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
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
The objectives of this thesis, aimed to reduce overtreatment of ductal carcinoma in situ (DCIS) of the breast, were : 1) to evaluate the risk of underestimation after a diagnosis of DCIS and the... Show moreThe objectives of this thesis, aimed to reduce overtreatment of ductal carcinoma in situ (DCIS) of the breast, were : 1) to evaluate the risk of underestimation after a diagnosis of DCIS and the interrater reliability in the histopathological classification of DCIS, important conditions in order to safely adopt an active surveillance strategy for low-risk DCIS, 2) to investigate associations of clinicopathological factors with the risk of developing ipsilateral invasive breast cancer after treatment of DCIS and 3) to analyze the extent of response of DCIS, adjacent to HER2-positive breast cancer, to neoadjuvant systemic therapy and to investigate associations of clinicopathological factors with DCIS response.We have taken significant steps on the road towards conquering overtreatment of DCIS: by having identified several clinicopathological prognostic factors in pure DCIS, by providing reassuring evidence regarding underestimation in the context of active surveillance, by stressing the need for improvement of interrater reliability in histopathological classification, and by showing that the presence of DCIS adjacent to HER2-positive breast cancer should not preclude the option of breast conserving surgery. Show less
As with all cancer screening programmes, the expected reduction in cancer cases and deaths must be weighed against the burden of screening and possible side effects. The aim of this thesis is to... Show moreAs with all cancer screening programmes, the expected reduction in cancer cases and deaths must be weighed against the burden of screening and possible side effects. The aim of this thesis is to provide insights in consequences of colorectal cancer screening participation from a surgical perspective. We investigated potential harm in terms of serious morbidity from colonoscopy, additional findings on imaging, and psychological impacts following a positive faecal immunochemical test (FIT) result. Second, studies were performed to gain more in-depth insight into surgical referral patterns for benign colorectal lesions and CRC lesions with only submucosal invasion (pT1), thereby contributing to the understanding of whether early diagnosis following CRC screening results in better surgical outcomes. Third, surgical outcomes of screen-detected patients were compared with symptomatic 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
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
