An investigation of the relationship between tumour proliferation, systemic and local inflammatory responses and survival in patients with transitional cell carcinoma of the bladder

Hilmy, Mustafa (2007) An investigation of the relationship between tumour proliferation, systemic and local inflammatory responses and survival in patients with transitional cell carcinoma of the bladder. MD thesis, University of Glasgow.

Abstract

Bladder cancer is the fourth most common malignancy in the Western world. The relationship between tumour proliferation, systemic and local inflammatory responses and outcome remains unclear. The thesis involved three cohorts of patients with transitional cell carcinoma of the urinary bladder. The first cohort consisted of patients in whom either pre and/or post resection systemic inflammatory response (C-reactive protein) measurement together with other clinicopathological variables were related to outcome. The second cohort consisted of patients in which pre-operative measurement of C-reactive protein was related to tumour proliferation (measured by Ki-67), local inflammatory reaction measured by infiltration of CD4+ and CD8+ and tumour associated macrophage (CD68+), microvessel density (CD34+) and COX-2 expression in the tumour tissue. The third cohort consisted of patients in whom C-reactive protein measurements were related to circulating cytokines/chemokines concentration involved in the regulation of the T-lymphocytes and other immune responses to the tumour. The results of the first study were that on univariate analysis, stage (p<0,001), grade (p<0.001) and elevated C-reactive protein pre-operatively (p<0.05) and post-operatively (p<0.01) were significantly associated with cancer-specific survival. On multivariate analysis of patients who had a pre-operative C-reactive protein determination, stage (p<0.008), grade (p<0.017) and pre-operative C-reactive protein (p<0.035) were independently associated with cancer-specific survival. Those patients with an elevated pre-operative C-reactive protein concentration had a mean cancer-specific survival of 65.5 months compared with 103.7 months in those patients with a C-reactive protein concentration in the normal range (≤10 mg/1). These findings would suggest that C-reactive protein is associated with disease progression and poor survival in patients with transitional cell carcinoma of the urinary bladder. The results of the second study were that on univariate analysis, stratified by stage, C-reactive protein (p<0.05), increased Ki-67 labelling index (p<0.05), increased tumour associated macrophage (p<0.01), increased tumour microvessel density expression (p<0.001) increased COX-2 expression (p<0.05) and adjuvant therapy (p<0.01) were associated with poorer cancer-specific survival. On multivariate analysis of these significant factors, stratified by stage, only C-reactive protein (p=0.004), increased tumour associated macrophage (p<0.001) and adjuvant therapy (p<0.01) were independently associated with poorer cancer-specific survival. These findings would suggest that tumour macrophage infiltration is an important local inflammatory response associated with disease progression and poor survival in patients with transitional cell carcinoma of the urinary bladder. The results of the third study were that, using multiple cytokine analysis technology, Th0-type cytokines/chemokines (IL-6, IL-7, IL-8, IL-15 and GM-CSF), Thl-type cytokines/chemokines (IL-2, interferon-gamma and TNF-alpha) and Th2-type cytokines/chemokines (IL-4, IL-5, IL-10 and IL-13) measurement showed median plasma concentrations below the limit of detection (5pg/ml) irrespective of their C- reactive protein concentrations, stage and grade. However, macrophage/monocyte-type cytokines/chemokines (MIP-1 alpha, MIP-1 beta and MCP-1) and eosinophils-type cytokines/ehemokines (EOTAXIN) had detectable median plasma concentrations but also were not associated with elevated C-reactive protein concentrations, stage and grade. These findings were inconclusive because of the low concentrations measured in the plasma. Further work is required to obtain reliable measurements in the plasma of patients with transitional cell carcinoma using multiple cytokine analysis technology. Therefore, the results suggest that an elevated C-reactive protein concentration would be a useful marker of poor cancer-specific survival in patients with transitional cell carcinoma of the urinary bladder, in addition to tumour-based factors, and enable the stratification of patients for study and follow-up. Furthermore, that tumour macrophage infiltration is also an important predictor of outcome and is directly associated with C-reactive protein concentration and may be, through IL-6, an important mediator of C-reactive protein and the systemic inflammatory response. (Abstract shortened by ProQuest.).

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from the Scottish Executive Health Department through the Chief Scientist Office Award.
• Keywords: Oncology, Immunology.
• Subjects: Q Science > QR Microbiology; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: McMillan, Dr. Donald C .
• Date of Award: 2007
• Depositing User: Enlighten Team
• Unique ID: glathesis:2007-71130
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 May 2019 10:49
• Last Modified: 30 Jun 2021 16:09
• URI: https://theses.gla.ac.uk/id/eprint/71130

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