The aim of this thesis was to develop novel treatment strategies for different types of eye melanoma utilizing zebrafish models. We first establish orthotopic and ectopic xenograft models for uveal... Show moreThe aim of this thesis was to develop novel treatment strategies for different types of eye melanoma utilizing zebrafish models. We first establish orthotopic and ectopic xenograft models for uveal and conjunctival melanoma by engraftment of the immortalized cells derived from these tumors into zebrafish embryos. Next, we expanded these models with spheroids and zebrafish patient-derived xenografts for pre-clinical, personalized screening of anti-uveal melanoma drug responses. We demonstrated that these models can be harnessed to explore the in vivo interactions of the tumor cells with blood vessels and macrophages leading to angiogenic response. We finally apply the conjunctival melanoma model to clarify the inhibitory effects of ginsenosides and correlate their structures with potential antitumoral mechanisms. Show less
Ocular melanoma and colorectal carcinoma are two malignancies with a predilection for metastasizing to the liver. Patients with liver-only or liver-dominant metastatic disease might be eligible for... Show moreOcular melanoma and colorectal carcinoma are two malignancies with a predilection for metastasizing to the liver. Patients with liver-only or liver-dominant metastatic disease might be eligible for locoregional or so-called liver-directed therapy. Liver-directed therapies include surgery and thermal ablation, as well as various arterial therapies such as percutaneous hepatic perfusion with melphalan (M-PHP). Although M-PHP is well-tolerated by most patients, hematologic events due to bone marrow suppression were quite common in M-PHP using the first-generation filter. In an attempt to reduce bone marrow suppression by increasing the filter extraction rate, a new second-generation filter (GEN 2 filter) was developed and became commercially available in 2012. In this thesis, it was demonstrated that M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile and it seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. This thesis contributes to the scientific evidence showing that M-PHP using the GEN 2 filter is an effective treatment for liver metastases from ocular melanoma. In contrast, M-PHP seems to have no additional value in the current treatment of unresectable liver metastases from colorectal carcinoma. 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
