Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

The concordance between the volume hotspot and the grade hotspot: a 3-D reconstructive model using the pathology outputs from the PROMIS trial.

OBJECTIVES: The rationale for directing targeted biopsy towards the centre of lesions has been questioned in light of prostate cancer grade heterogeneity. In this study, we assess the assumption that the maximum cancer Gleason grade (Gleason grade hotspot) lies within the maximum dimension (volume hotspot) of a prostate cancer lesion. METHODS: 3-D histopathological models were reconstructed using the outputs of the 5-mm transperineal mapping (TPM) biopsies used as the reference test in the pilot phase of Prostate Mri Imaging Study (PROMIS), a paired validating cohort study investigating the performance of multi-parametric magnetic resonance imaging (MRI) against transrectal ultrasound (TRUS) biopsies. The prostate was fully sampled with 5 mm intervals; each core was separately labelled, inked and orientated in space to register 3-D cancer lesions location. The data from the histopathology results were used to create a 3-D interpolated reconstruction of each lesion and identify the spatial coordinates of the largest dimension (volume hot spot) and highest Gleason grade (Gleason grade hotspot) and assess their concordance. RESULTS: Ninety-four men, with median age 62 years (interquartile range, IQR= 58-68) and median PSA 6.5 ng ml(-1) (4.6-8.8), had a median of 80 (I69-89) cores each with a median of 4.5 positive cores (0-12). In the primary analysis, the prevalence of homogeneous lesions was 148 (76%; 95% confidence interval (CI) ±6.0%). In all, 184 (94±3.2%) lesions showed concordant hotspots and 11/47 (23±12.1%) of heterogeneous lesions showed discordant hotspots. The median 3-D distance between discordant hotspots was 12.8 mm (9.9-15.5). These figures remained stable on secondary analyses using alternative reconstructive assumptions. Limitations include a certain degree of error within reconstructed models. CONCLUSIONS: Guiding one biopsy needle to the maximum cancer diameter would lead to correct Gleason grade attribution in 94% of all lesions and 79% of heterogeneous ones if a true hit was obtained. Further correlation of histological lesions, their MRI appearance and the detectability of these hotspots on MRI will be undertaken once PROMIS results are released.

The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies.

PURPOSE: Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS: In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS: Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS: According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

PROMIS--Prostate MR imaging study: A paired validating cohort study evaluating the role of multi-parametric MRI in men with clinical suspicion of prostate cancer.

BACKGROUND: Transrectal ultrasound-guided prostate biopsies are prone to detection errors. Multi-parametric MRI (MP-MRI) may improve the diagnostic pathway. METHODS: PROMIS is a prospective validating paired-cohort study that meets criteria for level 1 evidence in diagnostic test evaluation. PROMIS will investigate whether multi-parametric (MP)-MRI can discriminate between men with and without clinically-significant prostate cancer who are at risk prior to first biopsy. Up to 714 men will have MP-MRI (index), 10-12 core TRUS-biopsy (standard) and 5mm transperineal template mapping (TPM) biopsies (reference). The conduct and reporting of each test will be blinded to the others. RESULTS: PROMIS will measure and compare sensitivity, specificity, and positive and negative predictive values of both MP-MRI and TRUS-biopsy against TPM biopsies. The MP-MRI results will be used to determine the proportion of men who could safely avoid biopsy without compromising detection of clinically-significant cancers. For the primary outcome, significant cancer on TPM is defined as Gleason grade >/= 4+3 and/or maximum cancer core length of ≥ 6 mm. PROMIS will also assess inter-observer variability among radiologists among other secondary outcomes. Cost-effectiveness of MP-MRI prior to biopsy will also be evaluated. CONCLUSIONS: PROMIS will determine whether MP-MRI of the prostate prior to first biopsy improves the detection accuracy of clinically-significant cancer.

A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: The INDEX study.

INTRODUCTION: Focal therapy offers the possibility of cancer control, without the side effect profile of radical therapies. Early single centre prospective development studies using high intensity focused ultrasound (HIFU) have demonstrated encouraging genitourinary functional preservation and short-term cancer control. Large multi-centre trials are required to evaluate medium-term cancer control and reproduce functional recovery. We describe the study design of an investigator-led UK multi-centre, single arm trial using HIFU to deliver focal therapy for men with localised prostate cancer. METHODS: One-hundred and forty men with histologically proven localised low or intermediate risk prostate cancer (PSA < 15, Gleason ≤ 7, ≤ T2cN0M0) will undergo precise characterisation of the prostate using a combination of multi-parametric (mp)MRI and transperineal template prostate mapping (TPM) biopsies. Unilateral dominant tumours, the so-called index lesion, will be eligible for treatment provided the contra-lateral side is free of 'clinically significant' disease (as defined by Gleason ≥ 7 or maximum cancer core length ≥4 mm). Patients will receive focal therapy using HIFU (Sonablate 500®). Treatment effect will be assessed by targeted biopsies of the treated area and TPM biopsies at 36-months. RESULTS: Primary outcome is the absence of clinically significant disease based on 36-month post-treatment TPM biopsies. Secondary outcomes address a) genitourinary function using validated patient questionnaires (IPSS, IPSS-QoL, IIEF-15, EPIC-Urinary, EPIC-Bowel, FACT-P, EQ-5D), b) the predictive validity of imaging, and c) risk factors for treatment failure. CONCLUSIONS: INDEX will be the first multi-centre, medium term follow-up trial to evaluate the outcomes of a tissue preserving strategy for men with localised prostate cancer using the TPM-ablate-TPM strategy.

Laparoscopic partial nephrectomy using the potassium titanyl phosphate laser in a porcine model.

INTRODUCTION: To evaluate the potential and feasibility of the potassium titanyl phosphate (KTP) Greenlight laser to perform partial nephrectomy in a porcine model. TECHNICAL CONSIDERATIONS: A total of 15 laparoscopic partial nephrectomies were performed in 4 Danish land-raised pigs under anesthesia. Transperitoneal access was obtained, and using a total of four ports, the 80-W KTP laser was used to perform bilateral upper and lower pole partial nephrectomy. The procedures were done successfully without renal cooling or clamping of the vessels. The estimated blood loss for each procedure was less than 30 mL. Only in one operation, in which a secondary renal vein was transected, was any additional hemostasis required (a single Endoclip). The mean operating time was 42 minutes (range 31 to 59) for each partial nephrectomy. As demonstrated on video, smoke formation was, at times, a problem during the procedure, because it reduced visibility, making only intermittent application of laser energy possible. Histopathologic analysis of the specimens showed a zone of loss of substance (less than 1 mm) at the resection line and narrow adjacent zones on both sides of the resection line with minimal changes. CONCLUSIONS: We have shown for the first time that normally perfused laparoscopic partial nephrectomy using the KTP laser is feasible and efficacious in the porcine model. This represents a novel application for the KTP laser, which produced excellent renal parenchymal hemostatic ablation. We are currently working on ways to improve the visibility by reducing smoke formation before undertaking a clinical trial in humans.

Measles, mumps and rubella -- the urologist's perspective.

In recent years there has been a decline in the uptake of the MMR vaccine and a significant increase the number of reported case of mumps. This condition has number of important extrasalivary manifestations including mumps epididymo-orchitits. The article reviews the pathophysiology, clinical symptoms, diagnosis, and long-term sequelae of this increasingly prevalent condition and provides a reference for all practising urologists treating this disease.

Prostaglandin E2 and bethanechol in combination for treating detrusor underactivity.

OBJECTIVE: To test the hypothesis, in a prospective randomized double-blind study, that the combination of intravesical prostaglandin E2 (PGE2) and oral bethanechol chloride (BC) are additive or synergistic in improving bladder emptying, as they have been used alone for treating impaired detrusor contractility with little clinical benefit. PATIENTS AND METHODS: Nineteen patients with detrusor underactivity (17 men and two women) were eligible and randomized to one of two treatments. All had postvoid residual urine volumes (PVR) consistently of > 300 mL, most being reliant on clean intermittent self-catheterization (CISC). The experimental treatment group (nine patients) received once-weekly intravesical PGE2 (1.5 mg in 20 mL 0.9% saline) plus BC 50 mg four times daily, for a total of 6 weeks. The second group of 10 patients received a once-weekly instillation of saline together with placebo tablets, again for 6 weeks. RESULTS: Before treatment the median (interquartile range) PVR was 426 (405-480) mL for those receiving both drugs; this decreased to 325 (290-352) mL after completing the treatment (P < 0.015). In the placebo group the respective values were 576 (539-777) and 538 (350-775) mL (P = 0.09). Four of the patients receiving the active combination reported symptomatic improvement and were able to reduce the frequency of CISC. CONCLUSION: Although there was evidence of a pharmacological effect, BC and PGE2 had a limited therapeutic effect compared with placebo. Whilst we would not recommend this treatment as routine, it may be considered for the occasional treatment of a patient with detrusor underactivity.

Impalpable testis cancer.

OBJECTIVE: To assess the significance of ultrasonographically detected hypoechoic lesions of the testis when the clinical examination is normal, and to highlight the management difficulties thereafter. PATIENTS AND METHODS: Over a 2-year period four patients underwent radical orchidectomy where the sole indication for surgery was a hypoechoic lesion detected on ultrasonography (US). The indications for US were persistent scrotal discomfort in two men, contralateral orchitis, and the follow-up of testicular microlithiasis. The lesions were 4-11 mm in size and one man had several. None of the lesions were palpable; the tumour markers were normal in all patients. RESULTS: Three of the testes contained seminoma; in one there were two foci of seminoma and in all intratubular germ cell neoplasia was also identified. The remaining case was a Leydig-cell tumour. All tumours were staged as pT1 after radical inguinal orchidectomy. CONCLUSION: Impalpable lesions of the testis are likely to be malignant if they are hypoechoic on US and should be considered as seminoma until proved otherwise. The management thereafter is not straightforward, but must ensure an adequate histological diagnosis if the US appearances do not resolve.

A prospective controlled quantitative study of ultrastructural changes in the underactive detrusor.

PURPOSE: We quantify and compare ultrastructural changes seen at high power on electron microscopic examination of detrusor biopsies from underactive and control bladders. MATERIALS AND METHODS: The detrusor underactivity group consisted of 14 patients (mean age 64.0 years) with post-micturition residuals greater than 300 ml., impaired contractility and no obstruction on urodynamics. A total of 17 patients who voided normally voiders with residual volume less than 50 ml. served as the control group. Bladder biopsies were obtained endoscopically using cold cup technique and processed using standard methods. All specimens were randomized and studied at high power (x12,000 to x24,000) by an examiner who was blinded to the groups. All complete cells within each random grid field were counted up to a total of 500. The number of disrupted cells per 500 cells was noted. RESULTS: Disruptive cell profiles were found in all biopsies. Median cell count was 20 cells/500 in 14 controls and 96.5 cells/500 in the underactive detrusor group (p <0.001). The number of disruptive cell profiles did not correlate with age in the control group (r = 0.34, p = 0.18). CONCLUSIONS: There were distinct morphological changes in the detrusor associated with bladder dysfunction with approximately 4 times more disruptive cells in patients with an underactive bladder. However, there was no correlation between age and number of disruptive cells, suggesting that this is not a process of aging per se. Ultrastructure studies may have a role as an adjunct to urodynamics in the diagnosis of bladder dysfunction.

"Urological cold shower"--a novel treatment for intraoperative erection.

Intraoperative penile tumescence during endoscopic surgery is a troublesome complication and a challenge to the urologist. We describe a novel, convenient, safe, and readily available technique. We used an intracavernosal injection of epinephrine using a standard dental syringe and a cartridge of lidocaine 2% and epinephrine 1:80,000 to induce detumescence reliably.

A prospective evaluation of detrusor ultrastructural changes in bladder outlet obstruction.

OBJECTIVES: To characterize the ultrastructure of detrusor smooth muscle from the bladders of symptomatic men with bladder outlet obstruction (BOO) caused by benign prostatic enlargement (BPE) and compare this with a matched control group; to determine how detrusor morphology relates to urodynamic findings and to develop a better understanding of the natural development of bladder dysfunction related to BOO. PATIENTS AND METHODS: Twelve men (mean age 66 years, range 52-77) with urodynamically confirmed BOO caused by BPE and 12 age-matched asymptomatic normally voiding controls (mean age 67.8 years, undergoing cystoscopy for other conditions) had detrusor biopsies taken endoscopically. The biopsies were processed for electron microscopy using standard methods. The specimens were randomized and examined at medium power (x 4000) by an examiner unaware of the urodynamic findings. Any ultrastructural patterns identified subjectively were noted. RESULTS: In the BOO group eight of the 12 men had a myohypertrophic pattern, half of which were associated with a degenerative pattern of hypocontractility. Of the remaining four patients, two had the degenerative pattern alone and two were normal. The six men whose biopsies had a degenerative pattern had consistent postvoid residual volumes of > 150 mL; the remainder all had volumes of < 150 mL. There were no ultrastructural abnormalities in the control patients. CONCLUSIONS: There are interesting qualitative ultrastructural changes in the obstructed detrusor, but they are not consistent enough to provide a reliable diagnostic tool. However, there may be an important relationship between the degenerative pattern and postvoid residual volume in BOO.

A qualitative ultrastructural study of the hypocontractile detrusor.

PURPOSE: It has been proposed that precise and specific ultrastructural patterns exist in the dysfunctional human detrusor. We evaluated ultrastructural changes in the hypocontractile detrusor and examined the technique of detrusor muscle biopsy and its clinical application. MATERIALS AND METHODS: After clinical and urodynamic evaluation 19 male and 2 female patients with severe hypocontractility were entered into this prospective study. All patients had a post-void residual urine volume of consistently greater than 300 ml. and were classified as weak or very weak according to the Schäfer nomogram. Multiple biopsies were obtained with the patient under general anesthesia using the cold cup technique. Subsequent specimens were processed for electron microscopy using standard methods. Biopsies were also obtained from 6 controls with normal voiding parameters. RESULTS: Cold cup detrusor biopsy provided muscle of sufficient quality for detailed electron microscopic analysis in 26 of the 27 specimens obtained. Previously described criteria of the degeneration pattern were present in all cases of severe hypocontractility. These criteria include widespread disruptive muscle cell profiles with sarcoplasmic vacuolation, disruption of cell organelles and ultimately cell lysis. These features were evident in more than half of the randomly studied fields. In addition, 7 patients had an indistinct muscle fascicle cell arrangement with excessive deposits of collagen and elastic fibers between widely separated muscle cells and in the interstitium. It was suggested that these features represent the hyperelastosis pattern in the chronically over distended bladder. These morphological appearances were not present in any controls. CONCLUSIONS: This early study would appear to support a morphological basis for detrusor hypocontractility and it reinforces the feasibility of electron microscopy as a potential diagnostic tool. The hypocontractile detrusor has distinct ultrastructural appearances that are easily distinguishable from those of the normal age matched detrusor.

The 2-year symptomatic and urodynamic results of a prospective randomized trial of interstitial radiofrequency therapy vs transurethral resection of the prostate.

OBJECTIVE: To assess the 2-year symptomatic and urodynamic results of a prospective randomized trial of interstitial radiofrequency therapy of the prostate (IRFT) vs transurethral resection of the prostate (TURP). PATIENTS AND METHODS: Patients with lower urinary tract symptoms (LUTS) and urodynamic evidence of bladder outlet obstruction (BOO) were randomized to undergo IRFT or TURP and were followed up using the International Prostate Symptom Score (IPSS) and urodynamic assessment for 2 years. RESULTS: At 2 years there was a clinically relevant reduction in the IPSS in the IRFT (20 to 9) and TURP groups (22 to 4). There was also a statistically significant reduction in the detrusor pressure at maximum urinary flow in both groups, but the reduction in the IRFT group was probably not sufficient to explain the observed symptomatic improvements solely from a reduction in BOO. CONCLUSION: IRFT can produce a sustained improvement in LUTS for at least 2 years. However, such improvements are unlikely to be entirely the result of a reduction in BOO. The effects of radiofrequency energy may, at least partly, be independent of any thermal effect and depend instead on neuromodulation of lower urinary tract nerves.