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
This thesis focused on risk factors and outcomes based on colorectal cancer auditing and aimed to provide new insights into outcome indicators, treatment modalities, and outcomes in high-risk... Show moreThis thesis focused on risk factors and outcomes based on colorectal cancer auditing and aimed to provide new insights into outcome indicators, treatment modalities, and outcomes in high-risk patients, and to monitor outcomes after implementation of minimally invasive surgery. Nationwide population-based studies with data of the Dutch ColoRectal Audit (DCRA) were used to provide information regarding colorectal cancer care on different levels (hospital, national, and international level) and in specific high-risk subpopulations. Show less
Although clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children,... Show moreAlthough clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children, patients with multiple primary melanoma and those with familial melanoma, are frequently excluded from clinical studies. The studies presented in this thesis were aimed to assess prognostic factors and management of patients with clinically localized melanoma, in particular among the aforementioned special populations. Show less
Survival of patients with colorectal cancer improved markedly over the past decades, as a result of advances in screening, staging procedures, treatment, and surveillance. However, still about 20%... Show moreSurvival of patients with colorectal cancer improved markedly over the past decades, as a result of advances in screening, staging procedures, treatment, and surveillance. However, still about 20% of patients with colorectal cancer develop metachronous metastases and 20% of all patients with colorectal cancer have metastatic disease at diagnosis. Several treatment modalities, such as total mesorectal excision (TME) and preoperative (chemo)radiotherapy for rectal cancer, as well as adjuvant chemotherapy for stage III colon cancer, have been studied extensively and showed to improve cancer-related outcomes. On the contrary, the effectiveness of other treatment modalities including adjuvant chemotherapy for rectal cancer and for stage II colon cancer, and surgery of the primary tumour in incurable metastatic colorectal cancer are still subject of debate. Moreover, there is considerable short-term and long-term morbidity after (chemo)radiotherapy or surgery which should be taken into account. Further defining optimal treatment strategies is therefore of great importance. This thesis focused on improving evidence for treatment modalities that are currently subject of debate for patients with colorectal cancer. This was done using data from randomised controlled trials as well as cancer registry data. Show less
The aim of this thesis was to answer currently unanswered questions regarding health-related quality of life (HRQoL) in glioma patients by undertaking powerful detailed secondary analyses of... Show moreThe aim of this thesis was to answer currently unanswered questions regarding health-related quality of life (HRQoL) in glioma patients by undertaking powerful detailed secondary analyses of existing pooled individual HRQoL patient data, which was previously collected in 15 RCTs in glioma patients.In total, data of 6048 glioma patients was included in the CODAGLIO database and 5 manuscripts were written that provide relevant information both for clinical practice as well as for clinical trials. Results of these studies entailed information on the added prognostic value of HRQoL at baseline in predicting survival. Furthermore, symptom clusters were identified and their association with functioning was investigated, and the impact of both (progression of) the disease and treatment on HRQoL deterioration was studied. Moreover, the ‘net clinical benefit’, weighing HRQoL and survival was calculated and different analytical methods to calculate change in HRQoL were compared.The CODAGLIO project, the largest individual patient data (IPD) project in neuro-oncology research so far, showed to represent an unique opportunity for secondary hypothesis testing, to answer clinically relevant questions with respect to HRQoL. Show less
The main objective of this thesis was to determine the value of dialysis and conservative care for older patients with advanced chronic kidney disease. To do so, we compared a combination of... Show moreThe main objective of this thesis was to determine the value of dialysis and conservative care for older patients with advanced chronic kidney disease. To do so, we compared a combination of patient-relevant outcomes and treatment costs in a cohort of older patients (≥70 years old) who chose either dialysis or conservative care after a shared decision-making process. Overall, we observed that older patients who chose dialysis lived longer compared with older patients who chose conservative care. There was, however, little or no significant survival advantage in patients aged ≥80 years old and patients aged ≥70 years old with severe comorbidity who chose dialysis over conservative care, while similar outcomes on quality of life and symptoms were observed between both patient groups, and lower treatment burden and treatment costs were observed in patients who chose conservative care. Therefore, we conclude that conservative care is a viable treatment alternative to dialysis in selected older patients. In clinical practice, conservative care needs to become available and openly discussed as one of the possible treatment pathways for advanced chronic kidney disease in older patients. Moreover, a shift towards a person-centered process of shared decision-making is needed that aims to focus on all that matters to the patient as person, in order to come to a treatment plan that fits best with the patient. Show less
In this thesis we showed the clinical impact of several methodological issues that should be taken into account when studying chronic kidney disease progression and in order to find an answer to... Show moreIn this thesis we showed the clinical impact of several methodological issues that should be taken into account when studying chronic kidney disease progression and in order to find an answer to the question when to start dialysis. From a methodological point of view, the observations from this thesis provide several recommendations for future research with regard to studying associations of risk factors with CKD progression: the use of an inception cohort of incident patients, and using linear mixed effects models for analyses. Ultimately, patients with kidney failure could be subjected to dialysis. The optimal timing for dialysis initiation is unclear. Ideally, a randomized trial with all possible starting moments would be performed. However, this seems to be unfeasible due to the high patient number needed in each treatment arm. We have to rely on observational data, where methodological issues such as lead-time and immortal time bias arise. In this thesis, we showed the clinical impact of lead-time bias and how both types of bias were avoided by emulating a randomized trial using observational data in a pilot study. The methodology and recommendations provided in the thesis will be highly useful to find a more definitive answer in future research. Show less
One of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse... Show moreOne of the main questions in Ewing sarcoma treatment is to identify low-risk patients that can be treated with less intensive treatment so that toxicity and the occurrence of long-term adverse effects can be limited while still maintaining high cure rates or to identify those patients for whom treatment is expected to have limited benefit. Furthermore, to identify high-risk patients in which treatment needs to be intensified to improve outcome. Selection of risk groups and adjusted treatment allows for early decision making, will help to improve future outcomes and assists in clinical trial design. Additionally, treatment of Ewing sarcoma is multimodal and surgery, if feasible, is crucial for curative management. However, accurate detection and localization of tumor boundaries, especially in anatomical complex locations such as the pelvic is challenging. Inadequate surgical margins lead to a higher risk of local recurrence which has major impact on oncological outcome. Developments in intra-operative imaging, like CT-based navigation systems and near infrared (NIR)fluorescence guided surgery (FGS) make accurate defining and localization of surgical margins possible. They represent a whole new field of precision medicine and provide new treatment options for patients, thereby improving function outcome and healthcare quality. Show less
This thesis focus on the quality assurance in the surgical treatment of gastric cancer. This has been investigated using data of the CRITICS trial. In this randomized clinical patients underwent... Show moreThis thesis focus on the quality assurance in the surgical treatment of gastric cancer. This has been investigated using data of the CRITICS trial. In this randomized clinical patients underwent preoperative chemotherapy, followed by surgery, followed by adjuvant chemotherapy or chemoradiotherapy. Surgical quality in the CRITICS trial was investigated and was excellent (PART I). Furthermore, the influence of hospital volume on surgical quality and survival was analyzed using data of the CRITICS trial (PART II). Surgery performed in hospitals with high hospital volume was associated with better surgical quality and better survival. In part III of this thesis analyses were performed to analyze treatment strategy and survival in patients with resectable gastric cancer and in patients with metastatic gastric cancer. 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
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
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
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
