Yes / Purpose: Despite positive responses in phase II clinical trials, the bioreductive prodrug apaziquone failed to achieve statistically significant activity in non-muscle invasive bladder cancer in phase III trials. Apaziquone was administered shortly after transurethral resection and here we test the hypothesis that haematuria inactivates apaziquone. Methods: HPLC analysis was used to determine the ability of human whole blood to metabolise apaziquone ex vivo. An in vitro model of haematuria was developed and the response of RT112 and EJ138 cells following a 1-h exposure to apaziquone was determined in the presence of urine plus or minus whole blood or lysed whole blood. Results: HPLC analysis demonstrated that apaziquone is metabolised by human whole blood with a half-life of 78.6±23.0 min. As a model for haematuria, incubation of cells in media containing up to 75% buffered (pH 7.4) urine and 25% whole blood was not toxic to cells for a 1-h exposure period. Whole blood (5% v/v) significantly (p<0.01) reduced the potency of apaziquone in this experimental model. Lysed whole blood also significantly (p<0.05) reduced cell growth, although higher concentrations were required to achieve an effect (15% v/v). Conclusions: The results of this study demonstrate that haematuria can reduce the potency of apaziquone in this experimental model. These findings impact upon the design of further phase III clinical trials and strongly suggest that apaziquone should not be administered immediately after transurethral resection of non-muscle invasive bladder cancer when haematuria is common. / Financial support from Spectrum Pharmaceuticals Inc. for the conduct of the experiments.

Conclusion. Impairment in bladder and brain functions was identified in children with severe NE. Post-treatment studies indicated that brain function normalized in parallel with amelioration of bladder dysfunction. Interaction between brain and bladder dysfunction is likely to have an important implication in the pathophysiology and resolution of NE. / Objective. To (1) investigate sleep pattern and cortical arousals in enuretic children; (2) assess brain and bladder function in enuretic children; (3) evaluate post-treatment brain and bladder functional changes in enuretic children and correlate these with the treatment outcomes. / Part II. Fifty-two patients with severe PNE and 15 normal controls were recruited. Bladder and brain functions (sleep arousal threshold, P300 ERPs latency and PPI of startle amplitude) in enuretic children were evaluated, and brain function was compared with normal controls. / Part II. Markedly reduced nocturnal FBC and impaired brain function were found in enuretic patients. Higher sleep arousal threshold was negatively correlated to lower FBC. Prolonged P300 ERPs and higher PPI of startle amplitude were positively correlated to a higher sleep arousal threshold. / Part III. NE episodes and bladder function were re-evaluated in 52 severely enuretic children (Part II) at 3 and 6 months on treatment. Brain function was re-evaluated in 41/52 enuretic children at 6 months on treatment. / Part III. Post-treatment FBC significantly increased, and sleep arousal threshold, number of awakenings, P300 ERPs latency and PPI of startle amplitude normalized in treatment responders. NE episodes reduction was significantly correlated to the improvement in FBC and brain function. Greater decrease in sleep arousal threshold was positively correlated to higher FBC increase. Higher P300 ERPs latency and PPI of startle amplitude reduction were positively correlated to greater decrease in sleep arousal threshold. / Patients and methods. Part I. Thirty-five children with refractory PNE and 21 normal controls were recruited. Overactive bladder contractions, NE episodes and volume in enuretic children, sleep stages and cortical arousals in all children were recorded. / Results. Part I. Underlying bladder dysfunction, abnormal sleep architecture and increased cortical arousal index were found in enuretic children. Cortical arousal index was positively correlated to the frequency of overactive bladder contractions. / Diao Mei. / "May 2005." / Adviser: Chung-Kwong Yeung. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3693. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 135-159). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

Chan Wing Yan Michael. / "August 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 168-200). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Background and purpose. Recent studies have shown that the children with severe nocturnal enuresis, or bedwetting, often have underlying bladder dysfunction as well as various types of brainstem disorders, including arousal inability, a deficient response to startle sounds, or prepulse inhibition. Since the pontine micturition centre is anatomically very close, even overlapping with the nuclei responsible for sleep arousal, one may speculate that there may be close inter-relationships between abnormal bladder function, brainstem dysfunction and sleep-arousal disturbance. We hypothesize that the brainstem function would be changed in response to alteration of bladder function. Using conventional-fill cystometric study, functional magnetic resonance imaging (fMRI) scanning and immunohistochemistry approaches, we propose to characterize the functional changes in the brainstem in response to altered bladder function (i.e. surgically reduced bladder capacity). / Conclusions. Our results showed that bladder dysfunction elicited by surgical reduction in bladder capacity can induce functional changes in the central nervous system. In response to surgical reduction in bladder capacity, deactivation in the vlPAG was detected suggesting that the vlPAG plays a role in the biofeedback of bladder dysfunction. / Data are expressed as the mean +/-1SD unless otherwise specified. Appropriate statistical tests were used for parametric and non-parametric testing between the groups by using the SPSS computer program. In all comparisons a statistical significance level of 95% (p&lt;0.05) was chosen. / Immunohistochemistry study showed a significant decrease in the reaction of dopaminergic neuron in the correspondent regions, suggesting a dopaminergic dependent change in the vlPAG in response to the bladder dysfunction. / In addition, we will explore the use of electroacupuncture (EA), a traditional Chinese therapy that has been broadly used for treatment of bladder functional disorders, to modulate functional changes in the central nervous system. We hypothesize that functional change in various nuclei in the central nervous system that are responsible for micturition control can also be affected by acupuncture treatment. A further aim of this study was to identify brain areas involved in EA to acupoint Chiliao (BL 32), a special acupoint broadly used for the treatment of bladder disorders. / Materials and methods. The study was divided into four parts. Seventy-five male New Zealand white rabbits (14-16 weeks, mean body weight: 3.0-3.5 kg) were used. / Moreover, in this study, we also found a notable activation in the vlPAG and dlPONS in response to the acupuncture stimulations to acupoint Chiliao (BL 32). The changes were identical to that induced by the bladder distension, suggesting a neuromodulation in central nervous system in response to acupuncture therapy. / Results. Study I: Bladder dysfunction elicited by surgical reduction in bladder capacity. Compared to sham animals, the maximum cystometric capacity in animals with RBC operation was markedly decreased at week 4 (35.3+/-8.2 ml vs. 71.6+/-12.9 ml, p&lt;0.05), and week 8 (46.2+/-12.1ml vs. 82.7+/-20.1 ml, p&lt;0.05) groups respectively; however, the maximum voiding detrusor pressure was significantly increased at week 4 (24.4+/-7.0 vs.16.5+/-7.2 cm water, p&lt;0.05) and week 8 (27.7+/-8.p vs. 16.8+/-7.5 cm water, p&lt;0.05) groups respectively, and their corresponding vesical pressure was also enhanced. Other parameters including maximum flow rate, and bladder emptying efficiency did not change significantly in between the sham and RBC subgroups. / Study I: Establishment of the dysfunctional bladder animal model with small bladder capacity. Forty rabbits underwent either sham operation (n=20) or operation for reduced bladder capacity (RBC) (n=20). The sham-operated and the RBC animals were further divided into two groups, i.e. four, and eight weeks after operation (n=10 in each sham and RBC subgroup). A conventional-fill cystometric study was performed on these animals whilst awake in order to evaluate the functional changes (if any) in response to surgical bladder capacity reduction, compared to sham subgroup. / Study II: Detection of functional changes in the brainstem in response to bladder dysfunction. FMRI scanning was performed at the brainstem region in sham-operated and RBC rabbits (12 in each group) at four weeks postoperatively. Bladder stimulation was provided by warm saline (37&deg;C) infusion through a urethral catheter until bladder distended to 70% of the maximum capacity. Area(s) of brainstem activation were assessed by comparing the fMRI scans performed before and after warm saline infusion. / Study II: Functional changes in brainstem in response to bladder dysfunction. FMRI scanning results demonstrated that for the sham animals, there were two activated regions in the brainstem in response to bladder distention, one in the ventrolateral region of periaqueductal gray (vlPAG, 83.3%, 10/12), and the other in the dorsolateral region of pons (dlPONS, 91.7%, 11/12). In animals with RBC operation, only 25% (3/12) showed vlPAG activation compared to 83.3% (10/12) in sham group (p&lt;0.05); however, 83.3% (10/12) of animals showed similar dlPONS activation compared to 91.7% in sham group (p>0.05). / Study III: Catecholaminergic neurotransmitters changes in the brainstem affected areas in response to bladder dysfunction. Brainstem immunohistochemistry results showed that a large number of dopaminergic neuron scattered throughout the whole vlPAG, rarely appeared in dlPAG (dorsolateral region of periaqueductal gray) (lambda +6.0 to +3.0 mm); and an abundant noradrenergic neurons were also accumulated in a restricted region of dlPONS (lambda +3.0 to 0 mm). Compared with the sham group, the density of TH-positive neurons in the vlPAG was significantly decreased in RBC group (38.38+/-4.71 vs.51.57+/-8.38/field, p&lt;0.05); for the another region of dlPONS, although the density of TH-positive neurons decreased slightly in RBC group compared to sham group, the results showed no statistical difference between groups (106.89 +/- 21.61 vs.120.61 +/- 17.03/field, p>0.05). / Study III: Investigation of the catecholaminergic neurotransmitters changes in brainstem affected areas in response to bladder dysfunction. After fMRI examination, all animals were euthanized, and their brainstems were collected for immunohistochemistry study with tyrosine hydroxylase, dopamine-beta-hydroxylase assays to investigate the changes of catecholaminergic neurotransmitters including dopaminergic, noradrenergic and adrenergic in response to bladder dysfunction elicited by surgical reduction in bladder capacity. / Study IV: Electroacupuncture modulation via acupoint Chiliao (BL 32) on bladder and the brainstem activated sites. FMRI study showed that the two brainstem micturition centers of the vlPAG (72.7%, 8/11) and dlPONS (82.8%, 9/11) can be activated by EA on BL 32, and there were no significant difference compared with stimulation of bladder distention (72.7% vs. 83.3% in vlPAG and 82.8% vs. 91.7% in dlPONS respectively, p>0.05). Urodynamic results showed that, bladder contraction obviously evoked in response to EA on BL 32 (ON-EA state) compared to before EA state (OFF-EA state), displaying a significantly increased detrusor pressure (14.04+/-3.17 vs. 8.19+/-0.69 cm water, p&lt;0.05) and vesical pressure (13.48+/-1.61vs. 7.90+/-0.81 cm water, p&lt;0.05). In addition, dissection of BL 32 showed that the stem of S1 and S2 pass through the region 0.5 cm around the acupuncuture needle. / Study IV: Investigation of electroacupuncture modulation via acupoint Chiliao (BL 32) on bladder and the brainstem activated sites. FMRI scanning and urodynamic evaluation were performed respectively during ON/OFF EA on acupoint Chiliao (BL 32) on sham-operated animals (n=12) at four weeks post-operation. At last, dissection of acupoint BL 32 was performed on seven sham animals. / We also found that surgically induced bladder dysfunction, mainly displaying as reduced bladder capacity and maximum voiding detrusor pressure enhanced, was elicited at four to eight weeks after the surgical reduction in bladder capacity in rabbit. / Xiang Bo. / "August 2006." / Adviser: Chung Kwong Yeung. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1551. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 161-196). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Objectives: To establish a mouse orthotopic bladder cancer model with consistent tumor-take rate. This orthotopic model was subsequently used to evaluate small animal imaging techniques and investigate new therapeutic agents for bladder cancer treatment. / Materials and Methods: Different orthotopic implantation techniques have been tested. MBT-2 cells and syngeneic C3H/He mice were used in all experiments. Chemical bladder pre-treatment with different agents (saline, hydrochloric acid, trypsin and poly-L-lysine) and different concentration of instilled tumor cells (1 x 10⁶ or 2 x 10⁶) were investigated. In the second part of the experiment, trans-abdominal micro-ultrasound imaging (MUI) technique was investigated and validated. Bladder tumor growths were monitored with longitudinal measurement. Mice were killed at every MUI session. Bladder tumor volumes were measured and correlated with gross stereomicroscopy. Using the optimized orthotopic bladder cancer model, targeted contrast enhanced micro-ultrasound imaging has been investigated. VEGFR2 targeted contrast agent was prepared and injected intravenously before imaging sessions. The intra-tumoral perfusion, VEGFR2 expression and blood volume in real time were quantified. Contrast enhanced MUI was performed on Days 14 and 21. The feasibility of targeted contrast enhanced micro-ultrasound imaging was confirmed. After the establishment of orthotopic model and in vivo molecular imaging techniques, this robust platform was used for investigating new treatment agent in localized bladder cancer. Tumor-bearing mice were randomized into control and sunitinibtreated (40 mg/kg) groups. Tumor volume, intra-tumoral perfusion, and in vivo VEGFR2 expression were measured using a targeted contrast-enhanced micro-ultrasound imaging system. The effects of sunitinib malate on angiogenesis and cellular proliferation were measured by CD31 and Ki-67 immunohistochemistry. The clinical outcomes including total bladder weight, tumor stage, and survival were evaluated. / Results: A consistent tumor take-rate of over 90% was achieved by using poly-L-lysine pretreatment with 2 x 10⁶ MBT-2 cells in all of the experiments. MUI identified all tumors that were present on final histology. Measurements of tumor size by MUI and gross microscopy had a high correlation coefficient (r = 0.97). Measurements of intra-tumoral perfusion and in vivo VEGFR2 expression were also proved to be feasible. After the technical refinement and modification, complete measurements could be performed in all mice (n = 10) at 2 consecutive imaging sessions. No adverse effects occurred due to anesthesia or the ultrasound contrast agent. This is the first report of applying targeted contrast enhanced MUI in orthotopic bladder cancer model. Finally, sunitinib was found to have significant tumor growth inhibition in both in vitro and in vivo experiments. In the orthotopic model, tumors in sunitinib-treated mice had reduced tumor volume and stage, lower proliferation index and micro-vessel density. Sunitinib prolonged survival in tumor-bearing mice as compared to control group. / Conclusions: The development of reliable orthotopic animal models assists in the discovery of novel therapeutic agents. The establishment in the methods of implantation with improved tumor-take rate and the advances in imaging technology form the important foundation of basic research in bladder cancer. Trans-abdominal MUI is proven to be a valuable tool for translational studies involving orthotopic mouse bladder cancer models. Furthermore, the first report of the application of targeted contrast enhanced MUI in deep-seated tumor in bladder has been published. It enables investigators to monitor tumor angiogenesis and vascular changes after treatment. It will be useful for direct, noninvasive, in vivo evaluation of anti-angiogenesis therapeutic agents. The preclinical study has demonstrated the activities of a new class of targeted therapy against localized bladder cancer in an orthotopic mouse model. Sunitinib inhibits tumor growth and thus decreases the tumor burden and prolongs survival compared with placebo. These results provide a rationale for future clinical trials using VEGFR-targeted treatments of localized bladder cancer in the neo-adjuvant and adjuvant settings. / Chan, Shu Yin Eddie. / Thesis (M.D) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 189-212).

La sensibilité vésicale est un pré-Requis au contrôle normal de la vessie. Les objectifs de cette thèse après une analyse de la littérature étaient d'étudier les outils d'évaluation de la sensibilité de la vessie et les possibles facteurs influençant les sensations vésicales. Une première étude démontre l'effet de sensibilisation de l'eau froide pendant une cystomanométrie sur la sensation de besoin d'uriner et les interactions entre les voies afférentes du besoin d'uriner et thermique. Une seconde étude a montré l'effet d'un remplissage rapide lors d'une cystomanométrie sur la sensation de besoin avec un besoin d'uriner retardé. Une troisième étude a mis en évidence chez un certain nombre de patients l'influence de la suggestion verbale sur les sensations vésicales. L'apport des séquences de diffusion en IRM pelvienne pour distinguer le syndrome douloureux vésical chronique /cystite interstitielle d'autres syndromes douloureux pelvi-Périnéaux a été étudié. La validation psychométrique d'un questionnaire sur les circonstances de déclenchement des urgenturies a été commencée. Un protocole de remplissage vésical physiologique a également été développé permettant d'étudier les interactions entre la sensation de besoin d'uriner et les performances attentionnelles. Les deux dernières études ont porté sur l'effet de certains stimuli environnementaux sur les sensations vésicales chez des sujets atteints de syndrome clinique d'hyperactivité vésical et des volontaires sains. Ce travail a permis de souligner certains facteurs pouvant influencer la sensibilité vésicale et de développer des outils prometteurs pour son évaluation. / Urinary bladder sensation is a pre-Requisite of a normal bladder control. Understanding the physiological mechanisms leading to bladder sensation generation and transmission to a conscious perception which can lead to a socially acceptable void is fundamental. The aims of this thesis after a comprehensive literature analysis were to study bladder sensation evaluation tools and possible influencing factors. A first study demonstrate the sensitization effect of cold water during cystometry on bladder need to void and the interaction between need to void and thermic afferent pathways. A second study showed the effect of a high filling rate on bladder sensation during a cystometry with a delayed need to void. A third study brought out the influence of verbal suggestion of bladder filling on bladder sensation in a number of patients. The sensibility and specificity of diffusion weighted MRI sequences to detect bladder pain syndrome / interstitial cystitis among pelvic pain was underlined in a fourth study. Then the first steps of the psychometric validation of a new questionnaire about circumstances triggering urinary urgency were developed. A water loading protocol was also developed to study the influence of possible factors on bladder sensation. This protocol allowed studying the interactions between bladder sensation and attentional performances. The two last studies studied the effect of classical environmental urgency triggers on bladder sensation in overactive bladder patients and healthy volunteers. In conclusion this work permitted to underline some possible influencing factors of bladder sensation and to develop new promising tools for bladder sensation evaluation.

Intravesical electrical stimulation (IVES) has been used in treatment of patients with urinary bladder dysfunctions for more than four decades. While some investigators have reported excellent results others have observed less convincing effects or outright failures. The discrepancies may reflect differences in patient selection or stimulation procedure. A better theoretical understanding of the IVES working mechanism might help to improve the success rate of the treatment. The aims of the present study were to provide such information. Experiments were performed on adult female cats and rats under /alpha/-chloralose anesthesia. IVES was delivered by a catheter electrode in the bladder. At proper intensity and frequency, IVES evoked reflex detrusor contractions that were abolished by bilateral rhizotomy of sacral dorsal roots. Stimulation parameters and response characteristics revealed that bladder mechanoreceptor A/delta/ afferents were activated by the IVES, the same afferents that drive the normal micturition reflex. Five minutes of continues IVES at 20 Hz induced a prolonged, significant decrease in the micturition threshold volume of anesthetized rats. Similarly, selective bladder A/delta/ afferent stimulation induced a long-lasting enhancement of micturition reflex discharges in cats. A comparable prolonged inhibitory effect on the micturition reflex was demonstrated after ano-genital afferent stimulation. Both modulatory effects occurred without changes in response sensitivity of stimulated afferents. The IVES induced modulation was prevented by transient exposure of the bladder to a local anesthetic and by systemic administration of a glutamate NMDA receptor antagonist. In conclusion, IVES induces a prolonged modulation of the micturition reflex by an LTP like enhancement of excitatory synaptic transmission in the central micturition reflex pathway. The findings provide an experimental explanation for the neuronal mechanisms underlying the curative effect of IVES in patients with bladder evacuation problems. / On the day of the public defence the status of article V was: Accepted.

Bladder cancer is one of the most common urogenital cancers worldwide. Two techniques commonly used for bladder cancer diagnosis are urine cytology and cystoscopy. Cytology is not sensitive for detecting tumors. Cystoscopy is an invasive technique which disturbs patient comfort. In the current study, we used Fourier transform infrared (FT-IR) spectroscopy as a novel method which is rapid and non-invasive to investigate the bladder tumor recurrence using the bladder wash samples collected in the course of control cystoscopy. This study is unique since it is the first one to use the bladder wash sample in the diagnosis of the bladder tumor by using FT-IR spectroscopy. Molecular investigation of the FT-IR spectra revealed many differences between control and tumor samples such as a considerable increase in protein, carbohydrate and nucleic acids content, and changes in protein and carbohydrate structure. On the basis of the spectral differences, cluster analysis was performed to differentiate between the control and tumorous spectra and we reached to an overall sensitivity (including all individuals with tumor) of 91.8%, a PUNLMP sensitivity of 83.3% and a papilloma sensitivity of 77.8% in spectral range 1444-1457 cm-1. Other spectral ranges also gave similar results. Our results showed that FT-IR spectroscopy can be used to detect the bladder tumors in bladder wash sample with higher sensitivity compared to cytology. In summary, we propose the utilization of the FT-IR spectroscopy for the detection of bladder tumors since specific spectral regions might be used as effective markers for the diagnosis.

The purpose of this study is to investigate whether a prolonged delay in diagnosis of bladder cancer will result in worse outcomes for those patients, compared to those patients with a shorter diagnostic time interval. Data was collected on 247 patients newly diagnosed with transitional cell carcinoma of the bladder from January 1996 to December 2006 (10 years). The medical records of these patients were reviewed for demographics, pathological stage, date of consultation to the genitourinary (GU) service, and date of diagnosis by transurethral resection of bladder tumor (TURBT). The specialty delay was calculated as the time between the date of consultation to the GU service to the establishment of a diagnosis by TURBT. Univariate analyses were performed to test the association of specialty delay with clinical features and all-cause mortality. The median specialty delay in this study was 100 days. There was a trend towards a longer specialty delay for muscle-invasive disease (T2-T4) in comparison to superficial disease (Ta and T1). There was a significant correlation between all-cause mortality and increasing clinical stage (p=0.01). There was a paradoxical finding that patients with a specialty delay greater than 100 days had a significant reduction in all-cause death in comparison to patients with a specialty delay of 100 days or less (relative risk=0.59; 95% CI 0.36-0.90; p=0.01). In conclusion, this study did not confirm the hypothesis that a prolonged specialty delay in patients diagnosed with bladder cancer would result in a worse prognosis. In fact, there was a paradoxical finding that patients with a specialty delay greater than the median delay of 100 days had a better prognosis.

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