Cutaneous melanoma is associated with significant morbidity and mortality representing the most significant cutaneous malignancy. As it is known that early diagnosis and treatment are the most efficient approaches to cure cutaneous melanoma, an improved understanding of the molecular pathogenesis of melanoma and exploration of more reliable molecular biomarkers are particularly essential. Two different types of molecular biomarker for melanoma have been investigated in this thesis. microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotides in length that are found in both animal and plant cells. miRNAs are involved in the RNA interference (RNAi) machinery to regulate gene expression posttranscriptionally. miRNAs have important roles in cancer: by controlling the expression level of their target genes they can affect cell signalling pathways and have been shown to have both prognostic and therapeutic potential. Importantly for melanoma research, reproducible miRNA expression profiles from formalin-fixed paraffin-embedded (FFPE) tissues can be obtained that are comparable to those from fresh-frozen samples. The aims of the miRNA project were: first, to identify a melanoma-specific miRNA expression profile; secondly, to investigate roles of some of the melanoma-specific miRNAs identified in melanomagenesis. Using miRNA microarray on FFPE samples, I obtained a melanoma-specific miRNA expression profile. 9 of these differentially expressed miRNAs between benign naevi and melanomas (7 downregulated, 2 upregulated in malignancies) were verified by qRT-PCR and the functions of four of these miRNAs were studied. Ectopic overexpression of miR- 200c and miR-205 in A375 melanoma cells inhibited colony forming ability in methylcellulose, an in vitro surrogate assay for tumourigenicity. Moreover, elevation of miR-200c resulted in increased expression levels of E-cadherin through negative regulation of the zinc finger E-box-binding homeobox 2 (ZEB2) gene. Ectopic overexpression of miR-211 in A375 melanoma cells repressed both colony formation in methylcellulose and migratory ability in matrigel, an in vitro surrogate assay for invasiveness. These findings indicate that miR-200c, miR-205 and miR-211 act as tumour suppressors in melanomagenesis. The second biomarker investigated, mutated BRAF, has been seen in 50-70% of spontaneous cutaneous melanoma. The commonest mutation in melanoma is a glutamic acid for valine substitution at position 600 (V600E). Oncogenic BRAF controls many aspects of melanoma cell biology. The aim of this part of the work was: firstly, to study BRAF V600E mutation status in our melanoma tissue microarray (TMA) panel; secondly, to correlate this mutation to various clinicopathological features and evaluate its prognostic value through statistical analyses. BRAF V600E mutations were seen in 20% of the primary and 69% of the metastatic melanomas, respectively. More BRAF V600E mutations were seen in males relative to females. The mutation was also related to cell pigmentation, but not to age, ulceration or solar elastosis. Melanoma patients with the BRAF V600E mutation relapse earlier than patients without this mutation. However, no significant association between the BRAF V600E mutation and overall survival and melanoma specific survival was found.

Thesis (Ph.D.)--University of Alberta, 2010. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy, Medical Sciences - Medical Genetics. Title from pdf file main screen (viewed on March 19, 2010). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Background: While death from melanoma of the skin has been gradually decreasing over the past few decades, melanoma continues to be the leading causes of death among skin cancers. Less is known about specific causes of mortality among patients with melanoma and how or whether trends in cause of death among patients diagnosed with melanoma have changed in recent years. Objective: To examine temporal trends in the cause-specific mortality among adult patients diagnosed with melanoma in the US between 2000-2013. Methods: US patients ≥ 45 years when diagnosed with melanoma were identified using data from the Surveillance, Epidemiology, and End Results Program, 18 Registries (SEER-18). Joinpoint regression analysis was used to examine the trends in cause-specific mortality among patients who were diagnosed with melanoma and died from either melanoma or other causes of death. Trends were also examined separately by age, sex, and geographic region. Results: A total of 52,675 patients diagnosed with melanoma who died from either melanoma or other cause of death (median age 74 years, 67% male) were included in the analysis. Overall, 31% of deaths were due to melanoma specifically, whereas 69% died from various other causes. A marked decline in melanoma-specific mortality was observed overall and across strata by age, sex, and region in the US beginning around 2013-2014. Among all causes of death, 55% were due to melanoma within 1 year after diagnosis and declined to 25% over the course of 6 years. A marked decline of at least 2.5% in mortality per year from other causes was observed among females, males, those 65 – 74 years or 75 years and older, and those living in northeastern, midwestern, western, and southern regions of US who were diagnosed with melanoma. Conclusions: Changes in cause-specific mortality rate among patients with melanoma were observed overall and across different subgroups. Our findings show that, among those diagnosed with melanoma, the risk of melanoma-specific death is decreasing within the last two decades, and that the deaths among those with melanoma are more likely to be from other causes such as heart disease, lung cancer, and other conditions. Future studies are needed to assess the trends in melanoma mortality as treatments and diagnostic methods continue to advance.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Up to date, only four cases of primary intradural extramedullary spinal cord melanoma (PIEM) have been reported. No previous reports have described a case of PIEM located in the lower thoracic spine with long-termfollow-up. Purpose. Demonstrating an unusual, extremely rare case of melanoma manifestation. Study Design. Case report. Methods. We report a case of a 57-year-old female suffering from increasing lower extremity pain, left-sided paresis, and paraesthesia due to spinal cord compression caused by PIEM in the lower thoracic spine. Results. Extensive investigation excluded other possible primary melanoma sites and metastases. For spinal cord decompression, the tumor at level T12 was resected, yet incompletely. Adjuvant radiotherapy was administered two weeks after surgery. The patient was recurrence-free at 104 weeks after radiotherapy but presents with unchanged neurological symptoms. Conclusion. Primary intradural extramedullary melanoma (PIEM) is extremely rare and its clinical course is unpredictable.

No description available.

Melanoma is a highly aggressive tumour with a poor prognosis for patients with advanced disease because it is resistant to current therapies. Therefore, the development of novel strategies for melanoma treatment is important. The characterization of the molecular mechanisms underlying melanoma proliferation, progression, and survival could help the development of novel targeted melanoma treatments. The MAPK and PI3K pathways both play important roles in melanoma progression. In the MAPK pathway, DUSP6, which acts as a phosphatase to negatively control the activation of ERK1/2, is involved in the development of human cancers. The MAPK pathway also regulates expression of the DNA repair gene ERCC1 following EGF treatment. ERCC1 is essential for nucleotide excision repair, which is one of the major systems for removal of cisplatin induced DNA lesions. The aims of this project were: 1, to investigate the molecular changes in our immortal mouse melanocyte cell lines that were needed for them to form tumours in a xenograft model; 2, to investigate whether the MAPK pathway regulates ERCC1 following cisplatin treatment and protects melanoma cells from death. Through comparison of the RAS/RAF/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signalling pathways between our immortal mouse melanocyte cell lines and their tumour derivatives in our xenograft model, we identified a molecularly distinct subtype of mouse melanoma characterized by reduced ERK and AKT activity and increased expression of DUSP6. Functional analyses employing ectopic overexpression indicated that increased expression of DUSP6 enhanced anchorage independent growth ability and invasive ability in our mouse melanocytes, suggesting that increased DUSP6 expression may contribute to melanoma formation in the xenograft assay. We also demonstrated that higher expression of p-ERK suppressed invasion, but not anchorage independent growth, in our subtype of mouse melanoma by enforced expression of constitutively active MEK1 and MEK2. In addition, the role of DUSP6 in classical human melanoma was investigated in this Genetic changes in melanoma progression study. Inhibition of anchorage independent growth and invasion were observed after exogenous expression of DUSP6 in human melanoma cells. This suggested that DUSP6 played different roles in classic human melanoma than in our distinct subtype of mouse melanoma. Our study also investigated the phosphorylation level of ERK1/2 and the mRNA and protein level of ERCC1 and its partner XPF in the human melanoma cell line following cisplatin treatment. Significant increases in expression of p-ERK, ERCC1 and XPF were found in cisplatin treated cells. Moreover, a MEK inhibitor inhibited ERCC1 induction by cisplatin, but did not significantly affect XPF induction. This suggested that the MAPK pathway was involved in regulation of ERCC1 but not XPF. Furthermore, the DUSP6 level decreased after cisplatin treatment and overexpression of DUSP6 inhibited ERCC1 and XPF induction and reduced resistance to cisplatin. DUSP6 seems to play a crucial role in resistance of melanoma to cisplatin. In addition, a novel larger ERCC1 transcript was identified in human cell lines and was found to be upregulated by cisplatin. The ratio of larger ERCC1 transcript relative to the normal ERCC1 transcript increased following cisplatin treatment. The functions of this larger ERCC1 transcript in cisplatin resistance deserve further study.

Examining surface shape appearance by touching and observing a lesion from different points of view is a part of the clinical process for skin lesion diagnosis. Motivated by this, we hypothesise that surface shape embodies important information that serves to represent lesion identity and status. A new sensor, Dense Stereo Imaging System (DSIS) allows us to capture 1:1 aligned 3D surface data and 2D colour images simultaneously. This thesis investigates whether the extra surface shape appearance information, represented by features derived from the captured 3D data benefits skin lesion analysis, particularly on the tasks of segmentation and classification. In order to validate the contribution of 3D data to lesion identification, we compare the segmentations resulting from various combinations of images cues (e.g., colour, depth and texture) embedded in a region-based level set segmentation method. The experiments indicate that depth is complementary to colour. Adding the 3D information reduces the error rate from 7:8% to 6:6%. For the purpose of evaluating the segmentation results, we propose a novel ground truth estimation approach that incorporates a prior pattern analysis of a set of manual segmentations. The experiments on both synthetic and real data show that this method performs favourably compared to the state of the art approach STAPLE [1] on ground truth estimation. Finally, we explore the usefulness of 3D information to non-melanoma lesion diagnosis by tests on both human and computer based classifications of five lesion types. The results provide evidence for the benefit of the additional 3D information, i.e., adding the 3D-based features gives a significantly improved classification rate of 80:7% compared to only using colour features (75:3%). The three main contributions of the thesis are improved methods for lesion segmentation, non-melanoma lesion classification and lesion boundary ground-truth estimation.

Ultraviolet radiation (UVR) has been associated with various health outcomes, including skin cancers, vitamin D insufficiency, and multiple sclerosis. Measurement of UVR has been difficult, traditionally relying on subject recall. We investigated trends in satellite-derived UVB from 1978 to 2014 within the continental United States (US) to inform UVR exposure assessment and determine the potential magnitude of misclassification bias created by ignoring these trends. Monthly UVB data remotely sensed from various NASA satellites were used to investigate changes over time in the United States using linear regression with a harmonic function. Linear regression models for local geographic areas were used to make inferences across the entire study area using a global field significance test. Temporal trends were investigated across all years and separately for each satellite type due to documented differences in UVB estimation. UVB increased from 1978 to 2014 in 48% of local tests. The largest UVB increase was found in Western Nevada (0.145 kJ/m(2) per five-year increment), a total 30-year increase of 0.87 kJ/m(2). This largest change only represented 17% of total ambient exposure for an average January and 2% of an average July in Western Nevada. The observed trends represent cumulative UVB changes of less than a month, which are not relevant when attempting to estimate human exposure. The observation of small trends should be interpreted with caution due to measurement of satellite parameter inputs (ozone and climatological factors) that may impact derived satellite UVR nearly 20% compared to ground level sources. If the observed trends hold, satellite-derived UVB data may reasonably estimate ambient UVB exposures even for outcomes with long latency phases that predate the satellite record.