Exercise training as a novel primary treatment for localised prostate cancer: a multi-site randomised controlled phase II study.

Alternative management strategies for localised prostate cancer are required to reduce morbidity and overtreatment. The aim of this study was to evaluate the feasibility, safety and acceptability of exercise training (ET) with behavioural support as a primary therapy for low/intermediate risk localised prostate cancer. Men with low/intermediate-risk prostate cancer were randomised to 12 months of ET or usual care with physical activity advice (UCwA) in a multi-site open label RCT. Feasibility included acceptability, recruitment, retention, adherence, adverse events and disease progression. Secondary outcomes included quality of life and cardiovascular health indices. Of the 50 men randomised to ET (n = 25) or UCwA (n = 25), 92% (n = 46) completed 12 month assessments. Three men progressed to invasive therapy (two in UCwA). In the ET group, men completed mean: 140 mins per week for 12 months (95% CI 129,152 mins) (94% of target dose) at 75% Hrmax. Men in the ET group demonstrated improved body mass (mean reduction: 2.0 kg; 95% CI -2.9,-1.1), reduced systolic (mean: 13 mmHg; 95%CI 7,19) and diastolic blood pressure (mean:8 mmHg; 95% CI 5,12) and improved quality of life (EQ.5D mean:13 points; 95% CI 7,18). There were no serious adverse events. ET in men with low/intermediate risk prostate cancer is feasible and acceptable with a low progression rate to radical treatment. Early signals on clinically relevant markers were found which warrant further investigation.

Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Interventions to improve exercise behaviour in sedentary people living with and beyond cancer: a systematic review.

BACKGROUND: To systematically review the effects of interventions to improve exercise behaviour in sedentary people living with and beyond cancer. METHODS: Only randomised controlled trials (RCTs) that compared an exercise intervention to a usual care comparison in sedentary people with a homogeneous primary cancer diagnosis, over the age of 18 years were eligible. The following electronic databases were searched: Cochrane Central Register of Controlled Trials MEDLINE; EMBASE; AMED; CINAHL; PsycINFO; SportDiscus; PEDro from inception to August 2012. RESULTS: Fourteen trials were included in this review, involving a total of 648 participants. Just six trials incorporated prescriptions that would meet current recommendations for aerobic exercise. However, none of the trials included in this review reported intervention adherence of 75% or more for a set prescription that would meet current aerobic exercise guidelines. Despite uncertainty around adherence in many of the included trials, the interventions caused improvements in aerobic exercise tolerance at 8-12 weeks (SMD=0.73, 95% CI=0.51-0.95) in intervention participants compared with controls. At 6 months, aerobic exercise tolerance is also improved (SMD=0.70, 95% CI=0.45-0.94), although four of the five trials had a high risk of bias; hence, caution is warranted in its interpretation. CONCLUSION: Expecting the majority of sedentary survivors to achieve the current exercise guidelines is likely to be unrealistic. As with all well-designed exercise programmes, prescriptions should be designed around individual capabilities and frequency, duration and intensity or sets, repetitions, intensity of resistance training should be generated on this basis.

Nuclear targeting of dystroglycan promotes the expression of androgen regulated transcription factors in prostate cancer.

Dystroglycan is frequently lost in adenocarcinoma, but the mechanisms and consequences are poorly understood. We report an analysis of ß-dystroglycan in prostate cancer in human tissue samples and in LNCaP cells in vitro. There is progressive loss of ß-dystroglycan immunoreactivity from basal and lateral surfaces of prostate epithelia which correlates significantly with increasing Gleason grade. In about half of matched bone metastases there is significant dystroglycan re-expression. In tumour tissue and in LNCaP cells there is also a tyrosine phosphorylation-dependent translocation of ß-dystroglycan to the nucleus. Analysis of gene expression data by microarray, reveals that nuclear targeting of ß-dystroglycan in LNCaP cells alters the transcription of relatively few genes, the most unregulated being the transcription factor ETV1. These data suggest that proteolysis, tyrosine phosphorylation and translocation of dystroglycan to the nucleus resulting in altered gene transcription could be important mechanisms in the progression of prostate cancer.

Competing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients.

BACKGROUND: Bladder cancer (BC) predominantly affects the elderly and is often the cause of death among patients with muscle-invasive disease. Clinicians lack quantitative estimates of competing mortality risks when considering treatments for BC. Our aim was to determine the bladder cancer-specific mortality (CSM) rate and other-cause mortality (OCM) rate for patients with newly diagnosed BC. METHODS: Patients (n=3281) identified from a population-based cancer registry diagnosed between 1994 and 2009. Median follow-up was 48.15 months (IQ range 18.1-98.7). Competing risk analysis was performed within patient groups and outcomes compared using Gray's test. RESULTS: At 5 years after diagnosis, 1246 (40%) patients were dead: 617 (19%) from BC and 629 (19%) from other causes. The 5-year BC mortality rate varied between 1 and 59%, and OCM rate between 6 and 90%, depending primarily on the tumour type and patient age. Cancer-specific mortality was highest in the oldest patient groups. Few elderly patients received radical treatment for invasive cancer (52% vs 12% for patients <60 vs >80 years, respectively). Female patients with high-risk non-muscle-invasive BC had worse CSM than equivalent males (Gray's P<0.01). CONCLUSION: Bladder CSM is highest among the elderly. Female patients with high-risk tumours are more likely to die of their disease compared with male patients. Clinicians should consider offering more aggressive treatment interventions among older patients.

Endocrine therapy in prostate cancer: time for reappraisal of risks, benefits and cost-effectiveness?

In the 70 years following the first description of the benefits of surgical castration, despite advances in medical therapy e.g. cabazitaxel, enzalutamide, abiraterone, androgen deprivation therapy (ADT) remains the cornerstone of treatment for advanced prostate cancer. However, with increasing numbers of men undergoing PSA testing, the disease is being diagnosed earlier and the costs of ADT, with uncertain survival benefits and associated risks, have risen dramatically. Clinical studies of potent novel agents have shown survival benefits in advanced disease, but timing, risks and cost-effectiveness of treatment remain controversial. As new agents enter clinical practice, a comprehensive research strategy is essential to optimise benefits whilst minimising harm.

An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer.

BACKGROUND: Urinary biomarkers are needed to improve the care and reduce the cost of managing bladder cancer. Current biomarkers struggle to identify both high and low-grade cancers due to differing molecular pathways. Changes in microRNA (miR) expression are seen in urothelial carcinogenesis in a phenotype-specific manner. We hypothesised that urinary miRs reflecting low- and high-grade pathways could detect bladder cancers and overcome differences in genetic events seen within the disease. METHODS: We investigated urinary samples (n=121) from patients with bladder cancer (n=68) and age-matched controls (n=53). Fifteen miRs were quantified using real-time PCR. RESULTS: We found that miR is stable within urinary cells despite adverse handling and detected differential expression of 10 miRs from patients with cancer and controls (miRs-15a/15b/24-1/27b/100/135b/203/212/328/1224, ANOVA P<0.05). Individually, miR-1224-3p had the best individual performance with specificity, positive and negative predictive values and concordance of 83%, 83%, 75% and 77%, respectively. The combination of miRs-135b/15b/1224-3p detected bladder cancer with a high sensitivity (94.1%), sufficient specificity (51%) and was correct in 86% of patients (concordance). CONCLUSION: The use of this panel in patients with haematuria would have found 94% of urothelial cell carcinoma, while reducing cystoscopy rates by 26%. However, two invasive cancers (3%) would have been missed.

Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.

BACKGROUND: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. METHODS: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. RESULTS: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38-66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. CONCLUSION: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.

Does Silybum marianum play a role in the treatment of chronic hepatitis C?

OBJECTIVES: The recent boom in patient education on chronic hepatitis C has resulted in a worldwide increase in the diagnosis of this condition. Available treatment is expensive and associated with significant side effects; therefore, many patients seek for alternative medicine. Silybum marianum is a natural herb known to mankind for over 2,000 years that has been used as a liver-protecting agent due to its antioxidant properties. The objective of this study is to evaluate the safety profile and the effects of this herb, using a commercially available extract; in the liver chemistry and viral load of hepatitis C in chronically infected patients. METHODS: Patients aged 21-65 years old with a diagnosis of chronic hepatitis C who were not using antiviral therapy were asked to participate. Patients were randomized to treatment with S. marianum 160 mg orally three times a week for four weeks or to no-treatment (control). Blood tests for viral load and liver enzymes (ALT and AST) were done at randomization and at the end of treatment. Paired-t test was used to measure differences between baseline and week 4 values for ALT, AST and viral load. The percent change for ALT, AST and viral load of both groups was analyzed using the Mann Whitney statistical test. RESULTS: 34 patients were enrolled. Men and women were equally distributed. Mean age was 50 years old. Mean baseline measurements of AST, ALT and viral load in the treatment group were 85 +/- 12.41 IU/ml, 120 +/- 20.57 IU/ml and 8.77 +/- 4.12 copies x 10(6)/ml while for the no-treatment group were 71 +/- 9.46 IU/ml, 97 +/- 15.35 IU/ ml and 1.8 +/- 0.62 copies x 10(6)/ml respectively. For treated subjects the mean values of AST, ALT and viral load demonstrated a decrease from baseline values, but this difference was not statistically significant. For control patients the values of ALT (p= .049), AST (p = .005) and viral load (p = .005) showed a statistically significant increase at week 4. Week 4 measurement chang...

Investigation of neurokinin-2 and -3 receptors in the human and pig bladder.

OBJECTIVE: To investigate the role of neurokinin (NK)-2 and -3 receptors in mediating the contraction of detrusor muscle strips from human and pig, to determine whether the pig is a good model for the study of tachykinin receptors in the human bladder, as the biological actions of tachykinins, e.g. substance P and NKA are mediated via three distinct receptor subtypes, NK-1, -2 and -3. MATERIALS AND METHODS: Strips of detrusor muscle were obtained from the bladder dome and neck of female pigs and from patients undergoing cystectomy. Cumulative concentration-response curves to NKA were obtained in the absence and presence of either the NK-2 receptor-selective antagonist SR48968 or the NK-3 receptor-selective antagonist SB223412. RESULTS: NKA produced concentration-dependent contractions in the human and pig detrusor muscle; the curves were shifted to the right by SR48968, with high affinity (pKB 8.9, 8.3 and 8.0 in the human, pig dome and pig neck, respectively), whereas SB223412 had a minimal effect (pKB 5.8, 5.8 and 6.3, respectively). CONCLUSION: These data confirm that the NK-2 receptor subtype mediates NKA-induced contraction of the human and pig detrusor muscle. The NK-3 receptor appears to have no role in detrusor contraction of either species. The results also provide evidence that the NK-2 receptor in human and pig are the same, and the latter may be an appropriate species to study tachykinin-induced contractions in human bladder.

Conventional and ambulatory urodynamic findings in women with symptoms suggestive of bladder overactivity.

PURPOSE: We compared ambulatory urodynamics and conventional video cystometry findings in women with symptoms of bladder overactivity. MATERIALS AND METHODS: In a prospective randomized crossover study 106 women with symptoms of urinary urgency with or without incontinence were comprehensively investigated by video cystometry and ambulatory urodynamics in random order. In addition, all women completed a validated symptoms questionnaire and voiding diary. RESULTS: Involuntary detrusor activity was detected in 32 and 70 cases on video cystometry and ambulatory urodynamics, respectively (p <0.001). Video cystometry done according to International Continence Society standards diagnosed detrusor instability in 4 women with no involuntary detrusor activity on ambulatory urodynamics. Involuntary detrusor activity resulting in incontinence was observed in 39 cases on ambulatory urodynamics, including 20 (51%) with stable video cystometry results. Stress incontinence was diagnosed in 42 cases on video cystometry and in 34 on ambulatory urodynamics (p = 0.629). Increasingly severe urge and stress incontinence reported in the symptoms questionnaire correlated positively with the subsequent detection of detrusor overactivity and stress incontinence, respectively, on the 2 urodynamic tests. CONCLUSIONS: In contrast to video cystometry, ambulatory urodynamics provides objective evidence of clinically important bladder overactivity in the majority of women with symptoms suggestive of bladder overactivity. The correlation of symptoms with ambulatory urodynamic findings implies that greater reliance may be placed on symptomatic diagnosis of bladder overactivity. Improved objective assessment of detrusor function provided by ambulatory urodynamics has implications for the definition of bladder overactivity and relevance of conventional cystometry in this context. In women who complain of urgency stable conventional cystometrography findings should be interpreted with caution.

Review of current practice to establish success after vasectomy.

BACKGROUND: This study aimed to examine the criteria used by surgeons in a district general hospital to confirm success following vasectomy, to establish the proportion of men undergoing vasectomy in whom the procedure was unsuccessful according to those criteria, and to evaluate their subsequent management. METHODS: All 15 surgeons performing vasectomy indicated that they required two consecutive azoospermic postvasectomy semen specimens before they advised couples that the vasectomy was successful. Results of postvasectomy semen analysis (PVSA) for all 240 primary vasectomies performed over a 12-month interval were analysed. Minimum follow-up was 30 (range 30-42; median 37) months. RESULTS: At follow-up 72 men (30 per cent) had not returned postvasectomy samples that fulfilled the criteria, including 18 who were azoospermic on the first PVSA 3 months after vasectomy but who failed to produce a second specimen. In 24 men (10 per cent) who failed to comply with the PVSA protocol, there was no documentation of any further action being taken. No pregnancies were reported in the partners of the study group during this interval and only one patient underwent repeat vasectomy. CONCLUSION: The results suggest that the strict requirement of two consecutive azoospermic postvasectomy semen specimens may be unjustified, leads to a high level of non-compliance and causes unnecessary delay in confirming success of the procedure.

The changing pattern of mortality and morbidity from radical cystectomy.

OBJECTIVES: To examine the morbidity and mortality of radical cystectomy as currently practised, and to compare the findings with historical data. PATIENTS AND METHODS: The operative mortality and early and late complications were recorded in 101 consecutive patients (median age 65 years, range 38-81; 33 aged >70 years) undergoing radical cystectomy between April 1992 and October 1997. Fifteen patients had relapsed after previous radical radiotherapy. RESULTS: The median postoperative stay was 14 days (range 8-44). There were two deaths within 60 days of surgery (of patients aged 46 and 59 years) from respiratory failure and sepsis, respectively. The mortality in the elderly was not more than in other age groups. The early morbidity included two cases of lower limb insufficiency, both in the salvage cystectomy group, where the morbidity was significantly higher than in those undergoing primary cystectomy (chi-squared, P<0.01). Three patients underwent early re-exploration. There were four clinically significant episodes of deep vein thrombosis and two pulmonary emboli that were not fatal. CONCLUSION: As currently practised, radical cystectomy is associated with a lower mortality (<2%) and morbidity than described previously. The added morbidity of salvage cystectomy and the acceptable mortality of primary cystectomy suggests that the treatment of choice for muscle-invasive disease is primary cystectomy, with external beam radiotherapy reserved for those patients unfit for major surgical intervention. Age alone should no longer be considered a contraindication to cystectomy.

Urodynamic assessment of the bashful bladder.

PURPOSE: We prospectively studied the potential contribution of ambulatory urodynamic monitoring in men with urinary symptoms unable to initiate a void on conventional video cystometrography. MATERIALS AND METHODS: A total of 40 consecutive symptomatic men with a median International Prostate Symptom Score of 19 (range 1 to 29) and median age of 51.9 years (range 30 to 75) who were unable to void during video cystometrography underwent ambulatory urodynamic monitoring. Solid-state transducers mounted on silicone coated catheters were inserted urethrally and rectally, and connected to a portable recorder. Subjects voided in private into a specially designed flow meter, which they connected to the recording device. RESULTS: Of the patients 2 (5%) failed to attend ambulatory urodynamic monitoring, despite multiple reminders, and in 1 (2.5%) the trace was uninterpretable. Pressure flow data were available for the remaining 37 patients with mean plus or minus standard deviation 2.72+/-0.1 storage void cycles recorded per patient. All 6 patients (15%) with obstruction were older than 40 years. In 6 cases (15%) obstruction was equivocal and the remainder were unobstructed. Transurethral prostatic resection in 2 and urethrotomy in 1 of 6 patients with obstruction resulted in subjective and objective improvement. CONCLUSIONS: The bashful bladder syndrome was not associated with any specific urodynamic diagnosis. Ambulatory urodynamic monitoring will yield a urodynamic diagnosis in more than 90% of cases after failure to record void data on video cystometrography. A surgically correctable cause of symptoms can be found in about 20% of men older than 40 years. The contribution of ambulatory urodynamic monitoring compared to more conventional evaluation in men younger than 40 years is negligible.

Pharmacodynamics of anticholinergic agents measured by ambulatory urodynamic monitoring: a study of methodology.

The aim of the study was to establish a methodology whereby ambulatory urodynamic monitoring (AUM) may be used in the assessment of the effects of darifenacin on urodynamic measures of detrusor function and symptoms associated with detrusor instability. Six patients (one man and five women) with detrusor instability (DI) on conventional urodynamic monitoring were recruited into this placebo-controlled crossover study. The study was divided into two periods of 7 days of treatment with either darifenacin 5 mg t.d.s. or placebo with the patient crossing over to the alternative treatment after a washout period of 7 days. On the 7th day of each treatment, AUM was carried out. Parameters used to quantify detrusor activity on AUM were the number, amplitude, and duration of detrusor contractions and the total area under the detrusor pressure/time curve. "Events" recorded were urge, leakage episodes, voids, and pain. Six comparable hours of AUM for each treatment period could be analyzed in four patients and 4 hr in one. In three of the five patients, reduction in activity on AUM while on darifenacin was apparent. Symptom data closely matched the changes in detrusor activity measured on AUM. This is the first study reporting the use of AUM in the development of a drug with an effect on detrusor activity. AUM has clear advantages over conventional cystometry, which can only measure surrogate urodynamic parameters at a single time point. The optimal duration of monitoring in this context appears to be 6 hr with prolongation of monitoring time beyond this being unlikely to yield additional useful information. Correlation between symptoms and findings on AUM is good with changes in parameters recorded on AUM relating closely to the improvement in symptoms.