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
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
The aim of this thesis was to define prognostic and predictive biomarkers in colorectal cancer for improved risk stratification and treatment benefit in the individual patient, with the... Show moreThe aim of this thesis was to define prognostic and predictive biomarkers in colorectal cancer for improved risk stratification and treatment benefit in the individual patient, with the introduction of precision medicine in the near future as the ultimate goal. By __definition, precision medicine is a multi-faceted approach to medicine that integrates molecular and clinical research with patient data and clinical outcome, and places the patient at the center of all elements. This thesis is divided in three parts. In Part one prognostic biomarkers in CRC are investigated, in Part two aspirin treatment and related predictive biomarkers for aspirin treatment benefit in colon cancer are investigated and finally, in Part three, the use of predictive and prognostic biomarkers in clinical practice, its utility and the road to precision medicine are discussed. Show less
Growth and progression of cervical carcinoma is dependent on a complex interaction between cervical carcinoma cells and composition of the extracellular matrix. For local progression as well as... Show moreGrowth and progression of cervical carcinoma is dependent on a complex interaction between cervical carcinoma cells and composition of the extracellular matrix. For local progression as well as metastasizing, the extracellular matrix needs to be rearranged creating space for tumor cells to expand and angiogenesis to secure supply of nutrients and oxygen and removal of waste products. The net result of all contributing factors will lead to either progression or degradation of cervical cancer. In this thesis the role of contributing factors is investigated, e.g. cytokines, chemokines, inflammatory cells, the role of extracellular matrix and angiogenesis Show less
This thesis describes the sentinel node procedure in colorectal carcinoma and the possible value of in-depth analysis of this sentinel node. The sentinel node procedure can be successfully... Show moreThis thesis describes the sentinel node procedure in colorectal carcinoma and the possible value of in-depth analysis of this sentinel node. The sentinel node procedure can be successfully performed in colon carcinoma. However, it is not reliable in rectal carcinoma treated with total mesorectal excision after preoperative short-course radiotherapy, which is the current protocol in The Netherlands and other countries. RT-PCR with CEA, on mRNA extracted from paraffin-embedded sentinel nodes, upstages 17 __ 25 % of patients and accurately predicts lymph node status. A 5-year follow-up of the sentinel node procedure in colon carcinoma -with, but even without, in-depth pathological examination- shows excellent results of the patients in de node-negative group with 100 % cancer-specific 5-year survival and 96 % disease-free 5-year survival. These node-negative patients do not need further treatment. The sentinel node procedure can be easily introduced in clinical practice in every clinic, and should be considered for all patients with colon carcinoma. Show less
Uveal melanoma is a highly malignant intraocular tumor with quite homogeneous tumor tissue and a diffuse leukocytic infiltration. In contrast with many other malignancies, the presence of... Show moreUveal melanoma is a highly malignant intraocular tumor with quite homogeneous tumor tissue and a diffuse leukocytic infiltration. In contrast with many other malignancies, the presence of infiltrating macrophages and T cells is associated with a poor prognosis rather than a good one. The clear link between inflammation and this malignancy provides a paradigm for macrophage plasticity and function. Macrophages in uveal melanoma have an M2-like phenotype and are associated with the loss of one specific chromosome - monosomy 3. The central players involved in this process and discussed include macrophages, T lymphocytes, chemokines and cytokines, including the macrophage-attraction molecules. When a tumor acquires the ability to release significant amounts of macrophage-attraction molecules it causes the expansion of a population of myeloid immature cells that may not only help the tumor to suppress immune reactions but also aid in the construction of new blood vessels for tumor growth. A better understanding of the molecular basis of a local myelomonocytic cell population will bring a better understanding of the immunopathology of this disease and will lead to therapeutic interventions in uveal melanoma. This thesis focuses on the roles of the local inflammatory microenvironment in the development and progression of uveal melanoma. Show less
It can be concluded from this thesis that high-grade osteosarcoma is at clinical, pathological and molecular level a heterogeneous disease. To treat high-grade osteosarcoma, neo-adjuvant... Show moreIt can be concluded from this thesis that high-grade osteosarcoma is at clinical, pathological and molecular level a heterogeneous disease. To treat high-grade osteosarcoma, neo-adjuvant chemotherapy should be combined with radical surgery, irrespective the localization. There are only 4 effective cytostatic agents for osteosarcoma treatment: methotrexate, doxorubicin, cis-platin and ifosfamide. Patients with pulmonary metastases should receive surgery in case of resectable disease, whereas the use of chemotherapy is not of proven value. Patients with irresectable metastatic osteosarcoma should be offered phase-I studies, because no response can be expected from other conventional cytostatic drugs. New drugs, such as the monoclonal antibody trastuzumab against HER2 is not supported by us, because we did not find this receptor on osteosarcoma cells. At molecular level, a disturbed Wnt signalling, an abnormal cell c ycle regulation and a disturbed p53/apoptotic pathway was present in osteosarcoma cells. The hypothesis is that failure of the mesenchymal stem cell to differentiate into the osteoblastic lineage, due to abnormal proliferation and lack of differentiation commitment results in chromosomal instability, which is the hallmark of osteosarcoma. In Patients with an inactive Wnt3a/_-catenin signalling the proteasome inhibitor bortezomib might be a candidate drug, to explore its suggested differentiation inducing properties. Show less
The studies presented in this thesis focused on cutaneous CD30-positive lymphoproliferations, particularly on primary cutaneous anaplastic large cell lymphoma (C-ALCL), a distinct type of cutaneous... Show moreThe studies presented in this thesis focused on cutaneous CD30-positive lymphoproliferations, particularly on primary cutaneous anaplastic large cell lymphoma (C-ALCL), a distinct type of cutaneous T-cell lymphoma (CTCL). In the initial staging of patients with an anaplastic large cell lymphoma first presenting in the skin, bone marrow examination has limited value (chapter 4). C-ALCL patients usually have an excellent prognosis, although some patients follow an unfavorable course. These patients often have extensive disease with leg involvement (chapter 2). Several phenotypical markers have been reported to aid in the differentiation between different types of cutaneous CD30-positive lymphoproliferations, however, TRAF1, MUM1 and BCL2 are not useful for this purpose (chapter 3). The miRNA expression profile of C-ALCL does show differences with that of tumor stage mycosis fungoides (MF), another type of CTCL, suggesting a different contribution to the pathogenesis of these lymphomas (chapter 5). In patients with transformed MF, several parameters can be used as prognostic factors, including CD30 expression, folliculotropic MF, extent of skin lesions and extracutaneous transformations (chapter 6). Show less
CRT has evolved as a successful treatment strategy in selected patients with drug refractory heart failure. Evidence of large clinical trials established the beneficial effects of CRT in addition... Show moreCRT has evolved as a successful treatment strategy in selected patients with drug refractory heart failure. Evidence of large clinical trials established the beneficial effects of CRT in addition to optimal medical treatment on both morbidity and mortality. Nonetheless, about 30% of patients do not demonstrate response to CRT. Several patient characteristics have a strong influence on both response at 6 months follow-up and prognosis during long-term follow-up. In addition to these patient characteristics, the position of the LV pacing lead in relation to the site of latest activation and potential scar tissue may have a great influence on outcome. Integration of patient characteristics, LV lead position with information on LV dyssynchrony and scar tissue may help to improve patient selection and response to CRT. It is not unlikely that the favorable effects of CRT will be extended to other patient groups in the coming years. These groups include asymptomatic (NYHA class I) patients, patients with a narrow QRS complex (<120 ms) or patients with heart failure but preserved LVEF (__45%). CRT also seems to improve other conditions frequently observed in patients with heart failure. The improved LV systolic function induced by CRT increases cerebral blood flow and also results in stabilization of renal function. Finally, patients with severe functional MR and high operative risk also derive benefit from CRT. Perhaps CRT may one day be used as an effective treatment strategy in these patient groups. Show less
The general introduction of this thesis gives an overview of the epidemiology of ST-segment elevation myocardial infarction (STEMI) and the current focus of the guidelines concerning the management... Show moreThe general introduction of this thesis gives an overview of the epidemiology of ST-segment elevation myocardial infarction (STEMI) and the current focus of the guidelines concerning the management of these patients. In the past decades changes in the treatment and outcome of STEMI patients have influenced the risk stratification of this population and the focus has been shifted to the evaluation of infarct size. Furthermore, the role of echocardiography in the risk stratification after STEMI is addressed including the evolving echocardiographic techniques. The aim of the current thesis was to evaluate the clinical characteristics of this contemporary population of STEMI patients and to assess the value of echocardiography for the improvement of the risk stratification of these patients. First, the current population of STEMI patients treated with primary percutaneous coronary intervention is described in Part I, where clinical parameters are being evaluated in relation to short- and long-term outcome. In Part II, the role of conventional and novel echocardiographic techniques is being evaluated for the assessment of left ventricular (LV) systolic function and the importance of LV diastolic function is addressed in Part III. Finally, the role of echocardiography in patients with chronic ischemic heart disease is studied in Part IV. Show less
This thesis describes the diagnostic management, short term prognosis and long term complications of pulmonary embolism. We have validated a newly derived clinical decision rule, the revised Geneva... Show moreThis thesis describes the diagnostic management, short term prognosis and long term complications of pulmonary embolism. We have validated a newly derived clinical decision rule, the revised Geneva score, for predicting the pre-test probability of having acute pulmonary embolism. This rule can be used in clinical practice to managge patients with suspected pulmonary embolism. We further found that NT-pro-BNp levels are the best predictors of benign clinical course, when compared to troponin and D-dimer levels, and CT derived maesurements of the right ventricular volume and function. Finally, we demonstrate that although the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism is very low, the long term clinical course after pulmonary embolism is complicated frequently by mortalitity, recurrent venous thombosis, newly diagnosed maligancies and arterial cardiovascular events. Show less
Despite major improvements in immunosuppressive agents and a reduction in acute rejection episodes, there has been no significant improvement in overall kidney transplant survival beyond the first... Show moreDespite major improvements in immunosuppressive agents and a reduction in acute rejection episodes, there has been no significant improvement in overall kidney transplant survival beyond the first 3 months after transplantation1. Up to sixty percent of all renal allografts are lost within 10 years after transplantation. Apart from death, the main cause of graft loss is chronic allograft nephropathy (CAN)2;3. CAN is characterized by the deterioration of graft function and structure as a consequence of immunological processes (i.e., chronic rejection) and/or a variety of often co-existing non-immunological factors that include: advanced donor age, ischemic injury to the graft during implantation, chronic calcineurin inhibitor induced nephrotoxicity, hypertension, reflux, infection, increased ureteral pressure, and glomerular hyperfiltration. The initial histological characteristics of CAN are the presen ce of tubulointerstitial fibrosis and tubular atrophy (IF/TA)4. Over time, additional features evolve including vasculopathy, glomerulopathy, and glomerulosclerosis. Unfortunately, functional studies significantly underestimate the incidence of graft injury. One of the largest studies with repeated protocol biopsies clearly showed that CAN is a process that develops early after transplantation. Up to 94% of protocol biopsies obtained one year after renal transplantation exhibited IF/TA in patients with stable graft function5. In addition, Solez et al. have shown that 2 years after transplantation two thirds of all kidney allografts exhibit CAN without deterioration of renal function 6. The most significant predictors for the development of CAN were the occurrence of acute rejection episodes, acute calcineurin toxicity, and the initial quality of the transplanted kidney. Often, the first clinical sign of CAN is the progressive decline in renal function as measured by increasing serum creatinine or the development of overt proteinuria2. Although renal function correlates with glomerulosclerosis, unfortunately the clinical tests currently available for renal function are not sensitive enough to detect early lesions associated with CAN. Inulin and iothalamate clearances are more reliable and precise techniques for measuring renal function, but they are expensive, difficult to perform, and time consuming; thus they are unlikely to become routine in daily practice. This situation has given rise to intensified interest in studies using protocol biopsies that may identify surrogate markers and provide insight into the development of CAN. Ideally, a surrogate marker is minimally invasive and amenable to frequent assessment. However, the least invasive markers in blood or urine samples can only identify qualities and quantities of structural lesions i n the renal allograft that typically occur in the advanced stages of disease. Currently, protocol biopsies are considered __the gold standard__ for discovering novel surrogate markers that better predict long-term outcomes for patients. In this thesis, we focused on identifying molecular markers in kidney transplant biopsies that could predict long-term allograft survival. The identification of molecular markers provides a means for superior monitoring of the transplant condition in order to maintain drug efficacy and limit drug-related nephrotoxicity. Moreover, potential new therapeutic targets might be discovered for developing therapies that improve long-term graft survival. Show less
Non-haematogenic tumours arising primarily in the bone are rare. They are classified based on their histomorphology. Within the osteofibrous group the spectrum ranges from benign, exclusively... Show moreNon-haematogenic tumours arising primarily in the bone are rare. They are classified based on their histomorphology. Within the osteofibrous group the spectrum ranges from benign, exclusively fibrous lesions to high-grade osteosarcoma. These osteofibrous tumours show histological variability in a given entity as well as similarities between entities. The purpose of this thesis was to reveal the meaning of the phenotypic spectrum of osteofibrous tumours. In retrospect, the histological subtype of osteosarcoma is a predictive factor for response to chemotherapy, late relapse and risk of a hereditary cancer syndrome, but not for survival. However, the poor histological response of chondroblastic osteosarcomas to neo-adjuvant chemotherapy did not translate in a lower survival rate. On the other hand, overlapping histological and/or clinical parameters between certain tumour entities such as for example adamantinoma and Ewing sarcoma, and desmoplastic fibroma of bone and desmoid type fibromatosis of soft tissue, does not justify to classify these tumours as part of one disease entity as was demonstrated in this thesis. Thus, the correct classification, reclassification of known entities on new insights and sub-classification on phenotypic differences, when related with biological behaviour, has implications for clinical practice and disease management, and contributes to optimal patient care. Show less
Prognostic factors are used for making treatment decisions regarding adjuvant systemic therapy. The major prognostic variables that are used in clinical practice are the number of positive axillary... Show morePrognostic factors are used for making treatment decisions regarding adjuvant systemic therapy. The major prognostic variables that are used in clinical practice are the number of positive axillary lymph nodes and tumour size. A number of other variables are associated with disease recurrence and survival as well. In particular UPA and PAI-1 appear to be strong prognostic variables. No differences in prognostic value of oestrogen receptor and progesterone receptor detected by immunocytochemical assay or enzyme immuno assay were found. In the study presented no significant association between mitotic counts and disease recurrence or survival was found, which was explained by the favourable tumour characteristics of the group of patients and the associated low number of events. Several tools have been developed to make individualised estimates of baseline prognosis and absolute survival benefit of adjuvant systemic therapy. Two of these tools, Adjuvant! and Numeracy, were compared. Adjuvant! was the preferred prognostic model. The administration of adjuvant chemotherapy concurrently with radiotherapy appeared too toxic. As anthracyclin-containing regimens have become standard for adjuvant chemotherapy in early breast cancer which are considered more toxic than the regimens studied the concurrent administration of adjuvant chemotherapy and radiotherapy is dissuaded. Show less
Primary cutaneous lymphoma form a seperate group of non-Hodgkin lymphoma. Apart from the usual nodal presentation of a lymphoma, less frequently a lymphoma develops in an extranodal site. The skin... Show morePrimary cutaneous lymphoma form a seperate group of non-Hodgkin lymphoma. Apart from the usual nodal presentation of a lymphoma, less frequently a lymphoma develops in an extranodal site. The skin is, after the gastrointestinal tract, the most frequent site of extranodal lymphoma. If the skin is the primary site of involvement, i.e. no extracutaneous sites are involved at diagnosis, these lymphomas are called primary cutaneous lymphoma. In this thesis different types of primary cutaneous lymphoma are evaluated and discussed. In chapter 2 a large group of primary cutaneous CD30+ lympoproliferations is described and compared with a group of systemic CD30+ ALCL with skin localisations. Lymphomatoid papulosis and primary cutaneous CD30+ CTCL are closely related conditions and should be considered as a spectrum, with a comparable, excellent, prognosis. Multiagent chemotherapy (MAC) could not induce long lasting remissions, in fact all patients treated with MAC developed one or more (cutaneous) relapses. Therefor MAC is only indicated in case of extracuteneous localisations. In chapter 3 a group of CD30-negative T-cell lymphomas presenting in the skin that could not be diagnosed as MF, SS or SPTL are evaluated. In this group there were few survivors, apart from a rare group of patients with primary cutaneous lymphoma with small-medium sized CD4+/CD8-neoplastic T-cells (less than 30% large cells). In particular, patients with localized disease had an excellent prognosis. In chapter 4 haematological malignancies presenting in the skin and expressing CD56 were collected, both from the Dutch cutaneous lymphoma group and literature. In general these types of malignancies had a poor prognosis, except for patients with primary cutaneous CD30+ LPD, that showed a similar good prognosis as CD56-negative cases. Most cases belonged to the group of nasal-type NK/T-cell lymphoma and the group of CD4+, CD56+ hematodermic neoplasm (formerly also designated as blastic NK-cell lymphoma. In addition, CD56 was expressed in some SPTL, rare primary cutaneous CD30-negative large T-cell lymphomas, skin localisations of acute myeloid leukemia and CD30+ CTCL. In most of these groups CD56 expression did not affect prognosis. However, in SPTL CD56 expression proved a marker for gamma/delta T-cell origin and these cases showed a poorer prognosis as compared to SPTL with an alpha/beta phenotype (that were usually CD56-negative). In the new WHO-EORTC classification the category of SPTL only includes cases with an alpha/beta-positive phenotype, whereas cases with a gamma/delta positive phenotype are included in the provisional category of cutaneous gamma/delta-positive T-cell lymphoma. In chapter 5 a rare case of lymphomatoid papulosis with CD56-expression was presented and the frequency of co-expression of CD56 in primary cutaneous CD30+ LPD was analyzed. CD56 expression was found in approximately 10% of CD30+ LPD (both LyP and primary CD30+ CTCL). However, these CD56+ cases were not found to have a different prognosis from CD56 negative cases. In chapter 6 a European multicenter study on primary cutaneous large B-cell lymphomas is presented. Patients with primary cutaneous large B-cell lymphoma of the leg showed a poorer prognosis as patients with primary cutaneous follicle center cell lymphoma (PCFCCL). Moreover, round cell morphology was identified as a poor prognostic parameter. Although this was closely related to presentation on the leg(s), also in the group of PCFCCL the presence of a predominance of cells with round nuclei (centroblasts and immunoblasts) was associated with a poorer prognosis. The results of this study contributed to a new category in the WHO-EORTC classification, designated primary cutaneous large B-cell lymphoma (PCLBCL), leg-type, indicating that both patients with the classical presentation on the leg(s) as patients showing the same morphology and immunophenotype (bcl-2+, Mum-1/ IRF4+) on other sites are included in this group. Presentation with multifocal lesions proved to be a poor prognostic parameter for PCLBCL-leg-type, but not for PCFCCL. In chapter 7 treatment results in multifocal primary CBCL were analyzed. The main question in this study was if PCFCCL presenting with multifocal skin lesions should be treated with MAC. The study showed that MAC is only indicated in PCLBCL, leg-type and not in (multifocal) PCFCCL. Radiotherapy on multiple sites appeared equally effective as MAC in these patients. In chapter 8 the frequency of CNS-involvement in CBCL patients of the Dutch cutaneous lymphoma group. was evaluated. The frequency was low. Only 4/140 patients with a primary CBCL developed CNS involvement in the course of their disease. Interestingly 3 of these 4 patients were PCFCCL, a lymphoma usually with an excellent prognosis. Only 4 disease related deaths were reported in this group of which 3 with CNS involvement. The reason for this relatively high prevalence of CNS involvement in PCFCCL is unclear. The studies presented in this thesis have provided important information, which has contributed to the recent development of the WHO-EORTC classification. Moreover, they have contributed to updated guidelines for the treatment of the different types of primary cutaneous lymphomas, as presented in TABLE 2 in chapter 9. Show less
