Surgery (Austin & Northern Health) - Theses
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ItemHealth economic analysis and the role of multiparametric magnetic resonance imaging in prostate cancer( 2023-08)Prostate cancer is the most common solid organ malignancy diagnosed in men. Its diagnosis has historically relied on clinical examination, prostate-specific antigen (PSA) screening and biopsy based on transrectal ultrasound. However, ultrasound is not sensitive in identifying abnormal, potentially cancerous areas in the prostate and therefore biopsy has been performed in a ‘random’ fashion that has led to missing clinically significant disease and over-diagnosing indolent disease. Developments in multiparametric magnetic resonance imaging (mpMRI) technology have suggested that it may be superior modality for local imaging of the prostate gland. This thesis will assess the role of mpMRI in the prostate cancer diagnostic pathway. The diagnostic accuracy of mpMRI was assessed to determine the sensitivity of abnormal mpMRI findings and the negative predictive value of a normal mpMRI. The latter is especially important in the proposal to use mpMRI as a tool to identify which men with an elevated PSA need to proceed to prostate biopsy. I will also assess which MRI findings in different populations of men should be recommended for biopsy. In addition, I will develop a nomogram to determine which men needed systematic sampling at the time of their prostate biopsy for accurate diagnosis of their disease and which men can be accurately diagnosed using targeted biopsy alone. Finally, I will perform an economic assessment to determine the cost-effectiveness of incorporating mpMRI in the primary biopsy setting and for men on active surveillance.
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ItemThe role of hypoxia inducible factor 1 alpha (HIF1α) in prostate cancer( 2016)Prostate cancer (PC) is one of the most prevalent cancers in men. Although many PCs are indolent, a significant proportion will metastasize and develop resistance to therapy. Contemporary screening tests lack the finesse to accurately differentiate aggressive PCs from indolent tumours, potentially leading to over-diagnosis and over-treatment. While cellular hypoxia often plays an integral role in carcinogenesis and tumour progression, this connection has been difficult to demonstrate in PC. However, a downstream marker of hypoxia, Hypoxia inducible factor 1α (HIF1α), which is a transcription factor that protects cells against noxious stimuli, is frequently over expressed in PC. Therefore, the role of HIF1α in PC was investigated in this thesis. The Castrate resistant PC (CRPC)-like human PC cell lines PC3 and DU145 were found to over-express HIF1α protein compared to an androgen-sensitive cell line LNCaP under normoxic conditions. Using HIF1α 5’UTR-luciferase constructs in PC3 cells, further experiments revealed that increased translation of HIF1α mRNA regulated by a 70bp GC-rich, secondary structure in the 5’UTR of the HIF1α promoter may be responsible for normoxic HIF1α overexpression. Cell proliferation assays revealed that PC3 cells over-expressing HIF1α were more resistant to destruction by cytotoxic agents (H2O2 and 5-fluorouracil) than androgen-dependent LNCaP cells. Reduction of HIF1α expression in PC3 cells using RNA interference decreased both the resistance towards cytotoxic agents and cell migration. Conversely, in the androgen-dependent LNCaP cells overexpression of HIF1α increased the resistance to cytotoxic agents. One hundred prostate tumours were then immune-stained for HIF1α and outcomes measured. On multivariate analysis HIF1α was an independent risk factor for progression to metastatic PC (Hazard ratio (HR) 9.8, p = 0.017) and development of CRPC (HR 10.0, p = 0.021) in patients on androgen-deprivation therapy (ADT). Notably the tumours that did not express HIF1α did not metastasise or develop CRPC. Next, the effects of non-specific HIF1α inhibitors (digoxin, metformin and angiotensin-2 receptor blockers) were investigated in ninety-eight patients who had continuous ADT as first line therapy and developed CRPC. The median CRPC-free survival was longer in men using HIF1α inhibitors compared to those not on inhibitors (6.7 yrs vs. 2.7yrs, p=0.01) and there was a 71% reduction in the risk of developing CRPC (p=0.02) and an 81% reduction in the risk of developing metastases (p=0.02) after adjustment for Gleason score, age and PSA. Finally, the effects of metformin were investigated in 2055 men treated for PC with external beam radiotherapy. Surprisingly, metformin did not result in any improvement in time to biochemical failure, time to metastases or overall survival in men undergoing radiotherapy, but there was an 1.5 fold increase in PC-specific deaths (p<0.05) in men on metformin who received ADT when adjusted for cancer risk and co-morbidities. In conclusion, the results presented in this thesis indicate that HIF1α is a promising marker in PC, which may be used for early identification of cancers that potentially will progress to metastases and develop resistance to ADT. HIF1α is likely to contribute to metastasis and chemo-resistance of CRPC, targeted reduction of HIF1α may improve outcomes of aggressive PC.