current thesis, we evaluated new possibilities to inhibit and image intraplaque angiogenesis. Show less
In this thesis the focus was on diagnosing axSpA early using clinical features as well as imaging modalities. We have studied multiple elements diagnosing axSpA among patients presenting with... Show moreIn this thesis the focus was on diagnosing axSpA early using clinical features as well as imaging modalities. We have studied multiple elements diagnosing axSpA among patients presenting with chronic back pain. We have emphasized two main themes: (1) the importance of clinical SpA features; and (2) the contribution of imaging to an axSpA diagnosis and classification. We have learned how rheumatologists use imaging results in their diagnostic considerations and thereby have helped reduce certain fears regarding the way diagnosis is made in clinical practice. We have shown that the use of MRI-spine in classification is not efficient. The common thread in all of the studies in this thesis is that axSpA diagnosis is the interaction between the clinical aspects of chronic back pain and imaging findings highly suggestive of axSpA. Clinicians should be aware of mindlessly ‘stacking up’ SpA features in chronic back pain patients in order to avoid unnecessary (biologic) treatment. Additional studies are needed to investigate the numerous phenotypes of axSpA and to predict in which chronic back pain patient axSpA diagnosis is likely. Show less
The diversity in medicine and the scope of both non-invasive and invasive diagnostic instruments and treatments for ischemic heart disease have grown exponentially the last few decades. The... Show moreThe diversity in medicine and the scope of both non-invasive and invasive diagnostic instruments and treatments for ischemic heart disease have grown exponentially the last few decades. The objective of this thesis was to establish the value of different imaging techniques and treatments targeting different stages of ischemic heart disease. The results reported have demonstrated that multimodality imaging is of high relevance in patients with ischemic heart disease, facilitating the decision-making process in different groups of patients and allowing medical and (non-)invasive treatments to be better tailored to individual cases from prevention to treatment while potentially improving prognoses. Show less
Studies in this thesis focused on the use of MRI in patients with early inflammatory arthritis. Studies were focused on: the diagnostic value of MRI, predictive value of MRI findings for the... Show moreStudies in this thesis focused on the use of MRI in patients with early inflammatory arthritis. Studies were focused on: the diagnostic value of MRI, predictive value of MRI findings for the development of erosions, associations between age and MRI findings, the use of MRI for the development of new disease activity scores and patient reported outcomes in patients with rheumatoid arthritis. Show less
The breakthrough of immunotherapy for cancer has introduced promising new options, but nonetheless only a minority of cancer patients show significant clinical benefit. This situation has inspired... Show moreThe breakthrough of immunotherapy for cancer has introduced promising new options, but nonetheless only a minority of cancer patients show significant clinical benefit. This situation has inspired two avenues of research to find solutions to this problem: mechanistic studies to decipher the working mechanisms of immunotherapies and to investigate why many patients do not respond, and studies developing combination treatments to achieve clinical benefit in situations where immunotherapy alone is not sufficient. This thesis explores both these avenues by investigating applications of visible light in immunotherapy of cancer in pre-clinical models. We developed optical imaging platforms for visualization of immune cells and immunotherapies, which can shed light on the immunological events after administration of immunotherapy. In addition, we investigated novel therapies based on the combination of tumor ablation by Photodynamic Therapy and different types of immunotherapy. Our findings may prove useful in understanding success and failure of immunotherapy, and provide new combination treatment options when the efficacy of monotherapy is insufficient. Show less
This thesis has shown that significant lead-induced TR due to the mechanical presence of an RV-lead though the tricuspid valve was associated with worse long-term prognosis. CRT is one of the... Show moreThis thesis has shown that significant lead-induced TR due to the mechanical presence of an RV-lead though the tricuspid valve was associated with worse long-term prognosis. CRT is one of the main therapeutic breakthroughs in heart failure of the last decade but patients included in landmark trials do not completely mirror patients undergoing CRT in the clinical practice, who are usually older and have more frequently associated comorbidities such as renal dysfunction, diabetes or atrial fibrillation. This thesis shows a beneficial, although limited, effect of CRT also in elderly, in patients with diabetes and CKD stage 4, and therefore suggests that this therapy should not be withheld based on certain co-morbidities or on age alone. Furthermore, it shows that RBBB in patients referred to CRT and favourable RV-function improvement after CRT were associated with CRT outcomes. To improve clinical risk-stratification, this thesis proposed a CRT-SCORE using CRT-specific parameters and showed to be valuable in risk-estimation that may assist clinicians in counseling patients and guide clinical shared decision-making. Finally, novel approaches to optimize patient selection are presented in this thesis. SDI, a 3D-echocardiography LV-dyssynchrony measurement and T1-mapping, a novel CMR-technique to quantify diffuse myocardial fibrosis were significantly associated with CRT outcomes. Show less
The work presented in this thesis describes the improvement and application of on-tissue chemistry for in-situ biomolecular analysis using matrix assisted-laser desorption/ionization mass... Show moreThe work presented in this thesis describes the improvement and application of on-tissue chemistry for in-situ biomolecular analysis using matrix assisted-laser desorption/ionization mass spectrometry imaging (MALDI-MSI). We have proposed new methodologies, applying on-tissue (enzymatic) chemistry, to increase the molecular information obtained in a MALDI-MSI analysis. We have also developed an automated histology-guided MSI platform, based on state-of-the-art image processing tools, to facilitate high mass and spatial resolution MALDI-MSI while maintaining reasonable data loads and acquisition times. We have shown the importance of these methods in a clinical biomarker discovery study on myxoid liposarcoma tissues. Show less
Intraoperative imaging using near-infrared (NIR) fluorescence is a fast developing imaging modality as it provides real-time visual information during surgery (Chapter 1). The ability to detect... Show moreIntraoperative imaging using near-infrared (NIR) fluorescence is a fast developing imaging modality as it provides real-time visual information during surgery (Chapter 1). The ability to detect lymph nodes and tumours that need to be resected can assist the surgeon to improve surgery by reducing time of the procedure, reducing iatrogenic damage, and improve the number of radical resections. This thesis focuses on the introduction of NIR fluorescence imaging into the clinic. Part 1 of this thesis describes the optimization of NIR fluorescence imaging for sentinel lymph node (SLN) biopsy using the clinically available NIR tracer Indocyanine green (ICG) in various cancer types. Moreover, these studies show both the limitations as the clinical benefit of NIR fluorescence for SLN biopsy. Part 2 describes the use of NIR light for tumour detection. Tissue absorption and scattering in the NIR light spectrum was used for neoadjunvant treatment response monitoring in breast cancer patients. Moreover, NIR fluorescence imaging using NIR contrast agents was used for the intraoperative detection of otherwise difficult to localize liver metastases of colorectal cancer. Show less
Gold nanorods are ideal candidates for complementing fluorophores in labelling applications. The presence of the surface plasmon resonance generates large absorption and scattering cross sections,... Show moreGold nanorods are ideal candidates for complementing fluorophores in labelling applications. The presence of the surface plasmon resonance generates large absorption and scattering cross sections, thus making the detection of single nanoparticles possible under a light microscope. The plasmon of gold nanorods depends on the ratio between their width and length and covers the range between 540nm for spheres and even above 800nm for elongated particles, thus almost the entire visible and near-infrared spectrum. The surface plasmon presents great opportunities in (bio-)sensing, enhanced spectroscopies, photothermal therapy and for concentrating light below the diffraction limit. Show less
Early identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for... Show moreEarly identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for risk stratification and optimizing individual prevention and treatment strategies in patients with metabolic syndrome. This thesis evaluates MR and CT imaging techniques for identifying risk factors and subclinical disease in metabolic syndrome. Show less
The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable... Show more The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable of detecting this tracers. In part one, the reader is introduced to the concept of fluorescence image-guided surgery and the evolution thereof. Furthermore the hybrid approach for image-guided surgical guidance is presented. Part two describes the clinical evaluation of the hybrid approach using the hybrid tracer indocyanine green-technetium 99m-nanocolloid. To further refine the hybrid approach for surgical guidance, part three of this thesis describes the development and evaluation of different types of (hybrid) imaging modalities. Show less
