Räto T. Strebel

Experience With 100 Cases Treated With Botulinum-A Toxin Injections in the Detrusor Muscle for Idiopathic Overactive Bladder Syndrome Refractory to Anticholinergics

PURPOSE In this prospective, nonrandomized, ongoing study we evaluated the efficacy and safety of botulinum-A toxin injections in the detrusor muscle to treat patients with idiopathic overactive bladder resistant to conventional treatment, such as anticholinergic drugs. MATERIALS AND METHODS A total of 23 men and 77 women with a mean age of 63 years (range 24 to 89) with nonneurogenic overactive bladder, including urgency-frequency syndrome, and incontinence despite the administration of maximal doses of anticholinergics were consecutively treated with injections of 100 U botulinum-A toxin in the detrusor muscle at 30 sites under cystoscopic guidance. Micturition diary, full urodynamics, neurological status and urine probes were performed in all participants before treatment. Bladder biopsies were done only in cases of suspected bladder fibrosis or unclear findings. Special attention was given to reflex volume, maximal bladder capacity, detrusor compliance, post-void residual urine, urgency and frequency/nocturia. Clinical, urodynamic and quality of life assessments were performed at baseline, and 4, 12 and 36 weeks after botulinum-A toxin treatment. RESULTS Overall after 4 and 12 weeks 88% of our patients showed significant improvement in bladder function in regard to subjective symptoms, quality of life and urodynamic parameters (p <0.001). Urgency disappeared in 82% of the patients and incontinence resolved in 86% within 1 to 2 weeks after botulinum-A toxin injections. Mean frequency decreased from 14 to 7 micturitions daily (-50%) and nocturia decreased from 4 to 1.5 micturitions. Mean maximal bladder capacity increased 56% from 246 to 381 ml, mean detrusor compliance increased from 24 to 41 ml/cm H(2)O and pretreatment detrusor instability (mean reflex volume 169 ml) resolved in 74% of patients. Mean volume at first desire to void increased from 126 to 212 ml and mean urge volume increased from 214 to 309 ml. There were no severe side effects except temporary urine retention in 4 cases. Only in 8 patients was the clinical benefit poor and analysis revealed preoperative low detrusor compliance. Mean efficacy duration +/- SD was at least approximately 6 +/- 2 months and then symptoms began to increase. CONCLUSIONS Our results show that intradetrusor botulinum-A toxin injections may be an efficient and safe treatment option in patients with severe overactive bladder resistant to all conventional treatments.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the “Docetaxel Era”: Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa--the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)--includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

Is There a Role for Tamsulosin in the Treatment of Distal Ureteral Stones of 7 mm or Less? Results of a Randomised, Double-Blind, Placebo-Controlled Trial

BACKGROUND Numerous randomised trials have confirmed the efficacy of medical expulsive therapy with tamsulosin in patients with distal ureteral stones; however, to date, no randomised, double-blind, placebo-controlled trials have been performed. OBJECTIVE The objective of this trial was to evaluate the efficacy of medical expulsive therapy with tamsulosin in a randomised, double-blind, placebo-controlled setting. DESIGN, SETTING, AND PARTICIPANTS Patients presenting with single distal ureteral stones < or = 7 mm were included in this trial. INTERVENTION Patients were randomised in a double-blind fashion to receive either tamsulosin or placebo for 21 d. The medication was discontinued after either stone expulsion or intervention. Abdominal computed tomography was performed to assess the initial and final stone status. MEASUREMENTS AND LIMITATIONS: The primary end point was the stone expulsion rate. Secondary end points were time to stone passage, the amount of analgesic required, the maximum daily pain score, safety of the therapy, and the intervention rate. RESULTS Ten of 100 randomised patients were excluded from the analysis. No statistically significant differences in patient characteristics and stone size (median: 4.1 mm [tamsulosin arm] vs 3.8 mm [placebo arm], p=0.3) were found between the two treatment arms. The stone expulsion rate was not significantly different between the tamsulosin arm (86.7%) and the placebo arm (88.9%; p=1.0). Median time to stone passage was 7 d in the tamsulosin arm and 10 d in the placebo arm (log-rank test, p=0.36). Patients in the tamsulosin arm required significantly fewer analgesics than patients in the placebo arm (median: 3 vs 7, p=0.011). A caveat is that the exact time of stone passage was missing for 29 patients. CONCLUSIONS Tamsulosin treatment does not improve the stone expulsion rate in patients with distal ureteral stones < or = 7 mm. Nevertheless, patients may benefit from a supportive analgesic effect. CLINICALTRIALS.GOV: NCT00831701.

Robotic-Assisted Laparoscopic Extended Pelvic Lymph Node Dissection for Prostate Cancer: Surgical Technique and Experience with the First 99 Cases

BACKGROUND To date, there is still a paucity of data in the literature on robotic-assisted laparoscopic extended pelvic lymph node dissection (RALEPLND) in patients with prostate cancer. OBJECTIVE To assess the technical feasibility of RALEPLND and to present our surgical technique. DESIGN, SETTING, AND PARTICIPANTS From April 2006 to March 2008, we performed RALEPLND in 99 patients prior to robotic-assisted laparoscopic radical prostatectomy. Indications for RALEPLND were a prostate-specific antigen (PSA) > or = 10 ng/ml or a preoperative Gleason score > or = 7. The data were evaluated retrospectively. SURGICAL PROCEDURE The transperitoneal approach was used in all cases. In order to gain optimal access to the common iliac bifurcation, the five trocars were placed in a more cephalad position than in patients undergoing radical prostatectomy without RALEPLND. After identification of important landmarks, the lymphatics covering the external iliac vein, the obturator lymphatic packet, and the lymphatics overlying the internal iliac artery were removed on both sides. MEASUREMENTS The total lymph node yield, the frequency of lymph node metastases, and the complication rate. RESULTS AND LIMITATIONS The median patient age was 64 yr (range: 45-78). The median preoperative PSA level was 7.7 ng/ml (range: 1.5-84.6). The median number of lymph nodes harvested was 19 (range: 8-53). In 16 patients (16%), we found lymph node metastasis. Complications occurred in seven patients (7%). CONCLUSIONS RALEPLND is feasible, and its lymph node yield is well in the range of open series. The robotic-assisted laparoscopic approach in itself does not seem to limit a surgeons ability to perform a complete extended pelvic lymph node dissection.

Metformin in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Phase 2 Trial (SAKK 08/09)

BACKGROUND There is evidence linking metformin to improved prostate cancer (PCa)-related outcomes. OBJECTIVE To evaluate treatment with metformin in patients with castration-resistant PCa (CRPC) and the effect of the treatment on progression-free survival (PFS) and PSA doubling time (PSA DT). DESIGN, SETTING, AND PARTICIPANTS Forty-four men with progressive metastatic CRPC from 10 Swiss centers were included in this single-arm phase 2 trial between December 2010 and December 2011. INTERVENTION Patients received metformin 1000 mg twice daily until disease progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was the absence of disease progression at 12 wk. Simon two-stage optimal design was applied. With a 5% significance level and 90% power, 44 patients were required to test PFS at 12 wk ≤ 15% (H0) compared with ≥ 35% (H1). RESULTS AND LIMITATIONS Thirty-six percent of patients were progression-free at 12 wk, 9.1% were progression-free at 24 wk, and in two patients a confirmed ≥ 50% prostate-specific antigen (PSA) decline was demonstrated. In 23 patients (52.3%) we observed a prolongation of PSA DT after starting metformin. The homeostatic model assessment index fell by 26% from baseline to 12 wk, indicating an improvement in insulin sensitivity. There was a significant change in insulin-like growth factor-1 and insulin-like growth factor binding protein 3 from baseline to 12 wk. Sample size and lack of a control arm are the limitations of this trial; analyses are therefore exploratory. CONCLUSIONS Treatment with metformin is safe in nondiabetic patients, and it yields objective PSA responses and may induce disease stabilization. The activity of metformin in PCa, along with its low cost, favorable toxicity profile, and positive effect on metabolic parameters, suggests that further investigation of metformin as therapy for patients with PCa is of interest. PATIENT SUMMARY In this trial we assessed the use of the diabetes mellitus drug metformin in patients with advanced prostate cancer. We found disease stabilization and prolongation of prostate-specific antigen doubling time in some patients as well as effects on metabolic parameters. TRIAL REGISTRATION This study is registered with ClinicalTrials.gov with the identifier NCT01243385. PREVIOUS PRESENTATION The study was presented at ESMO 2012 (abstract 1460).

Improved detection of bladder carcinoma cells in voided urine by standardized microsatellite analysis.

Successful treatment of bladder cancer depends largely on early diagnosis of primary and recurrent disease. Sensitive, specific and noninvasive procedures for detection are especially needed for grade 1 and 2 bladder tumors, because of the relatively low sensitivity of cytology. Here we introduce a novel strategy to improve the sensitivity and reliability of microsatellite analyses by employing marker‐specific threshold values for loss‐of‐heterozygosity (LOH) at 10 loci. These individual cut‐offs were experimentally determined with 35 normal control tissues and subsequently validated in a retrospective study with bladder cancer biopsies from 86 patients. In a prospective analysis of voided urines samples and matched blood probes from 91 patients, LOH‐analysis, UroVysion FISH and conventional urine cytology were compared with histological findings of consecutive transurethral biopsies. Whereas all samples could be analyzed by our LOH assay, only 56 samples were suitable for all 3 analyses. The highest sensitivity was obtained with our LOH‐assay/cytology approach (G1–2: 72%; G3: 96%) being only surpassed by a combination of all 3 techniques (G1–2: 83%; G3: 100%). Since over 93% of the patients with recurrent disease were identified by LOH/cytology‐analyses of their voided urine samples, a monitoring scheme alternating cystoscopy with LOH/cytology‐examination could now be envisioned to reduce invasive interventions and consequently improve follow‐up compliance, especially in patients with low grade tumors.

Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer

The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system. The results were validated using an independent cohort of 209 ccRCCs with long‐term follow‐up. Cytogenetic alterations were identified in 96 of 126 ccRCCs, most of them involving chromosome 3 through loss, deletion or translocation. Expression of CKs and E‐cadherin in ccRCC was associated with lack of cytogenetic alterations and low nuclear grade. In the validation set, CK7 and CK19 protein expression was associated with better clinical outcome. At the multivariate level, the best model included metastatic status and CK19 expression. Expression microarray analysis on 21 primary ccRCCs and 14 ccRCC metastases identified genes significantly associated with CK7 and CK19 expressing ccRCCs. Two novel ccRCC biomarkers associated with the CK7 positive ccRCC phenotype, PMS2 and MT1‐MMP (MMP14), were further validated. We conclude that the variability observed for CK expression in ccRCC can be explained by genetic heterogeneity. Distinct molecular subtypes of ccRCC with prognostic relevance were identified, and the CK7/CK19 expressing subtype is associated with better outcome.

Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer - Results of a Phase IIb Randomized Controlled Trial.

Pomegranate has been shown to prolong PSA doubling time in early prostate cancer, but no data from a placebo controlled trial has been published yet. The objective of this study was to prospectively evaluate the impact of pomegranate juice in patients with prostate cancer. We conducted a phase IIb, double blinded, randomized placebo controlled trial in patients with histologically confirmed prostate cancer. Only patients with a PSA value ≥ 5ng/ml were included. The subjects consumed 500 ml of pomegranate juice or 500 ml of placebo beverage every day for a 4 week period. Thereafter, all patients received 250 ml of the pomegranate juice daily for another 4 weeks. PSA values were taken at baseline, day 14, 28 and on day 56. The primary endpoint was the detection of a significant difference in PSA serum levels between the groups after one month of treatment. Pain scores and adherence to intervention were recorded using patient diaries. 102 patients were enrolled. The majority of patients had castration resistant prostate cancer (68%). 98 received either pomegranate juice or placebo between October 2008 and May 2011. Adherence to protocol was good, with 94 patients (96%) completing the first period and 87 patients (89%) completing both periods. No grade 3 or higher toxicities occurred within the study. No differences were detected between the two groups with regard to PSA kinetics and pain scores. Consumption of pomegranate juice as an adjunct intervention in men with advanced prostate cancer does not result in significant PSA declines compared to placebo.

Apomorphine sublingual as primary or secondary treatment for erectile dysfunction in patients with spinal cord injury

To evaluate the effectiveness of apomorphine sublingual (SL) 3 mg, as a primary or secondary treatment for erectile dysfunction (ED) in patients with spinal cord injury (SCI), and to determine possible differences in efficacy considering clinical, urodynamic and neurophysiological findings.

Peri-operative morbidity and changes in symptom scores after transurethral prostatectomy in Switzerland: results of an independent assessment of outcome

To assess, in a prospective study, the contemporary outcome of transurethral resection of the prostate (TURP) in patients with benign prostatic hyperplasia (BPH) in Switzerland, by evaluating peri‐operative morbidity and changes in lower urinary tract symptoms (LUTS).