Predictors and prognostic implications of clinical decisions in patients with primary high-risk non-muscle-invasive bladder cancer - results of a cross country retrospective study.

Adjuvant diagnostic and therapeutic procedures are available to reduce the risk of recurrence or progression in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). However, their indications and efficacy remain a matter of debate. The aim of this study was to analyze therapeutic decisions in patients with primary high-risk NMIBC and to analyze the adherence to clinical guidelines in this field.545 consecutive patients, aged a median of 70.3 years, diagnosed with primary high-risk NMIBC in thirteen urological institutions, were enrolled into this retrospective study. Diagnostic and therapeutic decisions after transurethral resection (TUR) were recorded, and predictive factors were analyzed.Restaging TUR was offered to 260 patients (47.7%), up-front intravesical Bacillus Calmette-Guerin (BCG) therapy to 74 patients (13.6%), immediate radical cystectomy to 38 patients (7.0%), and intravesical chemotherapy with the maintenance therapy to 12 patients (2.2%). No additional procedure was performed in 161 patients (29.5%). The strongest predictive factor for restaging TUR was G3 or high-grade cancer (RR 1.68, p<0.01), for upfront BCG therapy it was carcinoma in situ (RR 3.20, p=0.01), for immediate cystectomy it was stage T1 tumor (RR 3.71, p<0.01), for no additional procedures it was G2 or low-grade cancer (RR 2.18, p<0.01).Clinical management of patients with high-risk NMIBC is suboptimal and not standardized. As this can directly influence patients' survival, urgent improvement of urological care in this field should be considered.

The influence of doxazosin on the contractility of the urinary bladder in female pigs with experimentally induced cystitis.

The present in vitro study investigated the influence of doxazosin on the contractility of the urinary bladder in female pigs with experimentally induced cystitis. Fifteen juvenile female piglets (18-20 kg body weight) were randomly assigned into three groups (n=5 animals each): i) control (clinically healthy animals, without doxazosin treatment), ii) animals with induced inflammation of the urinary bladder, but without doxazosin treatment (experimental group I) and iii) animals with inflamed bladder, treated orally with doxazosin (0.1 mg/kg body weight for 30 days; experimental group II). Thereafter, the pigs were sacrificed and strips of the bladder trigone were suspended in organ baths. The tension and amplitude of the smooth muscles was measured before and after exposition to 5-hydroxytryptamine (5-HT; 10-6-10-4 M), acetylocholine (ACh; 10-5-10-3 M) and norepinephrine (NE; 10-9-10-7 M). 5-HT caused an increase in the tension of contractions in all the groups and the amplitude in the experimental groups, however, the effect was higher in the experimental group I than in group II as compared to that found in the pre-treatment period. ACh caused an increase in the tension in the control group and a decrease in the amplitude in both experimental groups; these changes significantly differed between the control and doxazosin-treated group. NE caused a decrease in the tension in both experimental groups and amplitude in all the groups, however, the effect was most strongly expressed in doxazosine-treated group. The present study has revealed that long-term administration of doxazosin causes a desensitization of the detrusor smooth muscle to in vitro applied mediators in the autonomic nervous system.

The influence of resiniferatoxin on the chemical coding of caudal mesenteric ganglion neurons supplying the urinary bladder in the pig.

Resiniferatoxin (RTX) is used as experimental drug therapy for a range of neurogenic urinary bladder disorders. The present study investigated the chemical coding of caudal mesenteric ganglion (CaMG) neurons supplying the porcine urinary bladder after intravesical RTX instillation. The CaMG neurons were visualized with retrograde tracer Fast Blue (FB) and their chemical profile was disclosed with double-labelling immunohistochemistry using antibodies against tyrosine hydroxylase (TH), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), calbindin (CB), galanin (GAL) and neuronal nitric oxide synthase (nNOS). It was found that in both the control (n = 6) and RTX-treated pigs (n = 6), the vast majority (92.3 ± 2.7% and 93.1 ± 1.3%, respectively) of FB-positive (FB+) nerve cells were TH+. Intravesical instillation of RTX caused a decrease in the number of FB+ / TH + neurons immunopositive to NPY (91.0 ± 2.2% in control animals vs. 58.8 ± 5.0% in RTX-treated pigs) or VIP (1.7 ± 0.5% vs. 0%) and an increase in the number of FB+ / TH+ neurons immunoreactive to SOM (3.4 ± 1.5% vs. 20.6 ± 4.3%), CB (1.8 ±0.7% vs. 13.4 ± 2.3%), GAL (1.5 ± 0.6% vs. 7.5 ± 1.0%) or nNOS (0% vs. 10.9 ± 3.4%). The present results suggest that therapeutic effects of RTX on the mammalian urinary bladder can be partly mediated by CaMG neurons.

Clinical value of digital image analysis in the diagnosis of urinary bladder cancer, particularly in aggressive tumors: a preliminary report.

The aim of the project was to evaluate the clinical value of a computer analysis of cytological specimen images obtained from urine and bladder washing samples. Three sample types (voided urine, catheterized urine and bladder washing) from 59 patients with primary or recurrent tumor were analyzed. All patients underwent cystoscopy and biopsy or resection. The histological results were compared with the results of the image analyzing computer system of collected urine samples. The consistency between the computer diagnosis and the clinical or histological diagnosis both in the presence and absence of cancer was as follows: 77% for voided urine samples, 72.5% for catheterized urine samples and 78% for bladder washing samples. The specificity of the method at the standard pathology level was 71%, and the sensitivity was 83%. The positive and negative predictive values (PPV and NPV) were 87.5% and 63% respectively. The sensitivity for G3 or CIS or T2 or T3 tumors reached nearly 100%. Computer analysis of urine provided correct diagnoses in cancer and control patients with the sensitivity of 83% and specificity of 71% and gave excellent results in aggressive tumors such as T2, T3, G3 and in CIS.

Stage of bladder cancer in Central Europe - Polish perspective.

Mortality rate from bladder cancer in Europe is the highest in its Central Region. This study is an attempt to find underlying factors by proper characterisation of large cohort of Polish patients with bladder cancer.This is a multicentre study enrolling 1360 consecutive patients diagnosed with primary urothelial carcinoma of the bladder in years 2012-2013 in Poland. All patients underwent transurethral resection of the bladder tumor. Data on staging and grading of all cancers were collected, as well as several demographic and clinical factors were tested for the association with muscle invasiveness of the cancer.Mean age of the cohort was 69.6 years, male to female ratio was 3:1. Bladder cancer stage Ta, T1 and muscle-invasive (MIBC) was diagnosed in 533 (39.2%), 516 (37.9%) and 296 (21.8%) patients, respectively. Patients with MIBC were older (73 vs. 68 years, p<0.05), had lower body mass index (25.4 vs. 26.5 kg/m2, p<0.05), lower haemoglobin concentration (12.2 vs. 13.4 mg/l, p<0.05), longer history of haematuria (86.2 vs. 74.4 days) and longer time interval from first symptom to diagnosis (118.0 vs. 88.2 days), compared to patients with Ta and T1 tumors.High mortality rate from bladder cancer in Central Europe can result from very high incidence of high-risk T1 tumors and high prevalence of prognostic factors of poor survival.

Safety and tolerability of the ß3 -adrenoceptor agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled analysis of three 12-week randomised Phase III trials and of a 1-year randomised Phase III trial.

AIMS: To evaluate the safety and tolerability of the ß3 -adrenoceptor agonist, mirabegron, in patients with overactive bladder (OAB). METHODS: Tolerability and safety data from three 12-week, randomised, placebo-controlled, double-blind, Phase III trials (Studies 046, 047 and 074) were pooled by treatment group. The three studies were of a similar design, although the assessed doses of mirabegron [25, 50 or 100 mg once daily (qd)] varied, and tolterodine extended release (ER) 4 mg was included as an active-control arm in Study 046 only. Tolerability and safety data from a 1-year, randomised, double-blind, Phase III trial (Study 049) are also presented. Safety variables included the incidence and severity of treatment-emergent adverse events (TEAEs), vital signs and electrocardiogram data. RESULTS: Mirabegron (25, 50 or 100 mg qd) was safe and well-tolerated in patients with OAB over 12-week (n = 2736) and 1-year (n = 1632) periods. The incidence of TEAEs and treatment discontinuations as a result of TEAEs was low; the majority were mild in severity and few were serious. Hypertension, nasopharyngitis and urinary tract infection were the most common TEAEs with mirabegron. The mirabegron tolerability profile was similar to that seen with placebo and tolterodine ER 4 mg, except for dry mouth, which occurred, on average, five times less frequently with mirabegron than tolterodine ER 4 mg. In the pooled 12-week analysis, mirabegron 50 mg was associated with placebo-adjusted mean increases of 0.4-0.6 mmHg in blood pressure and approximately one beat per minute in pulse rate, both reversible upon treatment discontinuation. The incidence of Major Adverse Cardiovascular Events as adjudicated by an independent cardiovascular committee was low and similar across treatment groups. CONCLUSION: The favourable tolerability profile of mirabegron in patients with OAB may allow improved treatment compliance compared with antimuscarinics, with important implications for patient outcomes.

Phase II study on the efficacy and safety of the EP1 receptor antagonist ONO-8539 for nonneurogenic overactive bladder syndrome.

PURPOSE: We evaluated the efficacy, safety and tolerability of the EP1 receptor antagonist ONO-8539 in patients with overactive bladder syndrome. MATERIALS AND METHODS: This was a 12-week, randomized, double-blind, placebo controlled, parallel group, multicenter study with a 2-week single blind placebo run-in phase. The 435 patients were randomized to receive twice daily ONO-8539 (30, 100 or 300 mg), placebo or once daily tolterodine (4 mg). RESULTS: At the end of the 12-week treatment no statistically significant difference was found between ONO-8539 and placebo in the change from baseline in the number of micturitions per 24 hours. The primary end points for 30, 100 and 300 mg ONO-8539, and placebo were -1.02, -1.53, -1.31 and -1.40, respectively. There was no statistically significant difference between any ONO-8539 group and placebo in the change from baseline in the number of urgency or urinary urgency incontinence episodes per 24 hours, or the mean volume voided per micturition, which were secondary end points. Statistically significant differences for tolterodine vs placebo were observed in the change from baseline in the number of micturitions (p = 0.045), urgency episodes (p = 0.04) and mean volume voided per micturition (p <0.001). The incidence of adverse events was 54.1% in the placebo group, 43.0% to 54.0% in the ONO-8539 groups and 46.6% in the tolterodine group. The intensity of adverse events was similar among the treatment groups. Similar to other treatments, the most frequently reported adverse events after ONO-8539 were nasopharyngitis and diarrhea. CONCLUSIONS: The results of this study, which to our knowledge represents the first evaluation of ONO-8539 in patients with overactive bladder, suggest a minimal role for EP1 receptor antagonism in the management of overactive bladder syndrome.

Comparison of pathological staging and grading of urothelial bladder carcinoma in post-transurethral resection and post-radical cystectomy specimens.

Staging and grading of bladder cancer have a substantial impact on patients' prognosis. However, due to the relatively low quality and quantity of specimens from transurethral resection (TUR), initial histopathological examination may not be fully reliable. The aim of this study was to assess the repeatability of staging and grading in post-TUR and post-radical cystectomy (RC) specimens. Staging and grading in TUR and RC specimens were compared in a group of 181 consecutive patients. All microscopic examinations were performed by dedicated uropathologists. Median time from TUR to RC was 45 days. Additionally, an attempt to identify potential clinical variables influencing the risk of discrepancies was made. In post-RC specimens, the disease was down-staged in 13.8% and up-staged in 54.6% of patients (K = -0.03, p < 0.02). Muscle-invasive bladder cancer was diagnosed in 67.6% of patients initially staged as T1. Cancer was down-graded in 10.3% and up-graded in 17.9% of patients (K = 0.44, p < 0.02). Early onset of disease, female sex and time interval from transurethral resection of bladder tumor (TURBT) to RC had no effect on incidence of discrepancies. Pathological post-TUR examination is not predictive for the final stage of cancer. The incidence of under- or overgrading of bladder cancer is significant, and efforts should be made to reduce it.

Exogenously administered bombesin and gastrin releasing peptide contract the female rat urethra in vivo and in vitro.

BACKGROUND: Bombesin (BOM) and gastrin releasing peptide (GRP) have been located to the lower urinary tract (LUT). However, there is a paucity of data demonstrating the impact of these endogenous peptides. OBJECTIVES: The aim of the present study was to investigate the contractile actions of BOM and GRP on the female rat urethra in vitro and in vivo. Female Sprague-Dawley rats (n = 37) weighing approximately 225 g were used. Intraurethral pressure was recorded by a catheter placed at the maximum pressure zone corresponding to the intrinsic urethral sphincter. MEASUREMENTS: In vitro, changes in intraurethral pressure was conducted on perfused intact urethral/bladder preparations and are expressed as percentages of sphincteric intraurethral pressure achieved with noradrenaline. In vivo, changes in intraurethral pressure was conducted in anesthetized subjects and compared with the baseline intraurethral pressure and sham controls. RESULTS: In vitro, the increase in intraurethral pressure induced by BOM was 23.6 ± 3.2 cmH(2)O, exceeding the pressure evoked with NA by 9.6 cmH(2) O or 174.4% whereas GRP induced a maximum pressure of 10.7 ± 1.6 cmH(2) O, an increase of 2.2 ± 0.5 cmH(2) O or 82.9% (P < 0.05) of the NA evoked pressure. In vivo, the mean baseline pressure was 22.9 ± 1.4 cmH(2) O. The intraurethral pressure evoked by BOM was 50.6 ± 6.3 cmH(2) O (P < 0.05), and for GRP, the evoked intraurethral pressure was 56.2 ± 13.4 cmH(2) O (P < 0.05). CONCLUSIONS: The present data suggest that both BOM and GRP may contribute to the control of continence by their contractile action on the sphincters of the LUT outflow region.

Neurologic urinary incontinence.

INTRODUCTION: This manuscript summarizes the work of Committee 10 on neurologic bladder and bowel of the International Consultation on Incontinence in 2008-2009. As the data are very large the outcome is presented in different manuscripts. This manuscript deals with neurologic urinary incontinence. METHODS: Through in debt literature review all aspects of neurological urinary incontinence were studied for levels of evidence. Recommendations for diagnosis and treatment, and for future research were made. RESULTS: Pathophysiology was summarized for different levels of lesions. For epidemiology, specific diagnostics, conservative treatment and surgical treatment of neurologic urinary incontinence, levels of evidence and grades of recommendation were made following ICUD criteria. CONCLUSIONS: Though data are available that advice and guide in the management of urinary incontinence in neurologic patients, not many data have a high level of evidence or permit a high grade of recommendation. More and well-structured research is needed.

Neurologic fecal incontinence.

INTRODUCTION: This manuscript summarizes the work of Committee 10 on neurologic bladder and bowel of the International Consultation on Incontinence in 2008-2009. As the data are very large the outcome is presented in different manuscripts. This manuscript deals with neurologic fecal incontinence (FI). METHODS: Through in debt literature review all aspects of neurologic urinary and FI were studied for levels of evidence. Recommendations for diagnosis and treatment, and for future research were made. RESULTS: Pathophysiology was summarized for different levels of lesions. For epidemiology, specific diagnostics, conservative treatment, and surgical treatment of neurologic FI levels of evidence and grades of recommendation were made. CONCLUSIONS: Though data are available that advice and guide in the management of FI in neurologic patients, not many data are with a high level of evidence or high grade of recommendation. More and well-structured research is needed.

Multiple sclerosis produces significant changes in urinary bladder innervation which are partially reflected in the lower urinary tract functional status-sensory nerve fibers role in detrusor overactivity.

BACKGROUND: Detrusor overactivity is often observed in patients with multiple sclerosis (MS), and neurotoxins are emerging as second-line therapies albeit with different degrees of success per patient basis. OBJECTIVE: To investigate lower urinary tract (LUT) functional status and bladder innervation (calcitonin gene related peptide [CGRP] and substance P [SP] positive nerve fibers) in patients with MS. METHOD: Eighteen MS patients with LUT symptoms underwent urodynamic investigations, and six non-MS patients undergoing cystoscopy due to microscopic hematuria served as controls. Cold cut bladder biopsies were taken from the bladder trigone region. Neurotransmitter expression was determined by individual immunohistochemical staining. RESULTS: Two distinct groups could be distinguished: group 1 with pronounced neurogenic detrusor overactivity and mild outflow obstruction; group 2 with some degree of neurogenic detrusor overactivity, detrusor hypocontractility during voiding, and high degree of an outflow obstruction. The presence of SP and CGRP immunoreactive + fiber density was observed in greater numbers in group 1. CONCLUSION: Density of CGRP and SP positive nerve fibers within the urinary bladder of patients with MS may be suggestive of functional status of the lower urinary tract, namely denser innervation is observed in patients with mild outflow obstruction and strong detrusor overactivity. This observation could be useful when planning second-line treatment (neurotoxins) in these patients. Patients with denser innervation probably will respond better to such a therapy.

Distribution and neurochemical characterization of sensory dorsal root ganglia neurons supplying porcine urinary bladder.

UNLABELLED: Pig has been used recently as an animal model for studying diseases of human urinary tract, however, the sensory innervations of urinary bladder in this species has not been yet described. OBJECTIVE: The present study was aimed at neurochemical characterization of sensory neurons of dorsal root ganglia (DRGs) supplying porcine urinary bladder. METHODS: Retrograde tracer Fast Blue (FB) was injected into the right half of the urinary bladder wall of six juvenile female pigs. Three weeks later ipsi- and contralateral DRGs of interest were harvested from all animals and a neurochemical characterization of retrogradely-labeled neurons was performed using routine single-immunofluorescence labeling technique on 10 microm-thick cryostat sections. RESULTS: 85% of spinal sensory neurons supplying porcine urinary bladder was located in ipsilateral sacral S3-S4 ganglia and in first coccygeal ganglion (Cq1),whereas rest of FB-positive (FB+) nerve cells were found in lumbar L3-L6 DRGs. FB+ neurons belonged mostly to the medium-sized (54%) and small-sized afferent perikarya (45%). Bladder sensory neurons contained substance P (SP), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP), galanin (GAL), neuronal nitric oxide synthase (nNOS), somatostatin (SOM) and/or calbindin-28k (CB), and these neurons constituted 45%, 36%, 26%, 6%, 6%, 4% and 3% of all retrogradely traced DRGs perikarya, respectively. Distinct differences in the number of traced cells and their neuropeptide content were observed between the lumbar and sacral/coccygeal division of bladder-projecting DRG neurons. Thus, FB+ neurons expressing CGRP, GAL, nNOS or SOM were more numerous in lumbar DRGs (44%, 9%, 9% and 6%, respectively), than in sacral/coccygeal ganglia (23%, 2%, 1.5% and 0.3%, respectively). On the other hand, more FB+ cells expressed PACAP in sacral (31%) than in lumbar DRGs (23%). However, fractions of SP-IR or CB-IR bladder sensory neurons were similar in lumbar and sacral/coccygeal DRGs. CONCLUSIONS: This novel description of both spatial and neurochemical organization pattern of porcine urinary bladder sensory innervation constitutes a basis for further functional studies aimed at unraveling neurogenic mechanisms of urinary bladder diseases.

Significance of urodynamic assessment of lower urinary tract in dialysis patients before renal transplantation.

INTRODUCTION: Some dialyzed patients suffer from lower urinary tract (LUT) anatomic and functional disturbances. Complete LUT assessment should be performed to decide whether they can be included on the waiting list, because such disorders, if not diagnosed and properly treated before transplant, may lead to graft loss. PATIENTS AND METHODS: Based on data in the medical records of 4170 dialysis patients, 535 were selected for further investigation: 265 patients after undergoing urethrocystography or urethrocystoscopy, were included on the waiting list for transplantation and 145 patients underwent nephroureterectomy owing to reflux, nephrolithiasis, polycystic renal disease, or hydronephrosis. Five patients with urethral or bladder neck stricture underwent urethral dilation or bladder neck incision. These patients were also ultimately listed for transplantation. Twenty-two patients, with serious LUT disease were qualified for kidney transplantation after extra-anatomic urine outflow. Ninety-eight patients underwent a urodynamic study (URD) to assess LUT disturbances. RESULTS: Of 535 studied patients, 460 (86%), including those who underwent surgical or pharmacologic treatment, were ultimately listed for kidney transplantation. Out of 98 patients who underwent a URD, 45 (46%) were included for kidney transplantation, and 47 for transplantation with atypical urinary outflow. Six patients were excluded from transplantation owing to refusal of investigations or serious contraindications. CONCLUSIONS: All potential kidney recipients should undergo proper evaluation of the LUT before being qualified for kidney transplantation. This study allows selection of patients who should undergo surgical and/or pharmacologic treatment before transplantation.

Effects of several glucocorticosteroids and PDE4 inhibitors on increases in total lung eosinophil peroxidase (EPO) levels following either systemic or intratracheal administration in sephadex- or ovalbumin-induced inflammatory models.

Representative glucocorticosteroids (GCS) and phosphodiesterase IV (PDE4) inhibitors were compared in several models of pulmonary inflammation ranging in severity. Lung tissue eosinophil peroxidase (EPO) levels rather than bronchoalveolar lavage fluid (BALF) EPO or eosinophil percentages were used to indicate eosinophil recruitment after intratracheal instillation of sephadex beads in rats or nebulized ovalbumin in sensitized guinea pigs. A single oral or intratracheal administration of a GCS was effective against mild and robust sephadex-induced eosinophilia whereas the PDE4 inhibitors evaluated appeared more effective in the milder sephadex models. The GCS were also more effective against sephadex-induced than ovalbumin-induced eosinophilia. The effectiveness of the GCS and PDE4 inhibitors improved when the severity of the ovalbumin-induced eosinophilia was decreased. Multiple day dosing also improved activity. These studies indicated that activity was influenced greatly by administration protocols, the severity of the inflammatory response and possibly the method used for estimating eosinophil recruitment.

[Ambulatory diagnosis of urinary incontinence among women: the role of a one-hour pad weigh test]. / Diagnostyka ambulatoryjna nietrzymania moczu u kobiet: rola jednogodzinnego testu wkladkowego.

The aim of our studies was the evaluation of diagnostic usefulness of the 1-hour pad weight test in the different types of female incontinence. We examined 189 women at the age from 16 to 74 with the incontinence in anamnesis. The test was performed accordingly to the I.C.S. guidelines. The positive result of the test (more that 2 grams increase in the pad weigh) was found in 136 (71.6%) of examined women; including moderate urine leak in 24%, big in 55.1% and severe in 20.6% of them. The biggest average increase in pad weigh was found in urinary incontinence associated with the urgency, corresponding to 88.9 g in mixed incontinence and to 67.4 g in genuine urge incontinence. The sensitivity, specificity and efficacy of the test was 78.6%, 72% and 77% respectively. The shortened 1-hour pad weigh test is a simple and effective examination, especially in the stress incontinence. It is less effective in genuine urge incontinence and giggle incontinence. The negative effect of the 1-hour test, when the patients complaints coexist, should be the indication to repeat the test or to perform the 24-hour test. In the doubtful cases, before the surgery, the diagnostics should be extended to the full urodynamic examination.

Distribution of neuropeptide-, tyrosine hydroxylase- and nitric oxide synthase containing nerve fibers in the external urethral sphincter of the rat.

The occurrence and distribution of adrenergic, peptidergic and nitrergic nerve fibers were investigated within the part of the rat urethra that corresponds to the external urethral sphincteric mechanism. At this level, the urethral wall was found to be composed of the following layers: mucosa/urothelium, lamina propria, smooth muscle, mixed smooth and striated muscle and striated muscle. Nerve fibers containing immunoreactivity against either nitric oxide synthase (NOS) or any of the following peptides were visualised in various amounts in all three muscle layers of rats of both sexes: neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP), cholecystokinin (CCK), gastrin releasing peptide (GRP) and pituitary adenylate cyclase-activating peptide. (PACAP) Tyrosine hydroxylase (TH), marker for nonadrenergic nerves, was only found in nerve fibers of the smooth and mixed muscle layers, while enkephalin 8 (ENK-8) was only found in the striated muscle layer. The great number of putative neuromessengers and different nerve fiber populations suggest a complex innervation pattern of the sphincter area.

The morphological aspects of the innervation of the external urethral striated sphincter.

Innervation of the sphincter urethrae externus muscle was studied in 30 human fetuses with the aid of operation microscope. The investigated muscle receives direct branch from anterior roots of S2, S3, or S4, or from the trunk of the pudendal nerve. The branch to the muscle divides into 2 or 3 rami before it enters the muscle, or it divides into 2 or 3 terminal rami, and gives off the dorsal nerve of the penis or clitoris.