Fabrizio Longo

Non-Invasive Diagnostic Tests for Bladder Cancer: A Review of the Literature

Transitional cell carcinoma of the bladder is the second most common malignancy of the genitourinary tract. Cystoscopy and urine cytology are the traditional most used techniques for diagnosis and surveillance of superficial bladder cancer. Urine cytology is specific for diagnosis of bladder cancer but sensitivity results not high, particularly in low-grade disease. Voided urine can be easily obtained and therefore additional diagnostic urine tests would be ideal for screening or follow-up of transitional cell carcinoma. A number of studies have focused on the evaluation of urinary markers that hold promise as non-invasive adjuncts to conventional diagnostic or surveillance techniques. In this review we discuss several new urinary markers (test for bladder tumor antigen, NMP22®, fibrin degradation products, telomerase, fluorescence in situ hybridization test, flow cytometry) and their role in detection and follow-up of bladder cancer. Most of these markers have higher sensitivity than urine cytology, but voided urine cytology has the highest specificity.

Pharmacokinetic study of intravesical gemcitabine in carcinoma in situ of the bladder refractory to Bacillus Calmette-Guérin therapy

Introduction: Gemcitabine, a chemotherapeutic agent, has been shown to be active against transitional cell cancer of the bladder. The aim of the study was to determine the pharmacokinetic profile of gemcitabine, administered intravesically in patients with carcinoma in situ(CIS). Material and Methods: Nine patients with CIS refractory to intravesical bacillus Calmette-Guérin (BCG) therapy were enrolled. Gemcitabine was given in 50 ml 0.9% NaCl by catheterization and held in the bladder for 1 h, once weekly for 6 consecutive weeks. The pharmacokinetics for gemcitabine metabolites were performed in plasma and serum. Dose levels were: 1,000, 1,250, and 1,500 mg. Clinical evaluation was repeated 4 weeks after therapy and thereafter every 6 months. Results: Grade-1 neutropenia was observed only in 1 patient. Grade-1 urinary frequency and hematuria were observed in 1 and 3 patients, respectively. No grade 2–4 toxicity or clinically relevant myelosuppression were observed. Gemcitabine was detectable in serum, but with an irrelevant pharmacological effect, in only 1 patient treated with 1,500 mg of gemcitabine. With regard to activity, after 6 instillations of this drug, 4 complete responses were observed. Conclusion: Intravesical gemcitabine is well tolerated and safe. No systemic absorption with a clinical or pharmacological effect was detected and only slightly irritative bladder symptoms were observed. These results warrant further investigation in phase-II trials.

Tubular Sprouting as a Mode of Vascular Formation in a Colonial Ascidian (Tunicata)

Although phylogenetically related to vertebrates, invertebrate chordate tunicates possess an open circulatory system, with blood flowing in lacunae among organs. However, the colonial circulatory system (CCS) of the ascidian Botryllus schlosseri runs in the common tunic and forms an anastomized network of vessels, defined by simple epithelium, connected to the open circulatory system of the zooids. The CCS originates from epidermal evagination, grows, and increases its network accompanying colony propagation. New vessels are formed by means of mechanisms of tubular sprouting which, in their morphogenesis and molecular regulation, are very similar to those occurring in other metazoans, particularly during vertebrate angiogenesis. From the apex of new vessels, epithelial cells detach and migrate into the tunic, while exploring filopodia extend toward the tunic and possibly guide vessel growth. Immunohistology showed that growth factors fibroblast growth factor‐2 and vascular endothelial growth factor and the receptor vascular endothelial growth factor receptor‐1 participate in sprouting, associated with cell proliferation. As in vertebrates, these factors may regulate cell migration, proliferation, sprouting, and tube formation. Our data indicate that similar, conserved signals were co‐opted in the sprouting processes of two nonhomologous circulatory systems, that of ascidian CCS, and vertebrate circulatory systems, by recruitment of the same signaling pathway. Developmental Dynamics 236:719–731, 2007.

Intracavitary therapy of noninvasive transitional cell carcinomas of the upper urinary tract. A review of the literature.

Noninvasive (stages Ta, T1, Tis) transitional cell carcinomas of the upper urinary tract are suitable for a conservative therapeutic approach. Intracavitary therapy (alone or as adjuvant treatment) has recently been proposed and successfully used by some authors. Even though bacillus Calmette-Guérin is the most frequent agent employed, chemotherapeutic drugs, such as mitomycin C and thiotepa, have also been successfully used. The current information available in the literature is therefore reviewed. According to the data available, intracavitary therapy is a worthwhile conservative therapeutic option for noninvasive upper urinary tract urotheliomas with acceptable side effects. For this reason it may be included in the routine urological armamentarium.

Delayed High-Dose Intravesical Epirubicin Therapy of Superficial Bladder Cancer

Introduction: Intravesical epirubicin is a widely used agent for the treatment of superficial bladder cancer. A direct relationship between dose and activity has been reported: unfortunately the dose increase also increased the frequency and the intensity of treatment-related side effects. Materials and Methods: A phase 2 trial was designed to evaluate the toxicity and the activity of a delayed (biweekly) high-dose (80 mg) epirubicin therapy of superficial bladder cancer. Thirty patients with intermediate risk superficial bladder cancer (stage mTa, G2) have been treated with transurethral resection and epirubicin intravesical therapy: the patients were given 80 mg epirubicin in 50 ml sterile saline every 2 weeks for 6 times (delayed regimen). The follow-up ranged from 3 to 26 months. Eleven of 30 (37%) patients experienced a local adverse reaction to intravesical epirubicin requiring specific medication (grade ≧2 according to NCI-CTC v.2.0, 1999). No systemic toxicity related to the treatment was observed. Results: Out of the 29 evaluable patients, 22 (76%) were free of disease after the induction course, 6 (21%) had superficial bladder cancer recurrences and 1 (3%) experienced tumor progression. Conclusion: A delayed (biweekly instillation) high-dose (80 mg) intravesical epirubicin regimen was acceptable in terms of side effects and showed a worthwhile therapeutical impact in patients with intermediate risk superficial bladder cancer.

Medical Expulsive Therapy for Symptomatic Distal Ureter Stones: Is the Combination of Bromelain and Tamsulosin More Effective than Tamsulosin Alone? Preliminary Results of a Single-Center Study

Objectives: To assess the safety and efficacy of bromelain plus tamsulosin versus tamsulosin alone as medical expulsive therapy (MET) for promoting spontaneous stone passage (SSP) of symptomatic distal ureter stones. Patients and Methods: One-hundred-fourteen patients with a 4–10 mm distal ureteral stone were enrolled (Group A). Patients self-administered daily bromelain with tamsulosin for 30 days or until SSP or intervention was mandatory. Patients were compared to those from a control group taking tamsulosin as MET (Group B) and matched for the following factors: sex, age ±10%, stone diameter. A logistic regression model evaluated bromelain and the ureteral stone diameter as explanatory variables. Results: SSP rates were 87.7 vs. 75.4% for group A vs. group B respectively (p = 0.016); with no difference observed for the time to self-reported stone expulsion (11.68 vs. 11.57 days; p = 0.91). Considering larger stones (> 5 mm), the SSP rate was 83.3% in group A and 61% in group B (p < 0.01). With each millimeter increment of stone diameter, the probability of SSP decreased by 59.1% (p < 0.0001), while it increased of 3.3 when bromelain was present. Only 3 cases of tamsulosin-related adverse events were recorded. Conclusion: The association of bromelain and tamsulosin as MET increases the probability of SSP of symptomatic distal ureteral stones, with no bromelain-related side effects recorded.

Incidence and predictors of readmission within 30 days of transurethral resection of the prostate: A single center European experience

Hospital readmission rates have been analyzed due to their contribution to increasing medical costs. Little is known about readmission rates after urological procedures. We aimed to assess the incidence and predictors of 30-day readmission after discharge in patients treated with transurethral resection of the prostate (TURP). Data from 160 consecutive patients who underwent TURP from January 2015 to December 2016 were analysed. Intra hospitalization characteristics included length of stay (LOS), catheterization time (CT) and complications. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Mean (SD) age was 70.1 (8.1) yrs and mean prostate volume was 80 (20.1) ml. Mean LOS and CT were 4.9 (2.5) days and 3.3 (1.6) days, respectively. The overall 30-day readmission rate was 14.4%, but only 7 (4.4%) patients required hospitalization. The most frequent reasons for readmission were haematuria (6.8%), fever/urinary tract infections (4.3%) and acute urinary retention (3.1%). Multivariable logistic regression analysis revealed age, CCI and CT to be independent predictors of readmission. However, when analysed according to age at the time of surgery, a beneficial effect from longer CT was observed only for patients older than 75 years. These parameters should be taken in account at the time of discharge after TURP.

Role of Bed Assistant During Robot-assisted Radical Prostatectomy: The Effect of Learning Curve on Perioperative Variables

BACKGROUND A remote interaction between a console surgeon (CS) and a bedside surgeon (BS) makes the role of the latter critical. No conclusive data are reported about the length of the learning curve of a BS. OBJECTIVE To highlight the role of a BS during robot-assisted radical prostatectomy (RARP) and to analyze the effect of the learning curve of a BS on intra- and postoperative outcomes. DESIGN, SETTING, AND PARTICIPANTS From June 2013 to September 2016, 129 RARPs were performed by one expert CS (>1000 RARPs) and two BSs (residents). According to the learning curve of the BS, the patients were divided into three groups: group 1 (first 20 procedures), group 2 (21-40 procedures), and group 3 (>40 procedures). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Preoperative variables, pathological data, operating time (OT), blood loss (BL), number of lymph nodes excised (LE), length of hospital stay (LHS), and time to catheter removal (CR) were analyzed. Linear/logistic regression analyses tested the impact of BS experience on surgical outcomes. T test and chi-square test compared the outcomes of the two BSs. RESULTS AND LIMITATIONS Perfect interaction between CSs and BSs are requested to obtain the optimal exposure and avoid any conflict. On the linear regression model, BS learning curve was not related to OT, BL, LHS, and CR, but was related to LE (r2=0.09; p=0.03). On multivariate analyses, no correlation between BS experience and OT, BL, LHS, CR, LE, margin status, and complications (all p>0.05) was found. Comparing the two BSs, no difference was found for the abovementioned outcomes in the first 40 surgeries (all p>0.05). Study limitations include the limited cohort of patients and its retrospective nature. CONCLUSIONS In this study, BS learning curve does not appear to influence the surgical outcomes; good experience of the CS was probably the explanation. PATIENT SUMMARY In our experience, it is the primary surgeon who dictates the perioperative outcomes during robot-assisted radical prostatectomy.

FISH Assay for THE Detection of Bladder Cancer

We evaluated the sensitivity and specificity of fluorescence in situ hybridization (FISH) performed on the urine specimens of patients under follow-up for superficial bladder cancer. Thirty-seven patients were enrolled and underwent cystoscopy, urinary cytology or biopsy and FISH examination. Urinary cytology and FISH were evaluated in exfoliated urothelial cells from bladder washings. A mixture of fluorescent labeled probes to the centromere of chromosomes 3, 7 and 17, and locus 9p21 was used to assess urinary cells for chromosomal abnormalities indicative of malignancy. Nine patients (24.3%) showed an abnormal cystoscopy, but only five patients showed transitional cell carcinoma at histology. Eighteen patients (48.6%) showed an abnormal FISH: one patient (2.7%) had a positive cytology, and three patients (8.1%) showed an atypical cytology. Patients with both positive cystoscopy and histological examination had a positive FISH, while only one patient had a positive cytology. Patients with positive cystoscopy and negative histological examination had a negative FISH. Three patients with negative cystoscopy and suspicious cytology had a positive FISH. Ten patients (27%) with both negative cystoscopy and cytology had a positive FISH. The sensitivity of the FISH assay was 100%, 50% for the cytology and 62% for the cystoscopy. The specificity of the FISH assay, cytology and cystoscopy were 66%, 100% and 86%, respectively. The sensitivity of the FISH assay in detecting non-invasive urothelial tumors is worth further studies.