Neurostimulation in neurogenic patients.

PURPOSE OF REVIEW: To provide an overview of available electrical stimulation devices in neurogenic patients with lower urinary tract disease. RECENT FINDINGS: It is advocated to do more studies in neurogenic patients as results seem promising and useful but most studies did not include neurogenic patients or neurogenic patients were not analyzed or reported separately. Most studies included a small heterogenous neurogenic group with multiple pathophysiologic origin focusing on effect of a treatment instead of results of a treatment in a specific neurogenic group. Neuromodulation or stimulation has the advantage that it acts on different organs, like bladder and bowel, so can treat neurogenic patients, who mostly suffer from multiple organ failure. SUMMARY: Brindley procedure, sacral neuromodulation (SNM) and posterior tibial nerve stimulation (PTNS) are available for a while already. The Brindley procedure (including sacral anterior root stimulation in combination with a rhizotomy of posterior sacral roots) is developed for selected spinal cord injury patient with a complete spinal injury, and has shown results for many years in neurogenic patients. An alternative to the rhizotomy is not established yet. SNM and PTNS are other modalities that are used in nonneurogenic patients, but are not yet indicated and much studied in neurogenic patients.

[Penile cancer: diagnosis and staging]. / Peniskarzinom: Diagnose und Staging.

Penile cancer is often an obvious visual diagnosis but histologic verification should be obtained prior to treatment. The clinical examination should determine the tumor stage and whether it has infiltrated the cavernous bodies and/or the urethra and it should adequately assess the inguinal lymph nodes. Preoperative imaging of the lesion is only indicated in equivocal cases. Curative treatment requires the complete removal of the primary tumor and all metastatic lymph nodes. Lymph node management is the key prognostic factor in the treatment of penile cancer. No imagining technique such as the ultrasound, CT, MRI or PET/CT is able to adequately detect micrometastatic lymph nodes. Therefore, invasive (inguinal) lymph node diagnosis is indicated for all tumour stages from pT1G2. Over 90% of penile cancer cases can be cured with early diagnosis and adequate treatment if routine self-examination and physical examinations are regularly performed.

[Psychosocial stress in patients with prostate cancer : Experiences by using psychooncological screening questionnaires]. / Psychosoziale Belastungen bei Patienten mit Prostatakarzinom : Erfahrungen im Einsatz mit psychoonkologischen Screeningfragebögen.

BACKGROUND: Prostate cancer is the most common malignancy in men and accounts for most surgical procedures in uro-oncology. Stressful sequelae of radical prostatectomy are incontinence and erectile dysfunction. Hormone ablation and radiation therapy are also known stressors. Mental stress has a low prevalence compared to other tumor entities. It is highly probable that there is an underexpression of verbally reported emotional experiences. Therefore, a low-threshold access to psycho-oncological services and accurate identification of patients with mental comorbidities is important. The aim of this study was to identify the distress level with clarification of the stress in patients with prostate cancer. MATERIALS AND METHODS: Prospective evaluation of prostate cancer patients (n = 81, mean age 69 years) with regard to stress level, stress factors and the need for care using the Distress Thermometer, a standardized ultrashort stress-screening questionnaire. RESULTS: The mean stress level was 4.4 points. In total, 56% of patients indicated a stress level ≥5, i. e. a clinically relevant psychological burden was indicated. Main stressors were sexual problems (35%), reduced mobility (30%), pain (27.5%), tingling paresthesia (26%) and worries (26%). CONCLUSION: The psychological burden of prostate cancer patients is not as high as in other solid organ malignancies. However, some patients have a significantly increased psychosocial stress level. Identifying this subgroup and clarifying the correlation with specific stress and risk factors are important tasks of clinical care.

[Surgical positioning techniques in urology : Tips and tricks]. / Lagerungstechniken in der Urologie : Tipps und Tricks.

Correct positioning of patients during preoperative preparations is essential for success of the intervention to avoid any positioning trauma and to provide the best access to the targeted structures. The appropriate positioning (and optimal performance) means that complications are avoided and also makes an essential contribution to the smooth course of the surgical intervention. A correct position is essential particularly in urology because the organs assigned to the discipline of urology are anatomically mostly difficult to reach. A further important function of the correct positioning technique is the avoidance of injuries to the patient. This article summarizes the most common positioning techniques in urological interventions with special emphasis on the explanation of practical advice, helpful tips and possible complications that can enable even junior surgeons to correctly perform the appropriate positioning technique.

OnabotulinumtoxinA 100U provides significant improvements in overactive bladder symptoms in patients with urinary incontinence regardless of the number of anticholinergic therapies used or reason for inadequate management of overactive bladder.

INTRODUCTION: A prespecified pooled analysis of two placebo-controlled, phase 3 trials evaluated whether the number of prior anticholinergics used or reason for their discontinuation affected the treatment response to onabotulinumtoxinA 100U in overactive bladder (OAB) patients with urinary incontinence (UI). METHODS: Patients with symptoms of OAB received intradetrusor injections of onabotulinumtoxinA 100U or placebo, sparing the trigone. Change from baseline at week 12 in UI episodes/day, proportion of patients reporting a positive response ('greatly improved' or 'improved') on the treatment benefit scale (TBS), micturition and urgency were evaluated by number of prior anticholinergics (1, 2 or ≥ 3) and reason for their discontinuation (insufficient efficacy or side effects). Adverse events (AE) were assessed. RESULTS: Patients had taken an average of 2.4 anticholinergics before study enrolment. OnabotulinumtoxinA reduced UI episodes/day from baseline vs. placebo, regardless of the number of prior anticholinergics (-2.82 vs. -1.52 for one prior anticholinergic; -2.58 vs. -0.58 for two prior anticholinergics; and -2.92 vs. -0.73 for three or more prior anticholinergics; all p < 0.001). The proportion of TBS responders was higher with onabotulinumtoxinA vs. placebo (69.0% vs. 37.2% for one prior anticholinergic; 58.8% vs. 24.8% for two prior anticholinergics and 56.4% vs. 22.5% for three or more prior anticholinergics; all p < 0.001). Similar results were observed regardless of the reason for discontinuation. OnabotulinumtoxinA reduced the episodes of urgency and frequency of micturition vs. placebo in all groups. AEs were well tolerated, with a comparable incidence in all groups. CONCLUSION: In patients with symptoms of OAB who were inadequately managed by one or more anticholinergics, onabotulinumtoxinA 100U provided significant and similar treatment benefit and safety profile regardless of the number of prior anticholinergics used or reason for inadequate management of OAB. ClinicalTrials.gov: NCT00910845, NCT00910520.

[Cell-based therapy to treat stress urinary incontinence: which cell type at what cost?]. / Zellbasierte Therapie der Belastungsinkontinenz: Welche Zelle zu welchen Kosten?

In Germany, 6-8 million woman and men suffer urinary incontinence, which represents 12.5 % of the population. It is estimated that by the middle of this century, it will increase to almost 30 %. The primary reason will be primarily related to the aging population but also to patient awareness and seeking a solution. In addition to the cost which is covered by the health insurance, the patient will spend more than half a billion euro/year out-of-pocket, not to mention the social stigma associated with urinary incontinence. The current common treatment options are symptomatic but do not restore functionality. One option might be tissue engineering or stem cell therapy. This article describes the likelihood that this therapy will change the approach in treating stress urinary incontinence. Boundaries and legal aspects are highlighted as well as approximated cost. These treatment costs might be currently higher than the standard treatment options, but the investment to reduce these costs are paid indirectly by society.

Urgency and pain in patients with overactive bladder and bladder pain syndrome. What are the differences?

BACKGROUND: The Overactive Bladder Syndrome (OAB) and the Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) are different urological conditions sharing 'urgency' as a common symptom. The aim of this review is to address our existing knowledge and establish how these symptoms are interrelated and to determine whether or not there is a common link between both symptoms complexes that help to distinguish one from the other. METHODS: Pubmed was used to obtain references for this non-systematic review aiming to discuss differences between OAB and BPS/IC. Guidelines of several professional associations and discussions based on expert opinion from the authors were implemented. RESULTS: Whilst in BPS the hallmark symptom is pain on bladder filling, urgency is the defining symptom of OAB. Whilst it is likely that the pain in BPS/IC arises from local inflammation in the bladder wall, the nature of urgency as a symptom, its origin, and the relationship between urgency and pain, as well as the different afferent mechanisms associated with the genesis of these sensory symptoms, remains unknown. Although the aetiology of both OAB and PBS/IC is unclear, the influence of environmental factors has been suggested. Both are chronic conditions with very variable symptom resolution and response to therapy. The relationship with voiding dysfunction, gynaecological causes of chronic pelvic pain or the possible alteration of the hypothalamic-pituitary-adrenal axis and psychological disorders has not been established. Inflammation has been suggested as the common link between OAB and BPS/IC. CONCLUSIONS: OAB and BPS/IC are different symptoms complexes that share urgency as a common symptom. None of them have a specific symptom although pain on bladder filling is the hallmark symptom in BPS/IC. Bladder pain with urgency should be a trigger for referral to the provider with appropriate knowledge and expertise in this disease state, whereas the management of OAB should be part of normal routine care in the community.

[Stem cell therapy and tissue engineering in regenerative urology]. / Stammzelltherapie und "Tissue Engineering" in der regenerativen Urologie.

BACKGROUND: So far there is no clinically established, effective tissue engineering therapy for dysfunction or defects of the lower urinary tract. The concentration of experimental data, initial clinical studies and individual case reports underlines that stem cell treatment for bladder storage and voiding problems, erectile dysfunction and other urothelial defects of the lower urinary tract could close the gap between individualized therapy and potential biomedical applications. RESULTS: As a result of fundamental research work over the last decade a characterization of various stem cell populations and evaluation of different urological therapy options could be performed. Thereby, aspects of optimal administration, migration, secretion of bioactive factors and stage of differentiation of stem cells with respect to an improved efficiency of treatment were investigated. Because successful tissue regeneration depends on angiogenesis and innervation, particular attention was paid to these important factors. CONCLUSIONS: Various clinical indications for stem cell treatment and tissue reconstruction that may be required after radical prostatectomy, such as stress urinary incontinence, urethral reconstruction and erectile dysfunction have materialized and are currently being verified in preclinical studies and phase I trials.

[Urinary incontinence in the elderly: what can and should be done?]. / Inkontinenz im Alter: Was kann und soll man tun?

The demographic development of society shows a clear increase in the elderly population in the coming decades, which will result in an increasing prevalence of urinary incontinence. Diagnosis and treatment of many patients is not carried out for a myriad of reasons and thus incontinence care is often inadequate. A detailed medical history is the basis of identification of the problem and underpins the effective diagnostic and therapeutic management of the problem. In this context, the algorithms based on the national and international guidelines and age-specific characteristics should be considered. The initial focus should be on conservative management. In a few cases of elderly patients, invasive diagnostics using urodynamics or cystoscopy might be indicated. The increased use of medication in the elderly both from an etiological and therapeutic point of view, especially in terms of drug/drug interactions requires special consideration. In particular cognitive impairment using pharmacological approaches should be avoided. Although incontinence surgery of the patient applies less often with increasing age it still plays a role in the appropriate selection of treatment.

Prostate carcinoma cell growth-inhibiting hydrogel supports axonal regeneration in vitro.

Prostate cancer is the most common malignant tumor in men. Radical prostatectomy, the most common surgical therapy, is typically accompanied by erectile dysfunction and incontinence due to severing of the axons of the plexus prostaticus. To date, no reconstructive therapy is available as the delicate network of severed nerve fibers preclude the transplantation of autologous nerves or synthetic tube implants. Here, we present an injectable hydrogel as a regenerative matrix that polymerizes in situ and thus, adapts to any given tissue topography. The two-component hydrogel was synthesized from a hydrolyzed collagen fraction and stabilized by enzymatic crosslinking with transglutaminase. Physical analysis employing osmolarity measurements and cryosectioning revealed an isotonic, microstructured network that polymerized within 2min and displayed pronounced adhesion to abdominal tissue. Cell culturing demonstrated the biocompatibility of the gel and a general permissiveness for various neuronal and non-neuronal cell types. No effect on cell adhesion, survival and proliferation of cells was observed. A chemotherapeutic drug was integrated into the hydrogel to reduce the risk of fibrosis and tumor relapse. Significantly, when the hydrogel was employed as a drug release depot in vitro, aversive fibroblast- and prostate carcinoma cell growth was inhibited, while axonal outgrowth from peripheral nervous system explants remained completely unaffected. Taken together, these results suggest that the gel's adequate viscoelastic properties and porous microstructure, combined with its tissue adhesion and neuritotrophic characteristics in the presence of a cell type-specific cytostatic, may constitute an appropriate hydrogel implant applicable to patients suffering from prostatectomy associated side effects.

[New treatment strategies for male lower urinary tract symptoms]. / Neue Behandlungskonzepte von Symptomen des unteren Harntraktes beim Mann.

For patients with lower urinary tract symptoms (LUTS), α1-adrenoreceptor inhibitors and 5-alpha reductase inhibitors as well as their combination are considered the gold standard. In addition, anticholinergic agents are being introduced as monotherapy or in combination with α1-adrenocepetor inhibitors for patients with predominant storage disorders. Phosphodiesterase 5 (PDE5) inhibitors are often the best option for patients with LUTS who also suffer from erectile dysfunction. Recently, novel treatment options have been presented and intraprostatic injection of various agents, such as botulinum toxin A, NX-1207 and PRX302 has shown promising initial results. In addition, innovative minimally invasive treatment options, such as UroLift® appear to be efficacious and safe in this patient cohort. Particular emphasis should be laid on patients with LUTS and concomitant sexual disorders.

[Unconventional treatment procedures of the bladder in paraplegia and myelomeningocele]. / Behandlungsverfahren der Blase bei Querschnittlähmung und Myelomeningozele.

The established treatment of neurogenic lower urinary tract dysfunction (NLUTD) in patients with spinal cord injury (SCI) or meningomyelocele (MMC) is mainly conservative and is aimed at the lower urinary tract. For example, oral antimuscarinic medication is the standard treatment of neurogenic detrusor overactivity. Recently, however, treatment aiming directly or indirectly at the innervation of the urinary tract has gained increasing attention. Current evidence does not justify the use of nerve rerouting but the existing preliminary data are more promising for MMC patients than for those with SCI. Sacral neuromodulation is already a therapeutic option for incomplete SCI patients. Initial data from a pilot study indicate that in patients with complete SCI implementation in the spinal shock phase may prevent the development of NLUTD. Licensing of onabotulinum toxin A (Botox®) facilitated its clinical use for treating NLUTD but it is limited to the indication of neurogenic detrusor overactivity incontinence with a dosage of 200 IU. The mentioned unconventional treatments, although discussed controversially, are promising future treatment options for NLUTD.

Development of a porcine animal model for urethral stricture repair using autologous urothelial cells.

OBJECTIVE: To present a versatile large animal model for endoscopic stricture repair using autologous urothelial cells. MATERIALS AND METHODS: 12 male minipigs were used. An artificial stricture model was established using suture-ligation, thermo-coagulation and internal urethrotomy. A vesicostomy served for urinary diversion. Stricture formation was confirmed radiologically and histologically. Autologous urothelial cells were harvested from bladder washings, cultivated and labeled. Internal urethrotomy was done in all, and the cultivated cells were injected into the urethrotomy wound. All animals were sacrificed after 4 or 8 weeks. Immunohistology was done to confirm the presence of autologous urothelial cells within the reconstituted urethra. RESULTS: Stricture formation was verified with all three methods. Histologically, no significant differences in the severity of stricture development could be observed with regard to the method used. The autologous urothelial cells in the area of the urethrotomy could be detected in the urothelium and the corpus spongiosum until 8 weeks after re-implantation. CONCLUSIONS: We created a reliable and reproducible porcine model for artificial urethral strictures. Autologous urothelial cells can be implanted into an artificial stricture after urethrotomy. These cells retain their epithelial phenotype and are integrated in the resident urothelium. Further comparative studies are needed to ultimately determine a superior efficacy of this novel approach.

[Benefits and risks of orthotopic neobladder reconstruction in female patients]. / Nutzen und Risiko des orthotopen Harnblasenersatzes bei Frauen.

Orthotopic neobladder reconstruction is an established treatment option in female patients undergoing radical cystectomy for invasive bladder cancer. Long-term results have proven its oncological safety and functional efficacy in both organ-confined and locally advanced disease. The use of nerve-sparing procedures has the potential to further improve the functional results in terms of postoperative continence and sexual function as long as we adhere to basic oncological principles. One important contraindication for performing neobladder reconstruction in female patients with bladder cancer is a positive urethral margin at radical cystectomy. In this respect, frozen section analysis is associated with a high sensitivity and specificity for the detection of positive urethral margins. The risk of urethral recurrence at 5 years in patients with negative urethral margins at cystectomy is ≤ 1 % and may become clinically apparent as inguinal lymphadenopathy due to changes of the lymphatic drainge after neobladder reconstruction. The 5-year recurrence-free survival after neobladder reconstruction in female patients with organ-confined bladder cancer ranges between 63 and 75 %. In female patients with locally advanced node-negative disease (≥ pT3a-4a, pN0) who underwent an orthotopic neobladder the recurrence free survival at 5 years is 71 % and so does not significantly differ from that of female patients with node-positive disease treated with an cutaneous diversion. Whether robotic cystectomy has the potential to further improve the functional outcome after neobladder reconstruction in female patients and achieve oncological long-term results comparable to those of open series is still under investigation should further be evaluated in prospective trials.

[Bladder cancer screening with urine-based tumour markers - occupational medical experience]. / Das Screening von Harnblasenkarzinomen mittels urinbasierter Tumormarker - Erfahrungen aus der Arbeitsmedizin.

OBJECTIVE: Bladder cancer responds favourably to treatment and has a good survival rate, provided it is diagnosed at an early stage. Established methods exist for the early detection, however, their specificity and positive predictive value are not yet satisfactory. Innovative markers have been proposed, but still require validation in prospective studies. We provide a literature-based short overview on the currently available and some proposed markers for the early detection of bladder cancer and evaluate the need for validation in further studies. We further provide some first results of such a recently finished study in an occupational setting. MATERIAL AND METHODS: We conducted a prospective screening study over seven years in 1610 males with former occupational exposure to carcinogenic aromatic amines. Annual bladder cancer screening according to statutory requirements was offered. In addition to the regularly performed check for hematuria and urine cytology, the markers NMP22, UroVysion™ and survivin were performed in voided urine samples of the participants. Positive findings (not for survivin) were further followed through urethrocystoscopy. RESULTS AND CONCLUSIONS: A total of 7219 urine samples were screened. During the study period 16 incidental and 4 recurrent bladder tumours, thereof three papillomas, occurred in a total of 19 participants. 14 out of twenty tumours were marker-positive, and all but two were early stage findings. Cell-based markers (cytology, UroVysion™) und molecular markers (NMP22, survivin) were largely complementary, thus acting as a "multi-marker panel". Eight of the tumours were identified by a positive cytology. Six tumours were not detected by any of the tumour markers. The results will be further evaluated through the inclusion of confounding factors, which have so far rarely been examined in other studies. This may lead to the development of tiered diagnostic strategies with the aim to reduce the number of invasive diagnostic procedures in the future.

A novel clinical syndrome revealing a deficiency of the muscarinic M3 receptor.

OBJECTIVES: No clinical disorders have been caused by dysfunction of any of the 5 subtypes (M1-M5) of muscarinic receptors. We present a patient with a novel clinical syndrome that we suggest results from a deficiency of the muscarinic M3 receptor. METHODS: We conducted a comprehensive workup of autonomic function. The patient's disorder was compared to the phenotypic features of male M3 knockout mice. M3 protein quantity was assessed by Western blot and radioligand binding in peripheral blood lymphocytes. Tests for autoantibodies and genetic abnormalities were performed. RESULTS: The disease pattern was characterized by disturbances in micturition, pupil constriction, body weight, and sudomotor function, with normal accommodation, gastrointestinal motility, salivation, and lacrimation, similar to features of male M3 knockout mice. M3 protein quantity was reduced. Genetic tests were unrevealing, but unspecific antinuclear antibodies were present. CONCLUSIONS: The presented clinical syndrome suggests a deficiency of the muscarinic M3 receptor. These results and future evaluation of patients with autonomic deficits may provide insights into the site and functional role of the muscarinic M3 receptor in humans.

[Educational initiative of the German Society of Urology for innovative research : Workshops 2009]. / Ausbildungsinitiative der Deutschen Gesellschaft für Urologie für innovative Forschung : Workshops 2009.

The tasks of the Working Group on Urological Research (AuF) of the German Society of Urology (DGU) are to support communication and initiation of joint ventures in German urology and to cooperate with associated subjects and neighboring countries. The annual "wet lab workshops" needs a space between annual and "wet lab workshops" on the topics of tumor cell culture, gene silencing, proteomics, and tissue engineering and the use instead of annual topic-related symposium"urological research," organized and carried out by the AuF as of 2009, serve to achieve a close change to closer integration of praxis and theory. This should contribute to a lasting quality improvement of the scientific work in urology. Accomplishing these objectives seems urgently necessary to preserve the interests of urologists, because more than ever research has become indispensable in an increasingly difficult environment of health care policy.

[Long-term results after endoscopic subureteral injection for VUR using dextranomer/hyaluronic acid copolymer : a five years experience]. / Endoskopische Unterspritzung des vesikoureteralen Refluxes mit Dextranomer/Hyaluronsäure : 5-Jahres-Langzeitergebnisse.

BACKGROUND: A number of bulking agents have been used for the endoscopic correction of vesicoureteral reflux in children. We present the long-term results of endoscopic use of dextranomer/hyaluronic acid copolymer (Deflux) for VUR grade I-IV in children. PATIENTS AND METHODS: Between 2004 and 2008, 21 children underwent endoscopic subureteral injection of Deflux in 30 ureters as an outpatient procedure. Twelve children had a unilateral reflux (two duplicated systems) and nine had a bilateral reflux. The median age was 5 years (6 months to 14.9 years). Six weeks postoperatively a voiding cystourethrogram (VCUG) was performed. This study examined the disappearance of VUR and urinary tract infection (UTI) as well as the quality of life (parents' questionnaire) during long-term follow-up. RESULTS: No intra- and postoperative complications were noticed. In 25 ureters (83%) VCUG showed no VUR 6 weeks postoperatively. In three children a second injection was done (two were successful). After a median follow-up of 2.5 years 27 ureters in 17 children (90%) had no UTI and VUR. The results of the questionnaire regarding quality of life were very good in the successfully treated children and the parents would choose the same treatment option again. CONCLUSION: Subureteral injection of Deflux for children with VUR is an effective treatment option for VUR with a low complication rate.