Patient and Context Factors in the Adoption of Active Surveillance for Low-Risk Prostate Cancer.

Importance: Although active surveillance for patients with low-risk prostate cancer (LRPC) has been recommended for years, its adoption at the population level is often limited. Objective: To make active surveillance available for patients with LRPC using a research framework and to compare patient characteristics and clinical outcomes between those who receive active surveillance vs radical treatments at diagnosis. Design, Setting, and Participants: This population-based, prospective cohort study was designed by a large multidisciplinary group of specialists and patients' representatives. The study was conducted within all 18 urology centers and 7 radiation oncology centers in the Piemonte and Valle d'Aosta Regional Oncology Network in Northwest Italy (approximate population, 4.5 million). Participants included patients with a new diagnosis of LRPC from June 2015 to December 2021. Data were analyzed from January to May 2023. Exposure: At diagnosis, all patients were informed of the available treatment options by the urologist and received an information leaflet describing the benefits and risks of active surveillance compared with active treatments, either radical prostatectomy (RP) or radiation treatment (RT). Patients choosing active surveillance were actively monitored with regular prostate-specific antigen testing, clinical examinations, and a rebiopsy at 12 months. Main Outcomes and Measures: Outcomes of interest were proportion of patients choosing active surveillance or radical treatments, overall survival, and, for patients in active surveillance, treatment-free survival. Comparisons were analyzed with multivariable logistic or Cox models, considering centers as clusters. Results: A total of 852 male patients (median [IQR] age, 70 [64-74] years) were included, and 706 patients (82.9%) chose active surveillance, with an increasing trend over time; 109 patients (12.8%) chose RP, and 37 patients (4.3%) chose RT. Median (IQR) follow-up was 57 (41-76) months. Worse prostate cancer prognostic factors were negatively associated with choosing active surveillance (eg, stage T2a vs T1c: odds ratio [OR], 0.51; 95% CI, 0.28-0.93), while patients who were older (eg, age ≥75 vs <65 years: OR, 4.27; 95% CI, 1.98-9.22), had higher comorbidity (Charlson Comorbidity Index ≥2 vs 0: OR, 1.98; 95% CI, 1.02-3.85), underwent an independent revision of the first prostate biopsy (OR, 2.35; 95% CI, 1.26-4.38) or underwent a multidisciplinary assessment (OR, 2.65; 95% CI, 1.38-5.11) were more likely to choose active surveillance vs active treatment. After adjustment, center at which a patient was treated continued to be an important factor in the choice of treatment (intraclass correlation coefficient, 18.6%). No differences were detected in overall survival between active treatment and active surveillance. Treatment-free survival in the active surveillance cohort was 59.0% (95% CI, 54.8%-62.9%) at 24 months, 54.5% (95% CI, 50.2%-58.6%) at 36 months, and 47.0% (95% CI, 42.2%-51.7%) at 48 months. Conclusions and Relevance: In this population-based cohort study of patients with LRPC, a research framework at system level as well as favorable prognostic factors, a multidisciplinary approach, and an independent review of the first prostate biopsy at patient-level were positively associated with high uptake of active surveillance, a practice largely underused before this study.

Efficacy and safety profile of GreenLight laser photoselective vaporization of the prostate in ≥ 75 years old patients: results from the Italian GreenLight Laser Study Group.

BACKGROUND: Benign Prostatic Obstruction (BPO) is the most common non-malignant urological condition among men and its incidence rise with age. Among prostate treatments, GreenLight laser seems to reduce bleeding and would be safer in the aging population. AIMS: We aimed to compare the functional outcomes and safety profile of < 75 years old (Group A) and ≥ 75 years old (Group B) patients. METHODS: In a multicenter setting, we retrospectively analyzed all the patients treated with GreenLight Laser vaporization of the prostate (PVP). RESULTS: 1077 patients were eligible for this study. 757 belonged to Group A (median age 66 years) and 320 to Group B (median age 78 years). No differences were present between the two groups in terms of prostate volume, operative time, hospital stay, PSA decrease over time after surgery, complications and re-intervention rate with a median follow-up period of 18 months (IQR 12-26). Nevertheless, focusing on complications, GreenLight laser PVP demonstrated an excellent safety profile in terms of hospital stay, re-intervention and complications, with an overall 29.6% complication rate in older patients and only two cases of Clavien III. Functional outcomes were similar at 12 month and became in favor of Group A over time. These data are satisfactory with a Qmax improvement of 111.7% and an IPSS reduction of 69.5% in older patients. DISCUSSION AND CONCLUSIONS: GreenLight laser photoselective vaporization of the prostate is a safe and efficient procedure for all patients, despite their age, with comparable outcomes and an equal safety profile.

Post-Operative Acute Urinary Retention After Greenlight Laser. Analysis of Risk Factors from A Multicentric Database.

PURPOSE: Greenlight laser is a mini-invasive technique used to treat Benign Prostatic Obstruction (BPO). Some of the advantages of GreenLight photoselective vaporization (PVP) are shorter catheterization time and hospital stay compared to TURP. Post-operative acute urinary retention (pAUR) leads to patients' discomfort, prolonged hospital stay and increased health care costs. We analyzed risk factors for urinary retention after GreenLight laser PVP. MATERIALS AND METHODS: In a multicenter experience, we retrospectively analyzed the onset of early and late post-operative acute urinary retention in patients undergoing standard or anatomical PVP. The pre-, intra- and post-operative characteristics were compared betweene patients who started to void and the patients who developed post-operative urinary retention. RESULTS: The study included 434 patients suitable for the study. Post-operative acute urinary retention occurred in 39 (9%). Patients with a lower prostate volume (P < .001), an adenoma volume lower than 40 mL (P < .001), and lower lasing time (P = .013) had a higher probability to develop pAUR at the univariate analysis. The multivariate logistic regression confirmed that lower lasing time (95% CI: 0.86-0.99, OR = 0.93, P = .046) and adenoma volume (95% CI: 0.89-0.98, OR = 0.94, P = .006) are correlated to pAUR. Furthermore IPSS ≥ 19 (95% CI: 1.19- 10.75, OR = 2.27, P = .023) and treatment with 5-ARI (95% CI: 1.05-15.03, OR = 3.98, P = .042) are risk factors for pAUR. CONCLUSION: In our series, post-operative acute urinary retention was related to low adenoma volume and lasing time, pre-operative IPSS ≥ 19 and 5-ARI intake. These data should be considered in deciding the best timing for urethral catheters removal.

How uro-oncology has been affected by COVID-19 emergency? Data from Piedmont/Valle d'Aosta Oncological Network, Italy.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) pandemic has dramatically hit all Europe and Northern Italy in particular. The reallocation of medical resources has caused a sharp reduction in the activity of many medical disciplines, including urology. The restricted availability of resources is expected to cause a delay in the treatment of urological cancers and to negatively influence the clinical history of many cancer patients. In this study, we describe COVID-19 impact on uro-oncological management in Piedmont/Valle d'Aosta, estimating its future impact. METHODS: We performed an online survey in 12 urological centers, belonging to the Oncological Network of Piedmont/Valle d'Aosta, to estimate the impact of COVID-19 emergency on their practice. On this basis, we then estimated the medical working capacity needed to absorb all postponed uro-oncological procedures. RESULTS: Most centers (77%) declared to be "much"/"very much" affected by COVID-19 emergency. If uro-oncological consultations for newly diagnosed cancers were often maintained, follow-up consultations were more than halved or even suspended in around two out of three centers. In-office and day-hospital procedures were generally only mildly reduced, whereas major uro-oncological procedures were more than halved or even suspended in 60% of centers. To clear waiting list backlog, the urological working capacity should dramatically increase in the next months; delays greater than 1 month are expected for more than 50% of uro-oncological procedures. CONCLUSIONS: COVID-19 emergency has dramatically slowed down uro-oncological activity in Piedmont and Valle d'Aosta. Ideally, uro-oncological patients should be referred to COVID-19-free tertiary urological centers to ensure a timely management.

The safety and feasibility of the simultaneous use of 180-W GreenLight laser for prostate vaporization during concomitant surgery.

OBJECTIVES: To explore the safety and feasibility of photo-selective vaporization of the prostate (PVP) with GreenLight XPS 180 Watt laser (GL-180- W XPS) combined with other surgical procedures. MATERIAL AND METHODS: Data on patients in whom GL-180-W XPS was performed to relieve lower urinary tract symptoms/ benign prostatic hyperplasia (LUTS/BPH) symptoms were extracted from a multi-institutional database (2011-2016). Patients were stratified into two groups. In the first all patients who had GL-180-W XPS with a concomitant procedure during the same surgical session were included as cases while those who underwent GL-180-W XPS PVP only were included as control. RESULTS: A total of 487 patients were included. Fifty-eight (11.9%) patients underwent concomitant procedures. Multivariable linear regression models failed to find an association between concomitant procedures and longer laser time (p = 0.4). Similarly, multivariable linear regression models failed to find an association between concomitant procedures and laser time even when the analyses were repeated and stratified into endoscopic (p = 0.6) and open/laparoscopic (p = 0.4) procedures. Multivariable logistic regression models failed to demonstrate any association between concomitant procedures and early complications (OR:1.39, CI: 0.379-2.44, p = 0.2), late complications (OR:1.84, CI:0.78-3.98; p = 0.1) and acute urinary retention (OR:1.84, CI:0.78-3.98; p = 0.1). When the analyses were repeated and the concomitant procedures stratified into endoscopic and open/laparoscopic ones, they yielded virtually the same results. CONCLUSIONS: GL-180-W XPS PVP could be safely performed in concomitant endoscopic or open/laparoscopic surgery. These results should be taken into consideration in the counseling of the patient who might choose to undergo simultaneous procedures.

Operative profile, safety and functional outcomes after GreenLight laser prostate surgery: results from a 12 months follow-up multicenter Italian cohort analyses.

BACKGROUND: Over the two past decades, GreenLight laser therapy has been considered a valid alternative for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia/benign prostatic obstruction (BPH/BPO). However, the debate on the effectiveness of laser therapy compared to conventional techniques is still open. The aim of our study is to analyze and describe the use of GreenLight laser prostate surgery in Italy, with regard to the surgical techniques performed and the surgical and functional outcomes at mid-term follow-up. METHODS: From March 2012 to July 2018, patients who underwent GreenLight laser prostate surgery for LUTS due to BPH/BPO from 19 Italian centers were included. The following parameters were evaluated in the population: age, prostate volume, prostate adenoma volume, PSA tot, Qmax at uroflowmetry (UFM), International Prostatic Symptoms Score (IPSS), previous therapy for LUTS, use of anticoagulants and antiplatelet drugs. We recorded also the kind of anesthesia, mean laser time (min), mean irradiation time (min), TURP conversion/completion rate, postoperative day of catheter removal, postoperative acute urinary retention (AUR), hospital stay, variation of hematocrit (Ht) and hemoglobin levels (Hb). Early complications were classified according to the Clavien-Dindo classification, the re-operation rate within 30 days and after 30 days, the late complications and the Patient Global Impression of Improvement were also collected. Changes over time in terms of blood loss and functional outcomes (IPSS and Qmax at the UFM at 6 and 12 months) were tested with Student's test for paired samples. We assumed P≤0.05 as level of statistical significance. RESULTS: Overall, 1077 were enrolled in the study, 554 (56.4%) were treated with standard vaporization and 523 (48.6%) with anatomical vaporization. Student's t-test for paired samples showed no statistically significant differences in terms of reduction of Ht preoperative vs. Ht postoperative (42.80±3.91 vs. 39.93±5.35 95% CI P=0.3) and preintervention and postintervention Hb levels (14.28±1.46 vs. 13.72 P=0.35). Compared with the preoperative Qmax (8.60±2.64), the 6- and 12-month UFM showed a significant improvement [19.56±6.29, P<0.01 and 19.99±5.92 P<0.01]. In terms of IPSS variation, compared to the baseline level (22±5.51) the 6- and 12-month follow-up confirmed a significant reduction (8.01±4.41 P<0.01 and 5.81±4.12 P<0.01 respectively). Postoperative complications were CD0, CD1, CD2, CD3, CD4 in 33.0%,35.3%, 2.9%, 0.3%, and 0.6%. CONCLUSIONS: To the best of our knowledge, this is one of the most numerous surgical series of GreenLight laser vaporization and with the longest follow-up. This technique should be considered as a safe and effective alternative in the treatment of secondary LUTS to BPH.

Three-year follow-up in patients with urinary stress incontinence treated with Altis® single-incision sling.

BACKGROUND: The purpose of the study is to report three years follow-up of single incision slings for the treatment of stress urinary incontinence (SUI). The main outcomes are to evaluate the efficacy of the device and to assess safety, adverse events, quality of life, demographic features of treated women and prognostic factors for SUI. METHODS: We performed a retrospective, double-center, single-arm study. Data were collected by medical records and a telephone interview 3 years after the implant of the mini-sling. Complication rate, subjective efficacy and degree of satisfaction were investigated. RESULTS: Fifty-four patients were treated between March 2015 and March 2017, of which 47 answered the survey. Forty-one of 47 procedures (87.2%) were considered effective. Among more relevant complications, there was one case of extrusion of mesh and three cases of new onset of urinary disfunction, of which two cases of urgency urinary incontinence (UUI) and one case of de-novo SUI. Most complications were solved within few days after the procedure. Concerning the subjective impression of improvement, investigated by using the Patient Global Impression of Improvement (PGI-I) questionnaires, 41 patients reported subjective satisfaction, three reported no change in quality of life and three patients had worsening of symptoms. CONCLUSIONS: The procedure was safe and effective for the treatment of SUI but more data are needed to confirm our preliminary results.

Cost-effectiveness analysis of a single-use digital flexible cystoscope for double J removal.

INTRODUCTION AND OBJECTIVE: The novel single-use digital flexible cystoscope Isiris™ has been developed to perform in-office JJ stent removal, without the need of special equipment nor limitations linked to the disinfection of a reusable device. The aim of our study was to perform a cost-effectiveness analysis of Isiris™ in our institution. PATIENTS AND METHODS: A total of 127 consecutive patients undergoing in-office stent removal with Isiris™ were prospectively included in study. After each procedure, the urologist filled a questionnaire specifically developed to evaluate the efficiency of the device and the invasiveness of the procedure. We performed a cost analysis of the main variables involved in JJ removal using Isiris™ versus the traditional Storz™ reusable flexible cystoscope used for all our previous patients. RESULTS: The procedure was successful in all cases except for one, where the device did not work due to the failure of the grasper and had to be replaced. Overall, the performance of Isiris™ was judged by the physician "very good" and "good" in 90.6% of the cases. Both median pain and invasiveness felt by the patient were 0 (range = 0-8). The mean cost of procedure was estimated at €361 for in-office stent removal with Isiris™, and €1.126.8 for stent removal in operatory room with a reusable flexible cystoscope. Considering the 127 procedures performed in office, 64 h of operatory room time was saved. CONCLUSION: In institutions where JJ removal is performed in the operatory room, Isiris™ leads to a significant advantage in terms of money saved per procedure, operatory room time gained and patient satisfaction.

GreenLight Photoselective Vaporization of the Prostate: One Laser for Different Prostate Sizes.

Introduction: GreenLight laser vaporization of the prostate (photoselective vaporization of the prostate [PVP]) is a safe and effective procedure for Benign Prostatic Hyperplasia. Long-term results and advantages of PVP in patients with large and symptomatic prostate are still under evaluation. Materials and Methods: In a multicenter experience, patients who underwent standard or anatomical PVP were retrospectively reviewed. Patients with follow-up >12 months were divided into two groups based on prostate volume (<100 cc vs ≥100 cc). Pre- and perioperative data, as well as postoperative results and complications, were recorded after 3, 6, and 12 months and then annually. Results: One thousand and thirty-one patients were eligible, 916 of these had a prostate volume of <100 cc and 115 ≥ 100 cc. Median follow-up period was 25.0 months (interquartile range [IQR] 16.5-35.0) and 16.0 months (IQR 12.0-24.0) in ≥100 and <100 groups, respectively. No difference was found in terms of catheterization time, postoperative stay, and postoperative acute urine retention. Patients with prostate ≥100 required longer operative time (75 vs 55 minutes), lasing time (41.7 vs 24.9 minutes), and higher energy used but lower energy density. Patients with prostate ≥100 had a higher incidence of early (50.4% vs 35.7%) and late complications (21.7% vs 12.8%) and early urge/incontinence symptoms (40.9% vs 29.3%). No statistically significant differences were found for the maximum urinary flow (Qmax) and International Prostate Symptom Score (IPSS) results between the two groups. The reintervention rate in ≥100 group was 3.5% vs 2.3% in <100. Conclusions: In the midterm follow-up, GreenLight PVP guarantees the same results in different prostate volume groups. Early and late complications are more frequent in large prostates.

Accuracy of elastic fusion biopsy in daily practice: Results of a multicenter study of 2115 patients.

OBJECTIVES: To assess the accuracy of Koelis fusion biopsy for the detection of prostate cancer and clinically significant prostate cancer in the everyday practice. METHODS: We retrospectively enrolled 2115 patients from 15 institutions in four European countries undergoing transrectal Koelis fusion biopsy from 2010 to 2017. A variable number of target (usually 2-4) and random cores (usually 10-14) were carried out, depending on the clinical case and institution habits. The overall and clinically significant prostate cancer detection rates were assessed, evaluating the diagnostic role of additional random biopsies. The cancer detection rate was correlated to multiparametric magnetic resonance imaging features and clinical variables. RESULTS: The mean number of targeted and random cores taken were 3.9 (standard deviation 2.1) and 10.5 (standard deviation 5.0), respectively. The cancer detection rate of Koelis biopsies was 58% for all cancers and 43% for clinically significant prostate cancer. The performance of additional, random cores improved the cancer detection rate of 13% for all cancers (P < 0.001) and 9% for clinically significant prostate cancer (P < 0.001). Prostate cancer was detected in 31%, 66% and 89% of patients with lesions scored as Prostate Imaging Reporting and Data System 3, 4 and 5, respectively. Clinical stage and Prostate Imaging Reporting and Data System score were predictors of prostate cancer detection in multivariate analyses. Prostate-specific antigen was associated with prostate cancer detection only for clinically significant prostate cancer. CONCLUSIONS: Koelis fusion biopsy offers a good cancer detection rate, which is increased in patients with a high Prostate Imaging Reporting and Data System score and clinical stage. The performance of additional, random cores seems unavoidable for correct sampling. In our experience, the Prostate Imaging Reporting and Data System score and clinical stage are predictors of prostate cancer and clinically significant prostate cancer detection; prostate-specific antigen is associated only with clinically significant prostate cancer detection, and a higher number of biopsy cores are not associated with a higher cancer detection rate.

Perioperative major acute cardiovascular events after 180-W GreenLight laser photoselective vaporization of the prostate.

BACKGROUND: Major acute cardiovascular events (MACE) prevalence after 180-W GreenLight (180-W GL) laser photoselective vaporization (PVP) have never been explored. Aim of our study is to evaluate perioperative MACE that occurred concomitantly with 180-W GL PVP. MATERIALS AND METHODS: We relied on a multi-institutional database that included 14 centers. Data from 923 patients who underwent 180-W GL PVP were reviewed. We abstracted pre- and perioperative data of patients who experienced perioperative MACE, such as angina pectoris, acute myocardial infarction, other chronic ischemic heart disease, transient ischemic attack, or cerebrovascular accident as well as deep venous thrombosis with or without pulmonary embolism. We relied on a case-series format to report the main findings of our analyses. RESULTS: 18 (1.9%) patients reported MACE in 7 centers. Median age was 69.5 (IQR 66.0-79.2) years. Of all, 7 patients underwent standard PVP and 11 anatomical PVP. Eleven patients (61.1%) were not under anticoagulant/antiplatelet treatment, 6 (33.3%) were under low dose aspirin, and 1 (5.6%) was under clopidogrel. Four patients (22.2%) had an instrumental and laboratory diagnosis of myocardial infarction, 7 (38.9%) had an episode of angina pectoris with or without rhythm alteration, 3 (16.7%) reported symptomatic deep venous thrombosis, and 4 (22.2%) had other MACE-like events. CONCLUSIONS: Physician should take in consideration the possibility of MACE or MACE-like events. The real MACE rate may be different as only half of included centers reported MACE. Since the main target of laser surgery are high-risk bleeding patients, prospective observational trials focused on detection of these possible complications are warranted.

Standard vs. anatomical 180-W GreenLight laser photoselective vaporization of the prostate: a propensity score analysis.

PURPOSE: To compare the efficacy, safety, Patient Global Impression of Improvement (PGI-I), and complications rates after 180-W GreenLight laser (180-W GL laser) standard and anatomical photoselective vaporization (sPVP and aPVP). METHODS: Within a multi-institutional database, we identified patients who underwent sPVP or aPVP to relief BPH symptoms. IPSS, Q max, and prostate-specific antigen (PSA) were measured at baseline and during the follow-up. PGI-I score as well as early and late complications were recorded at follow-up visits. Log-binomial and multivariable proportional odds regression models were fitted to estimate the effect of aPVP vs. sPVP on PGI-I as well as on early and late complication rates, before and after adjustment for propensity score. RESULTS: 813 patients were included. Of those, the 50.4% underwent aPVP. Patients who underwent aPVP had larger prostate (64 vs. 55 mL, p < 0.001) and higher baseline PSA levels (3.1 vs. 2.5 ng/mL, p < 0.001). PGI-I score was signaled as very improved, improved, slightly improved, unchanged, or worsened in 55.5, 32.8, 8.3, 2.3, and 1.2% of the cases, respectively, with no differences according the technique used (p = 0.420). Acute urinary retention occurred in 9.2 vs. 8.9% of patients after aPVP vs. sPVP (p = 0.872). All models failed to find differences in: patients' satisfaction (OR 1.19, p = 0.256), early complications (RR 0.93, p = 0.387), early urge/incontinence symptoms (RR 0.97, p = 0.814), and late complications rates (RR 0.70, p = 0.053), after aPVP vs. sPVP. CONCLUSION: Our results showed similar functional results and complication rates after aPVP and sPVP. However, aPVP was used in larger prostates. Both techniques guarantee high patient's satisfaction.

Allium stent for the treatment of a malignant ureteral stenosis: A paradigmatic case.

OBJECTIVE: The aim of this study was to present a paradigmatic case where the new-generation Allium URS stent was the optimal choice to treat a malignant ureteral stenosis. METHODS: We describe in detail all the steps of our surgery, performed on a 69-year-old patient with left hydronephrosis caused by lumbo-aortic nodal metastases compressing the ureter. The patient was intolerant to double-J stent due to strong irritative urinary symptoms. Allium URS stent was positioned under fluoroscopy in replacement of pre-existing double-J stent. RESULTS: Our approach was successful and irritative urinary symptoms disappeared. At 6 months, the Allium URS was correctly positioned and no hydronephrosis was detected on ultrasound. The stent can be left in place for a maximum of 3 years. CONCLUSIONS: In complicated scenarios of chronic ureteral stenosis, the new-generation Allium URS can be an interesting option to treat the obstruction while sparing the patient the irritative urinary symptoms and periodic replacements typical of a double-J stent.

Therapeutic ureteral occlusion with Ifabond cyanoacrylate glue: an interesting solution.

OBJECTIVE: The aim of this study was to present a novel approach for complete and permanent ureteral occlusion using a percutaneous injection of Ifabond cyanoacrylate glue. METHODS: We describe in detail all the steps of our surgery, performed on a 79-year-old patient with urinary leakage from ureteral stump following radical cystectomy. N-hexyl-cyanoacrylate glue (Ifabond) was used to occlude the distal ureter and solve the leakage. RESULTS: Our approach was successful, sparing our already frail patient further surgical procedures. Six months pyelography confirmed the complete ureteral blockage with absence of extravasation. CONCLUSIONS: In complicated scenarios with urinary leakages and frail patients, synthetic glues such as Ifabond might represent an interesting therapeutic option to solve the fistulas, leading to durable success with a minimally invasive approach.

[Use of frozen sections to assess surgical margins during radical prostatectomy]. / Impiego dell'esame estemporaneo al congelatore per la valutazione dei margini chirurgici in corso di prostatectomia radicale

INTRODUCTION: At present there is no consensus on the use of frozen sections (FS) during radical prostatectomy. Several groups have proposed the benefit of FS although the studies differ widely in sampling methods and sites where FS were taken. This study aims to evaluate the usefulness and reliability of standard assessment of FS in multiple sites during radical prostatectomy. METHODS: During open radical prostatectomy in all patients we sampled tissue from the urethral stump, the neurovascular bundles, the Denonvillier fascia and the bladder neck after removing the prostate. Where FS showed positive margins, further periprostatic tissue was resected from the prostatic bed until negative margins were achieved. The results of FS were compared with margin status of final pathology. RESULTS: From 1998 to 2004 we performed FS during 250 consecutive open radical prostatectomies (104 nerve sparing procedures). 66 patients had positive FS (26.4%) and 53 patients had positive surgical margins at final pathology (21.2%). All patients with positive FS had negative margins when further tissue was resected in the prostatic bed. During nerve sparing procedures positive FS were found in 14 patients. In these cases the procedure was converted into standard prostatectomy by resecting the neurovascular bundles. Sensibility and specificity were both 90%. Positive and negative predictive values were respectively 72% and 97%. CONCLUSIONS: Standard assessment of FS in multiple sites during radical prostatectomy achieved sensibility and specificity as high as 90%. Although the resection of urethral stump and tissue close to the neurovascular bundles could compromise functional results, standard assessment of FS in multiple sites could help the surgeon to reduce the positive surgical margins, to monitor the oncological safety of a nerve sparing procedure and to improve the pathological staging.

Selective inhibition of carbonic anhydrase IX decreases cell proliferation and induces ceramide-mediated apoptosis in human cancer cells.

Recently, carbonic anhydrase (CA) inhibitors have been proposed as a potential new class of antitumor agents. The aim of this study was to evaluate the antitumor activity of three CA inhibitors, namely acetazolamide (AZ) and two newly synthesized aromatic sulfonamides with high affinity for CA IX, 2-(4-sulfamoylphenyl-amino)-4,6-dichloro-1,3,5-triazine (TR1) and 4-[3-(N,N-dimethylaminopropyl)thioreidophenylsulfonylaminoethyl]benzenesulfonamide (GA15), against human tumor cells. The effects of AZ, TR1, and GA15 on cell proliferation and apoptosis were evaluated in CA IX-positive HeLa and 786-O cells and CA IX-negative 786-O/von Hippel-Lindau (VHL) cells. We also investigated whether the potential antitumor activity of these molecules might be mediated by an increase in ceramide production. AZ, TR1, and GA15 could significantly reduce cell proliferation and induce apoptosis in HeLa and 786-O cells. Moreover, all three inhibitors could decrease intracellular pH (pH(i)) and increase ceramide production in the same cells. Treatment with the ceramide synthase inhibitor fumonisin B1 prevented the apoptotic effects of the three CA inhibitors. In all experiments, the effects of aromatic sulfonamides were more pronounced than those of AZ. The three inhibitors did not show any antitumor activity in CA IX-negative 786-O/VHL cells and failed to lower pH(i) or increase intracellular ceramide levels in the same cells. In conclusion, CA inhibition can decrease cell proliferation and induce apoptosis in human tumor cells. The ability of CA inhibitors to decrease pH(i) might trigger cell apoptosis through mediation of ceramide synthesis. Activation of this apoptotic cascade probably is mediated by inhibition of the CA IX isoform.

Periprostatic tissues intraoperative frozen section during retrograde radical retropubic prostatectomy.

OBJECTIVE: To evaluate usefulness of periprostatic tissues intraoperative frozen sections (PTs IFSs) during RRP for prostate cancer, in order to find local extraprostatic neoplastic spreading and to eventually modify intervention and resection limits during surgery. MATERIAL AND METHODS: From January 1998 to June 2004, 259 consecutive patients underwent RRP at our department for clinically organ-confined prostate cancer; PTs IFSs were prospectively performed in all cases at membranous urethra after removal of prostatic apex, at whole neurovascular bundle (NVB) or at fibroadipose tissue subtended between prostatic capsule and NVB during extrafascial or nerve sparing (NS) RRP respectively, at middle portion of Denonvillier's fascia, at detrusor ring after removal of the prostate. IFSs positivity was followed by further excision at the corresponding site during intervention. RRP pathological specimen was handled and examined according to European Association of Urology (EAU) guidelines. Student's t-test and chi-square test were used for statistic analysis, matching patients with or without positive PTs IFSs for bioptic Gleason sum, preoperative serum PSA, clinical stage and lymph nodal involvement. RESULTS: PTs IFSs were positive 75 times in 63 patients out of 259. Pathological stage considering PTs IFSs overlapped 2002 TNM definitive pathological stage in 228 patients. The remaining 31 cases showed PTs neoplastic involvement at IFSs. These latter patients did not show prostatic capsular infiltration at definitive pathology. We demostrated intraoperative extraprostatic cancer spreading that was unrecognizable at definitive pathology. PTs neoplastic spreading changed NS RRP in extrafascial procedure in 17 patients out of 121 with preoperative planned NS RRP There were no significant statistic differences between patients with or without positive periprostatic margins (PMs), regarding preoperative serum PSA, bioptic Gleason sum and clinical stage (Student's t-test); lymph nodal involvement rate was not significantly different in both groups (chi-square test). CONCLUSIONS: PTs IFSs during RRP were feasible and effective in order to achieve better local pathological staging in 12% of patients, to modify planned nerve sparing RRP in extrafascial procedure in 14% of cases and to wide intraoperatively surgical resection margins in 24% of patients.

Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozymes IX and XII with a library of aromatic and heteroaromatic sulfonamides.

The inhibition of the two transmembrane, tumor-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1) of human origin, hCA IX and XII, with a library of aromatic and heteroaromatic sulfonamides has been investigated. Most of them were sulfanilamide, homosulfanilamide, and 4-aminoethyl-benzenesulfonamide derivatives, to which tails that should induce diverse physico-chemical properties have been attached at the amino moiety, whereas several of these compounds were derived from metanilamide, benzene-1,3-disulfonamide or the 1,3,4-thiadiazole/thiadiazoline-2-sulfonamides. The tails were of the alkyl/aryl-carboxamido/sulfonamido-, ureido or thioureido type. Against hCA IX the investigated compounds showed inhibition constants in the range of 3-294 nM, whereas against hCA XII in the range of 1.9-348 nM, respectively. The best hCA IX inhibitors were ureas/thioureas incorporating 4-aminoethyl-benzenesulfonamide and metanilamide moieties. The best hCA XII inhibitors were 1,3,4-thiadiazole/thiadiazoline-2-sulfonamides incorporating 5-acylamido or 5-arylsulfonylamido moieties. These compounds also inhibited appreciably the cytosolic isozymes hCA I and II, but some selectivity for the transmembrane, tumor-associated isozymes was observed for some of them, which is an encouraging result for the design of novel therapies targeting hypoxic tumors, in which these carbonic anhydrases are highly overexpressed.

Skewing towards neuroendocrine phenotype in high grade or high stage androgen-responsive primary prostate cancer.

OBJECTIVE: The prognostic influence of neuroendocrine (NE) differentiation in prostate cancer patients is not yet properly established. In a series of primary hormone-naive prostate cancers from a patient population that underwent radical prostatectomy, we wanted to determine the relationship between NE phenotype expression and Gleason sum, disease stage, and serum PSA concentration. METHODS: Chromogranin A (CgA) expression was scored and compared in 105 consecutive primary prostate cancers with their homologous preoperative tumor prostate biopsies. RESULTS: High grade or high stage prostate cancers expressed a significantly higher CgA score than low grade or localized diseases (p < 0.005). Both the CgA score of the surgical specimens and the PSA level in the serum increased linearly (p = 0.001). In the samples of many corresponding tumor biopsies no significant CgA staining was found. CONCLUSION: NE differentiation in primary untreated prostate cancer is closely associated with the major prognostic parameters of survival. This association cannot be shown by evaluating the CgA staining in tumor biopsies.

Oral estramustine plus oral etoposide in the treatment of hormone refractory prostate cancer patients: a phase II study with a 5-year follow-up.

BACKGROUND: Chemotherapy regimens that target microtubular trafficking were repeatedly found to be active in the treatment of hormone refractory prostate cancer patients, but disease responses were reportedly short-lived on average. MATERIALS AND METHODS: From 1994 to 1997, 46 consecutive patients with hormone refractory prostate cancer were enrolled in a multicenter Phase II trial of oral etoposide 100 mg/day and estramustine 560 mg/day for 21 days, followed by a 7-day rest period. Final evaluation of this trial was performed after a follow-up of 5 years. RESULTS: Fifty-four percent of patients attained a PSA response and 46% attained a response on measurable lesions. Median time to progression (TTP) and overall survival were 7.4 and 18.4 months, respectively. Fourteen patients (30.4%) had a TTP greater than 12 months and 9 (19.5%) a TTP greater than 18 months. Sixteen patients (34.8.%) survived more than 2 years and 2 (4.3%) survived more than 5 years. One patient was still alive and free from progression more than 7 years after starting treatment. CONCLUSIONS: This Phase II trial with a long-term follow-up revealed that some patients with hormone refractory prostate cancer could obtain durable disease response and long survival with an oral etoposide and estramustine combination regimen.