Non-muscle invasive high grade urothelial carcinoma of the bladder. Which factors can influence understaging at the time of radical cystectomy?

OBJECTIVE: To evaluate the main factors which influence understaging in patients with T1G3 non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: 109 patients with T1/G3 underwent transurethral resection of bladder tumor (TURBT) and then radical cystectomy (RC) with pelvic lymph nodes dissection. A number of variables were considered when evaluating the detection of understaging. We considered the patients age and gender, as well as the size, number, location and morphology of their tumor. We also considered coexistence of bladder carcinoma in situ (CIS), microscopic vascular invasion and deep lamina propria invasion. The level of experience of the surgeon was also analyzed. RESULTS: in RC samples muscle invasion, that is understaging, was detected in 74 (67.9%) patients, while 35 (32.1%) patients were appropriately staged. In these cohort of patients with high grade tumors, understaging was associated with deep lamina propria and microscopic vascular invasion, multiple tumors, tumor size > 6 cm, tumor location (trigone and dome), presence of residual tumor; age, gender, tumor morphology, CIS associated, and experience of urological surgeon were not associated with clinical understaging. CONCLUSIONS: in our study, evaluating patients with high grade NMIBC at first TURBT, we identified some risk factors that need to be considered and that are able to increase the risk of understaging: deep lamina propria and microscopic vascular invasion, multiple tumors, tumor size > 6 cm, tumor location (trigone and dome), presence of residual tumor. When these risk factors are present, performing an early cystectomy, and not a re-TURBT, could lower the risk of worse pathological finding due to rapid disease progression of the high grade tumors, and can prolong survival.

Spontaneous recurrent hematuria and hematospermia: Unique manifestations of von Willebrand disease type I. Case report.

In this report we describe the case of a patient with unrecognized von Willebrand disease (vWD), in whom the only presenting symptoms were spontaneous and recurrent hematuria with bladder tamponade, associated with recurrent hematospermia. The diagnosis was made only after several admissions to the hospital. We suggest to include coagulopathies such as vWD as part of the evaluation in patients with unexplained genito-urinary bleeding.

Recent aspects of sunitinib therapy in patients with metastatic clear-cell renal cell carcinoma: a systematic review of the literature.

Sunitinib is an orally available inhibitor of multiple tyrosine-kinase receptors approved for the treatment of advanced clear-cell renal cell carcinoma (ccRCC), a disease which has habitually had a very poor patient survival rate. Although it has become the most widely used drug for this disease, it remains not completely clear the best treatment strategy with these agent. The aim of this review is to highlight the most recent and interesting aspects of the research on treatment of advanced ccRCC with sunitinib and eventually determine alternative treatment schedule to reduce the incidence of side effects; we also wanted to review recent biomarkers able to predict response to therapy and also to point out the mechanism of acquired resistance to this drug.

α1-Blockers for the treatment of recurrent urinary tract infections in women with dysfunctional voiding: a prospective randomized study.

OBJECTIVES: To evaluate the therapeutic effects of tamsulosin on recurrent urinary tract infections in women with dysfunctional voiding. METHODS: A total of 155 women with recurrent urinary tract infections and dysfunctional voiding were included and randomly assigned to the following groups: uroflowmetry biofeedback (group 1), α1-adrenoceptor antagonists (group 2), uroflowmetry biofeedback combined with α1-adrenoceptor antagonists (group 3) and no treatment (group 4). Patients were evaluated by the American Urological Association Symptom Index at 3, 6 and 12 months. Urodynamics was carried out in patients of groups 1, 2, and 3 at 3, 6 and 12 months, whereas urodynamics was only carried out at 12 months in group 4. All patients were followed up for 1 year with monthly urine cultures. RESULTS: The incidence of storage and emptying symptoms decreased significantly at 3, 6 and 12 months. Mean flow rate, flow time and voiding volume increased significantly (with a better outcome in patients of group 3), whereas post-void residual urine decreased. Mean opening detrusor pressure and detrusor pressure at maximum flow decreased significantly (with a better outcome in patients of group 3). Mean urethral closure pressure and maximum urethral closure pressure decreased significantly with a more significant decrease for patients in group 3. The prevalence of urinary tract infection decreased significantly in all groups after treatment, and this decrease remained stable during the follow up. CONCLUSIONS: In women with dysfunctional voiding and recurrent urinary tract infection, tamsulosin associated with uroflowmetry biofeedback might be an effective and safe treatment option for improving urinary symptoms and quality of life.

Is it possible to predict the need of inguinal lymphadenectomy in patients with squamous cell carcinoma of the penis? A clinical and a pathological study.

OBJECTIVE: to investigate the role of CD- 44 immunohistochemical expression within tumoural and non-tumoural tissue, aiming to understand if it can help us to predict the need of performing inguinal lymph nodes dissection to complete surgery of the penis. MATERIALS AND METHODS: CD44 immunohistochemical expression was investigated in tissue specimens from 39 patients with squamous cell carcinoma of the penis who underwent partial or total penectomy between 1987 and 2008. Patient age, tumour size, and grade; CD44 intensity score, cytological expression, topographic and distribution pattern were evaluated by immunohistochemistry on archived material and correlated with disease-specific survival. RESULTS: mean patients age was 67.7 years; mean followup was 130.44 months. Bilateral inguinal lymphadenectomy was performed in 14 patients; there were 8 N+ patients (23.5%). pTis-pT1 vs. > pT1 and the EAU classification of risk group resulted to be predictive of lymph nodal metastases at univariate analysis (respectively p = 0.006 and p = 0.045), but not the grading. The intensity score, cytological expression, topographic and distribution pattern of CD44 staining did not correlate with stage, grade and lymph nodes metastases. All disease related deaths occurred only in patients showing an high CD44 intratumoral expression, but this correlation is not statistically significant. Multivariate analysis showed that only lymph node metastasis was an independent prognostic factor predictive of lymph nodes metastases. CONCLUSIONS: CD44 expression in patients with squamous cell carcinoma of the penis is not able to predict the need of performing inguinal lymphadenectomy; staging and the EAU classification of risk group resulted to be predictive of lymph nodal metastases.

A conservative approach to perineal Fournier's gangrene.

Fournier's gangrene (FG) is a disease involving necrosis of perineum and external genitalia; in 95% of cases it is possible to diagnose the Fournier's gangrene just by physical examination. The clinical presentation of FG varies from an initial localized infection to large areas with necrotizing infection. The disease typically affect elderly men (6°-7° decade) with important systemic comorbidities; women are less frequently affected. Despite improvements in diagnosis and management, the mortality rate nowadays is between 20% and 43%. The severity and mortality of the disease is dependent upon the general condition of the patient at presentation and upon the rate of spread of the infection. Treatment involves a multidisciplinary approach: intensive systematic management, broad-spectrum antibiotic therapy, early surgical debridement (wide abscission of necrotic tissues and surgical drainage of peritoneum, scrotum, penis, and inguinal areas), hyperbaric oxygen therapy; surgery can eventually be repeated if necessary; reconstructive surgery has an important role in the final treatment of the disease. The technical difficulties frequently encountered and the inability to make a complete removal of the necrotizing tissues at the time of surgery in some cases has led to the application of combined techniques, in view of the enhancement effect of specific advanced medications, targeted antibiotic therapy and hyperbaric medicine. We have considered 6 patients affected by Fournier's gangrene treated at our institution; all the patients received treatment with the help of plastic surgeons of the same institution. After debridement, all the patients were treated with advanced specific dressings consisting of plates and strips made of calcium alginate, hydrogels and polyurethane and twodimensional cavity foams. Reconstructive surgery was necessary in one case. Hyperbaric oxygen therapy (HBO) has been performed in all cases. The multidisciplinary approach, the combined use of HBO therapy and the adoption of advanced specific dressings, have made possible the complete healing of the lesions in a shorter period, avoiding further surgery in 5 out of 6 patients.

Sacral neuromodulation in patients with multiple sclerosis.

PURPOSE: We present a case series of patients with multiple sclerosis (MS) and neurogenic lower urinary tract dysfunction treated by sacral neuromodulation (SNM). METHODS: We reviewed charts of 25 patients who were treated for refractory lower urinary tract symptoms; during the SNM testing phase, patient management included evaluation of number of daily voiding, number of episodes of incontinence, residual urine and quality of life score. Patients who experienced greater than 50% improvement in symptoms of frequency and incontinence episodes and/or a greater than 50% decrease in the number of catheterizations and a greater than 50% increase in voided volumes were offered placement of the permanent InterStim(TM) . RESULTS: Fifteen patients were implanted with InterStim(TM); mean duration of MS was 13.66 years; mean follow-up of patients was 49.4 months. Nine patients were on clean intermittent catheterization, and in all of them, a significant decrease in residual volume with increase in voided volume and number of voiding per day; in 6 patients, the main problem was incontinence, and in them incontinence, episodes decreased and voided volume increased. Sixty-six per cent of patients have a functioning device after a mean follow-up of 61.2 months. CONCLUSIONS: SNM is a good option in the treatment of voiding dysfunction in patients with MS in a medium to long-term follow-up. Urinary retention due to detrusor underactivity is not a good indication for SNM; it should be offered to MS patients with refractory urgency urinary incontinence and MS patients with urinary retention due to detrusor-sphincter dyssynergia (DSD).

Nitric oxide synthase expression in rat anorectal tissue after sacral neuromodulation.

BACKGROUND: Sacral neuromodulation is becoming established as a valid treatment option for patients with anorectal disorders. Nevertheless, despite its efficacy, little is known regarding its mechanism of action. The purpose of this study was to evaluate whether chronic sacral neuromodulation is able to influence the expression of nitric oxide synthetase (NOS) in the anorectum of rats. MATERIALS AND METHODS: Twenty-six female Sprague-Dawley rats were divided into three groups; normal control rats (n = 6); sham treatment (n =10) and group in whom, electrical sacral neuromodulation was performed (n = 10). Bilateral electrode wires were placed in the S1 and electrical stimulation was performed for 14 d. At the end of the procedures the rats were sacrificed, proctectomy was performed, and anorectal specimens were sent to the laboratory for immunostaining with n-NOS and i-NOS. RESULTS: In the anal and rectal specimens, n-NOS and i-NOS expression was significantly increased in epithelial and muscle cells after neuromodulation of the anus and rectum of the animals. CONCLUSION: Our results showed that this model can be applied in further experimental studies to better understand the mechanism of action of sacral neuromodulation in anorectal disorders.

Efficacy of tigecycline and rifampin alone and in combination against Enterococcus faecalis biofilm infection in a rat model of ureteral stent.

BACKGROUND: We investigated the efficacy of tigecycline and rifampin alone or combined in preventing ureteral stent infection due to Enterococcus faecalis. MATERIALS AND METHODS: The activities of the two antibiotics were previously studied in vitro in absence or in presence of biofilm. For in vivo research, the study included a control group without bacterial challenge to evaluate the sterility of surgical procedure, a challenged control group that did not receive any antibiotic prophylaxis and, for each bacterial strain, three challenged groups that received: (1) 2 mg/kg intraperitoneal tigecycline, immediately after stent implantation; (2) rifampin-coated ureteral stents where 0.2 cm(2) sterile ureteral stents were incubated in 10 mg/L rifampin solution for 30 min immediately before implantation; and (3) intraperitoneal tigecycline plus rifampin-coated ureteral stent at the above concentrations. Ureteral stents were explanted at d 5 following implantation and biofilm bacteria enumerated. RESULTS: The in vitro studies showed that the biofilm was strongly affected by the presence of rifampin and, in its presence, tigecycline had MICs and MBCs lower than those obtained in the absence of rifampin. Intraperitoneal tigecycline exerted stronger effect than rifampin on bacterial numbers. The combination rifampin plus tigecycline showed efficacies higher than that of each single compound. CONCLUSION: These results highlight the potential usefulness of tigecycline in preventing enterococcal ureteral stent infections and the role of rifampin as an interesting antibiotic enhancer.

Effect of the combination of clarithromycin and amikacin on Pseudomonas aeruginosa biofilm in an animal model of ureteral stent infection.

OBJECTIVES: An experimental study was performed to evaluate both in vitro and in vivo the efficacy of clarithromycin coating combined with systemic amikacin in preventing ureteral stent biofilm infection due to Pseudomonas aeruginosa. METHODS: The activities of the two antibiotics were studied in vitro in the absence or in the presence of biofilm. For the in vivo study we evaluated a control group without bacterial challenge to evaluate the sterility of the surgical procedure, a challenged control group that did not receive any antibiotic prophylaxis and three challenged groups that received (i) 15 mg/kg intraperitoneal amikacin immediately after stent implantation, (ii) clarithromycin-coated ureteral stents where 0.2 cm² sterile ureteral stents were incubated in 10 mg/L clarithromycin solution for 30 min immediately before implantation, and (iii) intraperitoneal amikacin plus a clarithromycin-coated ureteral stent at the above concentrations. RESULTS: The in vitro studies showed that the biofilm was strongly affected by the presence of clarithromycin and, in its presence, amikacin had MICs and MBCs lower than those obtained in the absence of clarithromycin. For the singly treated groups, intraperitoneal amikacin showed the strongest effect on bacterial numbers. A clarithromycin coating combined with systemic amikacin showed an efficacy that was higher than that of each single compound. CONCLUSIONS: The prevention of ureteral stent Pseudomonas biofilm infection was enhanced by impregnation of the stent with clarithromycin combined with systemic amikacin.

Normal human macula densa morphology and cell turnover: A histological, ultrastructural, and immunohistochemical investigation.

The aim was to analyze the morphology of normal human macula densa (MD), evaluate the cells that may be responsible for its turnover, and collect quantitative data. Of four samples of normal human renal tissue, two were embedded in resin to measure the longitudinal extension and examine the ultrastructure of the MD, the other two were embedded in paraffin to study apoptosis and cell proliferation. The MD is composed of a monolayer tissue about 40 µm long, which includes 35-40 cells arranged in overlapping rows. Ultrastructurally, MD cells show two polarized portions: an apical end, with sensory features, and a basolateral aspect, with paracrine function. MD cells are connected apically by tight junctions, with/without adherens junctions, which form a barrier between the distal tubule lumen and the interstitium. Cells in degeneration, often associated with macrophages, and undifferentiated cells were found in the MD and adjacent distal tubule. A filamentous mat previously described in proximal tubule scattered tubular cells (STCs) was detected in the basal cytoplasm in undifferentiated cells. The tissue was consistently negative for the proliferation marker Ki67 and for the apoptotic markers caspase-3 and caspase-9. This work confirms our earlier morphological findings and provides new data: (a) MD cells display both apical adherens and tight junctions, the latter forming a tubulo-mesangial barrier; (b) the MD is a monolayer made up of about 40 cells arranged in rows; (c) the simultaneous presence of degenerating (8-13%) and undifferentiated (4-13%) cells reminiscent of STCs suggests a non-negligible cell turnover.

Perineal ultrasound evaluation of dysfunctional voiding in women with recurrent urinary tract infections.

PURPOSE: We used urodynamics and perineal ultrasound to assess the function and morphology of the urethral sphincter and detrusor muscle in the evaluation of dysfunctional voiding in female patients with recurrent urinary tract infections. MATERIALS AND METHODS: Patients selected for study purposes completed the American Urological Association Symptom Index and underwent multichannel video urodynamics and perineal ultrasound to evaluate urethral sphincter volume and detrusor thickness. RESULTS: Of the 337 patients referred to our institution for recurrent urinary tract infections 166 were finally evaluated, including group 1-65 women with recurrent urinary tract infections and dysfunctional voiding, group 2-77 with recurrent urinary tract infections without dysfunctional voiding and group 3-24 healthy controls. Storage and emptying symptoms were recorded in 87.6% and 84.6% of group 1 patients, respectively. Opening and maximum flow detrusor pressure significantly correlated with urethral sphincter volume, and mean and maximum urethral closure pressure and detrusor thickness correlated with urethral sphincter volume. Dysfunctional voiding could be diagnosed by ultrasound when an increase in detrusor thickness and striated sphincter volume were observed. A threshold sphincter volume of 1.96 cm3 had 100% sensitivity and 63.2% specificity, and a threshold detrusor thickness of 4.95 mm had 100% sensitivity and 85.4% specificity for identifying patients with dysfunctional voiding. CONCLUSIONS: We think that perineal ultrasound is useful in the evaluation of dysfunctional voiding in women with recurrent urinary tract infections.

BMAP-28 improves the efficacy of vancomycin in rat models of gram-positive cocci ureteral stent infection.

An experimental study was performed to evaluate the efficacy of BMAP-28 alone and in combination with vancomycin in animal models ureteral stent infection due to Enterococcus faecalis and Staphylococcus aureus. Study included a control group without bacterial challenge to evaluate the sterility of surgical procedure, a challenged control group that did not receive any antibiotic prophylaxis and for each bacterial strain three challenged groups that received (a) 10 mg/kg vancomycin intraperitoneally, immediately after stent implantation, (b) BMAP-28-coated ureteral stents where 0.2-cm(2) sterile ureteral stents were incubated in 1mg/l BMAP-28 solution for 30 min immediately before implantation and (c) intraperitoneal vancomycin plus BMAP-28-coated ureteral stent at the above concentrations. Experiments were performed in duplicate. Ureteral stents were explanted at day 5 following implantation and biofilm bacteria enumerated. Our data showed that rats that received intraperitoneal vancomycin showed the lowest bacterial numbers. BMAP-28 combined with vancomycin showed efficacies higher than that of each single compound. These results highlight the potential usefulness of this combination in preventing ureteral stent-associated in gram-positive infections.

The antimicrobial peptide tachyplesin III coated alone and in combination with intraperitoneal piperacillin-tazobactam prevents ureteral stent Pseudomonas infection in a rat subcutaneous pouch model.

We investigated the efficacy of Tachyplesin III alone or combined with piperacillin-tazobactam (TZP) to prevent biofilm formation in vitro and in a rat model of Pseudomonas aeruginosa ureteral stent infection. We have observed that in vitro TZP, in presence of Tachyplesin III, showed minimal inhibitory concentrations (MIC)s twofold and minimal bactericidal concentrations (MBC)s eightfold lower. The in vivo study showed that rats that received intraperitoneal TZP showed the lowest bacterial numbers. Tachyplesin III combined with TZP showed efficacies higher than that of each single compound. Coating ureteral stents with Tachyplesin III is able to inhibit bacterial growth up to 1,000 times.

Prognostic role of BAP1 in pT1 clear cell carcinoma in partial nephrectomy specimens.

BAP1 is a gene situated on chromosome 3p in a region that can be modified in renal cell carcinomas (RCCs). Mutations that cause loss of expression of BAP1 frequently occur in primary clear cell renal carcinoma (ccRCC). In a previous work, we observed that loss of nuclear BAP1 expression was crucial in ccRCC progression; in the current study, we investigated BAP1 expression in a large series of small conventional ccRCCs treated with partial nephrectomy, to assess a possible role as biomarker and the prognostic value in terms of patients' survival at long-term follow-up. One hundred sixty-two patients with single pT1 ccRCC were selected from those who underwent surgery at our Institute of Urology between 1987 and 2000. The features considered in this study were gender, age, tumor size, grade, incidence of metastasis, and patient-specific survival; they were correlated with immunohistochemical BAP1 nuclear expression in tumoral tissue. Median follow-up was 197.24 months (range 19 to 274); median survival was 125.34 months (range 5 to 274 months). None of our pT1 ccRCCs showed total loss of nuclear BAP1 staining; we found a significant negative correlation between nuclear BAP1 expression and tumor size and between nuclear BAP1 expression and grade. In small ccRCCs, nuclear BAP1 staining was not correlated with disease-specific 5-year survival.Our data confirm the established role of BAP1 as a tumor suppressor protein. This is the first report where BAP1 has been studied in pT1 ccRCC tumors, but nuclear BAP1 expression cannot help identify patients having high-risk disease in these patients.

Loss of nuclear BAP1 protein expression is a marker of poor prognosis in patients with clear cell renal cell carcinoma.

INTRODUCTION: BRCA1-associated protein 1 (BAP1) is a gene situated on chromosome 3p in a region that is deleted in more than 90% of renal cell carcinomas (RCCs). In the present study, we studied BAP1 immunohistochemical expression in a large series of conventional clear cell RCCs (ccRCCs) treated with radical nephrectomy; we assessed the prognostic value of their expression in terms of patients׳ survival at long-term follow-up. MATERIALS AND METHODS: A total of 154 consecutive patients with ccRCC were selected from a prospective database and considered for the study purpose; all patients were treated with radical nephrectomy and lymphadenectomy at our Institute of Urology between 1983 and 1985. The features considered in this study were tumor size, grade and stage, vascular and capsular invasion, incidence of metastasis, and patient-specific survival; all these parameters were correlated with immunohistochemical cytoplasmic and nuclear expression of BAP1 in tumoral tissue. RESULTS: Median follow-up was 196.18 months and median survival was 125.34 months. Nuclear BAP1 expression showed a high frequency of loss in tumoral cells; nuclear BAP1-negative tumors had higher tumor size, higher Fuhrman grade, and higher stage, a greater amount of vascular and capsular invasion and a higher incidence of metastases. In multivariate analysis, pathological stage and nuclear BAP1 expression resulted independent prognostic factors. CONCLUSION: We have demonstrated that nuclear BAP1 expression is a marker of prognosis in ccRCC, having an influence on cancer-specific survival. The clinical importance for BAP1 will be realized with the identification and application of targeted therapies and with individualized approaches in the adjuvant setting or in the metastatic setting or in both the settings.

Enhanced Efficacy of Combinations of Pexiganan with Colistin Versus Acinetobacter Baumannii in Experimental Sepsis.

We investigated the efficacy of colistin combined with pexiganan in experimental mouse models of Acinetobacter baumannii infection.Adult male BALB/c mice received intraperitoneally 1 mL saline containing 2 × 10 CFU of susceptible and multiresistant A. baumannii. Two hours after bacterial challenge, animals received 1 mg/kg of colistin, 1 mg/kg of pexiganan, or 1 mg/kg of colistin plus 1 mg/kg of pexiganan.Blood culture positivity, the quantities of bacteria in the intra-abdominal fluid, the rate of lethality and immunological studies, such as immunophenotyping and NK cytotoxicity, were evaluated.In the in vitro study, A. baumannii showed susceptibility to colistin and pexiganan and a strong synergy was observed by testing colistin combined with pexiganan with fractionary inhibitory concentration index of 0.312 for both strains.In the in vivo study colistin or pexiganan alone showed a good antimicrobial efficacy. When colistin was combined with pexiganan, the positive interaction produced low bacterial counts that were statistically significant versus singly treated groups. For both strains the highest rate of survival was observed in combined-treated groups (90%).Pexiganan increased NK cytotoxic activity over the levels of infected and colistin-treated animals.In conclusion, pexiganan combined with colistin was found to be efficacious against A. baumannii infection.

Tolerability of prostate transrectal biopsies using gel and local anesthetics: results of a randomized clinical trial.

PURPOSE: To evaluate the role of intrarectal EMLA, a new topical anesthetic cream, and lidocaine gel as local anesthesia during transrectal prostate biopsy and to observe whether gel temperature can improve pain control. PATIENTS AND METHODS: A series of 210 consecutive patients were randomized. Group 1 (N = 60) underwent intrarectal instillation of EMLA cream, group 2 (N = 50) 2.5% lidocaine gel, group 3 (N = 40) placebo, and group 4 (N = 60) no treatment. Patients in groups 2 and 3 were subdivided into subgroups according to instillation of warm or cooled gel. Pain control was assessed by a 10-point visual analog scale. RESULTS: The median pain scores were 2.6 in group 1, 3.8 in group 2, 3.9 in group 3, and 3.6 in group 4. In 16 patients (7.6%), the procedure was suspended because of pain: none group 1, 6.0% in group 2, 10% in group 3, and 15% ing group 4. The temperature of the lidocaine gel did not affect tolerability. CONCLUSION: Intrarectal instillation of EMLA cream is a simple, safe, and effective method of local anesthesia during transrectal prostate biopsy, superior to lidocaine gel, placebo, and no treatment.