This thesis has shed light on RPL practice and the management of RPL couples in need of counselling towards future pregnancies. Both clinical practice research and prediction research indicate that... Show moreThis thesis has shed light on RPL practice and the management of RPL couples in need of counselling towards future pregnancies. Both clinical practice research and prediction research indicate that there is room for improvements in RPL practice and RPL counselling. We studied quality of care by diving into clinical practice variation and quality of counselling by diving into prediction research.In the absence of effective treatment options that increase live birth rates in RPL couples, counselling towards future pregnancies plays a key role and enables couples to make an informed decision regarding further pregnancy attempts. This will still be present when future treatment options are investigated or discovered, as these models could then evaluate the effects of these treatments on performance of the model. It is therefore of utmost importance that prediction models are well developed and validated for use in clinical practice.In an era of technological advancement bringing societies, researchers and clinicians from all over the world more closely together, it is time to step up and work together, to unify RPL care and to create collaborations that hugely impact RPL research which can lead to high impact publications that can unravel the mysteries of RPL. Show less
Children with immune thrombocytopenia (ITP) show a primary hemostasis defect due to reduced number of platelets (thrombocytopenia). This leads to bleeding. In children, ITP is often transient and... Show moreChildren with immune thrombocytopenia (ITP) show a primary hemostasis defect due to reduced number of platelets (thrombocytopenia). This leads to bleeding. In children, ITP is often transient and self-limiting (transient ITP), but some children show persistent thrombocytopenia or even chronic ITP. Treatment with immune-modulating medication like intravenous immunoglobulins (IVIg) leads to early recovery from thrombocytopenia and prevents bleeding. Unfortunately, treatment is only effective in a part of the patients. This dissertation aims to better understand, explain, and predict spontaneous recovery and favorable treatment outcomes after IVIg in a specific child with ITP. To that end, molecular disease mechanisms are being evaluated and analyzed together with clinical data. The dissertation provides novel data working towards individualized care for children with ITP. This is relevant for communication with the child and caregivers over the expected prognosis, treatment decisions (IVIg), and indications for early additional diagnostic testing for other causes of thrombocytopenia (such as genetic tests). Show less
The studies in this thesis contribute to more accurate risk assessment and prognosis prediction for DCIS and to better response evaluation of IBC treatment.For the Ductal Carcinoma In Situ (DCIS)... Show moreThe studies in this thesis contribute to more accurate risk assessment and prognosis prediction for DCIS and to better response evaluation of IBC treatment.For the Ductal Carcinoma In Situ (DCIS) studies, unbiased cohorts were used within the international Grand Challenge PRECISION consortium, funded by Cancer Research UK and KWF Dutch Cancer Society. DCIS is graded as low-, intermediate-, or high-grade depending on how abnormal the DCIS-cells look like. However, we showed that pathologists often disagree on grade. To overcome this limitation, we found that almost all DCIS scored as non-high-grade by the majority of pathologists express the estrogen receptor (ER) and are negative for the growth factor receptor HER2, whereas high-grade DCIS is mixed in expression for ER and HER2. We also provided insights in the recurrence risks of DCIS after treatment. See also https://cancergrandchallenges.org/teams/precision.The studies on Invasive Breast Cancer (IBC) were performed on a hospital-based cohort. We found for example substantial variation in tumour response evaluation for HER2-positive IBC after pre-operative chemotherapy due to different guidelines used. For accurate outcome analysis, reducing such variation is mandatory. Therefore, we are working on reaching international consensus of response evaluation. Show less
There is a pending need for prognostic and predictive biomarkers in the treatment of patients with colorectal cancer.This thesis describes the prognostic and predictive application of the tumor... Show moreThere is a pending need for prognostic and predictive biomarkers in the treatment of patients with colorectal cancer.This thesis describes the prognostic and predictive application of the tumor-stroma ratio (TSR) in colorectal cancer, focusing on expanding current clinical-pathological standards and combining TSR with other diagnostic parameters. The TSR is a microscopy scoring method performed on hematoxylin-eosin stained tissue slides used for routine pathology assessment, and has proven to be a robust prognostic maker. Here, we investigate whether the TSR also exhibits predictive value with regard to adjuvant targeted therapy in stage II and III colon cancer. Moreover, exploring the value of collagen fiber organization in the intratumoral stroma, as well as combining this parameter with the TSR. Finally, expanding the application of the TSR with radiological diagnostics in rectal cancer. Assessing is there is a correlation between TSR and apparent diffusion coefficient values obtained from diagnostically performed MRI-DWI scans, in order to determine if there is potential with regards to neoadjuvant treatment choices or patient follow-up. Show less
The fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved... Show moreThe fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved identification of patients with an unfavourable prognosis, early in their treatment course, which may facilitate proactive approaches to improve outcomes. We discussed two conceptually distinct constructs of predictors of prognosis in order to improve the identification of patients with an unfavourable prognosis. First, the level of control of the chronic condition as a predictor could reflect to some extent the presence of a multitude of other risk factors. Second, information on early treatment response had better predictive ability for long-term outcomes and so acts as a proxy for treatment effectiveness. Treatment effectiveness depends on different aspects e.g. adequateness of initial treatment and/or drugs, the mutual trust between clinician and patient and behavioral aspects such as treatment adherence. Treatment response adds an insight that can be acted upon; guiding personalized decisions in the treatment plan. In conclusion, this thesis leads to improvement of personalized medicine and thereby could increase the efficient use of healthcare resources, with the early identification of patients at risk of an unfavourable prognosis. Show less
This thesis describes the detailed method of scoring the tumor-stroma ratio and the different possibilities to use it in routine clinical diagnostics, for different types of cancer. It can be used... Show moreThis thesis describes the detailed method of scoring the tumor-stroma ratio and the different possibilities to use it in routine clinical diagnostics, for different types of cancer. It can be used not only for prognostic purposes, but it might also be useful for predicting the response on neo-adjuvant therapy. As it is an easy and cheap method, based on routine hematoxylin-eosin stained tissue slides used for daily pathology routine, it can be implemented in clinical diagnostics with little effort. Show less
This thesis comprises immunophenotypic and molecular studies in several types of cutaneous lymphomas. These studies provide a better definition of the clinicopathologic entities and provide... Show moreThis thesis comprises immunophenotypic and molecular studies in several types of cutaneous lymphomas. These studies provide a better definition of the clinicopathologic entities and provide adjunctive diagnostic markers that may aid in diagnosis of these patients in routine diagnostics, including TOX expression in cutaneous T-cell lymphomas and MYC expression and MYC rearrangements in cutaneous B-cell lymphomas (CBCLs). Also, the results demonstrate that adverse prognostic factors in systemic lymphomas are not directly transferrable to cutaneous lymphoma patients, including TP63 rearrangements in primary cutaneous CD30+ lymphoproliferative disorders and double hit status in CBCL, underlining the importance of a separate classification system for cutaneous lymphomas. Finally, these studies may have consequences for the management and treatment of patients with cutaneous lymphomas, because of the identification of recurrent molecular alterations that could provide attractive targets for novel therapeutics, including MYD88 and CD79B mutations in patients with intravascular large B-cell lymphomas. Show less
We used the corneal immunosuppressive environment to test the possibility of inserting a Fish Scale-Derived Collagen Matrix in a corneal pocket, and the excellent results and lack of primary... Show moreWe used the corneal immunosuppressive environment to test the possibility of inserting a Fish Scale-Derived Collagen Matrix in a corneal pocket, and the excellent results and lack of primary and secondary immune responses led to a clinical trial, which is currently underway. The immunosuppressive environment of the eye allows the growth of malignant melanocytes which leads to the formation of uveal melanoma. The association between increased numbers of macrophages and lymphocytes in uveal melanoma and an increased development of uveal melanoma metastases suggest an influence of pro-angiogenic macrophages, The relation between loss of BAP1 expression and a very bad prognosis and the influx of leukocytes into the primary tumor, suggests that BAP1 functions as a regulator of inflammation. Further research will focus on the role of BAP1 in the regulation of inflammation in the uveal melanoma microenvironment. Show less
Bone metastases of the long bones can cause pain and pathologic fractures. Local treatment consists of radiotherapy or surgical stabilisation. The most appropriate treatment depends on many factors... Show moreBone metastases of the long bones can cause pain and pathologic fractures. Local treatment consists of radiotherapy or surgical stabilisation. The most appropriate treatment depends on many factors, including the symptoms, the location and extent of the lesion, the wishes and expectations of the patient, and the expected remaining survival. Survival estimation of patients with symptomatic long bone metastases is crucial to prevent over- and undertreatment. This thesis aimed to develop a prognostic model for estimating survival in patients with cancer and symptomatic metastases of the long bones, evaluate current (surgical) treatment modalities and trends, and provide rationale for future prospective randomized trials. As a result, the OPTIModel was developed: an easy-to-use prognostic model that categorises patients into four clinically relevant survival categories based on only three variables (tumour type, Karnofsky Performance Score, visceral/brain metastases). To enable easy use of the model, an app was created (OPTIModel). Futhermore, this thesis shows that almost all treatments of pathologic fractures are based on expert opinion and small, retrospective cohorts, as opposed to large, prospective (randomized) trials, which is interesting in an era of evidence based medicine. This confirms the need of a prospective, multicenter cohort, which was designed and implemented accordingly. Show less
ANCA-associated vasculitis (AAV) is a systemic autoimmune disease which is associated with increased risk of mortality and morbidity. The outcomes of patients with AAV have improved... Show moreANCA-associated vasculitis (AAV) is a systemic autoimmune disease which is associated with increased risk of mortality and morbidity. The outcomes of patients with AAV have improved substantially as a consequence of earlier detection of the disease and more sophisticated therapy regimens. Despite these advances, the disease influences the lives of patients substantially. Therefore, this thesis focused on prognosis and outcomes with the aim to further improve the outcomes of patients with AAV. Show less
Uveal melanoma (UM) is an aggressive intraocular tumor with a high propensity to metastasize. Accurate prognostication is relevant for patient counselling, planning of follow-up and... Show moreUveal melanoma (UM) is an aggressive intraocular tumor with a high propensity to metastasize. Accurate prognostication is relevant for patient counselling, planning of follow-up and stratification of patients in clinical trials. Discoveries of prognostically relevant genetic markers in the last few decades have fuelled the advancement of prognostication in UM considerably. In this thesis, we explored ways of improving genetic prognostication in UM, evaluated the effect of irradiation on chromosome testing, and investigated the association of DNA repair genes and epigenetic regulators with prognosis. We reveal that chromosome markers of high malignancy such as monosomy 3 and chromosome 8q gain are less often observed in patients who die due to metastases at a late stage. We demonstrate that combining the AJCC staging and chromosome 3 and 8q status results in enhanced risk stratification. We provide evidence that supports the taking of biopsies before radiotherapy is applied since chromosome testing seems to fail more often in irradiated tumors. Furthermore, we show that evaluating the role of DNA repair and epigenetics in uveal melanoma can help in unraveling the biology of uveal melanoma and identifying new markers for prognostication. Show less
Vulvar cancer is a relatively rare gynaecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two... Show moreVulvar cancer is a relatively rare gynaecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two etiological pathways: a high risk human papillomavirus (HPV)-dependent route, which has usual vulvar intraepithelial neoplasia (uVIN) as a precursor lesion, and an HPV-independent route, which is associated with differentiated VIN (dVIN), lichen sclerosus, and genetic alterations, such as TP53 mutations. Although most cases of early stage vulvar cancer have a good prognosis, recurrence and rapid tumour progression can oc¬cur. The etiology of HPV positive vulvar cancer is quite well understood, but the HPV in-dependent axis remains to be unravelled. This thesis aims to gain knowledge on the origin of this type of vulvar cancer through the study of two mechanisms: genetic and morphological alterations in vulvar cancer. An overview of the literature on genetic and epigenetic changes in vulvar cancer was made. We designed a mass spectrometry based mutation panel and investigated the prevalence of somatic mutations in a cohort of vulvar cancer patients. Also, markers of Epithelial-to-Mesenchimal-Transition such as spindle cell morphology and L1CAM-expression were studied in a large group of patients. These results were related to a worse survival. https://www.gildeprint.nl/flippingbook/4336-vulvar-squamous-cell-carcinoma/Show less
The studies described in this thesis focused on identifying diagnostic and prognostic markers in tumor stage mycosis fungoides (stage IIB) and Sézary syndrome. Sézary syndrome is a type of... Show moreThe studies described in this thesis focused on identifying diagnostic and prognostic markers in tumor stage mycosis fungoides (stage IIB) and Sézary syndrome. Sézary syndrome is a type of cutaneous T-cell lymphoma, characterized by an erythroderma, lymphadenopathy and malignant T cells in skin, lymph nodes and blood. Especially in the early stages of disease, it can be difficult to differentiate Sézary syndrome from erythrodermic inflammatory dermatoses. The studies identified immunohistochemical (TOX), immunophenotypic (CD7, CD26), molecular (STAT4, TWIST1, DNM3/ PLS3) and epigenetic (CMTM2) markers that are useful as additional diagnostic markers to discriminate Sézary syndrome from erythrodermic inflammatory dermatoses. Of the molecular markers, PLS3 expression was an important prognostic factor in Sézary syndrome. In addition, it was shown that the number of tumors and time interval between tumor formation differs greatly among patients with mycosis fungoides stage IIB and these differences correlate with survival. Patients that developed four or more tumors during the first 6 months after diagnosis of stage IIB have a poor prognosis. Show less
The main objective of this thesis was to evaluate the role of new advanced multimodal CT imaging techniques in acute ischemic stroke.Important findings are that collateral assessment with dynamic... Show moreThe main objective of this thesis was to evaluate the role of new advanced multimodal CT imaging techniques in acute ischemic stroke.Important findings are that collateral assessment with dynamic CT angiography (CTA) better predicts radiological outcome and clinical outcome compared with conventional single-phase CTA. Dynamic CTA also enabled us to study dynamic cortical venous outflow in stroke which had not been described before. We have shown that venous outflow, as assessed with dynamic CTA, is a new predictor of functional outcome in acute large vesselvanterior circulation stroke. By combining the extent and velocity of optimal CVF, we observed a decreased risk of poor outcome in patients with good and fast optimal CVF. Moreover, we have demonstrated an interaction between IAT treatment effect and cortical venous filling which could potentially be useful for future treatment decision-making. Show less
While histopathologic assessment of lymph nodes is a core element of colorectal cancer staging algorithms, the prognostic value of lymph node metastases is restricted. This highlights the need... Show moreWhile histopathologic assessment of lymph nodes is a core element of colorectal cancer staging algorithms, the prognostic value of lymph node metastases is restricted. This highlights the need for approaches that detect occult tumor cells and define their prognostic value, to identify colorectal cancer patients who derive the greatest benefit from therapy. In an attempt to gain insights into prognosis in CRC, this thesis focuses on factors that play a role in the detection or behaviour of occult tumor cells. Especially clinical, pathological and molecular factors of CRC will here be discussed. Show less
Information on prognosis is essential for any physician for providing information to the patient and forms the basis for the decision-making process for therapy. Due to the heterogeneity of the... Show moreInformation on prognosis is essential for any physician for providing information to the patient and forms the basis for the decision-making process for therapy. Due to the heterogeneity of the disease, exploration of prognostic biomarkers in cirrhosis is a challenging, but important aspect of research in the field of chronic liver disease. Besides identifying patients who are at the highest risk of mortality, identification of reliable prognostic biomarkers may also help to improve treatment strategies. The aim of this thesis is to explore novel prognostic biomarkers throughout different stages of chronic liver disease and in acute-on-chronic liver failure (ACLF). Show less
This thesis describes studies that aimed to evaluate and improve the diagnostic work-up and management of pulmonary embolism. Age-adjusted D-dimer testing was found to be an effective and... Show more This thesis describes studies that aimed to evaluate and improve the diagnostic work-up and management of pulmonary embolism. Age-adjusted D-dimer testing was found to be an effective and safe strategy to reduce the need for CT-imaging in elderly patients with clinically suspected pulmonary embolism. Furthermore, this thesis demonstrates that patients with proven pulmonary embolism who fulfil the Hestia criteria can be safely treated at home, without the need for further prognostic assessment. In the vast majority of patients treated for pulmonary embolism, complete thromboembolic resolution had occurred after six months as assessed by CT pulmonary angiography. The last part of this thesis describes that the outcome of cancer patients incidentally diagnosed with pulmonary embolism mimics the outcome of cancer patients with symptomatic pulmonary embolism. Show less
Over the last decade, there has been an exponential development in cardiac imaging technology. Currently, cardiac imaging plays a central role in clinical management and decision making in the... Show moreOver the last decade, there has been an exponential development in cardiac imaging technology. Currently, cardiac imaging plays a central role in clinical management and decision making in the diverse and growing population of patients encountered in daily cardiology practice. Important outcome-related parameters can be derived from these techniques, allowing better risk stratification of patients with ischemic heart disease. Still, the large amount of information provided by the different imaging modalities can be overwhelming and it can be challenging for the cardiologist to make optimal use of all information that is provided by the different modalities. The purpose of this thesis was to optimize the clinical usefulness of specific cardiac imaging modalities for particular patient categories, with the purpose of improving risk estimation in patients with suspected coronary artery disease, patients who suffered from STEMI and heart failure patients. Show less
This thesis consists of a number of studies revolving around the leading research theme, i.e., the derivation of new vectorcardiographic diagnostic & prognostic information from the 12-lead... Show moreThis thesis consists of a number of studies revolving around the leading research theme, i.e., the derivation of new vectorcardiographic diagnostic & prognostic information from the 12-lead electrocardiogram (ECG). Various research questions have been addressed, but most studies use a similar data processing approach, consisting of initial mathematical synthesis of a vectorcardiogram (VCG) from a standard 12-lead ECG, followed by the measurement of general VCG characteristics like maximal QRS- and T vectors, QRS- and T integrals, the spatial QRS-T angle (SA) and the ventricular gradient (VG). Studies focus on methodological as well as on clinical issues, and are discussed in the thesis. Show less
Colorectal cancer is one of the most common diagnosed cancers worldwide, and is the second most important cause of cancer mortality in Europe. The current TNM staging system used at the time of... Show moreColorectal cancer is one of the most common diagnosed cancers worldwide, and is the second most important cause of cancer mortality in Europe. The current TNM staging system used at the time of diagnosis is insufficient, as patients with the same tumor stage show wide variations in survival and tumor recurrence. Therefore, there is a need for identification of new biomarkers in colorectal cancer in order to identify high-risk patients and to guide treatment decision-making. In this thesis, epigenetic markers, including DNA methylation and histone modifications were studied in colorectal cancer patients. Several epigenetic clinically prognostic biomarkers were identified in colorectal cancer in this thesis, including both genome-wide and gene-specific patterns of DNA methylation and histone modifications. Knowledge of tumor biology is of key importance in the development of new therapies and the making of informed treatment decisions. Pathway-focused approaches, as presented in this thesis, provide information regarding possible synergistic interactions of biomarkers. Epigenetic mechanisms are unquestionably tied to the tumorigenic process and should be considered as a grand new source of information not only for identification of prognostic and predictive biomarkers, but also for the development of new, possibly tumor- and therefore patient-specific, anti-cancer therapies. Show less
