Fibronectin urothelial gene expression as a new reliable biomarker for early detection of local toxicity secondary to adjuvant intravesical therapy for non-muscle invasive bladder cancer.

BACKGROUND: A marker of urothelial damage could be helpful for early detection and monitoring of local toxicity due to intravesical therapy for non-muscle invasive bladder cancer (NMIBC). The aim of the study was to investigate the correlation between fibronectin (FN) gene expression in bladder washings and local toxicity secondary to adjuvant intravesical therapy. MATERIALS AND METHODS: Patients undergoing adjuvant intravesical therapy for NMIBC and age-matched healthy patients were enrolled. Real time polymerase chain reaction was performed to analyze FN expression in bladder washings. Local toxicity was classified as: 0-1 mild (no medical therapy), 2 moderate (medical therapy and/or instillation postponed), 3 severe (discontinuation of therapy). RESULTS: Seventy-two patients and 21 controls entered the study. A useful pellet was obtained in 58 patients and 18 controls. Intravesical Bacillus Calmette-Guerin (BCG), Epirubicin and Mitomycin C was offered to 69%, 13.8% and 17.2% of patients respectively. Compared with healthy controls (FN = 1.0 fold), overall median FN expression before adjuvant intravesical therapy was 1.73 fold [interquartile range (IQR) 0.8-2.3], while during therapy median FN expression increased to 3.41 (IQR: 1.6-6.1) fold. Considering 40 intermediate and high-risk patients undergoing intravesical BCG, median FN expression before adjuvant treatment was 1.92 [(IQR: 1.0-2.7) fold, increasing up to 4.1 (IQR: 1.9-6.6) during therapy. In more detail, FN increased during BCG therapy, showing a median expression of 4.22 (IQR: 2.2-5.5) and 6.16 (IQR: 2.6-8.7) fold in presence of grade 2 and 3 toxicity respectively, while remaining more or less stable in asymptomatic patients. After receiver operating characteristic curve analysis, FN value of 3.6 fold resulted, corresponding to 75% sensitivity and 69% specificity to predict grade 2-3 toxicity events (area under the curve 0.74, 95% confidence interval 0.63-0.85, p = 0.001). CONCLUSION: Our study validated the correlation between FN expression and urothelial damage. BCG seems to induce a urothelial activation with FN overexpression during adjuvant intravesical therapy. Grade of toxicity was related to FN expression.

Does Smoking Cessation at Primary Diagnosis Reduce the Recurrence Risk of Nonmuscle-Invasive Bladder Cancer? Results of a Prospective Study.

INTRODUCTION: Evidence that smoking cessation at first diagnosis of nonmuscle-invasive bladder cancer (NMIBC) reduces the risk of recurrence is lacking. The aim of our prospective study was to analyze the association between patients' changes in smoking habits after diagnosis and recurrence-free survival (RFS). PATIENTS: After transurethral resection of primary NMIBC, patients were classified as "ex-smokers," i.e., those definitively stopping, and as "active smokers," i.e., those continuing or restarting to smoke. Smoking status was reassessed every 3 months during the first year and every 6 months thereafter. Data on patients' demographics, smoking status, tumor characteristics, treatments, and follow-up were collected. Statistical analysis was performed adopting SPSS 15.0.1 and R3.4.2 software. RESULTS: Out of 194 patients, 67 (34.5%) quit smoking after the diagnosis, while 127 (65.5%) did not. The clinical and pathological characteristics were homogeneously distributed. At a median follow-up of 38 months, 106 patients (54.6%) recurred, 33 (49.2%) ex- and 73 (60.3%) active smokers with a 3-year RFS of 42.3 and 50.7%, respectively (p = 0.55). No statistically significant association between recurrence, pathological features of the primary tumor, and patient smoking habits after diagnosis was detected. Results were not statistically influenced by the intensity (cigarette/day) and duration (years) of smoking. In multivariate analysis, cigarette smoking cessation at diagnosis did not significantly reduce tumor recurrence. CONCLUSION: In our prospective study, more than half of our patients recurred at 3 years. In multivariate analysis, smoking cessation did not significantly reduce tumor recurrence. However, the 8.4% reduction in favor of the ex-smokers suggests the need of larger studies with longer follow-ups. Surprisingly, only 35% of smokers definitively quit after diagnosis. The urologists should play a more active role to persuade the patients to stop smoking at first cancer diagnosis.

Radium-223 treatment in castration resistant bone metastatic prostate cancer. Should be the primary tumor always treated?

INTRODUCTION: Radium-223 (223Ra) improves symptoms and survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). STUDY AIM: To evaluate the impact of a previous radical prostatectomy (RP) on the outcome of 223Ra therapy in mCRPC patients. The primary prostate tumor left untreated could progress during 223Ra treatment. MATERIALS AND METHODS: mCRPC symptomatic patients treated with 223Ra were enrolled. Luteinizing Hormone-Releasing Hormone analogue was maintained. No other anticancer therapy was given. 223Ra was administered i.v. at the dose of 55 kBq/kg every 4 weeks for 6 cycles. Patients were stratified according to previous RP or not. Hematological toxicity was monitored. Statistical analysis of 223Ra discontinuations, progressions, and deaths were performed. RESULTS: Forty-four patients were enrolled, 16 (36.4%) previously received RP, 5 (11.3%) prostate radiotherapy and 23 (52.3%) maintained the primary prostate tumor after local treatment. All patients presented only bone metastases, 24 patients (54.5%) had more than 20. Twenty-six (59.1%) patients were treated after first or second line systemic chemotherapy. Treatment interruptions occurred in 14 patients (50%) with prostate and in 4 (25%) without (P = 0.04). After a median follow-up of 18 months (6-30 months), 15 (53.6%), and 7 (43.7%) progressions (P = 0.34) and 13 and 1 (6.2%) deaths (P = 0.04) occurred in patients with and without prostate respectively. CONCLUSION: The presence of the primary prostate tumor seems to play a detrimental role in mCRPC patients undergoing 223Ra treatment in absence of other concomitant anticancer therapy. On the other hand a previous RP might play a protective role.

Epidermal Growth Factor Receptor (EGFR) Cell Expression During Adjuvant Treatment After Transurethral Resection for Non-Muscle-Invasive Bladder Cancer: A New Potential Tool to Identify Patients at Higher Risk of Disease Progression.

BACKGROUND: The aim of the study was to investigate the feasibility of Epidermal Growth Factor Receptor (EGFR) measurement in bladder washings of patients affected by non-muscle-invasive bladder cancer (NMIBC) and its prognostic role in identifying risk subgroups and predicting disease recurrence and progression. PATIENTS AND METHODS: Patients with NMIBC treated with transurethral resection of bladder tumor (TURBT) from 2012 to 2015 were enrolled. Samples of bladder washings were collected and stored at -80°C until RNA extraction. The cDNA obtained from RNA was used to perform a gene expression analysis by a real time polymerase chain reaction. RESULTS: An adequate cellular pellet was obtained in 50 (86.2%) of 58 patients and in 18 (85.7%) of 21 controls. Patients had a median 2.5-, a 1.6- and a 2.8-fold EGFR expression compared with controls before, during, and after adjuvant treatment, respectively. Patients at higher risk had a significantly higher EGFR expression compared with patients at low and intermediate risk when EGFR was measured during (P = .04) and after (P = .001) adjuvant therapy. At a median follow-up of 35.5 months (interquartile range, 19.0-54.8 months), in the high-risk group, patients with overexpression had a significantly lower recurrence-free survival (27.9% vs. 58%), progression-free survival (75.9% vs. 90.2%), and cancer-specific survival (77.7% vs. 93.3%). At multivariable analysis, EGFR overexpression was an additional independent prognostic factor to the European Organisation for Research and Treatment of Cancer scoring system of disease recurrence (hazard ratio, 1.98; 95% confidence interval, 1.32-2.97) and progression (hazard ratio, 1.84; 95% confidence interval, 1.27-2.65). CONCLUSIONS: EGFR overexpression might represent an additional parameter to the current clinical tools for an individualized risk stratification.

Characterization of human infiltrating and circulating gamma-delta T cells in prostate cancer.

Purpose: The aim of our study was to prospectively evaluate the distribution of gamma-delta (γδ)1 and γδ2 T cells and their phenotypes in peripheral blood and prostate samples of patients diagnosed with or without prostate cancer (PCa) at prostate biopsy. Materials and Methods: A consecutive series of 43 outpatients underwent trans-rectal echo-guided prostate biopsy for suspected PCa. Flow cytometry analysis was used to identify and characterize the γδ T cells populations in peripheral blood and tissue samples. Patients were stratified according to the presence or not of PCa, and its International Society of Urological Pathology (ISUP) grade (1 vs. ≥2). Results: The distribution of γδ T cells in peripheral blood and prostate tissue showed wide variability and non-significant differences. A slightly higher percentage of δ2 T cells and a slightly lower percentage of δ1 T cells were found in peripheral blood of cancer patients. A non-significantly higher percentage of both Vδ1 and Vδ2 was expressed in cancer tissues, but a trend for lower distribution of δ1 and δ2 T cells was observed in ISUP grade ≥2. The "central memory" and "effector memory" were the most expressed T cells phenotype in peripheral blood and tissue samples. However no substantial differences in T cells subtypes distribution between cancer and healthy tissue were observed. Conclusions: No substantially different percentages of γδ T cells were found in peripheral blood and biopsy samples of healthy and PCa patients. However a non-significant trend for lower infiltrate in higher ISUP grade cancer tissue was observed, suggesting a possible role for the immunosurveillance of PCa.

Clinical implications of a rare renal entity: Pleomorphic Hyalinizing Angiectatic Tumor (PHAT).

Pleomorphic Hyalinizing Angiectatic Tumor (PHAT) is a rare benign lesion characterized by slow growth, infiltrative behavior and high rate of local recurrences. Only one case has been described in retroperitoneum, at renal hilum, but not involving pelvis or parenchyma. Here we present the first case of PHAT arising in the renal parenchyma. A nodular lesion in right kidney lower pole was diagnosed to a 61 year old woman. The patient underwent right nephrectomy. Microscopically, the lesion showed solid and pseudo-cystic components with hemorrhagic areas characterized by aggregates of ectatic blood vessels. Pleomorphic cells were characterized by large eosinophilic cytoplasm with irregular and hyperchromatic nuclei. Immunohistochemistry was performed and the lesion was classified as a Pleomorphic Hyalinizing Angiectatic Tumor (PHAT). Due to the clinical behavior of this tumor, in spite of its benign nature, review of the surgical margins and close follow up after partial nephrectomy are mandatory.

Mitomycin C from birth to adulthood.

Mitomycin C (MMC) intravesical therapy for "superficial" papillary bladder tumors was firstly introduced in the early seventies with promising results. In the following years, several pharmacokinetic studies investigated its mechanism of action to optimize the intravesical administration. Numerous studies confirmed thereafter both the ablative and the prophylactic efficacy and the low toxicity of MMC when intravesically given. In 1984, a complete response rate of 42% in 60 patients not responsive to thiotepa was reported with intravesical MMC at the dose of 40 mg diluted in 40 ml for 8 weeks. In the following decades, many large randomized studies showed the benefit of intravesical prophylaxis with MMC versus transurethral resection (TUR) alone. Since 2002, the role of adjuvant intravesical chemotherapy and of an early MMC instillation in preventing recurrence compared with TUR alone has been confirmed by large meta-analyses and stated by the European Association of Urology (EAU) guidelines. The need for further intravesical chemotherapy after the early instillation in patients at intermediate-high risk of recurrence has been proved by several trials. Although intravesical Bacillus Calmette-Guerìn (BCG) is considered the best choice for high-risk patients and MMC for the low-risk group, both MMC and BCG can be given to prevent recurrence in intermediate-risk patients. However, the higher efficacy of BCG over MMC is evident only if maintenance regimen is administered. Despite its proven efficacy, immediate intravesical MMC is not yet fully entered in common clinical practice and efforts should be made by the urologists to optimize its adoption.

An uncommon case of sarcomatoid urothelial carcinoma in covered bladder exstrophy.

We report a case of a woman affected by covered exstrophy, uterus didelphys and external genital malformation presenting with advanced bladder cancer. After neoadjuvant therapy and anterior pelvic exenteration, the abdominal wall was reconstructed with a pedicled myocutaneous muscle-sparing vastus lateralis flap.

Does the Compliance to Intravesical BCG Differ between Common Clinical Practice and International Multicentric Trials?

INTRODUCTION: The aim of this study was to analyze the reasons for intravesical BCG interruption in clinical practice. BCG for at least one year is advocated as the best regimen to treat high-risk non-muscle invasive bladder cancer (NMIBC). However, almost 50% of patients don't complete it. Toxicity accounts for 10% of dropouts in international trials. MATERIALS AND METHODS: Patients with T1HG NMIBC undergoing 1-year BCG were enrolled in this study. BCG was administered for one year. Toxicity and causes of treatment interruption were recorded. RESULTS: A total of 411 patients were enrolled in the study. Out of these total number of patients, 380 (92.5%) completed the induction cycle and 215 (52.3%) completed one year. Toxicity requiring interruption or postponement was recorded in 25 (6.1%) and 60 (14.6%) patients. Ninety-three patients (30.2%) stopped BCG, 9 (9.7%) for recurrence and 14 (15.1%) for grade-3 toxicity. Intriguingly, 55 (59.1%) patients refused BCG due to mild discomfort and deterioration in quality of social life. CONCLUSIONS: Grades 2-3 toxicity causes BCG interruption in a few cases. Almost 60% of interruptions are attributable to persistent grade-1 toxicity, which is inadequately treated.

Clinical pitfalls in diagnosis of nonmuscle-invasive bladder cancer.

Current global economic crisis imposes healthcare system to reduce unnecessary investigations and increase early detection of tumors, to decrease the costs of an advanced disease. Several diagnostic pitfalls may occur dealing with bladder cancer (BC), particularly in nonmuscle-invasive (NMIBC) one. Hematuria, the commonest sign in NMIBC, is often underestimated. Urinary cytology is highly specific for high-grade tumors, but has a low sensitivity for low-grade BC, is operator dependent, and not always obtainable in clinical practice. Numerous urinary tests are available to ameliorate the accuracy of cytology, but none of them is routinly used in urological practice. Ultrasound could hardly detect a small bladder tumor, especially if located in the bladder neck or in the anterior wall. Computed tomography (CT) is widely adopted as an alternative to conventional urography, but its usefulness in patients with hematuria is still debated. MRI has a higher accuracy than CT for staging BC and evaluate the bladder-wall invasion. A negative cystoscopy cannot exclude Tis and should be accompanied by urinary cytology in patients with suspected Tis or high-risk NMIBC; however, new techniques such as narrow band imaging (NBI) and photodynamic (PDD) increase the detection rate of BC and flat lesions. Nearly half of all diagnostic resections present omission of muscle in the specimen or its mention in the pathology report, which is associated with an increased mortality. An adequate muscle sampling during endoscopic resection is mandatory, particularly in patients with high-grade disease. Recognition of pitfalls in diagnosis and management of BC represents the first step for a correct approach.

Sexual dysfunctions after transurethral resection of the prostate (TURP): evidence from a retrospective study on 264 patients.

OBJECTIVES: Benign prostatic hyperplasia (BPH) and sexual dysfunctions are diseases with a high prevalence in aged men. Several studies have found a link between BPH and LUTS resulting from deterioration in sexual function in men aged 50 years and older for whom TURP is considered the gold standard. The impact of TURP on sexual functions still remain uncertain, nor is it clear what pathophysiological mechanism underlying the emergence of new episodes of Erectile Dysfunction (ED) following TURP in patients with normal sexual function before surgery, while retrograde ejaculation and ejaculate volume reduction represent a clear side effect; derived from BPH treatment. The aim of this study was to retrospectively evaluate the effects of transurethral resection of the prostate (TURP) on sexual function in patients operated in the period 2008-2012 at the Department of Urology of the University Hospital P. Giaccone, and at Villa Sofia-Cervello Hospital- Palermo. Secondary objective was to reconnect the sample data to interventional practice and international standards. MATERIALS AND METHODS: The retrospective longitudinal study was conducted on 264 of the 287 recruitable patients, aged between 50 and 85 years, suffering from BPH who underwent to TURP in the period 2008-2012. Telephone interviews were conducted and the International Index of Erectile Function (IIEF) was administered to assess sexual function. Patients enrolled were asked to respond to the test by referring at first to their sexual status in the period before surgery and subsequently to the state of their sexual function after treatment so as to obtain, for each patient, a pre- and post-TURP questionnaire in order to get comparisons that corresponding to reality and to avoid overestimation of the dysfunctional phenomenon. RESULTS: In the pre-TURP, the 94.32% of the sample reported being sexually active, with good erectile function in 41.3% of cases, ED mild/moderate in 51.5% and complete ED in 1, 5% of cases; good libido in 62.9% of cases, lack of libido in 31.4% of cases and absent in 5.7% of cases (the latter data corresponded to patients not sexually active); to be sexually satisfied in 29.5% of cases, slightly dissatisfied in 11, 7% of cases, moderately in 35.3% of cases, dissatisfied and very dissatisfied in 23.5% of cases (of which 17.8% sexually active and 5.7% non-active). In the post-TURP 89.4% of the sample reported being sexually active, with good erectile function in 39.1% of cases, DE mild/moderate in 46.9% and complete DE in 4% of cases; good libido in 53.8% of cases, lack of libido in 33.7% of cases and absent in 13.5% of cases (including 1.9% of sexually active and 10.6% of non-active); to be sexually satisfied in 29.5% of cases, slightly dissatisfied in 9.5% of cases, moderately in 35.3% of cases, dissatisfied and very dissatisfied in 17.8% of cases (of which 14.8% sexually active and 10.6% inactive). Retrograde ejaculation was referred in 47.8% of those sexually active after TURP (42.8% if we consider the whole sample). CONCLUSIONS: TURP had no negative impact on erectile function in contrast to ejaculatory function. Of the 109 patients with good erectile function in pre-TURP, 5.8% reported a worsening of erectile function after TURP. Among the 136 patients with ED moderate/mild pre-TURP 3.7% reported a worsening in the post-TURP, 16.2% reported an improvement, while 9.5% stopped any sexual activity. In 3.7% of the cases a complete ED was reported after TURP, while a decline of libido and sexual satisfaction was detected in all patients with worsening of sexual function. Retrograde ejaculation was observed in 48% of those sexually active after TURP. Particular attention has to be paid to the psychological aspects, both before surgery and in the postoperative period, which may become an important factor in the decline of sexual activity.

Genitourinary Symptoms-Patient Help-Seeking and General Practitioner Management: An Outpatient Based Survey at a Tertiary Hospital in Southern Italy.

INTRODUCTION: General knowledge of most common genitourinary diseases is often lacking. In this survey we evaluated the attention given by patients and general practitioners to genitourinary symptoms, and particularly to hematuria and potential early signs of genitourinary cancer. METHODS: A structured self-administered questionnaire was administered to outpatients before the urological consultation. The questionnaire consisted of 4 multiple choice questions to record the level of patient awareness of urological symptoms, the importance given to gross hematuria, the interval between the onset and the visit, the regularity of physical examination and the first-level investigations indicated by the general practitioner before the urological consultation. RESULTS: A total of 327 self-administered questionnaires were obtained from 358 consecutive patients for a compliance rate of 91.3%. Asymptomatic gross hematuria was present in 91 cases (27.8%). The first episode of hematuria was not reported by 20% of the patients, with a median delay of 11 months. Only 77 patients (23.6%) in the last 5 years had received a physical examination including the external genitalia. Laboratory and/or imaging investigations were indicated before urological counseling in 172 (52.6%) patients. CONCLUSIONS: The majority of patients underestimated urological symptoms. Less than 25% and 50% of patients had a physical examination and first-level investigations performed before urological counseling, respectively. Our survey reveals an important lack of awareness of genitourinary symptoms that could be responsible for delayed diagnosis and inappropriate treatment.

[Compliance to therapy with Dapoxetine in patients affected by Premature Ejaculation]. / Eiaculazione Precoce: compliance, effetti collaterali e benefici della farmacoterapia con Dapoxetina e un tradizionale inibitore del reuptake della serotonina (Citalopram) in 59 pazienti.

INTRODUCTION: Premature ejaculation (PE) is a sexual dysfunction with high prevalence. According to some reports, it is present in about 20-30% of the male population. Since 2009 PE has been treated with a novel inhibitor of serotonin re-uptake, Dapoxetine, which has been reported to be specifically active for PE. MATERIALS AND METHODS: 59 patients have been selected among the patients affected by PE observed at the outpatient department of Urology and Andrology of the "Paolo Giaccone" University Policlinic Hospital of Palermo. Diagnosis was confirmed unequivocally in all patients, who were suitable for drug treatment and accepted to participate in the study. They were divided in 2 groups: one receiving Dapoxetine (41 patients), another (18 patients) receiving Citalopram. Patients were followed up by telephone at monthly intervals, in order to compare compliance, efficacy and side effects: RESULTS: Compliance to treatment was obtained in 56% of patients treated with Dapoxetine and in 61% of those treated with Citalopram. In the Dapoxetine group side effects were reported in 14.6% versus 38.4% in the Citalopram group. Benefit from the treatment was reported in 82% and 69.2%, respectively.