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.

There will be an estimated 60,000 new cases and nearly 8000 deaths in the US this year due to malignant melanoma. People living in the US are expected to have a 1 in 71 lifetime risk of developing the disease. Activating mutations in BRAF occur in approximately 60% of melanomas and in 80% of benign melanocytic nevi. PTEN is a tumor suppressor that has been shown to be deleted or epigenetically silenced in approximately 30% of melanomas. Cdkn2a is a locus encoding 2 tumor suppressors in alternate reading frames that has been found to be mutated in up to 40% of familial melanomas and is near universally lost in human melanoma cell lines. We used these data to generate novel mouse models of metastatic melanoma involving an inducible Cre transgenic mouse (Tyr::CreER-T2). We demonstrate that Pten loss, Cdkn2a loss or Braf activation in isolation does not induce melanoma. In contrast, when Braf activation is combined with Pten loss, mice develop aggressive pigmented melanomas with 100% penetrance and a mean tumor free survival of 19.5 days. Melanocytic proliferation occurs immediately following induction with virtually no latency. Expansile metastases are observed in lymph nodes and isolated tumor cells are present in the lungs and brain. Both incipient and established melanomas are sensitive to the mTOR inhibitor rapamycin. Furthermore, mTORC1 signaling is prevented upon rapamycin treatment, but mTORC2, MAPK, and Akt signaling appear to be unaffected. Additionally, when Cdkn2a loss is combined with Braf activation, the mice develop a nevic phenotype with complete penetrance and stochastic progression to melanoma. Median melanoma free survival is 85.5 days and tumors are metastatic to lymph nodes in 100% of mice. These novel mouse models of melanoma will likely be useful in the study of the biology of metastasis, in tumor immunology, and in new models of preclinical testing.

Melanoma is the most aggressive skin cancer with high recurrence and low survival rate. In addition to genetic mechanisms, resistance also arises from phenotypic heterogeneity in which a proportion of cells, the so-called melanoma stem or initiating cells, survive therapy. Due to a lack of reliable markers, however, there is still debate about the existence of these cells in melanoma. Consistent with phenotypic heterogeneity, previous observations in our laboratory have demonstrated that cells in melanoma can reversibly segregate in vivo into different subpopulations with different properties, such as differentiation or increased invasive capacity (potentially attributed to the existence of de-differentiated stem-like cells). To characterise these cells, a dual reporter lentiviral system was engineered, expressing fluorescent proteins under cell stage/phenotype-specific promoters. The promoters for the transcription factors POU3F2 (Brn2) (to mark de-differentiated cells) and the microphthalmia-associated transcription factor (MITF) (to mark proliferating and differentiated cells) were chosen. Lentivirally-transduced cells were used to screen a library of kinase inhibitors for their potential to affect promoter activity in vitro. The RhoA/ROCK pathway, known to contribute to invasion and metastases, was identified to play a role in Brn2 promoter activity and exhibited differential effects on both the MITF and Brn2 promoters in 501mel and SKmel28 cell lines. Through investigation of other signalling pathways involved in melanoma metastasis, we also identified the co-activator Mastermind-like 1 (MAML1), previously reported to act in the Notch pathway, as an activator of the Brn2 promoter via the transcription factor TCF3, and the MITF promoter through the lymphoid-enhancer binding factor 1 (LEF1). The effects of MAML1 on Brn2 and MITF promoter activity were potentiated by β-catenin. These findings provide new opportunities for the identification of therapeutic targets to prevent metastases formation in melanoma.