A strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy... Show moreA strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy remained unknown. This thesis therefore studied the cardiovascular disease burden within this patient group. These results showed that the prevalence of atherosclerosis (i.e. cardiovascular disease burden), in contrast to abdominal aortopathy, is not increased within the thoracic aortopathy population. Show less
Thromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it... Show moreThromboembolic complications remain a major public health burden, making antithrombotic agents one of the most widely prescribed groups of medication, but the treatment is often challenging as it at the same time increases risk of bleeding. With nationwide data from Statistics Netherlands, antithrombotic therapy and relevant clinical outcomes were comprehensively examined in the patient population of atrial fibrillation, overall or among those with comorbid cancer. The results suggest the patient population was increasingly receiving anticoagulants, driven by the newly introduced medication- direct oral anticoagulant and guided by the CHA2DS2-VASc score, and meanwhile the patient population experienced fewer ischemic stroke and major bleeding. In spite of these promising changes, suboptimal medication adherence and potential underuse of anticoagulants remain directions for further improvement. Antithrombotic agent use during pregnancy was also examined in the general Dutch pregnant population, which featured a surge in antiplatelet prescriptions, and risk of preeclampsia/eclampsia decreased and several newborn outcomes improved simultaneously. Together, the studies presented in this thesis provide an overview of antithrombotic therapy in the Netherlands in recent years, providing insights for further improving this treatment and relevant patient outcomes. Show less
Palliative care is care improving the quality of life of patients and their families, who are facing a life-threatening condition or frailty, through prevention and relief of suffering by means of... Show morePalliative care is care improving the quality of life of patients and their families, who are facing a life-threatening condition or frailty, through prevention and relief of suffering by means of early identification and careful assessment, and treatment of problems of a physical, psychological, social, and spiritual nature. This thesis describes five studies that evaluated the support of clinicians not specialized in palliative care, or generalists in palliative care. The results show that generalists need education on basic palliative care principles and need support with the initiation of a palliative care approach on time, especially when they care for patients with life-limiting illness other than cancer. To have mor attention for alle problems in the physical, psychological, social and spiritual dimension of care, they can be supported with a more structured approach to the total burden of symptoms and problems. This could be achieved by supporting them with a clinical decision support system for symptom management in palliative care. Such a system can be used for every individual patient, includes a symptom predictor, and provides recommendations on treatment and referral possibilities. Show less
This thesis contributes to the evidence-base of the influence of patient factors, surgical approach and implant design on outcomes after total hip replacement (THA).A systematic review (SR) shows... Show moreThis thesis contributes to the evidence-base of the influence of patient factors, surgical approach and implant design on outcomes after total hip replacement (THA).A systematic review (SR) shows that there is strong evidence for BMI, age, comorbidity, preoperative functioning and mental health as predictors of physical functioning. A predictive model based on data from this thesis emphasizes preoperative functioning, mental health and pain as predictors.To treat hip fractures, the posterolateral (PLA) and direct lateral surgical approach (DLA) are the most commonly used. The PLA may cause more dislocations, but seems to result in less walking problems and abductor insufficiency than the DLA. All investigated surgical approaches for primary THA resulted in a significant improvement in patient reported outcome measures (PROMs). The anterior and posterolateral approaches provided greater improvement in physical function and pain, but clinical differences were small.A multicenter randomized trial comparing two hip stems is described. No significant difference has been demonstrated between the Collum Femoris Preserving (CFP) and Zweymüller stem in physical function at 5 years or implant survival at 12 years, although CFP may be inferior in cup revisions. A SR suggests lower dislocation rates and revisions for dual mobility cups in THA, but high quality evidence is lacking. Therefore, we designed an RCT comparing dual mobility cups with unipolar cups in older patients.In addition to providing insights into the influence of patient, surgical and implant characteristics on outcome after (total) hip arthroplasty, this thesis provides suggestions for the design of future clinical trials. Show less
The thesis assess the robustness of 4D flow MRI for analyzing aortic hemodynamics and valvular flow, as well as exploring the clinical potential of this technique in patients with aortic and... Show moreThe thesis assess the robustness of 4D flow MRI for analyzing aortic hemodynamics and valvular flow, as well as exploring the clinical potential of this technique in patients with aortic and valvular disease. The first part of the thesis evaluates the reproducibility of segmenting the aortic lumen and calculating various hemodynamic parameters, demonstrating that these processes can be performed accurately and consistently. The second part examines the natural course of aortic hemodynamics during aging, concluding that hemodynamic parameters remain relatively stable. Furthermore, different hemodynamic phenotypes are identified in patients with aortic root and ascending aortic dilatation, possibly explaining the presence of dilatation. Show less
The endothelium is a crucial component of the vascular system, and its proper function is vital for microcirculatory function and by extension cardiovascular health. Hence, endothelial dysfunction... Show moreThe endothelium is a crucial component of the vascular system, and its proper function is vital for microcirculatory function and by extension cardiovascular health. Hence, endothelial dysfunction is involved in a majority of cardiovascular disease and poses a high societal burden. Endothelial nitric oxide bioavailability is essential for a healthy microcirculation. The first half of this thesis investigates the reliability of imaging techniques that non-invasively assess the microcirculation and nitric oxide bioavailability, including laser speckle contrast imaging, Doppler flowmetry, dark field microscopy, skin fluorescence imaging and near infrared spectroscopy. In addition, the vascular effects of a mixed meal and a far-infrared light emitting patch, as measured with the imaging methods, are assessed. Finally, differences in microcirculatory function in people with mitochondrial disorders and healthy volunteers are explored. In the second half of the thesis, first-in-human and proof-of-mechanism studies with a soluble guanylyl cyclase stimulator and a phosphodiesterase inhibitor are described, drugs thought to enact some of their effects through modulation of vascular function downstream of nitric oxide. The thesis concludes with a critical appraisal of the investigated imaging modalities and their potential for inclusion in future clinical trials with drugs aiming to affect the microcirculation. Show less
Healthcare is under pressure: an ageing population, healthcare-staff shortage, quality (healthcare outcomes) must increase and costs must be reduced.Yet, what are the outcomes of healthcare?For... Show moreHealthcare is under pressure: an ageing population, healthcare-staff shortage, quality (healthcare outcomes) must increase and costs must be reduced.Yet, what are the outcomes of healthcare?For some conditions, quality of care is measured for every patient. Unfortunately, this is not the case for prostate cancer and lumbar disk herniation in the Netherlands. We used claims data to evaluate healthcare outcomes and volume-outcome relationships.Examples of our results:Prostate cancer:• More than 30% of patients is incontinent 1 year after radical prostatectomy• Large differences between hospitals (19%-85%)• Risk of incontinence is 52% lower at highest-volume hospitalsLumbar disk herniation:• One year after hernia surgery, 23% of patients have one or more undesirable outcomes (e.g. re-operation, use of opioids).• Wide variation in number of operations and outcomes per hospitalOur recommendations:• Reconsider the disproportionately strict interpretation of the GDPR (AVG) for healthcare research• Unlock the huge potential of healthcare research based on existing data • Make routine measurement of healthcare outcomes a national standard, for prostate cancer even on a per surgeon level• Centralization of care should be combined with outcome measurement• Hospitals should share healthcare outcomes with patients• Our results urge doctors, health insurers, patient organizations and policymakers to take action Show less
The first aim of this thesis was to evaluate the Late Effects Comprehensive Care & Follow-up (LEEF) program after pediatric stem cell transplantation for nonmalignant diseases at the LUMC, and... Show moreThe first aim of this thesis was to evaluate the Late Effects Comprehensive Care & Follow-up (LEEF) program after pediatric stem cell transplantation for nonmalignant diseases at the LUMC, and includes the assessment of various late effects and health-related quality of life. The second aim was to implement and evaluate aspects of VBHC at the LEEF program. This thesis describes lessons learned from the VBHC implementation in the Late Effects Comprehensive Care & Follow-up (LEEF) program and suggests possible future directions for VBHC implementation in similar comprehensive care programs. In this thesis, patient-reported outcomes (PROs) have demonstrated their value in research, such as long-term quality of life studies, but they have also proven to be valuable when used in clinical practice. The evaluation of PROs for both research purposes and clinical use can be expanded within the broader care path of pediatric stem cell transplantation. Furthermore, when discussing long-term HSCT outcomes, it is not solely about survival rates, but PROs are integral to capturing these long-term outcomes. Show less
Prostate cancer (PCa) is the second most prevalent cancer among men worldwide when assessing age-standardized incidence rates. The primary method for early PCa diagnosis involves measuring the... Show moreProstate cancer (PCa) is the second most prevalent cancer among men worldwide when assessing age-standardized incidence rates. The primary method for early PCa diagnosis involves measuring the serum concentration of prostate-specific antigen (PSA), with elevated levels (> 3 ng/mL in the Netherlands) indicating the potential presence of PCa. However, the conventional PSA test exhibits a low specificity. Thus, clinical challenges persist, including the differentiation between PCa and benign prostatic hyperplasia and distinguishing indolent PCa from aggressive forms. This underscores the need for a more specific biomarker for early PCa detection and stratification. Previous studies have reported altered glycosylation features in two prostate-secreted glycoproteins, PSA and prostatic acid phosphatase (PAP) in PCa patients, e.g. variation in sialylation, fucosylation and the level of LacdiNAc . The aim of this thesis was to identify PCa biomarkers for early detection and to improve patient stratification, focusing specifically on the glycomic profiles of PSA and PAP. In addition, as PSA plays an important role with regard to fertility, its glycosylation -in relation to male infertility- was also touched upon. For this purpose, mass spectrometry (MS) based glycoproteomic methods were established to map the glycoprofiles of PSA and PAP derived from various biofluids. Show less
A deeper understanding of the parameters driving response and resistance to immunotherapy is needed to improve the low response rates observed in breast cancer patients. Research into immunotherapy... Show moreA deeper understanding of the parameters driving response and resistance to immunotherapy is needed to improve the low response rates observed in breast cancer patients. Research into immunotherapy response has predominantly focused on T cells, however effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. By combining profiling of blood and tumors from metastatic breast cancer patients with mechanistic studies in mouse models, we uncovered the critical role of eosinophils in immunotherapy response, and we provide proof-of-principle for eosinophil engagement to enhance immunotherapy efficacy. Focusing on resistance mechanisms to immunotherapy, we demonstrate that neoadjuvant immunotherapy triggers persistent and systemic regulatory T cell activation which blunts therapeutic efficacy against metastatic spread of breast tumors. In addition, we demonstrate that neutrophils in the tumor microenvironment pose a barrier to immunotherapy response through T cell suppression. Lastly, we demonstrate that combining the immunomodulatory agent PD1-IL2v with cisplatin is a powerful approach to induce a broad activation of systemic and intratumoral adaptive and innate immunity, resulting in effective immunotherapy responses. Overall, this work identifies several key players and their interconnectivities in anti-tumor immunity and tumor-induced immunosuppression that may be therapeutically exploited to improve immunotherapy responses for breast cancer patients. Show less
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
After standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the... Show moreAfter standard surgery for neck hernias, about 25% of patients report low satisfaction. This thesis applied inferential statistics to clinical data and Machine Learning to medical imaging, with the goal of finding out where differences in functional outcomes after surgery come from and how artificial intelligence can improve the diagnostic and prognostic process. The initial idea that differences in functional recovery were due to surgical technique was refuted by an RCT from this dissertation. The differences in functional recovery between three different surgical groups (removal of the intervertebral disc without artificial material, placement of intervertebral disc prosthesis, and fusion of vertebrae with a cage) were found to be minimal. It was striking that not surgical technique, but patients' mental health and preoperative, radiological imaging were found to be predictive of clinical recovery after surgery. Although the intervertebral disc prosthesis did not deliver on the promise of preserving mobility and thus could not prevent degeneration at adjacent levels, using Deep Learning based solely on the preoperative MRI of the neck, researchers were able to predict, among other things, which patients would require reoperation after surgery for that adjacent degeneration. The Deep Learning model did that significantly better than an experienced neuroradiologist and neurosurgeon. Such Deep Learning models eliminate the need for time-consuming questionnaires and are thus more cost-effective and less stressful for the patient, while they can be used to identify radiological features important for predicting the postoperative course. After validation with larger radiological datasets, these models can support clinical decision-making and help physicians develop personalized treatment strategies. Challenges within image analysis research for the spine lies in integrating different models into one automated process, preferably built into the electronic health record. Show less
Prenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two... Show morePrenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two outflow-tract anomalies, by adding an additional mandatory plane to the national screening program. The second part of this thesis, studies the development of the fetal brain in children affected by congenital heart defects. These children are known to have worse neurodevelopmental outcome than their healthy counterparts. There is some evidence describing a prenatal origin of the delay in neurodevelopment. In the studies that were described in part two of this thesis, we have used a deep-learning algorithm that can assess the maturation (or development) of the fetal brain. We have found small delays in brain maturation as compared to healthy control fetuses. The clinical significance of these outcomes however, remains unclear. A multifactorial cause of brain damage in children with CHD is much more likely. Whatever the exact cause of the long-term neurodevelopmental delay in children with congenital heart defects is, the correlation is undeniable. And thus, expecting parents must be informed of this matter. Show less
To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
In this thesis, we unraveled the immunostimulatory potential of oncolytic reovirus and investigated how these immunostimulatory characteristics could be exploited for effective anticancer... Show moreIn this thesis, we unraveled the immunostimulatory potential of oncolytic reovirus and investigated how these immunostimulatory characteristics could be exploited for effective anticancer immunotherapy. We demonstrated that administration of oncolytic reovirus does not lead to strong oncolytic effects in tumors, but instead unleashes a very potent immune response, including the priming of reovirus-specific CD8 T cells. We showed that these reovirus-specific CD8 T cells can be effectively employed for anticancer immunotherapy, by either bypassing their specificity (with CD3-bsAbs) or by exploiting their specificity (via installing a preinduced pool using SLP vaccination). Besides the induction of reovirus-specific CD8 T cells, reovirus administration also leads to very fast B-cell responses. We demonstrated that the presence of neutralizing antibodies (NAbs) restricts the use of reovirus as an oncolytic agent, but that the reovirus-induced influx of CD8 T cells is retained and the use of reovirus in combination with T-cell-based immunotherapy can still result in potent antitumor responses. Lastly, we showed that blockade of Transforming Growth Factor-β (TGF-β) does not impair reovirus infection and reovirus-induced ISG expression or the reovirus-induced attraction and activation of T cells, but that intrinsic differences between preclinical tumor models can determine if TGF-β blockade is a beneficial addition to combined reovirus and T-cell-based immunotherapy. Show less
There is a lack of knowledge regarding the definition, classification and appropriate treatment of malignant lateral lymph nodes in patients with (locally advanced) rectal cancer. This thesis aimed... Show moreThere is a lack of knowledge regarding the definition, classification and appropriate treatment of malignant lateral lymph nodes in patients with (locally advanced) rectal cancer. This thesis aimed to increase this knowledge and improve treatment practices for this population. Show less
This thesis presents the development of quantitative imaging tools to study parasite migration. Since migration is crucial for malaria parasites to continue their life cycle, factors influencing... Show moreThis thesis presents the development of quantitative imaging tools to study parasite migration. Since migration is crucial for malaria parasites to continue their life cycle, factors influencing their migration capability may also impact the efficacy of malaria vaccine candidates. Here, imaging of parasite migration was used to gain insights that can support the development of antiparasitic vaccines. SMOOT (Sporozoite Motility Orienting and Organizing Tool) was developed and established as a quantitative software analysis tool for tracking the migration of malaria sporozoites in vitro and in human skin explant. This tool provides a readout with high kinematic detail, enabling the quantitative characterization of novel factors influencing the migration capability of malaria sporozoites. Subsequently, the study of sporozoite migration was expanded beyond in vitro and ex vivo models. A hybrid tracer labeling approach for malaria sporozoites was developed and used to reveal the in vivo dissemination of malaria sporozoites in a murine model. This multimodal imaging approach was also applied to investigate human skin invasion by helminth larvae. This thesis concludes with a review of the broader potential for imaging technology to advance the development of new diagnostic methods, therapeutic interventions and vaccines for combating parasitic infections. Show less
Rheumatoid arthritis (RA) is an autoimmune disease affecting joints which is hallmarked by the presence of autoantibodies against citrrulianted protein (ACPA). This thesis describes the phenotypic... Show moreRheumatoid arthritis (RA) is an autoimmune disease affecting joints which is hallmarked by the presence of autoantibodies against citrrulianted protein (ACPA). This thesis describes the phenotypic and functional characteristics of ACPA-expressing autoreactive B cells which suggest potential pathologic roles of these B cells in RA pathogenesis. The thesis also describes strategies to specifically deplete ACPA-expressing B cells to improve current RA therapeutic options. Show less
