Adjuvant Intravesical Chemohyperthermia Versus Passive Chemotherapy in Patients with Intermediate-risk Non-muscle-invasive Bladder Cancer (HIVEC-II): A Phase 2, Open-label, Randomised Controlled Trial.

BACKGROUND: Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital. INTERVENTIONS: Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat. RESULTS: A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51-69%) in the CHT arm and 60% (95% CI 50-68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control). CONCLUSIONS: CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment. PATIENT SUMMARY: The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non-muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment.

Loss of Janus Associated Kinase 1 Alters Urothelial Cell Function and Facilitates the Development of Bladder Cancer.

Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk of malignancy that may relate to impaired antitumor immune responses or a direct role for PID germline mutations in tumorigenesis. We recently identified germline loss of function mutations in Janus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterized by infections and associated with early onset, fatal high-grade bladder carcinoma. Somatic mutations in JAK1, required for immune cell signaling in response to interferon gamma (IFNγ), have been associated with several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanisms remain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFNγ response of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1-deficient urothelial cells showed reduced surface expression of major histocompatibility complex class II (MHC II), intercellular adhesion molecule-1 (ICAM-1) and programmed death-ligand-1 (PD-L1) after IFNγ stimulation and were resistant to IFNγ-induced apoptosis and lymphocyte-mediated killing. In addition, we identify a previously unknown role for IFNγ signaling in modulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1 in immune surveillance and development of bladder cancer. Our results have implications for patients with rare JAK1 PID and, more broadly, inform development of biomarker and targeted therapies for urothelial carcinoma.

Clinical and Patient-reported Outcome Measures in Men Referred for Consideration of Surgery to Treat Lower Urinary Tract Symptoms: Baseline Results and Diagnostic Findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM).

BACKGROUND: Clinical evaluation of male lower urinary tract symptoms (MLUTS) in secondary care uses a range of assessments. It is unknown how MLUTS evaluation influences outcome of therapy recommendations and choice, notably urodynamics (UDS; filling cystometry and pressure flow studies). OBJECTIVE: To report participants' sociodemographic and clinical characteristics, and initial diagnostic findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM). UPSTREAM is a randomised controlled trial evaluating whether symptoms are noninferior and surgery rates are lower if UDS is included. DESIGN, SETTING, AND PARTICIPANTS: A total of 820 men (≥18 yr of age) seeking treatment for bothersome LUTS were recruited from 26 National Health Service hospital urology departments. INTERVENTION: Care pathway based on routine, noninvasive tests (control) or routine care plus UDS (intervention arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome is International Prostate Symptom Score (IPSS) and the key secondary outcome is surgery rates 18 mo after randomisation. International Consultation on Incontinence Questionnaires were captured for MLUTS, sexual function, and UDS satisfaction. Baseline clinical and patient-reported outcome measures (PROMs), and UDS findings were informally compared between arms. Trends across age groups for urinary and sexual PROMs were evaluated with a Cuzick's test, and questionnaire items were compared using Pearson's correlation coefficient. RESULTS AND LIMITATIONS: Storage LUTS, notably nocturia, and impaired sexual function are prominent in men being assessed for surgery. Sociodemographic and clinical evaluations were similar between arms. Overall mean IPSS and quality of life scores were 18.94 and 4.13, respectively. Trends were found across age groups, with older men suffering from higher rates of incontinence, nocturia, and erectile dysfunction, and younger men suffering from increased daytime frequency and voiding symptoms. Men undergoing UDS testing expressed high satisfaction with the procedure. CONCLUSIONS: Men being considered for surgery have additional clinical features that may affect treatment decision making and outcomes, notably storage LUTS and impaired sexual function. PATIENT SUMMARY: We describe initial assessment findings from a large clinical study of the treatment pathway for men suffering with bothersome urinary symptoms who were referred to hospital for further treatment, potentially including surgery. We report the patient characteristics and diagnostic test results, including symptom questionnaires, bladder diaries, flow rate tests, and urodynamics.

Chronic prostatitis: Current concepts.

PURPOSE: Chronic prostatitis (CP) is a common condition. It causes significant suffering to the patients and constitutes a sizeable workload for the urologists. The purpose of this review is to describe the currently accepted concepts regarding the aspects of CP. MATERIALS AND METHODS: Relevant papers on the epidemiology, etiology, diagnosis, evaluation and management of CP were identified through a search of MEDLINE using text terms "prostatitis", "chronic prostatitis" and "chronic pelvic pain syndrome". The list of articles thus obtained was supplemented by manual search of bibliographies of the identified articles and also by exploring the MEDLINE option "Related Articles". RESULTS: The salient points of the relevant articles on each aspect of CP have been summarized in the form of a non-systematic narrative review. CONCLUSION: Chronic prostatitis is caused by a variety of infective and non-infective factors and is characterized by a rather long remitting and relapsing clinical course. The diagnosis is based on symptoms comprising pain and nonspecific urinary and/or ejaculatory disturbances and microbiological tests to localize bacteria and/or leucocytes in segmented urinary tract specimens. The contemporary classification was proposed by the National Institutes of Health/National Institute of Diabetes Digestive Kidney Diseases (NIH/NIDDK). National Institutes of Health - Chronic Prostatitis Symptom Index (NIH-CPSI) is the patient evaluation tool used extensively in clinical practice and research. Management should be individualized, multimodal and of an appropriate duration.

Sacral neurostimulation for urinary retention: 10-year experience from one UK centre.

OBJECTIVES: To report our 10-year experience of sacral neurostimulation (SNS) for women in urinary retention, comparing the original one-stage with the newer two-stage technique, as SNS therapy is a well-established treatment for urinary retention secondary to urethral sphincter overactivity (Fowler's syndrome). PATIENTS AND METHODS: Between 1996 and 2006, 60 patients with urinary retention had a SNS device inserted; their case records were reviewed and data on efficacy, follow-up, need for continued clean intermittent self-catheterization (CISC), complications and operative revision rate were assessed. RESULTS: Overall, 43 of 60 (72%) women were voiding spontaneously, with a mean postvoid residual volume of 100 mL; 30 (50%) no longer needed to use CISC. During a total of 2878 months of SNS experience, adverse event episodes included lead migration in 20, 'box-site' pain in 19, leg pain/numbness in 18 and loss of response/failure in 18 patients; 53% of the women required a surgical revision related to their implanted stimulator. The efficacy of the two-stage was similar to that of the one-stage procedure (73% vs 70%). Women with a normal urethral sphincter electromyogram had worse outcomes than women with an abnormal test (43% vs 76%). Although the efficacy was no different in those taking analgesia/antidepressant medication, this group of women had a higher surgical revision rate. Failure and complications for the one-stage procedure were not restricted to the early follow-up period. The mean battery life of the implant was 7.31 years. CONCLUSIONS: SNS has sustained long-term efficacy but the procedure has a significant complication rate. At present, the two-stage technique has comparable efficacy to the one-stage technique but a longer-term follow-up is required. The National Institute of Clinical Excellence recommended the use of SNS in women with urinary incontinence who fail to respond adequately to anticholinergic therapy, but patients choosing this treatment should be made aware of the high complication rate associated with the procedure.

A single-center experience of symptomatic male urethral diverticula.

OBJECTIVES: To describe our experience of the etiology, presentation, management and outcomes of male urethral diverticula, which are uncommon, with few reports of large series published. METHODS: Twenty-one patients with male urethral diverticula were treated at a single institution during a 7-year period. Their case notes were retrospectively reviewed. RESULTS: Of the 21 diverticula, 7 (33.3%) were congenital as determined from the history and histologic analysis. These 7 patients' mean age at presentation was 25 years, and they complained mainly of obstructive symptoms, poor bladder emptying, and a palpable perineal swelling. The 14 patients with acquired diverticula presented later, at a mean age of 35 years, but with almost identical symptoms and signs. The most common aetiolgical factors included trauma in 3, urethral stricture disease in 3, and previous urethroplasty in 3. The anterior urethra and penoscrotal junction were the most commonly affected sites in both groups (18 of 21). Overall, 12 patients underwent open surgical repair, 6 underwent endoscopy, and in 3, the diverticulum was left in situ. Postoperative complications were more frequent in the acquired group (64% versus 27%) and included urethrocutaneous fistula in 5, urethral stricture in 2, and wound infection in 4. CONCLUSIONS: Urethral diverticula are uncommon, but should always be considered in young men with lower urinary tract symptoms or in those with a history of urethral trauma. Treatment should be individualized and determined according to the patient's fitness and the site and size of the diverticulum.

Does intraprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia?

OBJECTIVE: To compare the incidence of acute and/or chronic intraprostatic inflammation (ACI) in men undergoing transurethral resection of the prostate (TURP) for urinary retention and lower urinary tract symptoms (LUTS), as recently a role was suggested for ACI in the pathogenesis and progression of BPH, and urinary retention is considered an endpoint in the natural history of this condition. PATIENTS AND METHODS: Details of TURPs done between January 2003 and December 2005 at one institution were obtained from the operating theatre database. Patients were divided by indication (retention/LUTS). Clinical data and histology reports were then reviewed and bivariate and logistic regression used to compare the pathological features between these groups. RESULTS: Of 406 patients, 374 had evaluable data; 70% of men with urinary retention had ACI, vs 45% of those with LUTS (P < 0.001). On logistic regression, the pathological factors associated with TURP for acute retention compared to that for LUTS were ACI, old age, and resection weight to a lesser degree. CONCLUSION: Inflammation appears to be important in the pathogenesis and progression of BPH. In this study, the risk of urinary retention due to BPH was significantly greater in men with ACI than in those without, and the association of TURP for retention with ACI was stronger than that with prostate weight. This finding might offer new avenues for the medical treatment of men with LUTS due to BPH.

Role of alpha-blockers in type III prostatitis: a systematic review of the literature.

PURPOSE: We examined the evidence for the effectiveness of alpha-blockers for type III prostatitis. MATERIALS AND METHODS: Studies were identified through a search of MEDLINE, EMBASE and The Cochrane Library as well as a manual search of bibliographies of identified articles and abstract books of recent major international urology conferences. Inclusion criteria included randomized, placebo controlled trials of treatment for type III prostatitis and use of the National Institutes of Health-Chronic Prostatitis Symptom Index outcome measure. RESULTS: Six unique trials in a total of 386 patients met inclusion criteria. One study showed no difference between alpha-blockers and placebo in terms of total or domain National Institutes of Health-Chronic Prostatitis Symptom Index scores and another did not report the p value. All of the remaining 4 studies showed a statistically significant difference in the total score in favor of alpha-blockers, while only 2 showed improved quality of life. Individual treatment effects were statistically significant more often when treatment was administered for 3 months or longer. Despite a common tool for outcome assessment meta-analysis of the results in individual trials was not possible due to differences in the manner of interpreting outcomes and reporting data. CONCLUSIONS: The current published literature is insufficient to conclude with certainty that alpha-blockers are effective for type III prostatitis. Future studies should incorporate uniformity in data collection and reporting with improved health related quality of life as the end point of therapy.

To what extent do real life practice studies differ from randomized controlled trials in lower urinary tract symptoms/benign prostatic hyperplasia?

PURPOSE OF THE REVIEW: To compare the real-life practice studies and randomized controlled trials on benign prostatic hyperplasia in order to understand the applications of the data from the two types of study. RECENT FINDINGS: Until recently, much of the available information on benign prostatic hyperplasia has come from randomized controlled trials conducted by secondary care urologists on selected populations of patients, who are likely to represent the more symptomatic among the cohort of men with lower urinary tract symptoms in the community. The strict inclusion criteria in these trials led to uncertainty about the applicability of the results to community populations. Moreover, as patients in randomized controlled trials are specially recruited, rather than being drawn from a general population of men with lower urinary tract symptoms, the calculations of incidence and prevalence rates may not be possible. In the last few years, there have been a few important real-life practice studies such as the Triumph project, the Quadraet study and the ALF-ONE study, which have provided very useful data regarding the incidence and prevalence of lower urinary tract symptoms/benign prostatic hyperplasia, the incidence of acute urinary retention, the impact of therapy on the risk of surgery related to benign prostatic hyperplasia and the predictors of disease progression during treatment with alpha-blocker. SUMMARY: As the results from randomized controlled trials cannot always be generalized to daily urological practice, it is important to complement them with data made available by the real-life practice studies. In order to do that, the salient features in the methodology of both types of study must be understood.

Voiding dysfunction after tension-free vaginal tape: a conservative approach is often successful.

The published literature has focused mainly on the efficacy of tension-free vaginal tape (TVT) in correcting stress incontinence with few reports of complications. We report our experience with the first 52 cases of TVT, specifically assessing voiding dysfunction after the procedure. We carried out a retrospective study of patients undergoing TVT surgery for stress urinary incontinence (SUI) between April 2001 and July 2003. Data were collected on period of catheterization, voiding and storage symptoms, their duration and management. Fifty-two women with a mean age 54 years (36-77) were included. Postoperatively, the urethral catheter was removed routinely within 12 h. Twelve patients (23%) failed to void spontaneously and needed recatheterization. Ten of them (83%) were able to resume spontaneous voiding within 3 months. Twenty patients (38%) complained of storage symptoms postoperatively. Sixteen (80%) responded to conservative treatment. Transient urinary symptoms after TVT sling for SUI are common but can usually be managed conservatively.

Role of i.v. urography in patients with haematuria.

OBJECTIVE: Traditionally, patients presenting with haematuria undergo a series of investigations, including urine cytology, cystoscopy, i.v. urography (IVU) and renal tract ultrasound (US). Studies have suggested that the omission of IVU as a routine investigation for painless haematuria does not dramatically reduce the detection rate of malignant conditions. In this large retrospective study we evaluated the impact of the omission of IVU on the diagnosis of renal tract malignancies and other non-malignant but significant conditions. MATERIAL AND METHODS: A retrospective analysis of all patients attending our haematuria clinic between January 2000 and August 2002 was carried out. The diagnostic yields of IVU and a US scan were compared and the significance of abnormalities missed by either modality was assessed with regard to the overall management of patients. Diagnoses were divided into those that were significant and potentially harmful [e.g. tumour, pelvi-ureteric junction (PUJ) obstruction, hydronephrosis] and those that were insignificant and harmless (e.g. simple cyst, non-obstructing calculus). Liddell's exact test for matched pairs was used to test for statistical significance and to give the relative risk of a positive result. RESULTS: A total of 1211 patients were included in the study. When cytology, cystoscopy and US were normal, IVU did not detect any additional malignant pathology. Performing IVU instead of a US scan would have resulted in 74 non-malignant conditions remaining undiagnosed. Similarly, US alone would have missed 64 non-malignant lesions. Six non-malignant but significant conditions, including PUJ obstruction (n = 5) and benign ureteric stricture with hydronephrosis (n = 1), were missed by US but detected by IVU. CONCLUSION: In this cohort of retrospectively studied patients attending a haematuria clinic, IVU could safely have been omitted without decreasing the overall detection of malignant pathologies. Nevertheless, significant non-malignant pathologies would have remained undiagnosed. The authors suggest that US combined with a MAG III renogram could be considered as a first-line investigation instead of IVU. This is likely to result in maximum detection of malignant and non-malignant conditions, while reducing the radiation exposure to the patient.