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
With the rising global health burden of aortic valve diseas and growing awareness of the consequences of severe AS, more patients are expected to be referred for aortic valve replacement.... Show moreWith the rising global health burden of aortic valve diseas and growing awareness of the consequences of severe AS, more patients are expected to be referred for aortic valve replacement. Multimodality imaging remains of paramount importance for proper patient selection, determining optimal timing of intervention and in the evaluation of therapy. For risk stratification and defining optimal timing of intervention, conventional and advanced echocardiography and computed tomography are crucial. Conventional echocardiography can be used to assess extra-aortic valvular cardiac damage in patients with severe AS. On top of conventional echocardiography, advanced echocardiography can provide additional insights. Left ventricular GLS by speckle tracking echocardiography has been suggested as a more sensitive marker of LV systolic dysfunction. LV GLS may be of help to define more optimal timing of intervention in asymptomatic patients with severe AS. Also, LV GLS may be of incremental value on top of conventional echocardiographic parameters for the assessment of cardiac injury. For the evaluation of prothesis function and durability after aortic valve implantation and detection of possible (late) complications, echocardiography is the mainstay imaging modality. Also, both conventional and advanced echocardiography can provide additional information on the effects of therapy on LV function and remodelling. Show less
Tricuspid regurgitation is a disorder in which the tricuspid valve does not close properly, causing backward flow of blood. It is a heterogeneous disease which can be classified based on the... Show moreTricuspid regurgitation is a disorder in which the tricuspid valve does not close properly, causing backward flow of blood. It is a heterogeneous disease which can be classified based on the underlying mechanism. The large majority of tricuspid regurgitation is secondary to conditions that cause tricuspid annulus dilation or leaflet tethering due to right ventricular or right atrial dilation. Part I focusses on the relationship between secondary tricuspid regurgitation and the right ventricle. Right ventricular dysfunction was demonstrated to be an important prognostic parameter in patients with secondary tricuspid regurgitation. A new staging system, incorporating right ventricular dysfunction and symptoms of right heart failure, may be valuable for risk stratification in patients with secondary tricuspid regurgitation. Patients who received tricuspid valve annuloplasty during left-sided valve surgery developed less right ventricular dilation and had less severe tricuspid regurgitation at long-term follow-up.Part II focusses on tricuspid regurgitation in specific patient populations: men and women, patients with atrial fibrillation and patients with obesity. An etiology-specific approach to detection and management of significant tricuspid regurgitation may be the most effective way to improve prognosis in all patients. Treatment of patients with tricuspid regurgitation remains challenging, but is developing rapidly with ongoing research. Show less
Severe secondary MR is known to be associated with a worse prognosis, whilst the effect of reducing MR on prognosis has still been unclear. The question remains what influences the prognosis of... Show moreSevere secondary MR is known to be associated with a worse prognosis, whilst the effect of reducing MR on prognosis has still been unclear. The question remains what influences the prognosis of these patients: is it the LV or the valve (i.e. the MR)? Characterization and risk-stratification of patients with secondary MR therefore remains challenging. Until recently the decision to intervene for secondary MR was based also on the LVEF. However, LVEF is subject to many limitations. Advanced echocardiography, such as speckle tracking echocardiography, from which LVGLS could be derived has shown to be of much more diagnostic and prognostic value in various valvular heart disease and is currently being implemented more in valvular heart disease guidelines. This supports the fact that LVGLS can detect LV dysfunction in an earlier stage and therefore guide physicians to refer patients for intervention before it is too late. Also the mitral valve geometry has an important role in the technical feasibility of intervention, but also could elaborate on which specific transcatheter intervention is more appropriate according to their targets (i.e. leaflets, annulus or sub apparatus). Additionally, multimodality imaging remains key in characterization and quantification of secondary MR and may help further risk-stratification. 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
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
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
