Relative Contribution of Cell Proliferation and Microvascularity to Metastasis in Malignant Uveal Melanoma

Uveal melanoma (UM) is the second most common primary intraocular cancer worldwide. It is a relatively rare cancer, but still the second most common type of primary malignant melanoma in humans. UM is a slowly growing tumor, and gives rise to distant metastasis mainly to the liver via the bloodstream. About 40% of patients with UM die of metastatic disease within 10 years of diagnosis, irrespective of the type of treatment. During the last decade, two main lines of research have aimed to achieve enhanced understanding of the metastasis process and accurate prognosis of patients with UM. One emphasizes the characteristics of tumor cells, particularly their nucleoli, and markers of proliferation, and the other the characteristics of tumor blood vessels. Of several morphometric measurements, the mean diameter of the ten largest nucleoli (MLN) has become the most widely applied. A large MLN has consistently been associated with high likelihood of dying from UM. Blood vessels are of paramount importance in metastasis of UM. Different extravascular matrix patterns can be seen in UM, like loops and networks. This presence is associated with death from metastatic melanoma. However, the density of microvessels is also of prognostic importance. This study was undertaken to help understanding some histopathological factors which might contribute to developing metastasis in UM patients. Factors which could be related to tumor progression to metastasis disease, namely nucleolar size, MLN, microvascular density (MVD), cell proliferation, and The Insulin-like Growth Factor 1 Receptor(IGF-1R), were investigated. The primary aim of this thesis was to study the relationship between prognostic factors such as tumor cell nucleolar size, proliferation, extravascular matrix patterns, and dissemination of UM, and to assess to what extent there is a relationship to metastasis. The secondary goal was to develop a multivariate model which includes MLN and cell proliferation in addition to MVD, and which would fit better with population-based, melanoma-related survival data than previous models. I studied 167 patients with UM, who developed metastasis even after a very long time following removal of the eye, metastatic disease was the main cause of death, as documented in the Finnish Cancer Registry and on death certificates. Using an independent population-based data set, it was confirmed that MLN and extravascular matrix loops and networks were unrelated, independent predictors of survival in UM. Also, it has been found that multivariate models including MVD in addition to MLN fitted significantly better with survival data than models which excluded MVD. This supports the idea that both the characteristics of the blood vessels and the cells are important, and the future direction would be to look for the gene expression profile, whether it is associated more with MVD or MLN. The former relates to the host response to the tumor and may not be as tightly associated with the gene expression profile, yet most likely involved in the process of hematogenous metastasis. Because fresh tumor material is needed for reliable genetic analysis, such analysis could not be performed Although noninvasive detection of certain extravascular matrix patterns is now technically possible,in managing patients with UM, this study and tumor genetics suggest that such noninvasive methods will not fully capture the process of clinical metastasis. Progress in resection and biopsy techniques is likely in the near future to result in fresh material for the ophthalmic pathologist to correlate angiographic data, histopathological characteristics such as MLN, and genetic data. This study supported the theory that tumors containing epithelioid cells grow faster and have poorer prognosis when studied by cell proliferation in UM based on Ki-67 immunoreactivity. Cell proliferation index fitted best with the survival data when combined with MVD, MLN, and presence of epithelioid cells. Analogous with the finding that high MVD in primary UM is associated with shorter time to metastasis than low MVD, high MVD in hepatic metastasis tends to be associated with shorter survival after diagnosis of metastasis. Because the liver is the main organ for metastasis from UM, growth factors largely produced in the liver hepatocyte growth factor, epidermal growth factor and insulin-like growth factor-1 (IGF-1) together with their receptors may have a role in the homing and survival of metastatic cells. Therefore the association between immunoreactivity for IGF-1R in primary UM and metastatic death was studied. It was found that immunoreactivity for IGF-IR did not independently predict metastasis from primary UM in my series.

The decline of malaria in Finland – the impact of the vector and social variables

Background: Malaria was prevalent in Finland in the 18th century. It declined slowly without deliberate counter-measures and the last indigenous case was reported in 1954. In the present analysis of indigenous malaria in Finland, an effort was made to construct a data set on annual malaria cases of maximum temporal length to be able to evaluate the significance of different factors assumed to affect malaria trends. Methods: To analyse the long-term trend malaria statistics were collected from 1750–2008. During that time, malaria frequency decreased from about 20,000 – 50,000 per 1,000,000 people to less than 1 per 1,000,000 people. To assess the cause of the decline, a correlation analysis was performed between malaria frequency per million people and temperature data, animal husbandry, consolidation of land by redistribution and household size. Results: Anopheles messeae and Anopheles beklemishevi exist only as larvae in June and most of July. The females seek an overwintering place in August. Those that overwinter together with humans may act as vectors. They have to stay in their overwintering place from September to May because of the cold climate. The temperatures between June and July determine the number of malaria cases during the following transmission season. This did not, however, have an impact on the longterm trend of malaria. The change in animal husbandry and reclamation of wetlands may also be excluded as a possible cause for the decline of malaria. The long-term social changes, such as land consolidation and decreasing household size, showed a strong correlation with the decline of Plasmodium. Conclusion: The indigenous malaria in Finland faded out evenly in the whole country during 200 years with limited or no counter-measures or medication. It appears that malaria in Finland was basically a social disease and that malaria trends were strongly linked to changes in human behaviour. Decreasing household size caused fewer interactions between families and accordingly decreasing recolonization possibilities for Plasmodium. The permanent drop of the household size was the precondition for a permanent eradication of malaria.