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.

Pre-biopsy 3-Tesla MRI and targeted biopsy of the index prostate cancer: correlation with robot-assisted radical prostatectomy.

OBJECTIVE: To study whether pre-biopsy 3-Tesla prostate magnetic resonance imaging (MRI) with targeted biopsy allows accurate anatomical and oncological characterization of the index prostate tumour, and whether this translates into improved positive surgical margin (PSM) rates after radical prostatectomy. PATIENTS AND METHODS: We conducted a retrospective analysis of all men (n = 201) who underwent robot-assisted radical prostatectomy (RARP) between July 2012 and July 2014. Patients were divided into a study group (n = 63) who had undergone pre-biopsy 3-Tesla MRI, followed by visual targeted and systematic prostate biopsy, and a control group (n = 138) who had undergone systematic biopsy alone. The two groups were well matched regarding patient and cancer characteristics. The primary study objective was to assess the accuracy of pre-biopsy MRI for localizing the index tumour. Secondary study objectives were to assess the accuracy of MRI in assessing the maximum tumour diameter (MTD) of the index tumour focus and accuracy of the targeted biopsy in determining the Gleason score and primary Gleason grade of the index tumour focus and whether PSMs were improved after RARP. The reference standard was whole-gland pathology of the resected prostate gland. Continuous variables and proportions were compared using the t-test and Mann-Whitney test or contingency tables, respectively. Pearson's correlation coefficient and Bland-Altman plots were used to compare measurement of MTD. RESULTS: The MRI accurately located the index tumour focus in 73% of patients. Accuracies, stratified according to use of the Prostate Imaging Reporting and Data System (PI-RADS) categories 5, 4 and 3, were 94, 75 and 60% respectively. Accuracies stratified according to MTD of ≤0.7, ≤1 and >1 cm were 50, 57 and 79%, respectively. There was a positive linear correlation between MRI and histological MTD (r = 0.42, 95% confidence interval [CI] 0.16-0.63; P = 0.002), but MRI generally underestimated the MTD: the mean MRI-measured MTD was 1.51 cm (95% CI 1.29-1.72) vs a mean pathological MTD of 2.15 cm (95% CI 1.86-2.43). Targeted biopsy identified 37% more cancer per core than non-targeted biopsy. The mean maximum core length was 8.9 mm (95% CI 7.8-10) vs 6.5 mm (95% CI 5.8-7.2) for the study vs the control group (P = 0.0002; non-paired t-test). Gleason scoring was significantly more predictive after targeted biopsies, with unchanged scores in 40/63 men (63%) vs 62/138 men (45%) in the study and control groups, respectively (P = 0.001; Fisher's test). The odds of Gleason upgrading were 2.5 times greater (P = 0.028) in the control group. The primary Gleason grade was not significantly different in the two groups [45/63 men (71%) vs 91/138 men (66%); study vs control group respectively (P = 0.51, Fisher's test)]. Overall PSMs were nonsignificantly lower in the study group (15.8 vs 18.8%; P = 0.84, Fisher's test); and the MRI location of the index tumour focus correlated with the site of PSM in 70% of men in the study group. CONCLUSIONS: Pre-biopsy MRI can accurately identify the index prostate tumour, especially in those with higher PI-RADS grades and tumour diameter. Targeted biopsy of this focus retrieves significantly more cancerous tissue per core, and is more accurate regarding Gleason scores, but not primary Gleason grade. MRI underestimated the MTD, and PSMs were not significantly improved in the present study.

The role of PSA in detection and management of prostate cancer.

The prostate specific antigen (PSA) test clearly provides the opportunity for clinically relevant prostate cancer to be detected at a stage when treatment options are greater and outcomes may be improved. However, in some patients the PSA test may lead to investigations which can identify clinically insignificant cancers which would not have become evident in a man's lifetime. In addition, a raised PSA may often indicate benign prostatic enlargement, and this may provide an opportunity for treatment of this condition before complications develop. The lack of sensitivity and specificity that characterises PSA testing in the initial diagnosis of prostate cancer largely disappears after treatment of localised prostate cancer, especially after surgery. Three monthly PSA measurement is usually recommended for the first year after primary treatment. Subsequently less frequent testing is required. A PSA rise after primary treatment usually indicates biochemical recurrence and often the need for further therapy. There are two promising urinary RNA biomarkers, prostate cancer antigen 3 (PCA3) and fusion gene TMPRSS2:ERG, both of which aim to distinguish between men with low-risk (indolent) and those with aggressive (clinically significant) cancers.

New developments in metastatic prostate cancer therapy.

Metastatic prostate cancer is still commonly a lethal condition. The concept that 'men with prostate cancer die with rather than of their cancer' has been shown to be false. It is estimated that 10-20% of men in the UK present with locally advanced disease. Median overall survival remains only 3.5 years for men presenting with metastatic disease. The use of LHRH analogues to achieve medical castration has become the gold standard for both locally advanced prostate cancer, combined with radiotherapy, and metastatic disease. Androgen deprivation therapy (ADT) is the standard first-line treatment for advanced disease resulting in improvements in symptoms, radiological findings and PSA levels. Ultimately the majority of men with advanced prostate cancer will develop resistance to ADT Docetaxel is the standard first-line therapy recommended by international guidelines for patients with symptomatic metastatic castrate refractory prostate cancer who are suitable candidates for chemotherapy. More than 90% of patients with castrate refractory prostate cancer have bone metastases. Radium-223 dichloride is a novel alpha-emitting radiopharmaceutical agent, which mimics calcium and therefore targets bone metastases. It is indicated in patients with metastatic castrate refractory prostate cancer who have symptomatic bone metastases without visceral metastases.

Organ-confined prostate cancer: are we moving towards more or less radical surgical intervention?

Treatment possibilities for clinically localised prostate cancer include radical prostatectomy (RP), external beam radiotherapy, brachytherapy, focal therapy and active surveillance. Conflicting and methodologically flawed observational data from the last two decades have led to uncertainty as to the best oncological option. However, recently, there has been a series of high-quality studies that point to disease specific and overall survival advantages for those men undergoing RP. This article reviews the latest evidence and argues that at the current time, RP must be considered the gold standard treatment for the majority of men with clinically localised prostate cancer.

Burden of male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) - focus on the UK.

KEY MESSAGES: Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) can be bothersome and negatively impact on a patient's quality of life (QoL). As the prevalence of LUTS/BPH increases with age, the burden on the healthcare system and society may increase due to the ageing population. This review unifies literature on the burden of LUTS/BPH on patients and society, particularly in the UK. LUTS/BPH is associated with high personal and societal costs, both in direct medical costs and indirect losses in daily functioning, and through its negative impact on QoL for patients and partners. LUTS/BPH is often underdiagnosed and undertreated. Men should be encouraged to seek medical advice for this condition and should not accept it as part of ageing, while clinicians should be more active in the identification and treatment of LUTS/BPH. To assess the burden of illness and unmet need arising from lower urinary tract symptoms (LUTS) presumed secondary to benign prostatic hyperplasia (BPH) from an individual patient and societal perspective with a focus on the UK. Embase, PubMed, the World Health Organization, the Cochrane Database of Systematic Reviews and the York Centre for Reviews and Dissemination were searched to identify studies on the epidemiological, humanistic or economic burden of LUTS/BPH published in English between October 2001 and January 2013. Data were extracted and the quality of the studies was assessed for inclusion. UK data were reported; in the absence of UK data, European and USA data were provided. In all, 374 abstracts were identified, 104 full papers were assessed and 33 papers met the inclusion criteria and were included in the review. An additional paper was included in the review upon a revision in 2014. The papers show that LUTS are common in the UK, affecting ≈3% of men aged 45-49 years, rising to >30% in men aged ≥85 years. European and USA studies have reported the major impact of LUTS on quality of life of the patient and their partner. LUTS are associated with high personal and societal costs, both in direct medical costs and indirect losses in daily functioning. While treatment costs in the UK are relatively low compared with other countries, the burden on health services is still substantial. LUTS associated with BPH is a highly impactful condition that is often undertreated. LUTS/BPH have a major impact on men, their families, health services and society. Men with LUTS secondary to BPH should not simply accept their symptoms as part of ageing, but should be encouraged to consult their physicians if they have bothersome symptoms.

Optimising the management of early prostate cancer.

One in eight men in the UK will be diagnosed with prostate cancer during their lifetime. The risk of prostate cancer is strongly age-related and is also linked with a Western lifestyle. Other risk factors include Afro-Caribbean ethnic origin and a positive family history. The more first-degree relatives affected the greater the risk of developing the disease. More than 70 familial prostate cancer susceptibility genes, including the important breast cancer gene BRCA2, have now been identified. A suspicion of a diagnosis of prostate cancer is usually based on either induration or nodularity of the prostate on digital rectal examination or, more commonly, a rise in serum prostate specific antigen (PSA) level. The usual cut-off point for PSA is taken as 4 ng/ml, but in men below 65 a value of more than 2.5 ng/ml should raise suspicion. A progressive rise in PSA over time may also indicate the possibility of the presence of a cancer within the prostate. When prostate cancer is suspected, increasingly urologists are requesting multiparametric magnetic resonance imaging of the gland before deciding whether or not a biopsy is indicated. The Gleason grading of any cancer identified is an important part of the decision-making process concerning the need for active treatment, as opposed to surveillance alone. Gleason pattern 6 cancers are regarded as low risk, Gleason 7 intermediate risk and 8-10 high risk. In patients diagnosed with intermediate- or high-risk prostate cancer further investigations are required to determine the local extent of the disease and to exclude the presence of metastases.

Oncological outcomes of robotic-assisted radical prostatectomy after more than 5 years.

INTRODUCTION: In the last 10 years, robotic-assisted radical prostatectomy (RARP) has become increasingly popular as witnessed by an increased number of publications. However, there is still little known about the long-term oncologic outcomes of this technique. The aim of this study is to assess the oncologic outcomes of patients who underwent RARP at least 5 years ago, with an emphasis on biochemical recurrence-free survival (BCRFS). MATERIALS AND METHODS: In 2004, RARP was introduced at our institutions. Records of all patients having RARP were prospectively collected in a dedicated database as part of the NUVOLA-BAUS project. For the present study, we selected only patients who had a follow-up of at least 5 years. Endpoints were BCRFS rate and 5-year cancer-specific survival (CSS). RESULTS: Overall, we identified 175 patients; 61.7 % of patients had Gleason 7-9 disease and 26.9 % had pT ≥ 3 disease at final pathology. Eight patients (4.5 %) had biochemical recurrence at follow-up. Overall 5-year BCRFS rate was 95.4 %, while it was 97.6, 91 and 50 % in pT2, pT3 and pT4 diseases, respectively. Among the patients who recurred, the mean time to recurrence was 22.1 ± 8.8 months. These patients received salvage external beam radiation treatment combined with hormonal therapy (anti-androgen + LHRH analogue) or hormonal therapy alone. 5-year CSS was 98.3 % (172/175): in 2 cases, the specimen showed pT4 cancer, while lymph node metastasis was noted in one case. CONCLUSION: The 5-year BCRFS and CSS after RARP are encouraging even in a population with significant high-risk disease.

Changes and challenges: a career in prostate surgery.

Roger Kirby speaks to Natasha Galukande, Assistant Commissioning Editor. Roger Kirby graduated in Medical Sciences from Cambridge University (Cambridge, UK) in 1972. He then trained in surgery at University of London (London, UK) before specializing in urology. Kirby is currently the director of The Prostate Centre (London, UK), which he established in 2005. Kirby is the founding editor of the journal Prostate Cancer and Prostate Diseases, in addition to being the associate editor of the British Journal of Urology International, and founding editor of Trends in Urology and Men's Health. He has written over 60 books, published over 300 papers and performed over 2000 radical prostatectomies. In 2005, Kirby was awarded the St Peter's Medal by the British Association of Urological Surgeons. Kirby has also helped to raise over £3 million as trustee and secretary of the Urological Foundation and former chair of Prostate UK.

Advances in the treatment of metastatic prostate cancer.

Prostate cancer is the most common cancer in men in the UK. It accounts for nearly a quarter of all male cancer diagnoses and is the second most common cause of male cancer death. Despite a large increase in prostate cancer incidence, mortality rates have remained relatively constant through improvements in survival. Most patients present with localised disease, but there are still many who present with metastatic disease. Prostate cancers are driven by androgens, such as testosterone. Androgen deprivation therapy (ADT), which is still the mainstay of systemic treatment, effectively reduces intraprostatic androgen levels resulting in reduced androgen receptor (AR) stimulation and increased apoptosis. Medical castration using LHRH analogues has become the gold standard in managing both locally advanced prostate cancer, in ombination with radiotherapy, and metastatic disease. Eventually most men with advanced prostate cancer become resistant to ADT. This is now called castrate refractory prostate cancer (CRPC), and is associated with a poor prognosis. There is now hope for patients who progress after chemotherapy with the emergence of several new agents that have been shown to benefit patients. The first AR-targeted drug to show a definite clinical benefit is abiraterone. It markedly decreases levels of androgens in CRPC and initial trials showed promising activity. Enzalutamide has a high affinity and selectivity for AR binding, blocks nuclear translocation and reduces recruitment of co-activators. Abiraterone, enzalutamide and other AR-targeted drugs are being studied in clinical trials for patients earlier in their disease, e.g. in addition to ADT at first presentation of metastatic disease, where it is likely that greater benefits will be seen.