This thesis aims to improve the treatment of patients with stage III melanoma. The first part describes different aspects of treatment with Talimogene Laherparepvec (T-VEC), a genetically modified... Show moreThis thesis aims to improve the treatment of patients with stage III melanoma. The first part describes different aspects of treatment with Talimogene Laherparepvec (T-VEC), a genetically modified herpes virus, which is used as oncolytic immunotherapy for skin and lymph node metastases in melanoma patients. We show that patients with a low tumor burden have the best outcomes, suggesting T-VEC should be used earlier on in the course of the disease. We present a prediction model, allowing a more accurate selection of patients for T-VEC monotherapy. Two studies focused on the use of T-VEC in clinical practice and the results allowed us to make recommendations on the use of PET/CT and dermoscopy during T-VEC treatment. Part two focuses on the value of surveillance and screening imaging in high-risk melanoma patients. We show that FDG-PET/CT is a valuable imaging tool to detect recurrence after complete resection of stage III disease, even shortly after surgery (before starting adjuvant therapy). Finally, we conclude that nodal staging with US as adjunct to SLNB is useful in the work- up of stage IIB/C melanoma, as it can lead to alterations in treatment and prevent unnecessary surgery. Show less
For people with chronic kidney disease (CKD), adhering to a range of self-management tasks—such as healthy eating, frequent physical activity, and non-smoking—is crucial. However, changing health... Show moreFor people with chronic kidney disease (CKD), adhering to a range of self-management tasks—such as healthy eating, frequent physical activity, and non-smoking—is crucial. However, changing health behaviors is difficult. To support patients in doing so, an eHealth care pathway was developed and evaluated. The results provide different insights into patients' priorities and care needs. Many individuals with CKD experience problems in self-management, which can be hindered by many different barriers of which a common one is psychological distress. Therefore, personalized interventions are needed with screening and treatment of both psychological distress and suboptimal self-management, tailored to the specific barriers and needs of the individual patient. The E-GOAL eHealth care pathway is an example of such a personalized intervention, combining cognitive behavioral therapy with self-management support. Patients were enthusiastic about the eHealth care pathway. However, in a randomized study, the intervention was not effective in reducing psychological distress compared with regular care only. Patients did experience improvements in areas of functioning and self-management that they prioritized themselves. These mixed results show that interventions could be implemented that are person-tailored, with personalized outcomes that reflect individually meaningful treatment goals and improvements for every patient. Show less
In individuals with tuberculosis-infection – until recently referred to as latent tuberculosis infection – the risk of progression to active tuberculosis (reactivation) varies strongly. Among those... Show moreIn individuals with tuberculosis-infection – until recently referred to as latent tuberculosis infection – the risk of progression to active tuberculosis (reactivation) varies strongly. Among those at increased risk of reactivation are patients with an impaired immune system, e.g. due to immunosuppressive therapy. Therefore, prior to planned immunosuppression, patients are screened for tuberculosis-infection and subsequently treated in case of infection. Current screening methods include the Mantoux test, Interferon-γ release assays (i.e., the QuantiFERON-TB Gold Plus and T-SPOT.TB) and chest X-ray. However, despite screening, cases of reactivation continue to occur – in part due to the lack of a gold standard test for tuberculosis-infection. Therefore, the aims of this thesis were to increase the diagnostic sensitivity for tuberculosis-infection prior to immunosuppression. Using various (novel) methods we showed that approximately two-thirds of all QuantiFERON-TB Gold Plus results just below the manufacturer’s cut-off (in the borderline range) are caused by Mycobacterium tuberculosis-infection, which now warrants preventive treatment in patients with such a result. Furthermore, we quantified the diagnostic accuracy of chest X-ray for tuberculosis-infection and showed that using a novel ultra-low dose CT scanning technique, sensitivity for tuberculosis-infection could be significantly increased by three-fold compared to chest X-ray. Show less
This thesis highlights, firstly, the importance of early CRC detection by presenting results of a CRC diagnostic proteomic biomarker signature with high discriminative power. Secondly, a strong... Show moreThis thesis highlights, firstly, the importance of early CRC detection by presenting results of a CRC diagnostic proteomic biomarker signature with high discriminative power. Secondly, a strong robust, independent prognostic tumor stroma ratio (TSR) biomarker, which confirms to be of important clinical value. The TSR has the ability to stratify colon cancer patients according to their prognostic outcome in a highly reproducible and low-cost manner. It has shown to link patients with a high intra tumor stromal content and a worse prognosis. Literature shows a wealth of evidence that supports this prognostic value in CRC as well as in other cancers. This PhD research therefore concludes that it should be implemented in the official guidelines of the TNM classification to improve stratification for CRC patients in daily routine pathological evaluation. The prospective, international, multicentre UNITED study will hopefully overcome the last hurdle for this clinical implementation. Lastly, this thesis offers more insight in the elusiveness of the tumor microenvironment and stromatogenesis that contributes to the aggressiveness of some CRC tumors. The biological differences, interconnections and changes in the microenvironment presented give multiple leads for further research and new personalized treatment possibilities. Show less
At the moment, over 350.000 chemicals are registered worldwide for production and use. Their application, however, may harm human health and the environment. To manage the safety of chemicals,... Show moreAt the moment, over 350.000 chemicals are registered worldwide for production and use. Their application, however, may harm human health and the environment. To manage the safety of chemicals, particular chemical legislations are in place, which make use of risk and hazard assessments. However, there are several challenges for current risk and hazard assessments, including i) a lack of (reliable) data, and ii) a relative slow and inefficient evaluation and regulation process. In this thesis, I investigate specifically whether more extensive and targeted use of chemical similarity within risk and hazard assessment has the potential to improve these aspects. Chemical similarity could be a valuable factor as similarities between two chemicals could be a sign of similar physicochemical and/or toxic properties. The separate sections within this thesis specifically focus on chemical similarity in relation to screening, data generation and evaluation of substances. The results of this thesis indicate that chemical similarity could be used to identify and evaluate hazardous properties of single and groups of chemicals. Accordingly, I promote more extensive use of chemical similarity within risk and hazard assessment as it has the ability to circumvent several issues related to a lack of data and evaluation efficiency. Show less
The post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE)... Show moreThe post-thromotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH) are the most feared long term complication of a deep venous thrombosis (DVT) and pulmonary embolism (PE) respectively. We have reviewed the literature on arguments for and against routine screening of CTEPH in patients after an episode of an acute PE. The incidence of CTEPH is relevant in this evaluation. In a systematic review and meta-analysis we showed a CTEPH incidence of 0.56% in all comers and of ~3% in the survivors. We showed that a very recent developed screening algorithm, the InShape II algorithm, is sensitive and reproducible for detecting early CTEPH in the course of an acute PE. Beside this, most patient who were diagnosed with CTEPH in the course of an acute PE already showed signs of CTEPH on the initial CT scan made for PE diagnosis.In the last chapter we focus on PTS in the course of a DVT. In patients included in the MEGA database the 0-1 year incidence was 21.8%, after 8 years of follow-up an additional 7% developed PTS. During follow-up PTS symptoms improves in almost 70% of patients. Show less
The number of older people in the population is rising and so is the number of older patients in the Emergency Department (ED). Older patients often have complex problems which leads to an... Show moreThe number of older people in the population is rising and so is the number of older patients in the Emergency Department (ED). Older patients often have complex problems which leads to an increased change of repeat ED visits, longer length of stay, higher chance of hospital admission and higher chance of negative health outcomes. Cognitive impairment is a frequent problem in older ED patients but often remains unrecognized and little is known about the association between cognitive impairment and adverse outcomes in older ED patients. In this thesis we show that cognitive impairment is associated with adverse outcomes in acutely presenting older patients. Secondly, we show that routinely collected parameters in addition to cognitive impairment can be used to screen for high risk of adverse outcomes in older ED patients. We investigated two delirium screeners and showed the CAM-ICU might not be suitable for early detection of delirium in the ED. Finally, vital signs that associate with decreased brain perfusion and oxygenation, such as low systolic blood pressure, were associated with cognitive impairment in older ED patients. Next steps would be to investigate if optimal resuscitation might improve cognition and decrease risk of subsequent delirium and adverse outcomes. Show less
In coeliac disease effective long-term management and screening programs are lacking for children as well as for adults. In this thesis we tried to contribute to this close this gap. We showed that... Show moreIn coeliac disease effective long-term management and screening programs are lacking for children as well as for adults. In this thesis we tried to contribute to this close this gap. We showed that nutritional deficiencies present at diagnosis recover within 1 year of gluten-free diet and demonstrated that standard blood investigations besides coeliac specific serology are not necessary after 1 year of follow-up. Furthermore, the short dietary questionnaire developed by Biagi does not provide more information on diet adherence than coeliac specific antibodies, whereas a standardized dietary interview does. In the domain of screening, we demonstrated that parents from coeliac families support HLA-typing in their children in order to assess risk for the disease. Detailed information should be offered to them in order to prevent misinterpretation of the results, Antibody-testing should be offered to all HLA-DQ2 and/or DQ8 positive pediatric first degree relatives, with regular intervals until the age of 10. With regard to screening in asymptomatic diabetic children, normal duodenal mucosa is present in 12% of the children when biopsied in case of a TG2A titer of > 3xULN. Follow-up serology seems safe and appropriate in such cases. Show less
The scope of this thesis spanned several issues in the measurement and evaluation of OD. The screening, assessment, and treatment effect for OD have been covered,with a special emphasis on... Show moreThe scope of this thesis spanned several issues in the measurement and evaluation of OD. The screening, assessment, and treatment effect for OD have been covered,with a special emphasis on patient self-evaluation. Show less
Cytomegalovirus (CMV) infection is a worldwide common infection that in a considerable proportion of individuals remains unnoticed. The congenital CMV infection (cCMV) can induce a variety of... Show moreCytomegalovirus (CMV) infection is a worldwide common infection that in a considerable proportion of individuals remains unnoticed. The congenital CMV infection (cCMV) can induce a variety of clinical manifestations at birth (symptoms at birth), and of permanent long-term impairments (LTI). Of the total of infected neonates at birth, 13% are symptomatic at birth, and half of them will develop LTI. However, 13% of the asymptomatic neonates will still develop the same LTI. Therefore, a quite high percentage of neonates will develop LTI. This thesis aimed to identify prognostic markers, for short- and long-term clinical outcome, and correlates of protection, for future vaccine development. In order to identify such biomarkers, a retrospective nationwide cohort of children with (n=125) and without (n=263) cCMV was used. The findings of this thesis allowed us to get more insights into cCMV pathogenesis, and into the potential processes leading to immune dysfunction, and therefore to a worse clinical outcome. Several approaches have been used to explore prognostic markers. The neonatal immune markers, through DNA quantification of the most common TCR and BCR rearrangements from DBS, together with the maternal-child HLA background, through typing DNA from buccal swabs, seemed to be quite promising for prognostic markers. Show less
Traditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three... Show moreTraditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three-dimensional (3D) environment that cannot generally be captured using cell culture methods. For this reason, cell-culture models have been developed where cells grow in a 3D-environment, which allows them to form structures that are more comparable to tissue in the body. However, the full complexity of these advanced cell-culture models can only be fully used for routine drug testing if the cell culture model can be used on a large scale (also termed high-throughput screening or HTS), and if the readout can capture all of the biological complexity reflected by the 3D-cultured cells (high-content screening or HCS). Due to these technological limitations, 3D cellular models are not yet routinely applied in drug and drug-target discovery. This thesis describes the development of fully-scalable 3D cell-culture screening platforms in the context of cancer and polycystic kidney disease. Show less
Without a proper treatment, critical congenital heart defects (CCHD) lead to death in the first month of life. Timely diagnosis is pivotal for reducing morbidity and mortality. Pulse oximetry is... Show moreWithout a proper treatment, critical congenital heart defects (CCHD) lead to death in the first month of life. Timely diagnosis is pivotal for reducing morbidity and mortality. Pulse oximetry is used in many countries to screen newborns for CCHD. However, this screening has not been implemented in the Netherlands, because of the unique perinatal care system, with a high home birth rate and early discharge after hospital deliveries. This thesis describes research performed to assess the feasibility, accuracy, acceptability and costs of neonatal screening for CCHD with pulse oximetry in the Dutch perinatal care system. To do this, the protocol that is used in the United States and Scandinavia was adapted to fit the working scheme of community midwives. Show less
This thesis describes new knowledge of FNAIT in preparation of a national wide screening program. It illustrates the prevalence of FNAIT among pregnant women and the risk of adverse outcome,... Show moreThis thesis describes new knowledge of FNAIT in preparation of a national wide screening program. It illustrates the prevalence of FNAIT among pregnant women and the risk of adverse outcome, outlines current management, evaluates risks of missing a diagnosis of FNAIT, studies the efficacy of a lower dose of immunoglobulins in preventing bleedingcomplications,shows the time of bleeding onset of fetal ICH during pregnancy and illustrates the longterm outcome of children with ICH. Show less
Fluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as... Show moreFluoropyrimidines are being used in the treatment of different types of cancer. The most common fluoropyrimidine is 5-flourouracil (5-FU), which is administered intravenously as a bolus or as prolonged infusion. Many tissues throughout the body express thymidine phosphorylase. Dihydropyrimidine Dehydrogenase (DPD) is involved in the degradation of endogenous pyrimidine nucleosides, but also in the degradation of fluoropyrimidines. More than 80% of the amount of 5-FU administered is catabolized primarily in the liver where DPD is abundantly expressed. DPD is encoded by the DPYD gene for which 567 coding variants are known to date, some of them being pathogenic by reducing enzyme capacity. Interindividual variability in the activity of DPD influences 5-FU pharmacokinetics and a reduced DPD activity can lead to severe toxicity and even death following administration of 5-FU or capecitabine. Knowledge regarding the clinical impact of reduced DPD activity on the pharmacokinetics and pharmacodynamics of fluoropyrimidines may be useful to dose individualize therapy. In this thesis, an in depth overview is given of methods and their potential to optimize fluoropyrimidine dosing based on individual DPD enzyme activity. Furthermore an oral uracil loading dose as probe for DPD deficiency in cancer patients treated with fluoropyrimdines for this purpose is studied. Show less
In this thesis mass spectrometry based protein profiling was applied as a new biomarker screening modality and it was evaluated whether or not this could be translated into early detection... Show more In this thesis mass spectrometry based protein profiling was applied as a new biomarker screening modality and it was evaluated whether or not this could be translated into early detection of breast cancer and pancreatic cancer. The status of breast cancer screening by proteomic profiling is discussed. Which steps have already been made? What is essential to implement this techniques in a clinical setting? Furthermore, the new protein profiling screening methods for pancreatic cancers are evaluated. Future studies will be suggested that are needed to translate this promising biomarker into a clinical application. Show less
The results of this thesis shed new light on two important issues for evidence-based general practice care for older people: 1) the feasibility of the (proactive) identification of older people... Show moreThe results of this thesis shed new light on two important issues for evidence-based general practice care for older people: 1) the feasibility of the (proactive) identification of older people with complex problems and 2) the effectiveness of proactive integrated care for older people with complex problems in general practice. We investigated five measures to identify older people with complex problems, i.e. a profile of laboratory measurements, handgrip and quadriceps muscle strength, Fried's frailty phenotype criteria, the clinical intuition of the GP, and the ISCOPE screening questionnaire. These measures each identified a complex group of older people, but none of these measures can be recommended as the most feasible for general practice. In the ISCOPE study, a proactive integrated care plan had no direct effect on functional decline and quality of life of older people with complex problems. This lack of effect might be attributed to the study design or to the intervention itself. Although this effect could not be demonstrated, in our opinion integrated care still remains the best type of care available for this age-group. We believe this is confirmed by the level of satisfaction of both older people and GPs who were included in the intervention group. Show less
Infectious diseases are everywhere around us, and we need to keep improving our knowledge about our defence mechanisms and the evasion strategies of the pathogens. The work in this thesis... Show moreInfectious diseases are everywhere around us, and we need to keep improving our knowledge about our defence mechanisms and the evasion strategies of the pathogens. The work in this thesis describes multiple techniques that can contribute to fast screening methods in order to come up with new strategies against infectious diseases. The use of automated micro-injectors in combination with large flow cytometers and automated microscopy has shown added value (chapters 2, 3 & 4) for research questions about (opportunistic) pathogens. The collaboration between scientists of different research areas has proved to be very successful in the development of an easy to use analysis platform for the analysis of RNAseq data (chapter 5). This has led to very detailed description of host molecular expression patterns following infection by these pathogens. This could be used to gain more insight in how biomaterials behave in a host environment in the presence or absence of infection (chapter 6). All together this has led this to a variety of research methods that can be used for studies of infections caused by many bacteria such as S. epidermidis and M. marinum described in this thesis, but, also by other microbes, such as fungi. zebrafish, Staphylococcus-epidermidis, Mycobacterium-marinum, high-throughput,screening, method-development, transcriptome-analysis, molecular-cell-biology, immunology, host-pathogen-interaction; disease-models Show less
Bij veel te vroeg geboren kinderen blijft prematurenretinopathie (ROP) een belangrijke oorzaak van blind- en slechtziendheid. Dit ondanks uitgebreid onderzoek. De oorzaak hiervan is, dat de... Show moreBij veel te vroeg geboren kinderen blijft prematurenretinopathie (ROP) een belangrijke oorzaak van blind- en slechtziendheid. Dit ondanks uitgebreid onderzoek. De oorzaak hiervan is, dat de leeftijd, waarop deze kinderen geboren en in leven gehouden kunnen worden daalt door een betere neonatologische behandeling. Het aantal kinderen, dat ernstige ROP kan oplopen neemt hierdoor toe. Een vroege opsporing en behandeling van ROP kan de kans op het ontwikkelen van een visuele beperking en de ernst daarvan verminderen. Een evidence-based richtlijn is een belangrijk hulpmiddel om de zorg voor deze hoog-risico prematuren te optimaliseren. Er is echter geen universeel screeningsprotocol op te stellen, omdat het niveau van de neonatologische zorg per land erg kan verschillen. Door middel van de NEDROP studie werden op nationaal niveau het screeningsproces, de invloed van overplaatsingen, de incidentie van ROP, de risicofactoren alsmede de behandelcriteria en de behandeling van ROP ge_nventariseerd. Dit heeft mede geresulteerd in een nieuwe richtlijn geschikt voor allen die betrokken zijn bij de screening (oogartsen, neonatologen, kinderartsen, verpleegkundigen en de ouders) en een uniforme, landelijke ouder-informatie folder. Het uiteindelijke doel van de NEDROP studie is om blind- en slechtziendheid door ROP te doen afnemen in Nederland. Show less
Consumers have many possibilities to undergo a form of screening to acquire health information via the Internet or otherwise by purchasing health checks, medical check-ups, total body scans and... Show moreConsumers have many possibilities to undergo a form of screening to acquire health information via the Internet or otherwise by purchasing health checks, medical check-ups, total body scans and direct-to-consumer (DTC) genetic tests. More and more providers place screenings on the market before they have been assessed properly. In the Netherlands the Act on population screening ( __Wet op het bevolkingsonderzoek__) sets strict quality criteria for screening. In accordance with this Act a licence is required for offering and performing screening with ionising radiation or for detecting (risk factors of) cancer and untreatable diseases. This system, which aims to protect individuals against health damage and also to ensure patients (rights), wards off __commercial screening__ of the Dutch market. In society this meets with criticism. Individuals increasingly perceive the limited access to screening as an unnecessary restriction of their self-determination. However, the Dutch State has a special responsibility regarding the health of individuals. This thesis focuses on the following central question: __What are the normative criteria for the access to and supply of genetic screening from constitutional and European law perspectives?__ As a corollary the author will explore what this means for the Dutch legal framework regulating genetic screening, particularly DTC genetic tests. Show less
The aim of preventive care traditionally refers to measures taken to prevent disease and injury. However, for vulnerable older people the aim to maintain independence and wellbeing seems to be... Show moreThe aim of preventive care traditionally refers to measures taken to prevent disease and injury. However, for vulnerable older people the aim to maintain independence and wellbeing seems to be appropriate. Although a 'gold standard' to stratify for vulnerability in the general older population is lacking, GPs share the same concept of vulnerability for somatic and psychological patient characteristics. However, within the vulnerable older population, there is no evidence (except for physical activity) that a collective screening approach, with a standardized intervention program, will be the most appropriate way to contribute to the maintenance of independence and wellbeing. Moreover, since te majority of vulnerable older people already receive medical care for their chronic disease(s), more benefit can be expected from improving the individual regular care than from a separate screening program. According to GPs, te main topic in the prevention of disease in the general older population is (apart from national programs) cardiovascular risk management. A collective approach, consisting of high risk stratification and treatment, appeared to be possible even at high age. Show less
