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Prognostic Factors in Malignant Melanoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Because of the failure so far to find effective treatment for patients with advanced stages of melanoma, increasing efforts have been made to find prognostic factors identifying patients in the risk zone for development of metastasis.

This thesis investigates the prognostic powers of a few selected serological and immunohistochemical biomarkers.

In the first and second study, patients operated on for localized malignant melanoma were investigated regarding the prognostic impact of angiogenic serological markers and circulating levels of S100. We concluded that the S100 assays, especially S100BB, are potential biomarkers in patients with malignant melanoma, correlated to both survival and disease free survival. However, no such conclusion could be drawn from the first study, where we found no correlation to survival and investigated angiogenic markers.

In the third and fourth study four new potential immunohistochemical biomarkers where investigated in collaboration with the Swedish Human Protein Atlas Program, and those where TRP-1, galectin-1, DLG5 and syntaxin-7.

We found that TRP-1 correlated inversely with tumor stage and galectin-1 correlated to Ki-67.

DLG5 showed a significant inverse correlation to Ki67 and the expression of STX7 was inversely correlated to tumor stage, suggesting that decreased expression is associated with more aggressive tumors.

None of the investigated markers in study III and IV correlated with disease free survival or overall survival.

In the fifth and last study, we examined the expression of SOX10, a transcription factor, in different melanocytic lesions. Also, a proliferation assay was carried out in a human melanoma cell line. The results reveal the presence of SOX10 in different melanocytic lesions, with a weak inverse correlation to survival and a significant inverse correlation to T-stage. A significant decrease in proliferation rate for SOX10 silenced cells was found and our data also suggests an increased migratory response in SOX10 silenced cells.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket , 2008. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 410Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 410
Keywords [en]
Malignant melanoma, prognostic factors, survival, chemotherapy, radiation
Identifiers
URN: urn:nbn:se:uu:diva-9511ISBN: 978-91-554-7378-5 (print)OAI: oai:DiVA.org:uu-9511DiVA, id: diva2:173060
Public defence
2009-01-16, Skoog Salen, Onkologkliniken, ing 78, Uppsala Universitetssjukhus, 751 85, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-12-22 Created: 2008-12-22 Last updated: 2013-06-20Bibliographically approved
List of papers
1. The Role of Circulating Angiogenic Factors in Patients Operated on for Localized Malignant Melanoma
Open this publication in new window or tab >>The Role of Circulating Angiogenic Factors in Patients Operated on for Localized Malignant Melanoma
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2007 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 27, no 5A, p. 3211-3217Article in journal (Refereed) Published
Abstract [en]

Malignant melanoma is a disease capable of rapid progression and rapidly developing metastases. Angiogenesis is a key event signalling tumour progression and elevated levels of angiogenic markers may indicate metastatic disease. No previously published work has, so far, examined plasma vascular endothelial growth factor (VEGF) and its receptor, VEGFR-1, in melanoma. This study investigated circulating levels of the angiogenic factors, VEGF-A and -D, their receptors 1-3 and hepatocyte growth factor (HGF)/scatter factor, in patients shortly after primary surgery for localized malignant melanoma. Elevated circulating levels of VEGF and its receptors, and of HGF, were found postoperatively, possibly derived from the reactive stroma adjacent to the tumours. Using univariate analysis, a correlation between levels of VEGFR-1 and relapse was found, but a correlation between the investigated angiogenic factors and survival could not be established. The results of the present study indicate that production of these angiogenic factors may be due to sources other than malignant melanoma cells.

Keywords
Malignant melanoma, angiogenesis, survival, relapse, vascular endothelial growth factor, hepatocyte growth factor, hepatocyte scatter factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97931 (URN)000250266600022 ()17970063 (PubMedID)
Available from: 2008-12-22 Created: 2008-12-22 Last updated: 2017-12-14Bibliographically approved
2. Serological and immunohistochemical analysis of S100 and derivatives as markers for prognosis of newly operated malignant melanoma patients
Open this publication in new window or tab >>Serological and immunohistochemical analysis of S100 and derivatives as markers for prognosis of newly operated malignant melanoma patients
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2008 (English)In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 18, no 6, p. 412-419Article in journal (Refereed) Published
Abstract [en]

The incidence of cutaneous malignant melanoma is rising, and tumour markers are attracting attention as a possible alternative to clinical examination in the follow-up situation. S100 is the preferred marker for malignant melanoma, and correlation between serum S100 and disease relapse and survival has been reported. S100 tests previously used in clinical studies were specified poorly regarding reactivity with S100A1B and S100BB. In this study, a newly designed S100 assay (designed to measure exclusively S100A1B and S100BB) and two newly developed serological assays, S100A1B, and S100BB, were investigated postoperatively in patients undergoing radical surgery for cutaneous malignant melanoma. Additionally, immunohistochemical analysis of S100A4 was performed on the primary malignant melanoma using tissue microarrays. The primary aim of the study was to investigate whether any of these assays, either singly or in combination, can contribute additional information concerning increased risk of relapse and death because of malignant melanoma. In total, 98 patients (54 males, 44 females) with malignant melanoma were included in the study. As a continuous variable, S100BB (P=0.016) was associated statistically with increased risk of relapse; this was not the case for increased values of either S100 (P=0.11) or S100A1B (P=0.92). The Kaplan-Meier overall survival as well as disease specific survival curve for the S100 serum level demonstrated a statistically significant association with better survival if the patient had a S100 level <or=150 ng/l (P<0.001). Survival analyses for S100A1B using a defined cutoff of 50 ng/l showed a statistically significant association concerning overall and disease specific survival (P<0.001). Furthermore, S100BB was associated with overall and disease specific survival using a defined cutoff of 50 ng/l (P<0.001). No statistically significant correlation was found between S100A4 and overall survival (P=0.96) and there was no correlation between elevated levels of S100 and the immunohistochemical staining of S100A4 (P=0.1), nor for serum S100A1B (P=0.1) nor serum S100BB (P=0.17). Circulating S100A1B and S100BB are potential biomarkers in patients with malignant melanoma. S100BB should be considered as the preferred biomarker, showing potential in predicting both relapse and survival, in contrast to both S100 and S100A1B.

Keywords
immunohistochemistry, malignant melanoma, prognosis, S100, S100A1B, S100A4, S100BB, serum marker, survival
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97932 (URN)10.1097/CMR.0b013e328315c690 (DOI)000261420200006 ()19011512 (PubMedID)
Available from: 2008-12-22 Created: 2008-12-22 Last updated: 2017-12-14Bibliographically approved
3. The protein expression of TRP-1 and galectin-1 in cutaneous malignant melanomas
Open this publication in new window or tab >>The protein expression of TRP-1 and galectin-1 in cutaneous malignant melanomas
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2008 (English)In: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 5, no 6, p. 293-300Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Patients with metastazing malignant melanoma have a poor outcome and determination of thickness of the primary tumor remains as the most important prognostic predictor. The aim of this study was to use an antibody-based proteomics strategy to search for new molecular markers associated with melanoma progression. Two proteins, TRP-1 and galectin-1, were identified as proteins with enhanced expression in cells from the melanocytic lineage. PATIENTS AND METHODS: Protein profiling of TRP-1 and galectin-1 together with proliferation marker Ki-67 and melanocyte marker Melan-A was performed in normal tissues from 144 individuals and in 216 different tumors using tissue microarrays and immunohistochemistry. The protein expression pattern was further analyzed in a defined cohort of 157 patients diagnosed with invasive cutaneous malignant melanoma. RESULTS: Both TRP-1 and galectin-1 were highly expressed in normal melanocytes and melanoma. The expression of TRP-1 was inversely correlated with tumor stage (p=0.002, (R=-0.28)). Neither TRP-1 or galectin-1 was associated with overall or disease free survival (p>0.14, p>0.46 respectively). Ki-67 was associated with tumor stage and survival (p<0.001). CONCLUSION: TRP-1 and galectin-1 protein expression patterns were determined in normal and cancer tissues and both proteins were expressed in the majority of the malignant melanomas. There was no correlation between TRP-1 or galectin-1 expression and survival.

Keywords
human Protein Atlas Program, malignant melanoma, TRP-1, galectin-1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-105314 (URN)19287070 (PubMedID)
Available from: 2009-06-03 Created: 2009-06-03 Last updated: 2017-12-13Bibliographically approved
4. Selective expression of Discs large homolog 5 and Syntaxin-7 in benign melanocytes and malignant melanoma
Open this publication in new window or tab >>Selective expression of Discs large homolog 5 and Syntaxin-7 in benign melanocytes and malignant melanoma
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In: Journal of Proteome ResearchArticle in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-97934 (URN)
Available from: 2008-12-22 Created: 2008-12-22Bibliographically approved
5. Altered Expression of the Transcription Factor SOX10 in Superficial Spreading and Nodular Malignant Melanomas
Open this publication in new window or tab >>Altered Expression of the Transcription Factor SOX10 in Superficial Spreading and Nodular Malignant Melanomas
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-97935 (URN)
Available from: 2008-12-22 Created: 2008-12-22 Last updated: 2010-01-13Bibliographically approved

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