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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Duncan, Timothy Jake
Languages: English
Types: Unknown
Subjects:
Advances in the treatment of ovarian cancer have had a limited impact on prognosis over recent decades. Alternatives to the traditional surgical and chemotherapeutic approach are being sought. Many novel therapies relate to a greater understanding of the molecular changes which occur during carcinogenesis and the development of targeted therapies to exploit these abnormalities. The aim of this thesis was to investigate the prognostic significance of markers relating to tumour immunology, angiogenesis and apoptosis, through the use of Tissue Microarray Technology. 339 cases of ovarian cancers diagnosed between 1982 and 1997 were assessed. Tumours were analysed immunohistochemically for expression of components of the IFNy (IFNGR1, STAT1, p27, caspase 1), TRAIL (DR4 and DR5) and angiogenic (VEGF) pathways. Loss of expression of IFNGR1 was an independent predictor of poor prognosis, although STAT 1 was not. High levels of cytoplasmic and nuclear p27 expression were associated with a reduced survival; cytoplasmic was independently prognostic. Tumours with reduced levels of caspase 1 had improved survival. These results suggest that only patients expressing IFNGR1 may benefit from IFNy therapy and provides evidence of immunoediting in ovarian cancer. DR4 and DR5 did not predict prognosis suggesting that the TRAIL pathway may not be significant in ovarian cancer apoptosis with implications for TRAIL-related therapy. High levels of VEGF occurred infrequently, being an independent marker of poor prognosis. This may identify a group of patients who may preferentially benefit from anti-angiogenic therapy. The thesis illustrates that ovarian cancers are heterogeneous and variations in expression of protein markers can predict tumour behaviour and stratify for therapy. Future targeted therapies may be selected on the basis of an immunohistochemical profile which predicts the pathways that are still functioning. New therapies as they arise should be trialed and targeted to tumours expressing the appropriate molecular markers.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1.1.12.2 Apoptosis inducers
    • 1.1.12.3 Anti-angiogenic therapy
    • The Immune System 1.2.1 Innate immune system
    • 1.2.1.1 Complement
    • 1.2.1.2 Phagocytes
    • 1.2.1.3 Natural killer (NK) cells
    • 1.2.1.4 Gammadelta () T cells
    • 1.2.1.5 Dendritic cells (DCs) 1.2.2 The adaptive immune system
    • 1.2.2.1 B-cells
    • 1.2.2.2 Antibodies
    • 1.2.2.3 T-cells
    • 1.2.2.4 Human leukocyte antigen (HLA)
    • 1.2.2.5 Regulatory T-cells
    • 1.2.2.6 Cytokines
    • Tumour Immunology 1.3.1 Cancer immunosurveillance in mice 1.3.2 IFN in cancer immunosurveillance 1.3.3 Specific effects of IFN on tumour cells 1.3.4 Immunosurveillance in humans
    • 1.3.4.1 Tumour formation in transplant patients
    • 1.3.4.2 Immune responses to tumours in humans
    • 1.3.4.3 Tumour infiltrating lymphocytes 1.3.5 Cancer immunoediting
    • 1.3.5.1 Refining the immunosurveillance theory
    • 1.3.5.2 Immunoediting in ovarian cancer 1.3.6 Immunotherapy in ovarian cancer
    • 1.3.6.1 Monoclonal antibodies
    • 1.3.6.2 Adoptive T-cell transfer
    • 1.3.6.3 Immuno-modulators
    • 1.3.6.4 Active vaccination
    • 1.3.6.5 Subverting immune escape mechanisms 1.3.7 Prognosis
    • 1.3.7.1 Established prognostic parameters
    • 1.3.7.2 Novel prognostic markers
    • 1.3.7.3 Serum biomarkers
    • 1.3.7.4 Tissue biomarkers 1.3.8 Exploring novel prognostic marker and tissue microarrays
    • Ovarian Cancer Tissue Microarray 2.1.1 Tissue microarray construction 2.1.2 Clinicopathological aspects of the tissue microarray
    • 2.1.2.1 Age
    • 2.1.2.2 Pathology
    • 2.1.2.3 Stage
    • 2.1.2.4 Surgery
    • 2.1.2.5 Survival
    • Immunohistochemistry 2.2.1 Processing of samples 2.2.2 Antigen retrieval 2.2.3 Preventing non-specific binding 2.2.4 Primary antibody
    • 2.2.4.1 Selection
    • 2.2.4.2 Titration
    • 2.2.4.3 Negative control 87 2.2.5 Washing 87 2.2.6 Signal amplification 88 2.2.7 Visualisation of the primary antibody 91 2.2.8 IHC protocol 92 2.2.9 Specific immunohistochemical protocols for individual markers 94
    • 2.2.9.1 IFNGR1 protocol 94
    • 2.2.9.2 Evaluation of IFNGR1 staining 95
    • 2.2.9.3 STAT1 protocol 95
    • 2.2.9.4 Evaluation of STAT1 staining 96
    • 2.2.9.5 p27 protocol 96
    • 2.2.9.6 Evaluation of p27 staining 97
    • 2.2.9.7 Caspase 1 protocol 97
    • 2.2.9.8 Evaluation of caspase 1 staining 98
    • 2.2.9.9 VEGF protocol 98
    • 2.2.9.10 Evaluation of VEGF staining 98
    • 2.2.9.11 DR4 and DR5 protocol 99
    • 2.2.9.12 Evaluation of DR4 and DR5 99
    • Statistical tests 101 2.3.1 Null and alternative hypothesis and p values 101 2.3.2 Univariate analysis - Persons Chi squared (2) test 101 2.3.3 Univariate analysis of associations with survival 102
    • 2.3.3.1 Mean and median survival times 102
    • 2.3.3.2 Kaplan-Meier plot 103
    • 2.3.3.3 Log rank statistic 104
    • 2.3.3.4 Multivariate analysis of associations with survival - Cox proportional
    • hazards model 104 The Interferon Gamma Pathway 106
    • Introduction 106 3.1.1 Interferons 106 3.1.2 Interferon gamma receptor 106 3.1.3 Interferon gamma signal transduction and STAT1 108 3.1.4 Interferon gamma regulated genes 111 3.1.5 Regulation of the IFN pathway 114
    • Results 115 3.2.1 IFNGR1 115
    • 3.2.1.1 Clinicopathological characteristics 115
    • 3.2.1.2 IFNGR1 staining 115
    • 3.2.1.3 Comparison of IFNGR1 expression and patient tumour characteristics
    • including survival 117
    • 3.2.1.4 Multivariate analysis 125 3.2.2 STAT1 127
    • 3.2.2.1 Clinicopathological characteristics 127
    • 3.2.2.2 Immunohistochemical expression of STAT1 in ovarian cancer 129
    • 3.2.2.3 Comparison of cytoplasmic STAT1 and clinicopathological variables
    • 3.2.3.6 Comparison of nuclear p27 expression and patient tumour
    • characteristics 143
    • 3.2.3.7 Cytoplasmic p27 expression and survival 145
    • 3.2.3.8 Nuclear p27 expression and survival 147
    • 3.2.3.9 Multivariate analysis of cytoplasmic and nuclear p27 expression and
    • survival 150
    • 3.2.3.10 Correlation between nuclear and cytoplasmic p27 expression 153
    • 3.2.3.11 Relationship of p27 expression with IFNGR1 and STAT1 expression
    • 153 3.2.4 Caspase1 155
    • 3.2.4.1 Clinicopathological characteristics 155
    • 3.2.4.2 Caspase 1 staining 155
    • 3.2.4.3 Comparison of cytoplasmic caspase 1 expression and patient tumour
    • characteristics 158
    • 3.2.4.4 Caspase 1 and survival 160
    • 3.2.4.5 Multivariate analysis of caspase 1 expression and survival 162
    • 3.2.4.6 Relationship of caspase 1 expression with IFNGR1 and STAT1
    • expression 163
    • Discussion 164 3.3.1 Interferon gamma receptor 164 3.3.2 STAT1 172 3.3.3 p27 175 3.3.4 Caspase 1 179
    • Conclusion 182 TRAIL Pathway 183
    • Introduction 183
    • Results 185 4.2.1 Clinicopathological characteristics 185 4.2.2 DR4 and DR5 staining 185 4.2.3 Comparison of DR4 and DR5 expression clinicopathological
    • characteristics including survival 189
    • Discussion 195
    • Conclusion 197 Vascular Endothelial Growth Factor 198
    • Introduction 198
    • Results 201 5.2.1 Clinicopathological characteristics 201 5.2.2 VEGF staining 201 5.2.3 Comparison of VEGF expression and patient tumour characteristics
    • including survival 204 5.2.4 Multivariate analysis 206
    • Discussion 207
    • Conclusion 211 General Discussion 212 Appendices 216
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