De-obstruction of bladder outlet in humans reverses organ remodelling by normalizing the expression of key transcription factors.

BACKGROUND: Benign prostatic hyperplasia in elderly males often causes bladder outlet obstruction termed benign prostatic obstruction (BPO). BPO induces lower urinary tract symptoms and quantifiable urodynamic alterations in bladder function. When conservative medical treatments are exhausted, surgical interventions like transurethral resection of the prostate (TURP) are employed for bladder outlet de-obstruction. Elucidating the molecular changes in the human bladder resulting from BPO and their reversal post-de-obstruction is pivotal for defining the "point of no return", when the organ deterioration becomes irreversible. In this study we carried out a comprehensive molecular and urodynamic characterization of the bladders in men with BPO before TURP and 3 months after the relief of obstruction. METHODS: We report integrated transcriptome and proteome analysis of bladder samples from male patients with BPO before and 3 months after de-obstruction surgery (TURP). mRNA and protein profiles were correlated with urodynamic findings, specifically voiding detrusor pressure (PdetQmax) before TURP. We delineated the molecular classifiers of each group, pointing at the different pre-TURP bladder status. RESULTS: Age-matched patients with BPO without DO were divided into two groups based on the PdetQmax values recorded by UDI before de-obstruction: high and medium pressure (HP and MP) groups. Three months after de-obstruction surgery, the voiding parameters PdetQmax, Qmax and RV were significantly improved in both groups, without notable inter-group differences in the values after TURP. Patients with high PdetQmax showed less advanced remodeling and inflammatory changes than those with lower values. We detected significant dysregulation of gene expression, which was at least partially reversed by de-obstruction in both patients' groups. Transcription factor SOX21 and its target thrombospondin 4 (THBS4) demonstrated normalization post-TURP. CONCLUSIONS: Our findings reveal substantial yet incomplete reversal of cell signalling pathways three months after TURP, consistent with improved urodynamic parameters. We propose a set of biomarker genes, indicative of BPO, and possibly contributing to the bladder changes. This study unveils the stages of progressive obstruction-induced bladder decompensation and offers insights into selecting an optimal intervention point to mitigate loss of contractility.

Sacral Neuromodulation for Neurogenic Lower Urinary Tract Dysfunction.

BACKGROUND: Neurogenic lower urinary tract dysfunction (NLUTD) is a highly prevalent and disabling condition; nevertheless, standard treatments often remain unsatisfactory. Sacral neuromodulation (SNM) is a well-established therapy for non-NLUTD, but there is a lack of randomized controlled trials to show benefit in patients with NLUTD. METHODS: For this sham-controlled, double-blind, multicenter trial, patients with refractory NLUTD (and intended SNM) were recruited at four Swiss SNM referral centers. After lead placement into the sacral foramina S3 (rarely, S4), all participants underwent SNM testing. If successful (≥50% improvement in key bladder diary variables), the neurostimulator was implanted for permanent stimulation. For 2 months, neuromodulation was optimized using subsensory stimulation with individually adjusted parameters. Thereafter, the neurostimulator remained on or was switched off (1:1 random allocation to group SNM ON or SNM OFF, respectively) for 2 months, followed by a neurourologic reevaluation. The primary outcome was success, as defined above, of SNM compared with baseline. RESULTS: Of 124 patients undergoing SNM testing, 65 (52%) had successfully improved lower urinary tract function. Of these, 60 patients (median age, 49.5 years; 43 women) were randomly assigned to the intervention. After 2 months of intervention, the SNM ON group demonstrated a success rate of 76%. In the SNM OFF group, 42% of patients showed sustained SNM effects despite their neurostimulator being switched off during the last 2 months (odds ratio, 4.35; 95% confidence interval, 1.43 to 13.21; P=0.009). During the entire study period, there were 11 adverse events (6 dropouts; no dropouts during the intervention phase). CONCLUSIONS: SNM effectively corrected refractory NLUTD in the short term in well-selected neurologic patients. (Funded by the Swiss National Science Foundation, Vontobel­Stiftung, Gottfried und Julia Bangerter­Rhyner Stiftung, Dr. Urs Mühlebach, and the Swiss Continence Foundation; ClinicalTrials.gov number, NCT02165774.)

Protocol for a randomized, placebo-controlled, double-blind clinical trial investigating sacral neuromodulation for neurogenic lower urinary tract dysfunction.

BACKGROUND: Sacral neuromodulation has become a well-established and widely accepted treatment for refractory non-neurogenic lower urinary tract dysfunction, but its value in patients with a neurological cause is unclear. Although there is evidence indicating that sacral neuromodulation may be effective and safe for treating neurogenic lower urinary tract dysfunction, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN: This study is a prospective, randomized, placebo-controlled, double-blind multicenter trial including 4 sacral neuromodulation referral centers in Switzerland. Patients with refractory neurogenic lower urinary tract dysfunction are enrolled. After minimally invasive bilateral tined lead placement into the sacral foramina S3 and/or S4, patients undergo prolonged sacral neuromodulation testing for 3-6 weeks. In case of successful (defined as improvement of at least 50% in key bladder diary variables (i.e. number of voids and/or number of leakages, post void residual) compared to baseline values) prolonged sacral neuromodulation testing, the neuromodulator is implanted in the upper buttock. After a 2 months post-implantation phase when the neuromodulator is turned ON to optimize the effectiveness of neuromodulation using sub-sensory threshold stimulation, the patients are randomized in a 1:1 allocation in sacral neuromodulation ON or OFF. At the end of the 2 months double-blind sacral neuromodulation phase, the patients have a neuro-urological re-evaluation, unblinding takes place, and the neuromodulator is turned ON in all patients. The primary outcome measure is success of sacral neuromodulation, secondary outcome measures are adverse events, urodynamic parameters, questionnaires, and costs of sacral neuromodulation. DISCUSSION: It is of utmost importance to know whether the minimally invasive and completely reversible sacral neuromodulation would be a valuable treatment option for patients with refractory neurogenic lower urinary tract dysfunction. If this type of treatment is effective in the neurological population, it would revolutionize the management of neurogenic lower urinary tract dysfunction. TRIAL REGISTRATION NUMBER: http://www.clinicaltrials.gov; Identifier: NCT02165774.

Microbiological tined-lead examination: does prolonged sacral neuromodulation testing induce infection?

OBJECTIVE: To investigate whether prolonged sacral neuromodulation (SNM) testing induces a substantial risk of infection because of the percutaneous passage of the extension wire. PATIENTS AND METHODS: A consecutive series of 20 patients with negative prolonged SNM testing for >or=14 days who underwent tined-lead explantation were prospectively evaluated. The explanted tined leads were sent for microbiological examination. The tined lead, gluteal, and extension wire incision sites were investigated for clinical signs of infection according to the Centers for Disease Control and Prevention classification system. RESULTS: In all, 17 patients had bilateral and three unilateral implanted tined leads. The median (range) test period was 30 (21-62 days). Bacterial growth (Staphylococcus species) was detected in four of 20 (20%) patients on seven of 37 (19%) explanted tined leads. There were clinical signs of infection in one of 20 (5%) patients at none of 37 tined lead, one of 20 (5%) gluteal, and none of 20 extension wire incision sites. There were no clinical signs of infection in the remaining three of four patients with bacterial growth. CONCLUSIONS: After prolonged tined-lead testing, we found an infection rate comparable to that reported with the usual short test period. In addition, most patients with bacterial growth on tined leads showed no clinical signs of infection. Thus, prolonged tined-lead testing does not seem to induce clinically relevant infection, warranting randomized trials.

Safety of prolonged sacral neuromodulation tined lead testing.

OBJECTIVE: Prolonged sacral neuromodulation (SNM) testing is more reliable for accurate patient selection than the usual test period of 4-7 days. However, prolonged testing was suspected to result in a higher complication rate due to infection via the percutaneous passage of the extension wire. Therefore, we prospectively assessed the complications associated with prolonged tined lead testing. PATIENTS AND METHODS: A consecutive series of 44 patients who underwent prolonged tined lead testing for at least 14 days between May 2002 and April 2007 were evaluated. Complications during prolonged tined lead testing, during and after tined lead explantation and during follow-up after implantation of the implantable pulse generator (IPG) were registered prospectively. RESULTS: Four patients suffered from urgency-frequency syndrome, 13 from urge incontinence, 18 from non-obstructive chronic urinary retention and nine from chronic pelvic pain syndrome. The median test phase was 30 days (interquartile range [IQR] 21-36). Thirty-two of the 44 patients (73%) had successful prolonged tined lead testing and 31 of these (97%) underwent the implantation of the IPG. The median follow-up of the IPG implanted patients was 31 months (IQR 20-41). The complication rate was 5% (2/44) during prolonged tined lead testing and 16% (5/31) during follow-up of the IPG implanted patients, respectively. None of the complications could be attributed to prolonged testing. No infections were observed during the study period. CONCLUSIONS: This prospective, observational non-randomised study suggests prolonged SNM tined lead testing is a safe procedure. Based on the low complication rate and the increased reliability for accurate patient selection, this method is proposed as a possible standard test procedure, subject to confirmation by further randomised, controlled clinical studies.

Effect of thalamic deep brain stimulation on lower urinary tract function.

OBJECTIVE: The precise mechanisms underlying cerebral regulation of lower urinary tract function are still poorly understood. In patients with disabling essential tremor (ET) refractory to pharmacotherapy, thalamic deep brain stimulation (DBS) is an effective treatment for tremor control. Here, we evaluated the effect of thalamic DBS on urodynamic parameters in patients with ET. PATIENTS AND METHODS: We investigated seven patients (two females, five males) with ET 15-85 mo after implantation of DBS leads into the ventral intermediate nucleus of the thalamus. We compared urodynamic parameters during thalamic DBS (ON state) and 30 min after turning the stimulator off (OFF state). RESULTS: In the ON compared with the OFF state, there was a significant decrease in bladder volume at first desire to void (median, 218 ml vs. 365 ml, p=0.031), at strong desire to void (median, 305 ml vs. 435 ml, p=0.031), and at maximum cystometric capacity (median, 345 ml vs. 460 ml, p=0.016). No significant differences between the ON and OFF state were detected for changes in detrusor pressure during filling cystometry, bladder compliance, maximum detrusor pressure, detrusor pressure at maximum flow rate, maximum flow rate, voided volume, and postvoid residual. CONCLUSIONS: Thalamic deep brain stimulation resulted in an earlier desire to void and decreased bladder capacity, suggesting a regulatory role of the thalamus in lower urinary tract function. Therefore, the thalamus may be a promising target for the development of new therapies for lower urinary tract dysfunction.

Sacral neuromodulation for refractory lower urinary tract dysfunction: results of a nationwide registry in Switzerland.

OBJECTIVE: To assess the efficacy and safety of sacral neuromodulation (SNM) in patients with refractory lower urinary tract dysfunction in Switzerland based on a nationwide registry. PATIENTS AND METHODS: A total of 209 patients (181 females, 28 males) underwent SNM testing between July 2000 and December 2005 in Switzerland. Subjective symptom improvement, bladder/pain diary variables, adverse events, and their management were prospectively registered. RESULTS: SNM testing was successful (defined as improvement of more than 50% in bladder/pain diary variables) in 102 of 209 patients (49%). An implantable pulse generator (IPG) was placed in 91 patients (89% of all successfully tested and 44% of all tested patients). Of the IPG-implanted patients, 71 had urge incontinence, 13 nonobstructive chronic urinary retention, and 7 chronic pelvic pain syndrome. After a median follow-up of 24 mo, SNM was successful in 64 of the 91 IPG-implanted patients (70%) but failed in 27 patients. SNM was continued in 15 of the 27 patients considered failures, because following troubleshooting SNM response improved subjectively and the patients were satisfied. However, improvement in bladder/pain diary variables remained less than 50%. In the other 12 patients both the leads and the IPG were explanted. During the test phase and during/following IPG implantation, 6% (12 of 209) and 11% (10 of 91) adverse event rates and 1% (3 of 209) and 7% (6 of 91) surgical revision rates were reported, respectively. CONCLUSIONS: SNM is an effective and safe treatment for refractory lower urinary tract dysfunction. Adverse events are usually transient and can be treated effectively.

Treatment of urethral recurrence following radical cystectomy and ileal bladder substitution.

PURPOSE: With the introduction of orthotopic bladder substitution after radical cystectomy in patients with invasive bladder cancer urethral recurrences have become a therapeutic challenge. MATERIALS AND METHODS: We retrospectively evaluated our patients with urethral recurrences treated with a urethra sparing approach after orthotopic bladder substitution. Depending on the extension of recurrence and eventual concomitant metastases patients were treated with urethrectomy, no treatment, systemic chemotherapy or intraurethral bacillus Calmette-Guerin (BCG). Three times the common dose of BCG (ImmuCyst, Aventis, Paris, France or OncoTICE, Organon, West Orange, New Jersey) in 150 ml NaCl 0.9% was used for intraurethral BCG perfusion therapy according to an institutional protocol using a modified Foley catheter. This regimen was repeated weekly for 6 weeks and patients were followed prospectively. RESULTS: Between 1985 and 2001, 15 of 371 patients (4%) who received an orthotopic bladder substitute had urethral recurrence. Two patients were treated with systemic chemotherapy (methotrexate, vinblastine, doxorubicin and cisplatin) alone due to metastatic disease and 10 received intraurethral BCG therapy. Five of 6 patients (83%) with carcinoma in situ remained free of recurrence following treatment with BCG, while in 4 with papillary or invasive disease treatment failed. Three patients underwent urethrectomy, including 2 following failed BCG therapy for papillary disease. CONCLUSIONS: Carcinoma in situ urethral recurrence following orthotopic bladder substitution can be treated successfully with intraurethral BCG perfusion therapy in approximately 80% of patients. However, papillary and invasive transitional cell urethral recurrence should be treated with urethrectomy.

Holmium laser enucleation of the prostate combined with electrocautery resection: the mushroom technique.

PURPOSE: The holmium laser allows bloodless enucleation of the prostate. A problem is how to remove a whole enucleated, free floating, large prostatic lobe from the bladder. A mechanical morcellator has been used to achieve tissue fragmentation but aspiration of and damage to the bladder wall are risks. Using the mushroom technique holmium laser enucleation and electrocautery resection can be combined without compromising the bloodless advantages of the laser procedure. MATERIALS AND METHODS: We treated 156 patients with benign prostatic hyperplasia using a holmium laser with the mushroom technique. Preoperatively all patients were assessed using the International Prostate Symptom Score, maximum urine flow, ultrasound estimation of prostate volume and post-void residual urine, and pressure flow study. Laser enucleation of the prostatic lobes was performed at 66 W. Instead of releasing the lobes into the bladder they were left attached at the bladder neck by a narrow mushroom-like pedicle. At that point the vascular supply was almost completely interrupted and the lobes could easily be electroresected into small pieces without bleeding. Patients were followed 6, 12 and 24 months after the procedure. RESULTS: No patient had significant blood loss or signs of the transurethral resection syndrome. A total of 19 patients were treated while under oral anticoagulation without major bleeding problems. Complete followup was available on 125 patients. Median baseline International Prostate Symptom Score decreased from 20 to 3 at 6 months (p <0.05) and remained stable at 12 and 24 months. Median maximum urine flow increased from 8 to 20 ml. per second at 6, 12 and 24 months (p <0.05). Median baseline post-void residual urine decreased from 190 to 30 ml. at 6 months (p <0.05) and remained low at 20 and 30 ml. at 12 and 24 months, respectively. Urodynamic evaluation preoperatively and 6 months postoperatively was available in 83 cases. Relief of obstruction was documented with a statistically significant decrease in median detrusor pressure at maximum urine flow from 87 to 48 cm. water (p <0.05). CONCLUSIONS: Combining holmium laser enucleation and prostate electroresection with the mushroom technique is safe, efficient and bloodless surgical treatment for benign prostatic hyperplasia with sustained relief of obstruction. With this technique there is no need for additional devices, such as a mechanical tissue morcellator.

Transurethral microwave therapy in 200 patients with a minimum followup of 2 years: urodynamic and clinical results.

PURPOSE: We investigated the long-term efficacy of the second generation Targis thermotherapy device (Urologix, Inc., Minneapolis, Minnesota) for decreasing outflow obstruction caused by benign prostatic hyperplasia. MATERIALS AND METHODS: At a minimum followup of 24 months 200 patients with bladder outlet obstruction documented on urodynamics and cystoscopy document with preserved detrusor function underwent transurethral microwave therapy while under local anesthesia. In 45% of cases the general American Society of Anesthesiologists health score was 3 or greater. RESULTS: After a median observation time of 42 months (range 2 to 72) 43 patients (22%) who required additional treatment (repeat thermotherapy, transurethral prostate resection or permanent cystostomy) were excluded from further analysis, as were 15 (7.5%) who died of causes unrelated to treatment during followup and 13 (6.5%) who were lost to followup or refused followup investigations. In the 162 patients evaluated 6 months after treatment the median International Prostate Symptom Score decreased from 23 points (range 10 to 34) before treatment to 3 (range 0 to 21) and remained stable at 12 and 24 months. Median maximum flow increased from 6 ml. per second (range 1 to 15) before treatment to 14.5 (range 4 to 50) 6 months after treatment and remained stable at 12 and 24 months. Median post-void residual urine volume decreased from 170 ml. (range 35 to 720) before treatment to 17 (range 0 to 327) after 6 months and then remained unchanged. Urodynamic evaluation in the 162 patients after 6 months showed a decrease from pretreatment median detrusor opening pressure of 87.5 to 53 cm. water. Median detrusor pressure at maximum flow decreased from 86 to 58 cm. water 6 (p <0.0001). At the 24-month followup 59 of the 129 evaluable patients agreed to undergo repeat urodynamic evaluation. Pressure flow analysis in these 59 cases revealed a decrease in median minimal urethral opening pressure from 70 to 40 cm. water at 6 months and to 38 cm. water at 24 months (p <0.0001). Median detrusor pressure at maximum flow decreased significantly from the pretreatment value of 86 to 55 cm. water at 6 months and 58 cm. water at 24 months (p <0.0001). CONCLUSIONS: In patients with a good initial response to treatment, which is achieved in approximately 80%, transurethral microwave therapy provides excellent long-term subjective and objective results. Improved urinary flow, decreased post-void residual urine volume and urodynamic parameters remain stable at 2 years. Transurethral microwave therapy with second generation microwave equipment did not compromise any conventional treatment needed in the 22% of patients who were nonresponders at 6 months.