Cutaneous and uveal melanoma are malignant tumours with no treatment available once the metastases occur. Despite both melanomas are highly immunogenic, and often despite the presence of potent... Show moreCutaneous and uveal melanoma are malignant tumours with no treatment available once the metastases occur. Despite both melanomas are highly immunogenic, and often despite the presence of potent anti-tumour immune cells in patients__ blood, in more than 95% of patients, tumour growth remains unaffected. Hereby we investigate the mechanisms that help melanomas to escape from the spontaneous or activated by vaccination cytotoxicity of T lymphocytes and discuss the impact of local microenvironment created by melanoma, focusing on the role of immunomodulatory dendritic cells. Show less
Aims and outline of the thesis. Since Fearon and Vogelstein in 1990 presented the genetic model for the adeno-carcinoma sequence of colorectal cancer, many prognostic studies varying from early... Show moreAims and outline of the thesis. Since Fearon and Vogelstein in 1990 presented the genetic model for the adeno-carcinoma sequence of colorectal cancer, many prognostic studies varying from early stage markers to markers involved in late progression and liver metastases have followed. As has become evident from this introduction there is an ongoing need for prognostic markers that can be used for individualized prediction of clinical outcome. Chapter 2. Many systems are available for the detection of occult tumor cells in the bone marrow, blood and lymph nodes of cancer patients. In this chapter an overview is given of the various commercially available automated microscopy systems, and their capabilities. Furthermore the current status of the application of these instruments for bone marrow, blood and lymph nodes is presented. Chapter 3. Spread to locoregional lymph nodes is one of the most important prognostic indicators of the TNM classification. Detection of micrometastases in node-negative patients might upstage patients in need for additional chemotherapy. In this chapter an approach is described by which immunohistochemical staining and multiple sectioning is combined and is subjected to novel high-throughput automated imaging. Chapter 4. The presence of tumor cells in the bone marrow (BM) of cancer patients has shown to be related to a worse prognosis. This paper describes the use of array-CGH to detect genome alterations (gains and losses) in primary tumor tissue from BM-positive patients compared to matched (on stage and site) BM-negative patients. A higher number of differential aberrations and a distinct chromosome pattern, confirmed by interphase FISH, were found in the BM-positive group as compared to the BM-negative group. Chapter 5. While analyzing primary tumor tissue for a pilot study for array-CGH it was noticed that the set of patients with bad prognosis could not be analyzed, due to the fact that the amount of tumor material was less than 50%. This lower threshold is important for array-CGH to obtain reliable DNA profiles of the tumor cells and to avoid contamination with normal cells. Morphological evaluation of H&E stained sections showed that these tumors with bad prognosis had a high proportion of stroma and few tumor cells. The tumors with good prognosis showed the opposite, abundant tumor and less stroma. This phenomenon has led to the prognostic evaluation of this parameter in a larger patient study of which the results are shown in this chapter. Chapter 6. In this chapter the work presented in chapter 4 was continued but now focused on stage I-II colon patients. This subgroup of patients is in need for additional markers to select specific __high risk____ patients. Immunohistochemical staining of three molecular markers known to be involved in stroma production was performed. SMAD4 expression status was found to further improve the prognostic value of the presence of stroma in the primary tumor. Chapter 7. The conclusions of the studies presented in this thesis and the future perspectives of the presented parameters are discussed in this chapter. Show less
