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.

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.

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.

[Urinary diversion in old patients (80+ years)]. / Harnableitung beim alten Patienten (80+).

With increasing life expectancy there is also an increased need for the management of older (≥ 80 years) patients with the diagnosis of muscle-invasive bladder cancer. Radical cystectomy with urinary diversion is the state of the art treatment (with neoadjuvant chemotherapy, as long as the patient is fit enough). Choosing the best urinary diversion with respect to morbidity compared to functionality and quality of life remains a challenge in these patients. Physical age alone is not decisive for making a decision. A thorough preoperative assessment of medical features, physical and cognitive impairments is more important. Older patients are generally provided with an ileal conduit as an incontinent urinary diversion, as the intervention involves reduced operating times and complexity compared to continent urinary diversions; however, in the case of good health status with an adequate life expectancy and sufficient compliance, continent diversions may be considered even in aged candidates. In the case of multimorbid patients with a high perioperative risk, ureterostomy with permanent ureteric stents is an important alternative. Most importantly, a thorough preoperative counselling enables patients to reach an informed decision.

Prostatic peripheral nerve distribution may impact the functional outcome of nerve-sparing prostatectomy.

PURPOSE: To study microscopic patterns of remaining peripheral nerves (PN) after nerve-sparing (NS) radical prostatectomy (RP) and possible consequences for nerve preparation. METHODS: Specimens from 27 patients (7 = non-NSRP, 20 = unilateral NS) were examined. Sections were investigated for PN content by immunoassaying. 120 whole-mounted slides were divided into four sectors, and extracapsular nerves were counted; the mean posterior/anterior ratio was calculated. Calculated ratios were correlated with the respective volumes of prostatic tissue (PV). After dividing the patient cohort into two subgroups, shared by the median value of the posterior/anterior nerve ratios, the absolute PN contents on the anterior surface of the NS sides were compared. RESULTS: Anatomical posterior nerve percentage in non-NS aspects ranged from 0.0-100.0 to 26.7-94.6% with a mean of 66.60 ± 25.4% and 68.83 ± 16.0% (>/<200 µm, respectively). Individual ratios from two nerve categories showed significant correlation (P < 0.008). Mean posterior ratios were 83.04/79.68 and 39.21/56.00, respectively. After unilateral NS, 3.17-fold (2.25 vs. 0.71 nerves, P = 0.05) and 2.26-fold (21.54 vs. 9.53, P = 0.08) nerve fibers were resected in the anterior area in comparison with type A. After unilateral NS, the variation impact on the anterior nerve content of the NS side could be demonstrated. CONCLUSIONS: The amounts of nerves localized on the anterior prostate after RP vary interindividually. Saving only a minor part of the anterior areas may have an impact on the quantity of excised nerves adjacent to the specimen and impair postoperative functional results. Especially for those patients without a major posterolateral bundle distribution, surgeons should adapt the procedure and start nerve preservation more anteriorly to maximize the probability of satisfactory postoperative functional results.

Different surgical approaches for stress urinary incontinence in women.

Stress urinary incontinence (SUI) constitutes involuntary voiding as a consequence of rising intra-abdominal pressure caused by sphincter weakness. In recent years studies were published according to surgical SUI management evaluating and comparing therapy options and outcomes. Therapy options were evaluated using a Medline search, including only publications in English between 2000-2012. Key words used were: SUI, conservative and surgical treatment, midurethral sling, colposuspension. Surgical treatment options demonstrate significantly better results than conservative treatment. MUS demonstrate better subjective and objective cure rates than colposuspension; it is less invasive and more cost-effective. First line SUI therapy such as RP MUS and TVT seem to be favored when compared to transobturator techniques. Retropubic and transobturator MUS showed equivalent objective and subjective success rates. Open colposuspension is an effective treatment possibility for recurrent SUI after failed MUS. TVT, compared with other MUS, seems to show slightly better cure rates. but perioperative complications appear to be similar. Long-term results (>10 years) of repeated SUI surgery showed that the Burch procedure had the lowest 9-year cumulative incidence of repeat SUI surgery. Mini-sling techniques may be underestimated but long-time results are pending and closer monitoring of the adverse event profile must be carried out. MUS are first choice in the treatment of SUI, of which TVT, has the best cure rate. Colpussupension continues to have its place in recurrent SUI. The new mini-MUS needs a longer follow-up for final evaluation.

Akt signalling parameters are different in oncocytomas compared to renal cell carcinoma.

PURPOSE: Renal oncocytomas are assigned as benign tumours, and their detailed molecular mechanism is poorly characterised. Activation of the PKB/Akt pathway is assumed to contribute to the pathogenesis and progression of malignant disease. For oncocytomas, hardly any data are available for Akt signalling parameters. Aim of the present work was to determine the alterations of Akt parameters PTEN, phosphorylated Akt (p-Akt) and p27(Kip1) in oncocytoma to better understand the dedifferentiation of renal tumours. METHODS: By tissue microarray analysis 15 oncocytoma, 18 clear cell renal cell carcinoma (ccRCC) and the corresponding benign tissue were investigated. Significant expression differences between PTEN, p-Akt and p27(Kip1) were determined by immunohistochemistry using One-way ANOVA with all pairs Tukey-Kramer as post hoc analyses. To investigate Akt parameter interactions in the oncocytoma, linear regression analyses were performed. RESULTS: Expression of all proteins was significantly different between the groups and in all groups the lowest for oncocytoma: PTEN: 32.9 ± 13.0 versus 75.5 ± 8.0 versus 123.7 ± 8.8; p < 0.001 for oncocytoma, benign parenchyma and ccRCC and 2.7 ± 1.2 versus 40.8 ± 9.5 versus 143.6 ± 12.2; p < 0.001 for p27(Kip1). p-Akt expression was significantly different between oncocytoma and ccRCC (67.3 ± 15.7 vs. 144.0 ± 26.6; p < 0.05). CONCLUSION: All three investigated parameters were the lowest in oncocytoma when compared to ccRCC. Expression of PTEN and p27(Kip1) seems to be exceedingly associated with malignant conditions of ccRCC. These findings might contribute to the understanding of tumorous signalling of the PKB/Akt axis in renal tumours.

[Transurethral resection of bladder tumors (TURBT)]. / Transurethrale Resektion von Blasentumoren (TUR-B).

Transurethral resection of bladder tumors (TURBT) is the standard of care for the diagnostics and primary treatment of bladder tumors. These are removed by fragmentation using loop diathermy. The resection area is coagulated for hemostasis. An important aspect is always a complete resection with an adequate amount of detrusor muscle in the specimen. Postoperative intravesical instillation of single-shot chemotherapy has been proven to reduce recurrence rates. Methods for improved tumor visualization (particularly photodynamic diagnostics) are used to enhance tumor detection rates particularly in multifocal tumors or carcinoma in situ (CIS). Thus, recurrence and progression rates can be reduced. Depending on the histological examination of the TURBT specimen, follow-up treatment for non-muscle invasive bladder tumors are adjuvant instillation treatment using chemotherapy or Bacillus Calmette-Guérin (BCG), second look TURBT and early cystectomy or for muscle invasive bladder tumors, radical cystectomy or (oncologically subordinate) trimodal treatment with renewed TURBT, radiotherapy and chemotherapy are indicated. Possible complications of TURBT include bleeding with bladder tamponade, extraperitoneal or intraperitoneal bladder perforation and infections of the urogenital tract.

[Safety and efficacy of en bloc vs. conventional transurethral resection of bladder tumors: a meta-analysis and systematic review]. / Sicherheit und Effizienz der en bloc vs. konventionellen transurethralen Resektion von Blasentumoren: eine Metaanalyse und systematic Review.

BACKGROUND: En bloc tumor resection of bladder tumors (ERBT) is a novel alternative procedure to conventional resection of bladder tumor (cTURBT), which might help to address common problems of the standard method, such as inadequate detrusor muscle in specimens, high re-resection rates and high recurrence rates. OBJECTIVE: To analyze current data on ERBT in efficacy and safety compared to cTURBT. DATA SOURCES: PubMed. STUDY SELECTION: Two independent authors identified trials based on keywords and inclusion criteria. A third author was consulted in case of discrepancies. Screening keywords: ERBT, en bloc transurethral resection of bladder tumor, TURBT en bloc. A meta-analysis of 13 studies was performed. The effect size was estimated based on odds ratios and mean differences including their corresponding two-sided 95% confidence intervals. DATA SYNTHESIS: The analyzed studies comprised a homogenous collective in terms of tumor size, tumor multiplicity and tumor stage. Operation time did not significantly differ between the methods. Differences were observed in hospitalization and catheterization time in favor of ERBT. Reported complications did not show clear differences. There was significantly more detrusor muscle in the specimens in the ERBT group. No significant differences were found in recurrence up to 2 years of follow-up. CONCLUSION: ERBT is a safe alternative to conventional TURBT with promising features regarding effective resection of detrusor muscle. More standardized data on recurrence rates, different resection modalities and resection margin results are needed.

Basic research and clinical applications of non-hematopoietic stem cells, 4-5 April 2008, Tubingen, Germany.

From 4 to 5 April 2008, international experts met for the second time in Tubingen, Germany, to present and discuss the latest proceedings in research on non-hematopoietic stem cells (NHSC). This report presents issues of basic research including characterization, isolation, good manufacturing practice (GMP)-like production and imaging as well as clinical applications focusing on the regenerative and immunomodulatory capacities of NHSC.

Economic aspects of bladder cancer: what are the benefits and costs?

OBJECTIVE: Bladder cancer (BC) has the highest lifetime treatment costs per patient of all cancers. The high recurrence rate and ongoing invasive monitoring requirement are the key contributors to the economic and human toll of this disease. The purpose of this paper was to utilize the recent literature to identify opportunities for improving the benefits and costs of BC care. METHODS: A PubMed search was performed of recent publications concerning (BC) cost-effectiveness. We reviewed studies, reviews, opinion papers and cost-effectiveness analyses, focusing primarily on non-muscle-invasive bladder cancer (Ta/T1; NMIBC). RESULTS: New diagnostic tools such as urine markers may assist in more cost-effectively detecting BC at an earlier stage, however, these markers cannot replace the cystoscopy, which is the current standard of care. A photodynamic diagnostic tool (PDD) using hexylaminolevulinate (Hexvix) enhances tumor visibility and improves transurethral resection of bladder cancer (TURB) results, potentially reducing recurrence rates and lowering treatment costs. While the importance of BC research has been acknowledged, research investment has been continuously reduced during the last 5 years. CONCLUSIONS: The economic burden of BC is well-characterized in the literature. This study suggests that new technologies (i.e., urine-based tests, PDD) and therapeutic regimes (intravesical chemotherapy, adjuvant immunotherapy) have significant potential to improve the diagnosis, treatment and on-going monitoring of BC patients, with potential improvements in clinical outcomes and concurrent cost-savings. A renewed interest and investment in BC research are required to ensure future advancements.

[Update on the second line management of idiopathic overactive bladder]. / Le point sur les traitements de seconde ligne de l'hyperactivité vésicale idiopathique.

The overactive bladder syndrome (OAB) negatively affects the daily life of many people worldwide and conservative treatments, such as antimuscarinics, not always bring relief and/or are associated with considerable side effects resulting in treatment failure. Second line treatment options used to be invasive surgical procedures. However, less radical, minimally invasive and reversible alternatives, such as sacral neuromodulation and botulinum toxin A have emerged. Of these, only sacral neuromodulation with InterStim Therapy has been approved for OAB and been recommended by the International Consultation on Incontinence (ICI) in 2004. Nevertheless, depending of country rules and habits, both seem to be used by urologists in clinical practice for treating idiopathic OAB (I OAB). Therefore, this review attempts to provide an update on the available clinical evidence concerning the efficacy and safety, and the current position of sacral neuromodulation and botulinum toxin A in the second line management of adults with I OAB.

[Endoscopic enucleation of the prostate]. / Endoskopische Enukleation der Prostata.

The spectrum of surgical procedures for the minimally invasive treatment of benign prostatic hyperplasia (BPH) has significantly increased over the last two decades. The simple suprapubic prostatectomy (subtotal prostatectomy, SP) has largely lost relevance in current practice. On the other hand, transurethral resection of the prostate (TURP) has been further standardized and potentially made safer by the introduction of the bipolar technique and low-pressure systems.Transurethral (endoscopic) enucleation techniques (endoscopic enucleation of the prostate, EEP) are increasingly competing with the current gold standard TURP and are replacing SP for treatment of larger adenomas. This approach is especially related to the rapid development of laser technology, which has sustainably changed the face of modern BPH treatment in a similar way to stone therapy. This has been incorporated in the clinical patient management, clinical studies and standardization of numerous surgical techniques that are systematically described in this article. Additionally, efforts have also been made to use other energy sources, such as bipolar current in EEP. With respect to scientific objectivity, high-quality clinical trials are regularly published which further strengthen the position of EEP.

[Urological infections and antibiotic management in geriatric patients]. / Urologische Infektionen und Antibiotikamanagement bei geriatrischen Patienten.

Both the demographic shift and progress in medicine are resulting in an increasingly longer life expectancy. It is presumed that a mean age of 90 years will be achieved within the next decade in many countries. Thus, geriatric medicine, which is committed to the specific needs of older, often frail and frequently comorbid patients, is becoming increasingly more important. The prevalence of infections of the genitourinary tract increases with age, simultaneously, a critical and conscious use of antibiotics is required in terms of antimicrobial treatment. The intention of the present review is to make the reader aware of the specific characteristics of urinary tract infections and asymptomatic bacteriuria in the older patient population in terms of epidemiology, spectrum of pathogens and resistance as well as the indications for and performance of antimicrobial treatment.

[Bioartificial urothelium generated from bladder washings. A future therapeutic option for reconstructive surgery]. / Bioartifizielles autologes Urothel etabliert aus Spülungen der Harnblase. Eine zukünftige Therapieoption für die rekonstruktive Urologie.

Reconstructive surgery of lower urinary tract disorders can be limited by a shortage of adequate autologous tissue. Tissue engineering is an option for surgical reconstruction with evolved biological substitutes. Urethral repair with bioartificial urothelial implants can be an innovative method for sustained urothelial regeneration in situ. The needed urothelial cells are commonly isolated from native urothelium requiring surgery.The aim of this study was to establish primary human urothelial cell cultures from bladder washings in serum-free media and to generate urothelial tissue without seeding of matrices in a feeder cell-free system. It could be demonstrated that under these conditions bioartificial urothelium can be developed successfully from bladder washings. Its multilayered cellular structure and the initial differentiation in vitro, similar to native-grown urothelial tissue, are promising with regard to intended clinical application. Current work focuses on establishing cell culture techniques according to legal regulations, terminal differentiation of the urothelial constructs in vitro, and techniques to surgically implant lab-grown bioartificial urothelium.

[Minimally invasive percutaneous nephrolitholapaxy (MIP)]. / Minimal-invasive perkutane Nephrolitholapaxie (MIP).

Minimally invasive percutaneous nephrolithopaxy (MIP) was developed to combine the excellent stone-free rates of the conventional percutaneous nephrolithopaxy (PCNL) technique with the low morbidity of the miniaturized PCNL (Mini-Perc) and, at the same time, achieve a high level of patient comfort. The procedure is characterized not only by the diameter of the miniaturized 18-Fr Amplatz sheath that was adopted from the Mini-Perc but also by the following features: ultrasound-guided puncture of the kidney; single-step dilatation of the access tract; ballistic lithotripsy; a low-pressure irrigation system together with stone retraction by irrigation with a specially designed nephroscope sheath, for the so-called vacuum cleaner effect; and a sealed and tubeless access tract with primary closure of the channel independent of hemorrhage and without a second-look procedure.The results of the first 57 patients demonstrate primary stone-free rates of 92.9% with operating times averaging 62 (25-123) min. Severe complications, such as sepsis or bleeding requiring blood transfusion, did not occur. The high and predictable stone-free rate and a low morbidity comparable to that of ureteroscopy and extracorporeal shock-wave lithotripsy make MIP an attractive option for patients and urologists. The "vacuum cleaner effect" with quick removal of stone fragments reduces operating time and prevents new stone formation by avoiding residual fragments. The direct and primary closure of the access tract increases patient comfort and is justified by the reintervention rate of less than 8% in the presented cohort.The lack of a need for second-look nephroscopies, the vacuum cleaner effect, improved patient comfort without nephrostomy tubes, as well as surgery times comparable to that of traditional PCNL demonstrate a consequent evolution of the Mini-Perc. MIP therefore represents a promising and future-oriented module in modern stone therapy.

[Psychosocial effects in patients with penile cancer : A systematic review]. / Psychosoziale Auswirkungen bei Patienten mit Peniskarzinom : Ein systematischer Überblick.

BACKGROUND: Psychological stress of patients with penile cancer arises from the cancer diagnosis itself and the treatment consequences. In addition, there is cancer-specific distress. There is the chance of cure in localized stages and in those with limited regional lymph node metastases but this requires surgery and often adjuvant chemotherapy. This systematic review gives a summary of the existing literature to date. MATERIALS AND METHODS: A critical database search using Medline was made in Ovid from 1946 to 2017, in the Cochrane Central Register of Controlled Trials (CENTRAL) and in the Web of Science from 1900 to 2017. This was complemented by a search of the World Health Organization's International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov. The reference lists of the included studies were manually searched for additional references. RESULTS: Selected studies (n = 10) addressed the psychosocial effects of penile cancer treatment on quality of life and sexual function. Due to the heterogeneity of the study designs only a narrative description of the results was possible. Defects or mutilation due to penile cancer cause psychological distress in a significant number of patients. Organ-sparing interventions have a positive impact on quality of life and sexual function. CONCLUSION: The external genitals are a focus of sexual identity. Mutilating treatment causes significant distress but organ-sparing treatment and reconstruction positively influence quality of life.

[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.

[Extracorporeal shock wave lithotripsy]. / Extrakorporale Stoßwellenlithotripsie.

Interventional treatment of stones essentially consists of three treatment modalities. Extracorporeal shockwave lithotripsy (ESWL), in addition to uterorenoscopy (URS) and percutaneous nephrolitholapaxy (PCNL) is an essential treatment pillar and is the only noninvasive therapy option for the treatment of urinary stones. After a long period of ESWL being the leading choice in stone treatment, the number of SWL interventions diminished in recent years in favor of the other two treatment modalities (URS and PCNL). This article describes the indications, surgical technique and management of complications of SWL.

[Value of stem cell therapy for the treatment of stress incontinence. Current status and perspectives]. / Stellenwert der Stammzelltherapie für die Behandlung der Belastungsinkontinenz. Aktueller Stand und Ausblick.

Parallel to a fundamental change in the therapeutic approach to managing stress incontinence, an increasing number of patients ask for reconstruction of the outer, striated urethral sphincter as therapy for urinary stress incontinence. Regenerative medicine is starting to offer solutions using stem cells as a part of oncological therapy or in reconstructive surgery. In addition to the many auspicious experimental approaches, one published study reports the effective therapeutic use of myogenic stem cells in urinary stress incontinent patients. Before this procedure is adopted into general clinical practice, further studies with validated evaluations and a sound legal basis are needed.