Health-related quality of life using intensity-modulated radiation therapy for post-prostatectomy radiotherapy.

INTRODUCTION: Post-prostatectomy radiotherapy (PPRT) with intensity-modulated radiation therapy (IMRT) has the potential to decrease toxicity by reducing dose to surrounding structures. We assessed its impact on health-related quality of life (HRQoL). METHODS: PPRT patients were enrolled in a prospective HRQoL database. To be eligible, patients were required to be treated with IMRT and have a minimum of 15-month follow up. HRQoL was assessed at baseline, 3, 9 and 15-24 months using the Expanded Prostate Cancer Index Composite questionnaire. Higher scores reflected better HRQoL. Results were analysed as both population means and as individual scores where a moderate change was 10-20 points and a substantial change was >20 points. RESULTS: There were 64 patients eligible and 83% of the cohort received salvage radiotherapy. Prescribed dose was 64 Gy in 32 fractions for adjuvant and 66 Gy in 33 fractions for salvage IMRT. Mean function scores for urinary, bowel and sexual domains were similar at baseline and 15 months (83.5, 94.2 and 16.9 vs. 82.2, 93.1 and 14.3, respectively). Mean global physical functioning (51.0 vs. 48.1) and mental functioning (51.6 vs. 54.2) showed no difference over time. Individual patient scores by 2 years showed a >20-point deterioration in urinary (12.5%), bowel (1.6%), sexual function (9.4%), physical functioning (3.1%) and mental functioning (1.6%). CONCLUSION: This report on HRQoL following post-prostatectomy IMRT demonstrates no variation in mean scores in any domain and only 1.6% of patients reporting a greater than 20-point deterioration between baseline and 15-24 months in bowel function.

Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa.

Recent studies have described muscarinic receptors on the mucosa and the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine, and trospium. Specimens were collected from asymptomatic patients (50-72 years old) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [3H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low-affinity sites in mucosa and 78% low-affinity sites in detrusor, probably representing M(2)/M(4) receptors. There was an excellent correlation (r(2) = 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates ( approximately 20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB.

Age-related changes of P2X(1) receptor mRNA in the bladder detrusor from men with and without bladder outlet obstruction.

The urinary bladder purinergic system is reported to change with age and with bladder dysfunction. Here, we examined the expression of purinergic P2X(1) receptors in detrusor and mucosa (urothelium+lamina propria) from male control bladder and investigated age-related P2X(1) receptor mRNA expression in control and obstructed detrusor. Biopsy specimens were obtained at cystoscopy from control patients (n=46, age range 30-86years) and patients diagnosed with outlet obstruction (n=29, 46-88years). Calponin expression (measured by RT-PCR) was similar in control and obstructed detrusor and did not change with age. Quantitative competitive RT-PCR was used to measure P2X(1) receptor and GAPDH mRNA in control and obstructed detrusor. P2X(1) receptor mRNA expression was 9-fold (p<0.0001) higher in the detrusor than in the mucosa. Expression of mRNA for the internal control GAPDH remained stable with age and across control and obstructed detrusor. No difference in P2X(1) receptor expression was observed between control and obstructed detrusor (p=0.35). However, an age-related decrease in P2X(1) mRNA expression was observed in control (n=27; p=0.0054; Spearman coefficient r=-0.520) but not obstructed detrusor (n=19; p=0.093; r=-0.396). Downregulation of P2X(1) mRNA expression might occur as a result of an increased component of neural ATP release in the aging bladder.

Molecular characterization of M2 and M3 muscarinic receptor expression in bladder from women with refractory idiopathic detrusor overactivity.

OBJECTIVE: To examine the expression of muscarinic M2 and M3 receptors in human bladder detrusor and mucosa, from controls and patients with idiopathic detrusor overactivity (IDO), as antimuscarinic agents are the primary pharmacological treatment for IDO. PATIENTS AND METHODS: Biopsies from the bladder body were collected at cystoscopy from 20 women with urodynamically confirmed refractory IDO (age range 25-86 years); biopsies were also collected from 30 asymptomatic female controls (age range 32-87 years). Samples were collected into RNA extraction medium and dissected into mucosa (urothelium plus lamina propria) and detrusor. RNA was extracted and the expression of M2 and M3 receptor mRNA determined by quantitative competitive reverse transcription-polymerase chain reaction. Results were normalized to beta-actin expression in the same sample. RESULTS: Expression of M3 receptor mRNA, in mucosa of IDO patients (median 0.057 pg M3/100 ng total RNA; interquartile range 0.03-0.13, 12 samples), was four times (P = 0.039, Mann-Whitney) lower than from the control (median 0.22 pg M3/100 ng total RNA; 0.13-0.51, 11 samples). The expression of muscarinic M3 receptor mRNA was higher (14-35 times) in detrusor (control median 3.17; 26 samples) than in mucosa and did not change in IDO (median 2.03; 14 samples). M2 expression was not significantly different with region or with IDO. CONCLUSIONS: These data show that M3 muscarinic receptor mRNA expression was significantly less in mucosa from IDO patients than from age-matched controls. The role of mucosal M3 receptors is unknown at present and elucidation of this role might provide a greater understanding of the aetiology of IDO.

The molecular basis of urgency: regional difference of vanilloid receptor expression in the human urinary bladder.

AIM: Treatments targeting vanilloid receptor TRPV1 are effective in some bladder disorders. Our aim was to determine the expression profiles of TRPV1 in regions of human bladder and test the hypothesis that there would be an upregulation of TRPV1 in mucosa of patients with bladder hypersensitivity but not idiopathic detrusor overactivity (IDO). MATERIALS AND METHODS: Women with sensory urgency (SU), interstitial cystitis (IC), and IDO were investigated by videourodynamics and cystoscopy. Control biopsies were used for comparison. Biopsies were dissected into mucosa and muscle, and evaluated for TRPV1 mRNA expression using quantitative competitive RT-PCR (QC-RT-PCR). RESULTS: TRPV1 mRNA from SU trigonal mucosa was significantly higher than control trigonal mucosa or SU bladder body mucosa. In contrast, in IDO patients, there was no difference between trigonal mucosa and body mucosa. In IC biopsies, RNA quality was substandard and unable to be used for analysis. The most striking finding was that TRPV1 mRNA expressed in SU trigonal mucosa was significantly inversely correlated with the bladder volume at first sensation of filling during cystometry. No such relationship was seen for IDO trigonal mucosa. No difference was seen in bladder body mucosa from any disease groups compared with age-matched control. CONCLUSIONS: The symptoms of SU were associated with the increased expression of TRPV1 mRNA in the trigonal mucosa. No upregulation or regional differences of TRPV1 mRNA were seen in IDO patients. TRPV1 may play a role in SU and premature first bladder sensation on filling.