PURPOSE:

Vascular Targeted Photodynamic (VTP) therapy with TOOKAD®Soluble is in phase III clinical trials through an interstitial transperineal approach for focal therapy of prostate cancer. Herein we investigated the safety and efficacy of the endourethral route in the context of Benign Prostatic Hyperplasia (BPH) in the dog model.

MATERIALS AND METHODS:

An optical laser fiber was positioned in the prostatic urethra of 34 dogs, including 4 controls, and connected to a 753nm diode laser at a fluence of 200mW/cm delivering 200-300J. TOOKAD®Soluble (5-15mg/Kg) was infused i.v. in two modes: continuous, starting 5-15min prior and during illumination or a bolus 5-10min before. Prostate ultrasound, cystourethrography, urodynamics and histopathology were performed. Follow-up ranged from 1-week to 1-year.

RESULTS:

Endourethral TOOKAD®Soluble-VTP was uneventful in all but one dog experiencing urinary retention but reached the 1-week enpoint. All prostates except controls presented hemorrhagic lesions. They consisted of two levels of concentric alterations: peri-urethral necrosis with destruction of the endothelial layer and adjacent inflammation/atrophy with normal blood vessels. Prostatic urethral width increased as early as 6 weeks post-treatment while prostatic volume decreased, reaching 25% by 18-26 weeks. A parallel decrease in urethral pressures was demonstrated at 6 weeks and lasted up to 1 year.

CONCLUSIONS:

We confirmed the vascular effect of endourethral TOOKAD®Soluble-VTP and showed for the first time that resulting peri-urethral necrosis lead to a significant and sustained widening of the prostatic urethra, accompanied by long-term improvement of urodynamic parameters. These findings support future clinical applications of this minimally invasive approach for BPH treatment.

PURPOSE:

To evaluate the utility in routine upper tract imaging in patients followed for non-muscle-invasive bladder cancer (NMIBC).

MATERIALS AND METHODS:

A retrospective review of patients treated for NMIBC between 2000 and 2006 was conducted. Kaplan-Meier curves were calculated to determine upper tract urothelial carcinoma (UTUC)-free probability for stage Ta and T1.Bladder cancer stage was included as a time-dependent covariate. Descriptive statistics were used to report rates of imaging studies used and the efficacy in diagnosing UTUC.

RESULTS:

Fifty-one of a total of 935 patients treated and followed for NMIBC were diagnosed with UTUC; median follow-up was 5.5 years. Five-year UTUC-free probability among Ta and T1 patients was 98% and 93%, respectively. Ten-year UTUC-free probability among Ta and T1 patients was 94% and 88%, respectively. Only 15 (29%) patients were diagnosed on routine imaging while the others were diagnosed after developing symptoms. Overall, 3074 routine imaging scans were conducted for an overall efficacy of 0.49%.

CONCLUSIONS:

Upper tract recurrence is a lifelong risk in patients with bladder cancer, but most will be missed on routine upper tract imaging. The majority of UTUCs can been diagnosed using a combination of thorough history taking, physical exam, urine cytology and sonography, indicating that routine surveillance imaging may not be the most efficient way of detecting upper tract recurrences.

PURPOSE:

This systematic review focuses on the relationship between nocturia and depression/anxiety. Our objective is to provide an overview of current data regarding the epidemiology, pathophysiology, and patient management implications of the association between nocturia and depression/anxiety.

MATERIALS AND METHODS:

Pubmed, Web of Science, and Embase were queried in July 2012 to identify abstracts, original, review and editorial articles on nocturia and mood disorders, specifically depression and anxiety. The search was conducted using the following keywords: "nocturia", "depression", and "anxiety". We complied with the Assessment of Multiple Systemic Reviews instrument. We retrieved a total of 500 records with 95, 81, and 324 from Pubmed, Web of Science, and Embase, respectively.

RESULTS:

Cross sectional (level 3) data indicate that nocturia and depression/anxiety are strongly associated. One prospective study contends that depression leads to nocturia in a unidirectional relationship. Nocturia poses a greater risk for depression in men versus women. Results are conflicting regarding the effect of SSRI's on nocturia.

CONCLUSIONS:

The results of this systematic review suggest a bidirectional association between depression and nocturia. The relationship between anxiety and noctuira is less clear. Practicing clinicians should consider administering a brief self-administered scale to assess for depression in nocturia patients.

PURPOSE:

The following eligibility criteria are used to enroll patients in active surveillance (AS) at Johns Hopkins: clinical stage T1, PSA density < 0.15, biopsy Gleason score ≤ 6, ≤2 positive biopsy cores, and ≤ 50% involvement of any biopsy core. We hypothesized that these criteria may be excessively strict, thereby precluding many men from AS.

MATERIALS AND METHODS:

We studied pathological outcomes in men treated between 1995 and 2012 with radical prostatectomy (RP) who met ≥ 4 of 5 AS criteria. Outcomes included a definition of significant tumor (pathological Gleason ≥ 7 or non-organ confined). Rates of adverse pathology were compared between men meeting all versus 4 of 5 AS criteria.

RESULTS:

Of 8261 men, 1890 (22.9%) met all AS eligibility criteria and 2133 (25.8%) met 4 of 5 criteria. Men exceeding PSA density and biopsy Gleason criteria were at increased risk of adverse pathological outcomes. Clinical stage > T1 was not associated with adverse pathology. Men with clinical stage T2 lesions, ≤3 positive biopsy cores, and < 60% core involvement were at comparable risk of significant tumors to men meeting all AS criteria.

CONCLUSIONS:

PSA density > 0.15 ng/ml and biopsy Gleason score ≥ 7 are strongly associated with adverse pathology at RP. Our findings suggest expanding AS criteria to include men with clinical stage T2 lesions and a greater number of positive biopsy cores of low grade. Based on these preliminary findings, we are in the process of reassessing AS eligibility criteria using more detailed pathological analysis.

PURPOSE:

We aimed to determine the positive and negative predictive values of multiparametric MRI (MP-MRI) for extraprostatic extension (EPE) at radical prostatectomy (RP) for different prostate cancer (PCa) risk groups.

MATERIALS AND METHODS:

We evaluated a cohort of 183 patients that underwent 3 Tesla (3-T) MP-MRI, including T2-weighted, diffusion-weighted MR Imaging (DWI) and dynamic contrast-enhanced (DCE) sequences, with an endorectal coil (ERC) before RP, pathological stage at RP was used as standard reference for EPE. The cohort was classified into low-, intermediate and high-risk groups according to the d'Amico criteria. We recorded prevalence of EPE at RP and determined sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MP-MRI for EPE in each group. Uni- and multivariable analyses were performed to identify predictors of EPE at RP.

RESULTS:

Overall prevalence of EPE at RP was 49.7% ranging from 24.7-77.1% between low- and high-risk categories. Overall staging accuracy of MP-MRI for EPE was 73.8%, with sensitivity, specificity, PPV and NPV of 58.2%, 89.1%, 84.1% and 68.3%, respectively. PPV of MP-MRI for EPE was best in the high-risk cohort with 88.8%. NPV was highest in the low-risk cohort with 87.7%. With an odds ratio (OR) of 10.3 MP-MRI is by far the best pre-operative predictor of EPE at RP.

CONCLUSIONS:

For adequate patient counselling, knowledge of predictive values of MP-MRI for EPE is of utmost importance. High NPV, important for decisions on nerve-sparing strategies at RP, is only reached in low-risk subjects.

PURPOSE:

We assess the risk of urinary incontinence (UI) after TURP in patients previously treated with prostate brachytherapy.

MATERIALS AND METHODS:

A total of 2,495 patients underwent brachytherapy with or without external beam radiation therapy for the diagnosis of prostate cancer between June 1990 and December 2009. Pre-implant patients TURP were excluded. Of these patients, 79 patients (3.3%) underwent channel TURP due to urinary retention or refractory obstructive urinary symptoms. Correlation analyses were performed using chi square (Pearson). Estimates for time to UI were determined by Kaplan Meier method with comparisons by logistic regression and Cox proportions hazard rates.

RESULTS:

Median follow up after implantation was 7.2 yrs. Median time to first post-implantation TURP was 14.8 months. Twenty of the 79 (25.3%) post-implant TURP patients had UI compared with 3.1% for implantation only patients (odds ratio 10.4; 95% CI, 6-18; p<0.001). Of the 15 patients who required more than 1 TURP, 8 (53%) developed UI compared with 19% of patients who had only 1 TURP (odds ratio 4.9; 95% CI, 1.5-16; p=0.006). Exclusion of patients with multiple TURPs still demonstrated significant differences (18.8% vs. 3.1%, odds ratio 7.1; 95% CI, 3.6-13.9; p<0.001). Median time from last TURP to UI was 24 months. On linear regression analysis, hormone use and post-implantation TURP were associated with UI (p<0.05). There was no correlation between timing of TURP after implantation and risk of incontinence.

CONCLUSIONS:

Urinary incontinence developed in 25.3% who underwent TURP following prostate brachytherapy. UI risk correlates with the number of TURPs. Patients should be counseled thoroughly prior to undergoing post-implantation TURP.

PURPOSE:

To investigate the pharmacokinetics of intravesical oxybutynin and discuss the clinical implications of the results.

MATERIAL AND METHODS:

Open-label, randomized, three period change-over clinical study including 20 healthy adult subjects. In period 1 and 2, subjects received single doses of either 10 mg oxybutynin-HCl solution intravesically or a 5 mg tablet orally. Period 3 comprised repeated intravesical applications (7 doses) of 10 mg oxybutynin-HCl. Enantioselective concentrations of oxybutynin and N-desethyloxybutynin (NDO) were quantified by LC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods, analyzed by descriptive statistics and compared using the average bioequivalence approach.

RESULTS:

Systemic exposure to racemic oxybutynin following intravesical administration was significantly higher, yielding 294% (90%-CI: 211-408%) of that after oral intake of immediate-release preparations, as measured by dose-normalized AUC. By contrast, systemic exposure to racemic NDO reached only 21% (90%-CI: 15%-29%). The AUC-ratio of NDO/oxybutynin was 14-fold reduced for intravesical administration. Following intravesical multi-dose administration, cumulation of oxybutynin (1.3-fold) and NDO (1.6-fold) was weak, absorption was prolonged and apparent elimination half-lives were longer. The study medication was well tolerated, with a third of participants reporting anticholinergic adverse effects.

CONCLUSION:

The present study provides evidence of a significantly higher bioavailability of intravesical versus oral oxybutynin administration by circumvention of the intestinal first-pass metabolism. Given the high efficacy and reduced rate of adverse effects, intravesical oxybutynin should be considered in patients with NLUTD who do not tolerate oral administration or in whom oral preparations fail to improve detrusor overactivity.

PURPOSE:

To examine symptoms of Bladder Bowel Dysfunction (i.e., severity of voiding dysfunction and stool consistency) and psychosocial difficulties in children who present to pediatric urology for voiding dysfunction and to pediatric gastroenterology (GI) for functional constipation.

MATERIALS AND METHODS:

Parents of children seen in the GI clinic were recruited during the child's outpatient clinic appointment and parents of children seen in the Urology clinic were randomly selected from the research database and were matched to the GI sample based on the child's age and sex. All parents completed the Dysfunctional Voiding Scoring System (DVSS), the Bristol Stool Form Scale (BSFS), the Pediatric Symptom Checklist (PSC), and the Parenting Stress Index/Short Form (PSI/SF) which assessed severity of voiding dysfunction, stool consistency, level of psychosocial difficulties, and level of parenting stress, respectively.

RESULTS AND CONCLUSIONS:

Children seen in the Urology and GI clinics did not significantly differ on any of the measures, indicating that the severity of their Bladder Bowel Dysfunction is similar. However, they had significantly more severe voiding dysfunction, more constipated stool, and more psychosocial difficulties than historical healthy controls. Additionally, level of parent stress was significantly correlated with the child's level of psychosocial difficulties and severity of voiding dysfunction. It is suggested that these children represent a homogenous group who would potentially benefit from a multidisciplinary approach involving urology, gastroenterology, and psychology.

PURPOSE:

To explore the correlation between hepatocyte cell adhesion molecule(hepaCAM) and activated mammalian target of rapamycin(p-mTOR) in transitional cell carcinoma of bladder(TCCB) and whether the anti-proliferation effect of hepaCAM is associated with AMPK/mTOR pathway.

MATERIALS AND METHODS:

QRT-PCR was used to examine the mRNA expression of hepaCAM and western blot was used to measure the protein level of hepaCAM and p-mTOR in 25 men and 5 women. Disease was Ta-T1 in 7 patients, T2-T4 in 23, G1 in 13, G2 in 9, G3 in 8, primary in 13 and recurrent in 17. WST-8 assay was used to study the effect of hepaCAM on the ability of cellular proliferation. P-AMPK, p-mTOR, total AMPK, total mTOR, c-Myc and cyclin D1 were also determined by western blot.

RESULTS:

HepaCAM mRNA and protein were significantly decreased, while p-mTOR protein was remarkably increased in TCCB compared to adjacent tissues(P<0.01, P<0.01). The analysis of spearman correlation showed that the decrease of hepaCAM level was associated with the increase of p-mTOR level (r=-0.533 P=0.002). Furthermore, hepaCAM inhibited the proliferation of human TCCB cells. Over-expression of hepaCAM activated AMPK, down-regulated p-mTOR and its targets, c-myc and cyclin D1. Treatment with AMPK inhibitor (Compound C) prevented the anti-proliferation effect of hepaCAM. Compound C completely blocked hepaCAM induced activation of AMPK, down-regulation of p-mTOR and its targets, c-Myc and cyclin D1.

CONCLUSIONS:

The results suggest an important correlation between hepaCAM and p-mTOR. HepaCAM can inhibit the proliferation of bladder cancer cells through an AMPK/mTOR-dependent pathway.