Multicriteria Decision Analysis Applied to the Clinical Use of Pharmacotherapy for Overactive Bladder Symptom Complex.

CONTEXT: The nonspecific storage symptom complex overactive bladder (OAB) is an important clinical condition in functional urology. Until recently, pharmacological therapy comprised antimuscarinic drugs, but more recently beta 3 agonists have added to the available agents. Traditional reporting of efficacy and safety of these agents relies upon regulatory placebo-controlled studies. There remains no head-to-head comparison of existing agents in the contemporary literature. Contemporary conclusions on comparative efficacy and safety drawn from the use of these agents are based on systematic reviews of the literature and associated meta-analyses. OBJECTIVE: In this study, we used the analytical model of multicriteria decision analysis (MCDA) to compare contemporary pharmacotherapy for OAB. EVIDENCE ACQUISITION: Efficacy and safety data from published, randomised, placebo-controlled trials of antimuscarinic antagonists, the beta 3 agonist, and the combination of an antimuscarinic and beta 3 agonist were used to populate the MCDA model. EVIDENCE SYNTHESIS: Experts assessed weights of the relative importance of favourable and unfavourable effects, which provided a common measure of benefits and safety that were combined in the MCDA model to give an overall ranking of the OAB drugs. RESULTS: When benefits are judged as more important than safety, fesoterodine 4 or 8mg used in a flexible dosing pattern provides the most favourable therapeutic option, over a wide sensitivity analysis relating to benefits and harms. CONCLUSIONS: In our analysis using an MCDA model, in both the flexible dosing pattern of fesoterodine and the solifenacin combination with mirabegron, the benefit-safety balance is better in terms of benefits and/or safety than any of the other available OAB drugs. Caution in interpretation of the data has to be expressed as the fesoterodine data are based on a flexible dosing regimen, which adds an additional dimension of personalising therapy. PATIENT SUMMARY: Overactive bladder (OAB) is a common condition with a significant impact on the quality of life. Possible symptoms include the following: (1) urgency-a compelling desire to urinate, which is difficult to defer; (2) urgency urinary incontinence-urgency leading to incontinence episodes; (3) frequency-increased frequency of wanting to pass urine; and (4) nocturia-increase in instances of getting up at night to urinate. To date, the mainstay of therapy for OAB has been antimuscarinic drugs and, more recently, the beta 3 agonist mirabegron. Ten international experts in urology, obstetrics, gynaecology, healthy ageing, and data analysis compared the benefit-risk balance of 14 OAB drugs licensed in Europe. The experts considered the importance of a favourable effect on the above four symptoms and also potential for side effects, but only three of these side effects, constipation, dry mouth, and dizziness, showed clinically relevant differences among the six drugs they considered. The observations recorded here suggest interesting differences between drugs across a wide range of possible trade-offs between benefit and safety. The different recruitment criteria used for each study may influence the results seen, so they need to be treated with caution. Comparison of flexibly dosed fesoterodine studies with fixed-dose fesoterodine studies introduces an additional potential bias; definitive conclusions can be drawn only if enough comparable placebo-controlled flexible dosing studies with other drugs were available.

Robotic Surgery as Applied to Functional and Reconstructive Urology.

CONTEXT: In recent years, there has been a rapid uptake in the use of laparoscopic and robotic surgery within urological oncological surgery. There is now growing interest in applying these surgical techniques to functional and reconstructive urology (FRU). OBJECTIVE: To provide an overview of the use of robotic surgery within the sphere of functional and reconstructive urology and discuss the research needs and the likely role of robotic technology in future. EVIDENCE ACQUISITION: A PubMed-based literature review performed in March 2019 identified all articles published regarding the use of robotic surgery within FRU for the reconstruction of the upper tracts, bladder, bladder neck, pelvic floor, and urinary sphincter; creation of urinary diversion; and repair of genitourinary fistulae. EVIDENCE SYNTHESIS: There is a need to study the robotic approach in carefully designed prospective studies to better establish safety and clinical efficacy as well as the economic viability as compared with laparoscopic and open approaches. CONCLUSIONS: The use of the robotic minimally invasive approach has many potential advantages; however, there is a need for a high level of technical expertise and experience, especially in some of the complex and technically challenging scenarios often seen within FRU. Surgeons should ensure that they have received sufficient training in not only the surgical principles of FRU, but also the assessment, management, and follow-up of patients. Moreover, it is imperative not to compromise important surgical steps. PATIENT SUMMARY: In this report, we looked into the use of robotic technologies in the treatment of functional and reconstructive problems of the urinary tract. We found that the robotic approach has not yet been evaluated in prospective clinical studies in this field. There is a need for carefully designed prospective studies to establish the safety and efficacy of robotic surgeries.

Recent advances in pelvic floor repair.

Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are conditions which result in significant physical, mental and social consequences for women worldwide. The high rates of recurrence reported with primary repair for POP led to the use of synthetic mesh to augment repairs in both primary and secondary cases following failed previous POP repair. The widely reported, unacceptably high rates of complications associated with the use of synthetic, transvaginal mesh in pelvic floor repair have severely limited the treatment options that surgeons can offer. This article summarises the recent advances in pelvic floor repair, such as improved quantification and modelling of the biomechanics of the pelvic floor and the developing technology within the field of tissue engineering for treatment of SUI/POP, including biomaterials and cell-based therapies. Finally, we will discuss the issues surrounding the commercial introduction of synthetic mesh for use within the pelvic floor and what lessons can be learned for the future as well as the current guidance surrounding treatment for SUI/POP.

Tissue engineering for the pelvic floor.

PURPOSE OF REVIEW: To set in context the challenge of developing tissue-engineered constructs for use in the female pelvic floor compared with at least 30 years of research progress in tissue engineering for other tissues. RECENT FINDINGS: The relative lack of information on the mechanical requirements of the pelvic floor in women who have suffered damage to these tissues is a major challenge to designing tissue-engineered materials for use in this area. A few groups are now using autologous cells and biomaterials to develop constructs for repair and regeneration of the pelvic floor. Progress with these has reached early stage evaluation in small animal models. Meanwhile the regulatory challenge of introducing laboratory-expanded cell therapy into the clinic is prompting groups to look at alternatives, such as using lipoaspirate retrieved in theatre as a source of adult stem cells for a number of tissues. In our group, we have begun to look at lipoaspirate for repair of the pelvic floor. SUMMARY: There is a need for research to harvest the advances made over the last 30 years in developing tissue-engineered constructs for several tissues to now tackle the problems of the weakened pelvic floor. At present, there are relatively few groups engaged in this challenge despite the growing clinical need.

A Comprehensive Review of Overactive Bladder Pathophysiology: On the Way to Tailored Treatment.

CONTEXT: Current literature suggests that several pathophysiological factors and mechanisms might be responsible for the nonspecific symptom complex of overactive bladder (OAB). OBJECTIVE: To provide a comprehensive analysis of the potential pathophysiology underlying detrusor overactivity (DO) and OAB. EVIDENCE ACQUISITION: A PubMed-based literature search was conducted in April 2018, to identify randomised controlled trials, prospective and retrospective series, animal model studies, and reviews. EVIDENCE SYNTHESIS: OAB is a nonspecific storage symptom complex with poorly defined pathophysiology. OAB was historically thought to be caused by DO, which was either "myogenic" (urgency initiated from autonomous contraction of the detrusor muscle) or "neurogenic" (urgency signalled from the central nervous system, which initiates a detrusor contraction). Patients with OAB are often found to not have objective evidence of DO on urodynamic studies; therefore, alternative mechanisms for the development of OAB have been postulated. Increasing evidence on the role of urothelium/suburothelium and bladder afferent signalling arose in the early 2000s, emphasising an afferent "urotheliogenic" hypothesis, namely, that urgency is initiated from the urothelium/suburothelium. The urethra has also recently been regarded as a possible afferent origin of OAB-the "urethrogenic" hypothesis. Several other pathophysiological factors have been implicated, including metabolic syndrome, affective disorders, sex hormone deficiency, urinary microbiota, gastrointestinal functional disorders, and subclinical autonomic nervous system dysfunctions. These various possible mechanisms should be considered as contributing to diagnostic and treatment algorithms. CONCLUSIONS: There is a temptation to label OAB as "idiopathic" without obvious causation, given the poorly understood nature of its pathophysiology. OAB should be seen as a complex, multifactorial symptom syndrome, resulting from multiple potential pathophysiological mechanisms. Identification of the underlying causes on an individual basis may lead to the definition of OAB phenotypes, paving the way for personalised medical care. PATIENT SUMMARY: Overactive bladder (OAB) is a storage symptom syndrome with multiple possible causes. Identification of the mechanisms causing a patient to experience OAB symptoms may help tailor treatment to individual patients and improve outcomes.

Time-to-diagnosis and symptoms of myeloma, lymphomas and leukaemias: a report from the Haematological Malignancy Research Network.

BACKGROUND: Prior to diagnosis, patients with haematological cancers often have multiple primary care consultations, resulting in diagnostic delay. They are less likely to be referred urgently to hospital and often present as emergencies. We examined patient perspectives of time to help-seeking and diagnosis, as well as associated symptoms and experiences. METHODS: The UK's Haematological Malignancy Research Network (http://www.hmrn.org) routinely collects data on all patients newly diagnosed with myeloma, lymphoma and leukaemia (>2000 annually; population 3.6 million). With clinical agreement, patients are also invited to participate in an on-going survey about the circumstances leading to their diagnosis (presence/absence of symptoms; type of symptom(s) and date(s) of onset; date medical advice first sought (help-seeking); summary of important experiences in the time before diagnosis). From 2004-2011, 8858 patients were approached and 5038 agreed they could be contacted for research purposes; 3329 requested and returned a completed questionnaire. The duration of the total interval (symptom onset to diagnosis), patient interval (symptom onset to help-seeking) and diagnostic interval (help-seeking to diagnosis) was examined by patient characteristics and diagnosis. Type and frequency of symptoms were examined collectively, by diagnosis and compared to UK Referral Guidelines. RESULTS: Around one-third of patients were asymptomatic at diagnosis. In those with symptoms, the median patient interval tended to be shorter than the diagnostic interval across most diseases. Intervals varied markedly by diagnosis: acute myeloid leukaemia being 41 days (Interquartile range (IQR) 17-85), diffuse large B-cell lymphoma 98 days (IQR 53-192) and myeloma 163 days (IQR 84-306). Many symptoms corresponded to those cited in UK Referral Guidelines, but some were rarely reported (e.g. pain on drinking alcohol). By contrast others, absent from the guidance, were more frequent (e.g. stomach and bowel problems). Symptoms such as tiredness and pain were common across all diseases, although some specificity was evident by sub-type, such as lymphadenopathy in lymphoma and bleeding and bruising in acute leukaemia. CONCLUSIONS: Pathways to diagnosis are varied and can be unacceptably prolonged, particularly for myeloma and some lymphomas. More evidence is needed, along with interventions to reduce time-to-diagnosis, such as public education campaigns and GP decision-making aids, as well as refinement of existing Referral Guidelines.