Background: At the time of diagnosis, approximately 75% of all bladder cancers are Non-Muscle Invasive Bladder Cancers (NMIBC) - the standard treatment for these cancers is a Transurethral Resection of the Bladder Tumour (TURBT). Although, the vast majority of these cancers are not life-threatening, they have a high risk of recurrence (and progression, particularly in higher risk NMIBC), despite the use of adjuvant intravesical chemotherapy. Consequently, patients are kept on long term cystoscopic surveillance with endoscopic removal if recurrences are detected - this impacts on patients' quality of life and contributes to the high cost for the healthcare provider. Aims: The fundamental aim of this series of clinical studies, spanning 12 years, was to identify and implement, means of improving the efficiency in both processing and operating on patients with NMIBC to not only reduce recurrence, but also to reduce the duration of follow up and repeat operations. It was an evolutionary process where the findings in the preceding studies formed the basis of the subsequent one - while the aim of the individual studies were different, there was a clear link to the essential principles, thus forming a coherent collection of studies. Methods and results: The project was carried out in 3 phases (with 2 or 3 main studies in each phase, augmented by 1 to 2 linked studies - making the entire submission for PhD by publications a series of 12 studies, to date): Phase 1 (5 studies in this phase): The aim was to demonstrate the natural history of non-invasive bladder cancer and identify sub-categories of patients who could be discharged from surveillance at 5 years. This was initially achieved by evaluating a prospectively maintained cohort of non-invasive bladder cancer patients diagnosed between 1978 and 1984 at the Western General Hospital, Edinburgh. This study identified the importance of the recurrence rate at the first follow up cystoscopy (RRFFC) as an essential prognostic marker. This finding was further validated using 2 separate cohorts from a different Centre (the Royal Infirmary, Edinburgh) managed in the 80s and the 90s, respectively. The data confirmed that over the decades, recurrence patterns do change, possibly as a result of differing techniques and improvements in optics and instruments; however, what remained the same was the prognostic value of the RRFFC. Phase 2 (3 studies in this phase): The early recurrence was deemed to be the result of missed and tumours left behind at the initial TURBT, i.e. a marker of quality. However, RRFFC was only known 3 months after the initial surgery. Since the RRFFC was such an important prognostic factor, the aim of this phase was to determine the surgical factors contributing to the quality of TURBT and subsequently implement changes to the principles in carrying out the surgery to improve this quality. This was achieved by prospective collection of information regarding all patients undergoing TURBT for new bladder cancers, recording the tumour features, surgeon experience, if the resection was deemed to have been complete or not, and the pathological results. We identified that the detrusor muscle in the resected specimen and the experience of the surgeon were independent determinants of TURBT quality. This finding was validated in a further study using cohorts from another time period and another Centre - this allowed me to develop the concept of Good Quality White Light TURBT (GQWLTURBT) as the benchmark for the white light TURBT. Phase 3 (4 studies in this phase): Photodynamic Diagnosis assisted TURBT (PDDTURBT) was demonstrated in randomised controlled trials as a technique that reduces the recurrences in NMIBC. In the absence of evidence with this technique in the 'real life' setting nor comparisons with standardised, benchmarked white light TURBT technique, we performed a prospective controlled study comparing PDD-TURBT and GQ-WLTURBT, evaluating early and delayed recurrence rates in 2 separate studies. I also performed a multicentre UK study on the outcomes with PDD-TURBT and collaborated with other experts in Europe in producing a review article around Photodynamic Diagnosis and the cost effectiveness of this technique. Summary: This coherent series of studies has contributed to knowledge in bladder cancer surgery by, among others: (a) mapping the individual patient natural history of non-invasive bladder cancer; (b) confirming the importance of early recurrence as a strong prognostic indicator; (c) identifying predictors of this early recurrence and the quality of TURBT; (d) introducing the concept of the benchmark Good Quality White Light TURBT and (e) demonstrating the benefits of photodynamic diagnosis within a 'real life' setting.

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