Mucosal melanomas (MM) are malignant tumours arising from melanocytes located at the mucosal lining of the head and neck region or the respiratory, gastrointestinal, anorectal, or genital tract.... Show moreMucosal melanomas (MM) are malignant tumours arising from melanocytes located at the mucosal lining of the head and neck region or the respiratory, gastrointestinal, anorectal, or genital tract. Due to the low incidence the disease is still poorly understood and management is mostly based on guidelines of cutaneous melanoma (CM). Survival of patients with MM is poor and regardless of stage is worse than that of CM. This is explained by the advanced stage at diagnosis and high recurrence rates of MM. Moreover, whilst immunotherapeutic agents have revolutionized the therapeutic landscape in CM, in MM, the efficacy is low and survival has not improved since the introduction of these therapies.The MM located at the vulva (VMM) account for 60% of the female genital tract MM and together with the head and neck region are the most common locations of MM. In line with the MM located at all other locations, prognosis is poor. Whilst the majority of the patients is diagnosed with local disease, the aggressive course of disease is demonstrated by the high recurrence rates with short time to recurrence with a median overall survival of 33 months. To improve outcomes in MM, there is a critical need for clinical trials specifically designed for this disease and international collaboration. Show less
The first part is focused on early recognition of Rheumatoid Arthritis (RA). Two large early arthritis recognition clinics were started in Leiden and Groningen. The results showed that this... Show moreThe first part is focused on early recognition of Rheumatoid Arthritis (RA). Two large early arthritis recognition clinics were started in Leiden and Groningen. The results showed that this initiative reduces the GP-delay significantly. Secondly, it was investigated whether an association between shorter symptom duration and a beneficial outcome in RA exists. Furthermore, it was questioned whether there was a confined period in which the start of DMARD therapy has a more beneficial effect. In the third part of the thesis certain disease features/ symptoms were investigated in more detail to assess if they had a prognostic or diagnostic value in arthralgia, early arthritis or RA patients. Finally, in the last part focused on mortality in RA. It was observed that patients that were treated early and with aggressive DMARD therapy had no increased mortality compared to the Dutch general population. In conclusion, the current thesis showed that lots of progress was made in the attempt to recognize rheumatoid arthritis earlier, that a therapeutic window of opportunity exits and that with prompt initiation of adequate DMARD-treatment RA should no longer be tagged as a chronic condition but that drug-free remission and improved survival are both achievable goals. 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
Insects are the most diverse group of animals on earth. They inhabit nearly all terrestrial habitats. One of the factors underlying this success is the ability of insect eggs to survive in adverse... Show moreInsects are the most diverse group of animals on earth. They inhabit nearly all terrestrial habitats. One of the factors underlying this success is the ability of insect eggs to survive in adverse conditions. For a long time the ability to survive these adverse conditions has been attributed to maternal investment in the form of a protective eggshell. In this thesis, I show that contrary to common belief, insect eggs are far from helpless. The insect egg itself develops a cellular layer around the egg called the serosa. This serosa protects the developing embryo from dehydration which enables it to survive in dry habitats. The serosa furthermore protects against infection, mounting an impressive immune response upon the entry of bacteria in the egg. The data presented in this thesis show the importance of the serosa in the survival of the insect egg. I propose that this multifunctional serosa contributed to the great success of insects. Show less
Hip replacements using a metal-on-metal (MoM) bearing surface were reintroduced with the promise of low wear rates and easy revision in case of the resurfacing design. Although initially mid-term... Show moreHip replacements using a metal-on-metal (MoM) bearing surface were reintroduced with the promise of low wear rates and easy revision in case of the resurfacing design. Although initially mid-term results were promising, local adverse soft tissure reactions to metal debris were detected around the year 2008. We studied the prevalence of these adverse reactions, known as pseudotumors, and analysed how well these could be identified with Metal Artefact Reducing Sequence Magnetic Resonance Imaging (MARS-MRI). We also studied the natural development of these pseudotumors and evaluated if measuring pseudotumor size in a clinical setting waa accurate. Based on metal ion analysis, symptoms and MARS-MRI scanning of a large cohort of MoM hip resurfacing patients, we proposed a treatment flow chart for these patients. Show less
Knowledge of physiological changes in renal function, EPO and haemoglobin level and their impact at old age are essential for clinicians especially those working with older patients. The results of... Show moreKnowledge of physiological changes in renal function, EPO and haemoglobin level and their impact at old age are essential for clinicians especially those working with older patients. The results of the studies presented in this thesis provide more insight in the physiological aspects of age related decline in renal function and the relation with erythropoietin production and the maintenance of haemoglobin levels at old age. Furthermore, these results allow us to speculate about the predictive value of renal function, EPO and haemoglobin as markers of mortality in a clinical population of oldest old patients. Proper knowledge of these markers could contribute to increased attention of clinicians for the increased mortality risk of their oldest old patients. Furthermore, knowledge of these markers could be helpful in tailor made medicine, individual prognostication and decision making procedures, in the oldest old patients. Show less
Colorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain.... Show moreColorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain. For example among certain subgroups of patients, such as elderly patients and patients with comorbidities. Besides, inequalities in the quality of care between European countries remain. Quality control on surgery, radiotherapy, and pathology have been introduced in trials, followed by incorporation in the general care. Another option to incorporate improved quality of care is via an audit structure in which hospitals and clinicians can improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group. Although all these audit structures have achieved excellent results within countries, differences in outcome between European countries remain. A next step will b e to combine these national audits. The combined audit structure will provide a network in which __best practices__ can be compared and identified, including for certain subgroups, which has been initiated as European Registration of Cancer Care (EURECCA). To achieve optimal care for all patients, multidisciplinary care is the only way. By comparing multidisciplinary audit structures across countries, optimal treatment strategies within subgroups can be identified Show less
The aim of this thesis was to identify new risk factors for first and recurrent venous thrombosis of both the upper and lower extremity, and assess the incidence of recurrence and mortality after a... Show moreThe aim of this thesis was to identify new risk factors for first and recurrent venous thrombosis of both the upper and lower extremity, and assess the incidence of recurrence and mortality after a first venous thrombosis. An overview was provided of the current literature on risk factors and treatment for a first venous thrombosis of the upper extremity (chapter 2). We investigated the association between levels of coagulation factors, blood group and a first venous thrombosis of the upper extremity (chapter 3), and studied risk factors for a recurrent event in patients with a first venous thrombosis of the upper extremity (chapter 4). Furthermore, we studied the association between venous thrombosis and long-term mortality (chapter 5). In this study we found that patients with thrombosis died more of chronic obstructive pulmonary disease (COPD) than expected from population figures. COPD was found to be a risk factor for a first venous thrombosis in chapter 6. We studied the incidence of recurrent venous thrombosis, as well as sex, age and an idiopathic first venous thrombosis as risk factors for recurrence (chapter 7). Body height was studied as a risk factor for both first and recurrent venous thrombosis in combination with mobility (chapter 8). 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
Colorectal cancer (CRC) is the second leading cause of cancer death in the Netherlands and the fourth worldwide. Matrix metalloproteinases (MMPs) are involved in the process of colorectal cancer... Show moreColorectal cancer (CRC) is the second leading cause of cancer death in the Netherlands and the fourth worldwide. Matrix metalloproteinases (MMPs) are involved in the process of colorectal cancer development and progression. MMPs are capable of degrading the extracellular matrix components of the intestinal basement membrane and facilitate invasion into the deeper layers of the bowel wall, lymph nodes and/or blood vessels. Furthermore, they are implicated in several processes in the microenvironment of colorectal cancer, like angiogenesis, cell death and inflammation. In this thesis, the focus is on the clinical impact of matrix metalloproteinases (MMPs) in the different stages of colorectal cancer development and metastasis. MMP-7, -8 and -9 were shown to be involved in the early stages of colorectal cancer development, whereas MMP-2 levels were only increased in cancer tissue but not in precancerous lesions. Furthermore, MMP-2, MMP-7 and MMP-9 were identified as predictors of outcome in patients with colorectal carcinoma, both at genetic (SNP) and protein level. The increased knowledge of the role of MMPs in the various stages of CRC might contribute to further development of specific anti-MMP therapies in the future. Show less
Colon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival)... Show moreColon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival) for stage IV patients and excellent (more than 90% 5 year survival) for stage I patients. The prognosis of patients with stage II varies between 80 and 60% 5-year survival. The causes of this variation remain unclear. Furthermore, the prognosis of patients with stage III has improved significantly, reaching 70% 5-year survival, since the introduction of adjuvant chemotherapy. However, still 30% of the patients with stage III disease that do not respond to chemotherapy. Therefore, reliable predictive and prognostic markers in stage II and III colon carcinoma are necessary to be able to elucidate whether a patient is going to respond to therapy or not and to be able to offer personalized treatment. In this research project, we aimed to identify predictive markers of therapy response in stage III disease and prognostic markers in stage II and III colon carcinoma. The first three chapters focus on the value of known single nucleotide polymorphisms (SNP) in genes involved in the activation, metabolism of chemotherapeutic drugs like 5-fluorouracil and oxaliplatin as well as in the repair of DNA damage caused by these drugs as predictive markers for therapy response. In the remaining chapters , the focus is placed on the identification of molecular prognostic markers in stages II and III. Several mutations in known cancer driver genes and genes involved in signal transduction have been studied. Show less
An intriguing question with regard to ageing research is why some people age successfully and why others are burdened with chronic diseases and functional disability. Researchers aim to identify... Show moreAn intriguing question with regard to ageing research is why some people age successfully and why others are burdened with chronic diseases and functional disability. Researchers aim to identify the candidate determinants associated with the preservation of vitality during a long life course. In this thesis the study of candidate determinants of muscular and functional vitality in a cohort of oldest old (85+) participants is described. The first part of this thesis focuses on the functional phenotype with handgrip strength, gait speed and functional ability as the parameters of this functional phenotype. The second part of this thesis focuses on candidate determinants of muscle weakness in oldest old people, such as blood pressure, insulin like growth factor-1, and cytokine production capacity. The results of the studies in this thesis allow us to speculate about the predictive value of functional measurements as markers of vitality in a clinical population of oldest old patients. Use of these markers of vitality could contribute to increased vigilance in clinicians for increased risk of health problems in their very old patients. Furthermore, these vitality markers could be helpful in individual prognostication and decision making in very old patients who are faced with serious illnesses. Show less
Large variation between hospitals and pathology laboratories was demonstrated in adherence to the guidelines. This is associated with type and volume of hospitals and pathology laboratories.... Show moreLarge variation between hospitals and pathology laboratories was demonstrated in adherence to the guidelines. This is associated with type and volume of hospitals and pathology laboratories. However, not all variation could be explained by these characteristics. The aim of this thesis was to identify factors influencing quality of care by investigating the variation in guidelines adherence of patients with colon and rectal cancer in the Netherlands. Considerable variation in lymph node evaluation between hospitals and pathology laboratories was revealed leading to suboptimal staging and potentially inaccurate treatment plans. Furthermore, large differences between hospitals were found in treatment according tot the guidelines. Based on the results of this thesis, it can be conclude that a part of the variation is associated with type and volume of hospitals and pathology laboratories. However, the large differences between individual hospitals suggests that these characteristics do not account for all variation. Therefore, further research is necessary to identify best practices and analyse factors which influence quality of care and outcome. Show less
Assessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to... Show moreAssessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to completely reverse once patients reach dialysis. b) Specific additional problems related to chronic kidney disease, in particular protein-energy wasting, may act as “competing risk”, overshadow effects and interfere in various hormonal regulations. c) In advanced chronic kidney disease, the pattern and composition of risk is changing. The aim of this thesis is to 1) Detect specific effects of metabolic alterations in dialysis patients 2) Provide explanations for conflicting results in the literature 3) Provide a rationale for novel interventions. In this thesis, the metabolic status of dialysis patients is adressed and its consequences for the decline in residual kidney function, cardiovascular events and survival. The metabolic status includes alterations in nutritional and hormonal status, focussing on: lipid metabolism, diabetes mellitus type 2, obesity, the role of adipokines, specific effects of protein-energy wasting, and Vitamin D status with the clinical consequences. The investigations are performed in two large cohorts of dialysis patients, the 4D and NECOSAD studies (The German Diabetes and Dialysis Study and The Netherlands Cooperative Study on the Adequacy of Dialysis). Show less
This thesis focuses on quality assurance of rectal cancer treatment, in particular of the surgical treatment. Both oncological short-term and long-term outcome parameters are studied, but also... Show moreThis thesis focuses on quality assurance of rectal cancer treatment, in particular of the surgical treatment. Both oncological short-term and long-term outcome parameters are studied, but also other end-points which are important for quality assurance are investigated, such as anastomotic leakage and stoma reversal. The introduction of total mesorectal excision (TME) surgery resulted in an improved survival of patients with rectal cancer. However, survival of the elderly patients and patients treated with an abdominoperineal resection improved less. For frail elderly patients, postoperative mortality is an important competitive risk factor and other treatment schedules might be more appropriate. The abdominoperineal resection itself was associated with a nonradical resection, decreased local control and decreased survival compared to patients treated with a low anterior resection. To improve these results, in selected cases preoperative treatment should consist of chemoradiotherapy and/or a widened resection. Anastomotic leakage is a feared complication after colorectal surgery. After surviving this complication, the overall survival rate in the long-term is still reduced. However, oncological outcome was not significantly affected. The presence of a stoma resulted in a lower symptomatic leakage rate. 20% of stomas was never reversed. Standardised postoperative surveillance resulted in an earlier confirmation of the diagnosis anastomotic leakage. Show less
This thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis... Show moreThis thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis of potential improvements in risk stratification and possible treatment adaptation, in order to decrease relapse frequency and disease-related death. Firstly, to study the role of chemokine receptor/ligand interactions in the context of extramedullary leukaemia, we analyzed the homing receptor expression on leukemic blast cells in skin or intestine, peripheral blood and bone marrow of patients with T-ALL en AML, respectively. Secondly, the treatment results of 132 children, who received an allogeneic HLA-identical SCT for acute leukaemia was evaluated, showing the effect of biologically effective TBI dose on relapse risk. Thirdly, to optimize the use of Cyclosporin A(CsA) for adequate Graft-versus-host disease(GVHD) prophylaxis and to avoid drug toxicity, we investigated the pharmacokinetics of CsA in children after SCT, and showed that monitoring CsA exposure early after SCT may provide a tool to influence outcome. Finally, to gain a better understanding of the mechanism of chimerism induction of endothelial and epithelial cells following allogeneic SCT, the occurrence of chimerism in relation to the conditioning regimen, time interval after SCT and development of GVHD was studied. Show less
There is accumulating evidence that the evolutionary trade-off between body maintenance and fertility is also present in humans. Several studies have shown this trade-off in historic data sets.... Show moreThere is accumulating evidence that the evolutionary trade-off between body maintenance and fertility is also present in humans. Several studies have shown this trade-off in historic data sets. Other studies found no evidence for the trade-off. This could, in part, be explained by the fact that the populations under study resided in a modern affluent environment characterized by low mortality and fertility rates, i.e. having past the epidemiologic transition. Lycett et al for instance demonstrated that the trade-off was stronger under conditions of poverty. Accordingly, it has been shown, that the trade-off disappeared in the British aristocracy when environmental conditions markedly improved after 1700 and initiated a demographic transition. Similar trends over time were found in other studies. The objective of this thesis was to test the hypothesis that fertility trades off with early survival in a contemporary population that is still exposed to adverse environmental conditions. Therefore all the studies were performed in the upper east region of Ghana, Africa. The results can be divided into two parts. Part A, Chapters 2, 3 and 4, describes the research population analyzes whether or not the epidemiologic transition has taken place. Part B, Chapters 5, 6 and 7, describes the actual testing of the hypothesis. Show less
The current thesis discusses the use of molecular and biological tumor markers to predict clinical outcome. By studying several key processes in the develepment of cancer as regulation of cell... Show moreThe current thesis discusses the use of molecular and biological tumor markers to predict clinical outcome. By studying several key processes in the develepment of cancer as regulation of cell motility (non-receptor protein tyrosin adesion kinases, FAK, Src and paxillin, Apoptosis (caspase-3 activity and M30 expression) and regulation of cell growth (COX-2 expression). In addition the use of selective COX-2 inhibitors for the treatment of colorectal cancer liver metastases is investigated and discussed. The main outcomes of the thesis are that combined FAK/Src immunohistochemical expression is predictive of tumor recurrence in colorectal cancer, but is not overexpressed in liver metastases. Increased tumor cell apoptosis can have a positive or a negative impact on survival and local recurrence, depending on the location of the tumor in the large bowel . In rectal cancer caspase-3 activity can be used to preoperatively select patients who will not benefit from radiation therapy. COX-2 expression in rectal cancer is only of prognostic significance in irradiated rectal cancer patients, not in non-irradiated. Liver metastases in an animal model show deminished growth in the abcence of COX-2 expression and prostaglandin production. Show less
To improve quality of cancer care treatment-related information is needed. This could be acquired by registries. Since January 1984, the Leiden University Medical Center (LUMC) collects... Show moreTo improve quality of cancer care treatment-related information is needed. This could be acquired by registries. Since January 1984, the Leiden University Medical Center (LUMC) collects prospectively more than 200 relevant clinical and pathological parameters of women with cervical cancer treated in the LUMC. The purpose of this thesis was to use the treatment-related information of this database, to get inside information and to become aware of possibilities for improvement in the current treatment procedures, in order to monitor the quality of treatment. Furthermore, when results of cancer treatment in terms of survival are good it is also important to focus on the sequelae of the treatment. The incidence of lymphedema, urinary and colorectal dysfunction has been reported with variable rates and sexual dysfunction after radical hysterectomy has been shown to occur in about 25% of the patients. Furthermore, a study assessed by vaginal plethysmography, showed that radical hysterectomy seems to be associated with a disturbed vaginal blood flow response during sexual arousal. The second purpose of this thesis was to monitor the sequelae of the treatment of women with a history of early stage cervical cancer in order to have measures in attempts to improve the quality of life. Show less
Cholesteatoma is a benign, gradually expanding destructive epithelial lesion of the temporal bone, often accompanied with inflammation. The complications can be severe, e.g., destruction of the... Show moreCholesteatoma is a benign, gradually expanding destructive epithelial lesion of the temporal bone, often accompanied with inflammation. The complications can be severe, e.g., destruction of the ossicular chain and otic capsule with consecutive hearing loss. Several hypotheses for the pathogenesis of human cholesteatoma have been proposed but are still controversial. In this thesis, protein signaling pathways were investigated which are involved in different aspects of cholesteatoma pathogenesis, such as hyperproliferation, aberrant differentiation, and extra-cellular matrix deposition. In cholesteatoma epithelium increased expressions of those proteins were found which are involved in proliferation (Ki-67), cell cycle arrest (p53, p21), early terminal differentiation (involucrin) and survival (pAKT). The proteins of which the expressions were decreased were those concerning late terminal differentiation (filaggrin) and apoptosis (active caspase 3). Moreover, increased activation of MAPK- and its association with TGF_ cellular signaling cascades were demonstrated. In cholesteatoma stroma, increased extracellular matrix deposition, visualized by accumulation of EDA-Fibronectin, was present. These results were placed in the context of the interconnected signaling processes of wound healing. Concluding: cholesteatoma behaves as a chronic wound in which a persistent inflammation appears to be a contributing factor to its chronicity. Research into pharmacological interventions aimed at control of inflammation is recommended. Show less
