Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I-II study.

PURPOSE: We report for the first time the activity and safety of Unithermia(®) (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). METHODS: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia(®) were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. RESULTS: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59%). Among the 14/34 (41%) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18% progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5%, respectively. Toxicity did not go beyond grade 2 except in five cases. CONCLUSIONS: Initial experience with MMC-HT with Unithermia(®) showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.

Penile Dysmorphic Disorder: Development of a Screening Scale.

Penile dysmorphic disorder (PDD) is shorthand for men diagnosed with body dysmorphic disorder, in whom the size or shape of the penis is their main, if not their exclusive, preoccupation causing significant shame or handicap. There are no specific measures for identifying men with PDD compared to men who are anxious about the size of their penis but do not have PDD. Such a measure might be helpful for treatment planning, reducing unrealistic expectations, and measuring outcome after any psychological or physical intervention. Our aim was, therefore, to validate a specific measure, termed the Cosmetic Procedure Screening Scale for PDD (COPS-P). Eighty-one male participants were divided into three groups: a PDD group (n = 21), a small penis anxiety group (n = 37), and a control group (n = 23). All participants completed the COPS-P as well as standardized measures of depression, anxiety, social phobia, body image, quality of life, and erectile function. Penis size was also measured. The final COPS-P was based on nine items. The scale had good internal reliability and significant convergent validity with measures of related constructs. It discriminated between the PDD group, the small penis anxiety group, and the control group. This is the first study to develop a scale able to discriminate between those with PDD and men anxious about their size who did not have PDD. Clinicians and researchers may use the scale as part of an assessment for men presenting with anxiety about penis size and as an audit or outcome measure after any intervention for this population.

Beliefs about penis size: validation of a scale for men ashamed about their penis size.

INTRODUCTION: No measures are available for understanding beliefs in men who experience shame about the perceived size of their penis. Such a measure might be helpful for treatment planning, and measuring outcome after any psychological or physical intervention. AIM: Our aim was to validate a newly developed measure called the Beliefs about Penis Size Scale (BAPS). METHOD: One hundred seventy-three male participants completed a new questionnaire consisting of 18 items to be validated and developed into the BAPS, as well as various other standardized measures. A urologist also measured actual penis size. MAIN OUTCOME MEASURES: The BAPS was validated against six psychosexual self-report questionnaires as well as penile size measurements. RESULTS: Exploratory factor analysis reduced the number of items in the BAPS from 18 to 10, which was best explained by one factor. The 10-item BAPS had good internal consistency and correlated significantly with measures of depression, anxiety, body image quality of life, social anxiety, erectile function, overall satisfaction, and the importance attached to penis size. The BAPS was not found to correlate with actual penis size. It was able to discriminate between those who had concerns or were dissatisfied about their penis size and those who were not. CONCLUSIONS: This is the first study to develop a scale for measurement of beliefs about penis size. It may be used as part of an assessment for men who experience shame about the perceived size of their penis and as an outcome measure after treatment. The BAPS measures various manifestations of masculinity and shame about their perceived penis size including internal self-evaluative beliefs; negative evaluation by others; anticipated consequences of a perceived small penis, and extreme self-consciousness.

Prognostic factors of 'high-grade' Ta bladder cancers according to the WHO 2004 classification: are these equivalent to 'high-risk' non-muscle-invasive bladder cancer?

OBJECTIVE: To determine the impact of prognostic factors of a series of high-grade Ta non-muscle-invasive bladder cancers (NMIBCs) according to the new International Society of Urological Pathology (ISUP) 1998/WHO 2004 grading system (previously classified as either TaG2 or TaG3). METHODS: One hundred and thirty-one high-grade Ta (105 G2 and 26 G3) cases were identified after independent review by two pathologists. Univariable and multivariable Cox regression models addressed recurrence and progression-free survival. Progression was defined as appearance of any T ≥1 recurrence after complete TUR (type 1) or occurrence of T ≥2 (type 2). RESULTS: Ten-year recurrence, type-1 and type-2 progression-free survival were 60, 75 and 95%, respectively. The previous grading system (G3 vs. G2) significantly predicted type 1 progression in the univariate model only. In the multivariate model, Ki67 was the only independent predictor of progression according to both definitions (HR = 5.25, p = 0.002 and HR = 6.16, p = 0.03, respectively). CONCLUSIONS: High-grade Ta NMIBC as defined by the WHO 2004 grading system cannot be equated with high-risk NMIBC. The risk of progression to muscle-invasive disease (type 2) is low, more in keeping with an intermediate-risk category of NMIBC. The previous WHO 1973 subcategorization into G2 and G3 is of little help in the prediction of outcome. Ki67 is a strong independent predictor of progression worthy of consideration for a clinical setting.

Prognostic factors including Ki-67 and p53 in Bacillus Calmette-Guérin-treated non-muscle-invasive bladder cancer: a prospective study.

OBJECTIVES: To prospectively evaluate the prognostic utility of the traditional prognostic factors and molecular markers p53 and Ki-67 in a homogeneous series of patients with non-muscle-invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: 192 intermediate- and high-risk NMIBC cases were enrolled. The variables in study were age, stage, grade, focality, tumour size, presence of associated carcinoma in situ, recurrence rate before BCG, maintenance for BCG, Ki-67 and p53. The endpoints considered were recurrence-free survival, progression-free survival, cancer-specific survival (CSS) and overall survival (OS). RESULTS: T stage resulted in being associated with CSS, whereas age with OS. BCG maintenance was a significantly favourable independent predictor of OS, CSS, recurrence and progression. In univariate analysis, the labelling index of Ki-67 was significantly associated with OS, CSS and progression. Multivariate analysis, however, confirmed this association only for OS. On the contrary, the labelling index of p53 was a significant predictor of recurrence, both in uni- and multivariate analyses, but with a HR inferior to 1. CONCLUSIONS: Ki-67 was an independent predictor of survival. p53 overexpression showed a significant yet inverse correlation with recurrence, thus showing little clinical utility. Age, stage and maintenance were confirmed as independent predictors of BCG response.

Pharmacokinetic study to optimize the intravesical administration of gemcitabine.

OBJECTIVES: To assess in a phase II pharmacokinetic study whether different pH levels, dilution volumes and exposure times affect intracellular bioavailability and systemic absorption of gemcitabine. SUBJECTS AND METHODS: Six arms of three patients each with a non-muscle-invasive bladder cancer (NMIBC) were planned to receive six combinations of two different dilution volumes (50 mL vs 100 mL), two pH levels (2.5-3.5 vs 5.5) and two exposure times (1 h vs 2 h) of the study drug. Blood samples were taken before, during and 1 h after drug instillation. Cold biopsy specimens from the exophytic tumor, its base of implant and a macroscopically healthy mucosa were taken during transurethral resection. High-pressure liquid chromatography/high-resolution mass spectrometry (HPLC/HRMSn) analysis of plasma and tissue samples was used to determine concentrations of gemcitabine (dFdC) and its inactive metabolite (dFdU). RESULTS: The arm at pH 5.5 in 50 mL was withdrawn as 2000 mg dFdC are insoluble in these conditions. The different instillation conditions resulted in negligible plasma dFdC concentrations but significant differences in intracellular content and metabolism of dFdC. The lowest intratissue concentration of dFdC was detected in a 50 mL solution at a pH of 2.5-3.5 kept in the bladder for 1 h (standard arm). A pH 5.5 solution in 100 mL with a 2-h exposure favored the maximal intratumoral dFdC absorption which was 90 times higher than that recorded in the standard arm. CONCLUSIONS: The most commonly reported administration scheme of gemcitabine produced the lowest tissue bioavailability of dFdC. Other combinations of pH, dilution volume and duration of instillation proved more advantageous and merit testing in clinical trials.

Fatal haematuria in a patient with an orthotopic neobladder and chronic liver failure.

Haematuria in orthotopic neobladder can be due to upper urinary tract recurrence of the primary bladder tumour, the rare occurrence of a primary bowel tumour or benign conditions such as stones and infections. We report the case of a 60-year-old man with chronic hepatopathy who suffered severe bleeding from neobladder varices, which ultimately led to his death.

New drugs currently available in non-muscle invasive bladder cancer: update on gemcitabine studies.

Intravesical gemcitabine has been tested in several phase I studies. The 2000 mg dose of gemcitabine in 50/100 ml normal saline when administered intravesically for up to 2 hours once a week for 6 weeks has unremarkable systemic and local side effects and therefore should be considered the most convenient schedule. Phase II studies have assessed the activity of intravesical gemcitabine on a marker lesion in intermediate risk non-muscle invasive bladder cancer (NMIBC), showing complete responses in up to 60% of cases. Few attempts have been made to test the activity of intravesical gemcitabine in high risk NMIBC achieving unexpected complete responses in BCG refractory CIS. Initial trials have also documented "clinically relevant" responses in prophylaxis. The current level of evidence indicates that gemcitabine possesses clinical activity but further confirmation is awaited from additional exploratory phase II and preferably phase III trials.

Relationship between self-discrepancy and worries about penis size in men with body dysmorphic disorder.

We explored self-discrepancy in men with body dysmorphic disorder (BDD) concerned about penis size, men without BDD but anxious about penis size, and controls. Men with BDD (n=26) were compared to those with small penis anxiety (SPA; n=31) and controls (n=33), objectively (by measuring) and investigating self-discrepancy: actual size, ideal size, and size they felt they should be according to self and other. Most men under-estimated their penis size, with the BDD group showing the greatest discrepancy between perceived and ideal size. The SPA group showed a larger discrepancy than controls. This was replicated for the perceptions of others, suggesting the BDD group internalised the belief that they should have a larger penis size. There was a significant correlation between symptoms of BDD and this discrepancy. This self-actual and self-ideal/self-should discrepancy and the role of comparing could be targeted in therapy.

Phenomenology of men with body dysmorphic disorder concerning penis size compared to men anxious about their penis size and to men without concerns: a cohort study.

Men with body dysmorphic disorder (BDD) may be preoccupied with the size or shape of the penis, which may be causing significant shame or impairment. Little is known about the characteristics and phenomenology of such men and whether they can be differentiated from men with small penis anxiety (SPA) (who do not have BDD), and men with no penile concerns. Twenty-six men with BDD, 31 men with SPA, and 33 men without penile concerns were compared on psychopathology, experiences of recurrent imagery, avoidance and safety-seeking behaviours. Men with BDD had significantly higher scores than both the SPA group and no penile concern group for measures of imagery, avoidance, safety seeking and general psychopathology. The groups differed on the phenomenology of BDD specific to penile size preoccupation clearly from the worries of SPA, which in turn were different to those of the men without concerns. The common avoidance and safety seeking behaviours were identified in such men that may be used clinically.

Intravesical thermo-chemotherapy based on conductive heat: a first pharmacokinetic study with mitomycin C in superficial transitional cell carcinoma patients.

PURPOSE: To evaluate, for the first time, the mitomycin C (MMC) pharmacokinetics during intravesical hyperthermia treatment based on conductive heat and the stability and recovery of the drug at the end of the instillation period. METHODS: Eleven patients with recurrent intermediate-risk superficial transitional cell carcinoma of the bladder were treated weekly for six cycles with intravesical MMC (40 mg MMC in 50 ml) in local hyperthermia (45 °C) with Unithermia(®) system. Each instillation lasted 45 min, with the solution being replaced after the first 22 min. The MMC recovery at the end of the two instillation period and the plasmatic pharmacokinetics of MMC were evaluated by high-pressure liquid chromatography. RESULTS: Nine patients completed all the six planned cycles, whereas two patients missed the last cycle because of allergic reactions. No other systemic toxicity was observed, and the local toxicities were mild. Median MMC concentration in the instillation residual solution decreases from the initial 0.8 to 0.22 mg/ml for the 0-22-min instillation period and to 0.38 mg/ml for the 22-45-min instillation period; the median percentage of MMC recovered after instillation was 66.2 and 99.6, respectively. In all patients, MMC plasmatic C max resulted considerably lower than the toxic threshold (400 ng/ml). CONCLUSIONS: The MMC is stable during the instillation, and its absorption occurs mainly during the first minutes of the treatment. The plasmatic MMC concentration is always well below the threshold level for myelosuppression, as confirmed by the total lack of hematological toxicity evidenced by the patients. In order to evaluate the efficacy of the treatment performed with UniThermia(®) in reducing the disease recurrence rate in short- and long-term follow-up, we are currently carrying out a clinical multicentric study involving a larger number of patients.

[Adverse events after intravesical therapy: are we always ready to recognize and prevent them?]. / Complicanze della terapia endovescicale. Siamo sempre attenti a prevenirle e pronti a riconoscerle.

Intravesical therapy is widely used in non-muscle-invasive bladder cancer (NMIBC) as adjuvant treatment after transurethral resection of bladder tumor (TURBT). Assuming that adjuvant therapy is necessary for NMIBC in order to reduce recurrence and progression rates, chemotherapy and BCG toxicity become a relevant issue. Both treatments may have local and systemic side effects, which can lead to treatment cessation, resulting in incomplete treatment and poor outcomes. Therefore, urologists, specialist nurses and patients must be aware of the possible adverse events in order to early recognize, prevent and treat them properly. This article summarizes the local and systemic side effects associated with intravesical therapy, presents the recommendations for an effective management of these adverse events based on currently available evidence, and highlights some open questions on these issues.

Phase II study of biweekly gemcitabine as first line therapy in CIS of the bladder: what does an aborted trial tell us?

OBJECTIVE: The objective of this study was to challenge the activity of a promising intravesical drug (gemcitabine), administered at an intensive regimen (2,000 mg twice a week for 6 weeks) in treatment naïve CIS of the bladder and to observe side-effects. The statistical design was conceived to provide sufficient information through the enrollment of a low number of patients. MATERIAL AND METHODS: Primary, secondary, and concurrent CIS with no prior intravesical therapy were eligible. Treatment schedule: 2000 mg gemcitabine in 50 ml saline, unbuffered, for 1 hour twice a week for 6 weeks. Complete response (CR) = negative cytology and negative cystoscopy + bladder mapping at 3 months. Failure (FA) = all other situations. Side-effects were recorded according to Common Terminology Criteria for Adverse Events (CTCAE). STUDY DESIGN: A 3-stage design. After testing the drug on 11 patients in the first stage, the trial had to be terminated if 3 or fewer CRs. After testing the drug on 21 patients in the first and second stages, the trial had to be terminated if 7 or fewer CRs. After testing the drug on 32 patients in all 3 stages, the drug was considered active in case of >12 CRs. Survival data up to 4 years from trial closure were collected. RESULTS: The study proceeded to stage II since 5/11 responded at stage I but it was stopped after including 18 patients due to side-effects; 6/18 had primary CIS, 7 had secondary CIS, and 5 concomitant CIS; 6/18 (33.3%) had grade 3 side-effects (4 G3 cystitis, 3 G3 leucopenia), leading to stopping the treatment in all 6 cases. CRs were observed in 8/18 patients (44.4%), FA in 10/18 (55.5%). Median overall survival (OS) was 44 months with a 4-year cancer-specific survival of 100%. CONCLUSION: Biweekly gemcitabine as first line treatment for CIS led to excess toxicity and suboptimal activity. Due to the peculiar statistical design, a negative response was generated enrolling a low number of patients. The absolute 4-year CSS suggests that no window of opportunity for disease cure may have been lost by assessing a new, non standard, treatment for CIS.

Leiomyomata of the genitourinary tract: a case series from the "rare urological neoplasm" registry.

OBJECTIVE: Leiomyomata are benign neoplasms that are rarely encountered in the genitourinary tract outside the uterus. Pathological confirmation is always needed for definitive diagnosis, in order to rule out malignancies such as leiomyosarcoma. In cases of small leiomyomata, a surveillance strategy can be suggested, although the preferred approach is complete resection. Prognosis seems to be excellent, but available data are based on few, inconsistent series, as is often the case with rare neoplasms. This article presents long-term follow-up data from the most heterogeneous series, in terms of anatomical location, currently available. MATERIAL AND METHODS: The present series of 33 genitourinary leiomyomata was retrieved after joining the "rare urogenital neoplasm" registry of two Italian regions. Two pathologists jointly reviewed all pathological slides and confirmed the diagnosis of leiomyoma. RESULTS: Sixteen cases were localized to the scrotum, eight to the bladder, five to the kidney, two to the prostate, one to the urethra and one to the penis. Mean patient age was 58.4 (range 32-80) years. Mean follow-up was 15.5 (range 2-20) years. CONCLUSIONS: In this highly heterogeneous series, the disease showed excellent long-term recurrence- and progression-free interval. The accuracy of pathological diagnosis, along with the indolent long-term course, make the role of active surveillance amenable for asymptomatic cases, particularly where surgery may result in overtreatment.

Multipathogenetic origin of a pelvic mass.

A 69-yr-old woman presented with a bulky hypogastric mass and abdominal pain. Computed tomography scan showed a mass anterosuperior and contiguous to the bladder wall, with a hypodense content, a voluminous bladder stone, and bilateral hydroureteronephrosis. Intraoperatively, the supravesical mass had the appearance of an infected urachal cyst. An unsuspected high-grade noninvasive papillary transitional cell carcinoma (TCC) of the bladder thoroughly surrounding the bladder stone became evident during the cystolithotomy. Postoperative videourodynamic study showed a normal voiding pattern with bilateral grade 4 vesicoureteral reflux. Early cystectomy was performed for uncontrolled recurrent bladder cancer, and the final pathology indicated pT1G3N0 TCC.