Thesis (M.Med. ( Anaesthesiology)) --University of Limpopo (Medunsa Campus), 2011 / Introduction: Multiple studies have described a variable incidence of transient hearing loss (hypoacousis) from 0.4% to 40% after subarachnoid block, especially in the low-frequencies range (125 – 500 Hz) (1, 2). The mechanism of transient hypoacousis is attributed to leakage of cerebrospinal fluid, which leads to a decrease in perilymph pressure within the cochlear. Hypothesis: The study hypothesis was based on an assumption that hearing loss is more frequent in young patients who undergo spinal anaesthesia in comparison with elderly patients. Objective: 1) To determine the incidence of hearing loss after spinal anaesthesia in the young versus elderly patients. Materials and Methods: Ninety-eight male patients (ASA 1 - 11) scheduled for cystoscopy under spinal anaesthesia were recruited for the study. Recruitment of patients for the study was age dependent and was divided into two groups: One group (49 patients) had patients aged between 17 and 44 years (Group Y) and the other group had 49 patients aged between 45 and 77 years made up group two (GROUP E). Subarachnoid injection at L3-4 was performed using a standard 22-gauge Quincke spinal needle with patients in the sitting position and 2,5 ml to 3 ml of 0.5% isobaric bupivacaine was administered. Patients were evaluated on the day before spinal anaesthesia by pure tone audiometry at three different frequency sounds viz. 125 – 500 Hz (Low frequency), 500 – 2000 Hz (Speech frequency) and at 2000 – 4000 Hz (High frequency). This assessment was repeated 48 hours after the spinal block was given Statistical Analysis: Analysis was descriptive providing information on the mean (or median) and standard deviation of the variables for each of the two groups. The results of the audiometry were analyzed using repeated measures analysis of variance and transformation to p-value. Differences in outcomes of the study between the two groups were recorded as being statistically significant if p-value is ≤ 0.05. Results: No patient from the two groups developed hearing loss either at low or high frequencies. However, there was a statistically significant improvement in audiometric results (p-value ranging from 0.0001 and 0.063) 48 hours post-surgery in the elderly group as compared with patients in the younger group. Conclusion: The study revealed no hearing loss post-spinal anaesthesia in both groups. It did, however, show that the elderly group have better hearing acuity at all three frequency levels of sound compared to the younger group after spinal anaesthesia

Introduction: Macroscopic hematuria is an important alarm symptom of cancer in theurinary tract. One single episode in patients over the age of 50 fulfills the criteria for referralto the standardized care pathway. Several patients included in the pathway with a negativeresult of the investigation will return with recurrent macroscopic hematuria for repeatinvestigation. Aim: To evaluate the diagnostic yield of repeat investigation in patients presenting withrecurrent macroscopic hematuria after a previous negative investigation and to estimate theincidence of false negative investigations in the standardized care pathway for cancer in theurinary tract. Material and Methods: A retrospective review of medical records was performed at theDepartment of Urology in Örebro County, including all patients investigated in thestandardized care pathway for cancer in the urinary tract during 2016 with a negative result ofthe investigation. Individuals with repeat investigation were identified. Results of theseinvestigations and the time interval between investigations were documented. Results: Repeat investigation was performed in 96 out of 627 patients (15.3%). Two (2.1%)were diagnosed with cancer, at a time interval from initial investigation of 4 and 27 months,respectively. Other results were benign urological conditions (n = 62) and normalinvestigations (n = 30). Conclusions: It appears that few tumors are missed when macroscopic hematuria isinvestigated in the standardized care pathway. We observed a very low number of newlydiagnosed cancers after repeat investigation of recurrent macroscopic hematuria. A moreselective approach regarding repeat investigations should be considered.

Cette thèse propose un algorithme de mosaïquage pour la construction d'images panoramiques des parois internes de la vessie. Le temps de construction de ces images correspondant aux parties intéressantes de la vessie doit être inférieur à la durée d'un examen clinique standard. La méthode de mosaïquage doit aussi être robuste vis-à-vis des variabilités inter-examens liées aux patients et aux instruments. Ces images panoramiques pourront être utilisées par le clinicien comme référence pour guider des examens ultérieurs, pour l'archivage des données et pour suivre l'évolution des lésions. La première étape de l'algorithme est le pré-traitement des images cystoscopiques consistant en l'atténuation des inhomogénéités d'illumination et du motif de fibres optiques visible dans les images acquises par un fibroscope. La deuxième étape est le recalage des images. La solution retenue consiste en la corrélation par les transformées de Fourier des images qui fournit des translations initiales à un algorithme itératif basé sur la différence d'intensité entre les images. Ce dernier délivre les paramètres de la transformation perspective reliant deux images successives de la séquence. Dans la troisième étape nous projetons les images dans un repère commun en utilisant des transformations globales calculées avec les résultats des recalages. Nous utilisons un moyennage pondéré des intensités des pixels pour atténuer les bords visibles lors de la projection. Les résultats quantitatifs obtenus avec un fantôme et des résultats qualitatifs calculés pour des séquences réelles montrent que notre approche automatique de mosaïquage est robuste et rapide (temps compatible avec la durée d'un examen cystoscopique clinique). Nos tests ont également prouvé que l'algorithme de recalage fonctionne pour des transformations géométriques plus grandes que celles rencontrées typiquement entre images d'une séquence vidéo (90% de recouvrement entre images consécutives pour ces dernières) / This work describes a mosaicing algorithm for constructing panoramic images of internal walls of the bladder. Time relating to the construction of panoramic images including the interesting parts must be shorter than that required by a standard cystoscopic examination. The mosaicing algorithm must be robust against lighting conditions, morphologic and texture variations relating to instruments and patient anatomy. These panoramic images could be used by a clinician for guiding further exams, storing non-redundant data and following-up evolution of lesions. The preprocessing of cystoscopic images is the first stage of the algorithm. Preprocessing consists of shading correction and fiber optics pattern attenuation occurring in fiberscope acquired images. The second stage is image registration. The chosen solution consist of cross-correlating images (using their Fourier transforms) in order to have initial translations for an iterative registration algorithm based on the sum of squared differences of images. In the third stage, images are projected in the coordinate system of the panoramic image using global transformations computed with matrices given by the iterative registration. We use a weighted average of pixel intensities to blend visible borders of images produced in the projection process. Numerical results obtained with a phantom and qualitative results obtained with real sequences show that our automatic approach is robust and allows for a fast construction of panoramic images in a period of time that is shorter than the duration of a clinical cystoscopic examination. Our experiments showed that the registration algorithm can handle geometric transformations that are larger than those existing typically in a video-sequence (90% of superposition between successive images in this case)

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.

Le cancer de la vessie est un cancer fréquent et extrêmement onéreux par patient puisque plusieurs patients subissent des récidives de cancer et ont recours parfois à des chirurgies complexes. Il est donc important de diagnostiquer efficacement ces cancers lors de la prise en charge initiale du patient. En effet, la procédure standard d’imagerie pour la détection du cancer est la cystoscopie de la vessie guidée par lumière blanche, toutefois cette méthode ne permet pas de bien distinguer les cellules qui sont propices à l’invasion musculaire des cellules de cancer de la vessie non infiltrant. Ce mémoire propose d’utiliser un nouvel immunoconjugué fluorescent ciblant la sous-unité alpha du récepteur de l’interleukine 5, un nouveau biomarqueur spécifique aux cellules du cancer de la vessie infiltrant, afin d’effectuer la cystoscopie de la vessie guidée par fluorescence. Pour ce faire, un protocole de conjugaison du fluorochrome cyanine-5 (Cy5) à un anticorps monoclonal a été développé. De plus, un protocole de conjugaison d’un peptide Cell Accumulator (ACCUM) sur cet anticorps fluorescent (A14-Cy5-ACCUM) a été optimisé. Ensuite, la capacité de cet immunoconjugué à marquer les cellules humaines de cancer de la vessie infiltrantes du muscle (MIBC), HT1376, a été testée. Par la suite, un nouveau modèle orthotpique murin de MIBC humain permettant la validation préclinique prochaine de l’A14-Cy5-ACCUM a été développé. Une banque de plasma et sérum sanguin, et d’urine de patients sains et atteints de cancer de la vessie a été compilé. Cette biobanque contient 111 échantillons de plasma sanguin et d’urine qui pourront être utilisé afin de tester l’hypothèse selon laquelle le niveau d’interleukine-5 sanguin pourrait être un facteur pronostique pour la progression du cancer de la vessie. Ce projet jette les bases pour l’évaluation potentielle de la cystoscopie guidée par fluorescence lors de la prise en charge initiale des patients atteints de cancer de la vessie afin d’améliorer la survie sans progression et la survie à long terme des patients atteints de MIBC. / Abstract: Bladder cancer is a frequent and extremely costly cancer when evaluated on a per-patient basis because of its high recurrence rate and patients undergoing complex medical procedures. It is of utmost importance to better identify the aggressiveness of this cancer at initial diagnosis. The standard procedure for bladder cancer detection is still white-light guided cystoscopy, which relies mostly on physicians experience in regard to identifying invasive malignancies. This memoir proposes the use of a new fluorescent immunoconjugate, targeting the alpha subunit of interleukin-5 receptor (IL-5R[apha]), a new biomarker specific to muscle-invasive bladder cancer (MIBC) cells for fluorescence-guided cystoscopy. To do so, a conjugation protocol to fluorescently label a monoclonal antibody with cyanine-5 fluorophores has been developped. Then, a conjugation protocol to attach Cell Accumulator (ACCUM) peptides to this fluorescent immunoconjugate (A14-Cy5-ACCUM) has been optimized. Moreover, the ability of A14-Cy5-ACCUM to stain MIBC cell line HT1376 has been tested. Most importantly, a novel orthotpic rat model of human MIBC for the future preclinical validation of fluorescence-guided cystoscopy in rat bladder has been developped. Finally, a new bladder cancer tissue repository at the CHUS has been established. This repository contains a total of 111 plasma and urine patient samples that will be helpful to evaluate if interleukin-5 blood levels could be used as a prognosis marker for bladder cancer progression. This project laid the basis for the potential evaluation of fluorescence-guided cystoscopy during initial diagnosis of bladder cancer patients to improve their disease-free and long-term survival.

This thesis addresses the three principal questions concerning the development of CT urography for investigating haematuria and each question is the subject of a separate chapter. The questions are: What is the reasoning behind using CT urography? What is the optimum diagnostic strategy using CT urography? What are the problems with using CT urography and how may solutions be provided? Haematuria can signify serious disease such as urinary tract stones, renal cell cancer, upper tract urothelial cancer (UTUC) and bladder cancer (BCa). CT urography is defined as contrast enhanced CT examination of kidneys, ureters and bladder. The technique used here includes unenhanced, nephrographic and excretory-phases for optimized diagnosis of stones, renal masses and urothelial cancer respectively. The reasoning behind using excretory-phase CT urography for investigating haematuria is based on results showing its high diagnostic accuracy for UTUC and BCa. Patients with haematuria are classified as low risk or high risk for UTUC and BCa, by a risk score, determined by the presence/absence of risk factors: age > 50 years, visible or nonvisible haematuria, history of smoking and occupational exposure. The optimum diagnostic strategy for patients at high risk for urothelial cancer, uses CT urography as a replacement test for ultrasonography and intravenous urography and as a triage test for flexible and rigid cystoscopy, resulting in earlier diagnosis and potentially improving prognosis. For patients at low risk, ultrasonography, unenhanced and nephrographic-phase CT urography are proposed as initial imaging tests. Problems with using CT urography include false positive results for UTUC, which are eliminated by retrograde ureteropyelography-guided biopsy, an innovative technique, for histopathological confirmation of diagnosis. Recommendations for the NHS and possible future developments are discussed. CT urography, including excretory-phase imaging, is recommended as the initial diagnostic imaging test before cystoscopy for patients with haematuria at high risk for urothelial cancer.