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Introduction: The gold standard treatment for high-risk NMIBC is BCG immunotherapy. Some studies suggested an immomodulatory effects for commonly used drugs (ie, ACE-I and ARBs). We aimed to determine whether these drugs impact the prognosis of patients with high-risk NMIBC treated with BCG., Materials and Methods: Retrospective analysis on 208 patients from a single academic center with primary high-risk NMIBC treated with transurethral resection followed by 6 weekly instillations of BCG and up to 12 monthly maintenance instillations. ARBs or ACE-I use at the time of treatment initiation was recorded. Inverse probability of treatment weighting (IPTW) was used to adjust for clinical and pathological covariates. IPTW-adjusted Kaplan-Meier curves and weighted Cox proportional hazards regression were used to compare 2-yr failure-free (2-yr FFS), failure-free (FFS), overall recurrence-free (RFS) and progression-free survival (PFS)., Results: A total of 68 patients were on ACE-I, and 38 on ARBs and treatment respectively. At a median follow-up of 26 months, ACE-I treatment had no significant impact on cancer-related outcomes. Conversely, patients treated with ARBs experienced significant improvements in 2-yr FFS (HR 0.3; 0.1-0.9, P = .004), FFS (HR 0.4, 0.1-0.9, P = .005), and PFS (HR 0.001; < 0.001-0.001, P < .001). No significant impact was found for ARB use in RFS (HR 0.6; P = .09). Sensitivity analyses confirmed these results., Conclusions: our findings support a potential role of the angiotensin-renin system in bladder cancer development. We identified ARBs as potential beneficial drugs that seems to act in synergy with BCG-immunotherapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The AngioVac system (AngioDynamics, Latham, NY) has already been described for treatment of thrombotic formations concerning the venous district and the tricuspid valve. We describe an innovative application of the AngioVac system to treat the inferior vena cava thrombosis associated with renal cell carcinoma. In a high surgical risk patient, we utilized a microinvasive and a modified venoarterial AngioVac circuit to remove the atrial thrombus, ensure temporary circulatory support during abdominal surgery, and prevent pulmonary embolism., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: COVID-19 pandemic represents a novel challenge for healthcare systems, and it affects even the daily urological practice. Italy was the first country after China to experience a lock-down period. Our objective is to determine whether, during the COVID-19 period, there has been any modification in urological emergencies., Methods: we retrospectively reviewed urgent urological consultations requested by the Emergency Department (ED) of Padua University Hospital in the 36-day period between February 22nd and March 30th, 2020 and compared them to the prior year cases within a similar time frame (February 24th to March 31st, 2019). Pediatric population (age < 15 years); surgical complications and traumas were excluded to avoid confounding from the reduction of activities during the lockdown. The number of daily consultations, the number of invasive procedures performed and admissions were evaluated, together with the predictors of admission were identified through multivariate logistic regression models., Results: The final sample resulted in 107 consultations performed in 2020 and 266 in 2019. A higher number of daily consultations was performed during 2019 (7.33 vs 2.97, p < 0.001). Similarly, the number of daily-invasive procedures was higher in 2019 (p = 0.006), while there was no difference in the number of daily admissions (15 vs 12, p = 0.80). On multivariate analysis, the year (2020 vs 2019, OR 2.714, 95% CI 1.096-6.757, p = 0.0297) was a significant predictor of admission., Conclusions: Urgent urology practice was affected during COVID-19 pandemic with a remarkable reduction in urgent urological consultations; furthermore, a higher risk of admissions was observed in 2020. The consequences of a potentially delayed diagnosis remain to be determined.

Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AC declared a shared affiliation with the authors to the handling editor at the time of review., (Copyright © 2021 Giacomini, Gianfanti, Desbats, Orso, Berretta, Prayer-Galetti, Ragazzi and Cocetta.)

Background: Open radical cystectomy (ORC) with pelvic lymph-node dissection (PLND) for bladder cancer (BCa) and urinary diversion is a morbid procedure, and advanced age has been associated with a higher incidence of Clavien-Dindo ≥ 3 complications., Aim: To investigate the association between chronological age, survival outcomes, incidence of perioperative complications, and quality parameters in patients undergoing ORC., Methods: We reviewed 413 patients who underwent ORC and PLND at a single academic centre between December 2009 and June 2018 for cT2-T4N0M0 BCa. Complete clinical, demographic, and pathological data were collected in the preoperative, preoperative, and postoperative setting. Patients were categorized as ≥ 75 years or < 75 years and statistical analysis was performed accordingly. Besides descriptive statistics, Kaplan-Meier log-rank test was used. Cox regression univariate and multivariate analyses were used to assess any potential predictor of OS and CSS., Results: There were 285 (69%) patients < 75 years and 128 (31%) patients ≥ 75 years old. There was no significant difference between the two age groups neither in terms of distribution of pathological stage nor in terms of overall incidence of postoperative complications. Chronological age was not significantly associated with survival outcomes on multivariate analysis. Finally, the comorbidity index was the only significant risk factor for the incidence of any complications (OR = 0.83, p = 0.002) at multivariate binary logistic regression., Conclusion: Open radical cystectomy (ORC) is a feasible and safe procedure in patients with high-risk non-metastatic bladder cancer. Uro-oncologists should consider evaluating elderly patients for surgery according to a thorough geriatric assessment despite chronological age.

Objective: The aim of the study was to assess results and quality of life after kidney transplant in adult patients with previously bladder augmentation or urinary diversion due to significant lower urinary tract dysfunction., Materials and Methods: This cross-sectional study examines the outcome of 19 renal allografts transplanted in patients with augmented bladder or urinary diversion over a ten years period; moreover we submitted SF36 questionnaire to evaluate quality of life of these patients and compared the results with the general population., Result: Between January 1, 2005 and 31 December 2015 we performed 19/1093 renal transplantations in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling. Current post-transplant follow-up was 47 months (range 18-188). No patient developed any episode of acute or chronic rejection. Mean serum creatinine after one year from transplant was 102 umol/L. Overall survival is 94.8% at the end of follow-up and graft survival is 89.6%. No significant differences emerged between patients undergoing transplant with lower urinary tract dysfunction and patients without, regarding to recurrent urinary tract infection. There was not statistically significant difference for vitality (p = 0.8088) and mental health (p = 0.8668)., Conclusions: Presence of a previously augmented bladder or other lower urinary tract dysfunction treated in kidney transplant patients doesn't worsen the final outcome. Mental health and the vitality of these patients are similar to the general population.

Introduction: Spermatic cord sarcomas represent a rare genitourinary malignancy with a challenging diagnostic and therapeutic pathway. Different histotypes have been described and prognostic factors remain poorly defined due to the paucity of data presented in literature. Methods: Retrospective chart review of 22 adult patients treated for spermatic cord sarcoma in a single institution in the last 20 years was performed. Clinicopathological characteristics of the tumors were collected with primary and subsequent treatment. Survival analysis was performed in order to identify prognostic factors of disease-specific survival. Results: The median age at diagnosis was 68 years (58-78), the most common histotype was liposarcoma (14/22), and most patients (63.6%) were found to have positive surgical margins after surgery. The 5-year cancer specific survival was 91.3%. Grading ( p = 0.480), histotype ( p = 0.327), and type of intervention ( p = 0.732) were not associated with survival. All patients dead of disease had positive surgical margins ( p = 0.172). Conclusion: We report a good prognosis at 5 years. Wide radical resection remains the first and probably the most important step; thus, according also to literature, negative surgical margins should be aimed., (Copyright © 2020 Iafrate, Motterle, Zaborra, Leone, Prayer-Galetti, Zattoni, Guttilla, Cappellesso, Dei Tos, Rossi, Del Fiore, Rastrelli and Mocellin.)

The recent COVID-19 pandemic represents a worldwide emergency and it is affecting healthcare at every level, including also urological care and especially oncologic patients. Recent epidemiological models show that, without effective treatment or vaccine, there will be a long-lasting phase of cohabitation with the virus. Current experts' opinions recommend performing only non-deferrable uro-oncological surgery and postponing other activities until the end of the emergency, with particular concerns regarding the safety laparoscopy. Veneto Region and Padua Province represent one of the first site of the pandemic spread of the virus outside China, thus we present our experience as a Urological Referral Center in applying a segregated-team work model of organization during the month of March 2020, with a stratified organization of activities, adequate screening and protection for patients and staff were adopted. Compared to the same period of last year even if a 19.5% reduction was experienced in overall surgical activity while maintaining a comparable proportion of oncologic robotic and laparoscopic surgery and guaranteeing care also for high priority non-oncological patients. No cases of COVID-19 infection were reported in staff members nor in patients and the number of surgical complications was comparable to that of last year. Therefore, in our opinion the recommended significant reduction in urological care, including surgical activities, is likely unrealistic in the long period with unknown effects affecting mostly oncological patients. Our experience introducing a segregated-team work model might represent a model for future planning., (Copyright © 2020 Prayer-Galetti, Motterle, Morlacco, Celso, Boemo, Iafrate and Zattoni.)

Erythroplasia of Queyrat (EQ) is an intraepidermal carcinoma in situ presenting clinically as a sharply demarcated, slightly raised erythematosus plaque on the glans penis or the inner side of the foreskin. Various treatment modalities for EQ have been proposed, including electrocautery and curettage, topical 5-floururacil cream, imiquimod cream, isotretinoin, cryotherapy, laser therapy, radiotherapy, ingenol mebutate gel and Photodynamic Therapy (PDT). Most of these treatments are limited by low clearance rates and frequent relapses. Surgical treatment including local excision, Mohs micrographic surgery and partial or total penectomy, ensures adequate healing rates. However, discomfort consequent to surgical treatment might be unacceptable. Topical PDT using the methyl ester of 5- aminolaevulinic acid (MAL) is an established non-surgical treatment of cutaneous precancerous lesions and skin cancers. We present the case of a 60-year-old uncircumcised man affected by EQ of the penis successfully treated with MAL-PDT, performed five times, two weeks apart, with no recurrences after 6 years., Competing Interests: Conflict of interests: The authors have no conflict of interest to disclose., (©Copyright: the Author(s).)

Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance., (Copyright © 2020 Desbats, Giacomini, Prayer-Galetti and Montopoli.)

Background: No compelling evidence is available about surveillance and follow-up of patients with testicular germ cell tumour (TGCT)., Methods: In the light of the best clinical evidence, the Italian Germ cell cancer Group (IGG) and the Associazione Italiana di Oncologia Medica (AIOM) set up a multidisciplinary national consensus conference, involving 42 leading experts and 3 TGCT survivors. A minimum of 50% of votes was required in order to achieve a consensus recommendation on 29 questions., Results: Recommendations have been summarized in three tables, divided by stage I seminoma, stage I nonseminoma and the advanced disease, which may be useful for clinicians to appropriately choose the clinical investigation and its timing during the surveillance and follow-up of TGCT patients based on an accurate estimation of their risk of disease relapse., Conclusions: The IGG-AIOM consensus recommendations may help clinicians to choose appropriate clinical investigations for the surveillance and follow-up of TGCT patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Multiparametric-magnetic resonance imaging (mpMRI) can accurately detect high-grade and larger prostate cancers (PC)., Aims: To evaluate the ability of 1.5 T magnetic field mpMRI-targeted Prostate Biopsies (PBx) in predicting PC in comparison with blind 24-core saturation PBx (sPBx)., Methods: We prospectively collected data from patients undergoing transrectal sPBx and, if needed, targeted PBx of suspected lesions based on the 16-'region-of-interest' (ROI) PI-RADS graph. Data remodeling: for each 'target' (each suspected lesion at mpMRI), we identified all the 16 'ROIs' into which the lesion extended: these single 'ROIs' were identified as 'macro-targets'. For each 'ROI' and 'macro-target', we compared the mpMRI result with that of a saturation and targeted biopsy (if performed)., Results: 1.5T mpMRI showed a PI-RADS value ≥ 3 in 101 patients (82.1%). We found a PC in 50 (40.6%). Negative-positive predictive values for mpMRI were 82-45%, respectively. Of the 22 patients with normal mpMRI, four had a PC, but none had a clinically significant cancer. After the data remodeling, we demonstrated the presence of PC in 228 'ROIs': (a) only in targeted biopsies in 15 'ROIs'/'macro-targets' (6.6%); (b) only in sPBx in 177 'ROIs' (77.6%); (c) in both targeted and sPBx in 36 'ROIs' (15.8%)., Discussion: 81.8% of patients with normal 1.5T mpMRI were negative at PBx. Performing only targeted PBx may lead to lack of PC diagnosis in about 50% of patients., Conclusions: In patients with suspected PC and a previous negative PBx, a normal mpMRI may exclude a clinically significant PC, avoiding sPBx.

Background: Prostate cancer (PC) represents the second most frequent cancer in the male population worldwide. It is mandatory to have a very accurate staging to choice the best possible treatment., Aims: To test the possibility of improving the performance of Partin's tables in predicting the pathological staging of PC by introducing bioptic parameters through an innovative statistic tool (Fagan's two-step nomogram)., Methods: We prospectivelly collected data of all 1048 consecutive patients undergoing saturation 24-core transrectal prostate biopsy. Then, in eligible 94 patients, we compared the prediction of presence/absence of extracapsular extension of neoplasm (EPE+/-), with pathological assessment of invasion through (pseudo)capsule in the prostatectomy specimens. Starting from the probability of EPE- (pre-test probability, calculated with formula "100%-risk of EPE+"), we used Fagan's nomogram to examine the diagnostic sensitivity (DSe) and specificity (DSp) of negative "lateral" bioptic cores., Results: We specifically analyzed the status of "lateral" cores in each side (94 patients × 2 sides = 188 sides). "Lateral" cores were negative in 42.5% of sides (80/188) with a DSe and DSp of 91.7 and 45.4%, respectively. In these sides, the mean probability of EPE+ according to Partin's tables was 21.6%. With Fagan's nomogram, the post-test probability of EPE+ when all "lateral" cores were negative was 14.1%, with a substantial gain of 7.5%., Discussion: The spatial distribution of bioptic positive cores allowed us to demonstrate the role Fagan's nomogram in increasing the accuracy of already existing, predictive tools for PC., Conclusions: This pioneering study may justify the use of the above nomogram in testing "local" predictive parameters in combination with pre-existing nomograms.

Background: Lower urinary tract symptoms (LUTS) and prostate specific antigen-based parameters seem to have only a limited utility for the differential diagnosis of prostate cancer (PCa). MALDI-TOF/MS peptidomic profiling could be a useful diagnostic tool for biomarker discovery, although reproducibility issues have limited its applicability until now. The current study aimed to evaluate a new MALDI-TOF/MS candidate biomarker., Methods: Within- and between-subject variability of MALDI-TOF/MS-based peptidomic urine and serum analyses were evaluated in 20 and 15 healthy donors, respectively. Normalizations and approaches for accounting below limit of detection (LOD) values were utilized to enhance reproducibility, while Monte Carlo experiments were performed to verify whether measurement error can be dealt with LOD data. Post-prostatic massage urine and serum samples from 148 LUTS patients were analysed using MALDI-TOF/MS. Regression-calibration and simulation and extrapolation methods were used to derive the unbiased association between peptidomic features and PCa., Results: Although the median normalized peptidomic variability was 24.9%, the within- and between-subject variability showed that median normalization, LOD adjustment, and log 2 data transformation were the best combination in terms of reliability; in measurement error conditions, intraclass correlation coefficient was a reliable estimate when the LOD/2 was substituted for below LOD values. In the patients studied, 43 peptides were shared by the urine and serum, and several features were found to be associated with PCa. Only few serum features, however, show statistical significance after the multiple testing procedures were completed. Two serum fragmentation patterns corresponded to the complement C4-A., Conclusions: MALDI-TOF/MS serum peptidome profiling was more efficacious with respect to post-prostatic massage urine analysis in discriminating PCa.

Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.

Study Question: To investigate whether sperm recovery is related to clinical features, hormone parameters and testosterone replacement therapy (TRT) in patients with Klinefelter syndrome (KS)., Summary Answer: This study provides three interesting insights: (i) the probability to retrieve sperm is not related to testicular volume; (ii) TRT does not affect sperm retrieval rate (SRR); and (iii) reduced levels of LH and FSH represent a negative predictor of sperm retrieval in patients with TRT., What Is Known Already: Classical KS shows a karyotype with one extra X chromosome in all of somatic cells and clinical manifestations characterized by hypergonadotropic hypogonadism and infertility., Study Design, Size and Duration: We performed a retrospective cohort study. Data from 111 consecutive KS azoospermic patients undergoing testicular sperm extraction (TESE) were collected from 2005 to 2016., Participants/materials, Setting and Methods: Data on anthropometric parameters, reproductive hormones and testicular volumes were collected. SRR was related to clinical characteristics and compared between TRT and untreated patients., Main Results and the Role of Chance: A total of 38 patients (34.2%) had successful sperm recovery. The comparison of clinical characteristics did not differ between patients with and without sperm recovery. Sperm retrieval was successful also in subjects with smaller testes. The comparison of SRR in patients with or without TRT was not different (33.3% vs 34.6%). In TRT group, LH and FSH levels were significantly lower in subjects with no sperm retrieval (P values, respectively, <.05 and <.001)., Limitations and Reasons for Caution: Well-designed controlled studies are necessary to confirm these data aimed to set the best therapeutic approach for fertility management in hypogonadal patients with nonmosaic KS., Wider Implications of the Findings: Age at TESE, anthropometric measures, testis volume, sex hormones levels and semen parameters are not predictive parameters of SRR. Among TRT patients, reduced gonadotropin is related to failure in sperm retrieval., (© 2018 John Wiley & Sons Ltd.)

Background: The role of PCa3 score in the diagnostics of prostate cancer (PCa) is still under debate, mainly due to the lack of a univocal cut-off useful alone or within nomograms proposed by Urologists. Aim of present study is to compare different PCA3 score cut-off values (20, 25, 35 and 50) observed in 734 patients with suspected PCa who were monitored for about three years with single or multiple biopsies., Methods: 734 patients who underwent first prostate biopsy for suspected PCa were enrolled. One month later the first biopsy result was obtained, both negative and positive PCa patients were investigated by means of PCA3 score, in order to establish risk of PCa presence on repeated biopsies., Results: PCA3 score was significantly higher (p<0.001) in PCa patients to the PCa negative ones, while tPSA did not significantly vary. The best negative predictive value (NPV 97.5%) and sensitivity (95.4%) result were obtained when a PCA3 score of 20 was used. At cut-off value of 50, the 75% of patients resulted as false positive., Conclusions: PCA3 score of 20 could be safely introduced in the prostate cancer screening diagnostic flow chart, since it provides important information regarding the outcome of re-biopsy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Spermatic cord tumors represent 4% of scrotal tumors. The most common neoplasms are lipomas. Spermatic cord sarcomas (SCS) of the genitourinary tract account for 2% of all urological tumors. Herein we presented our experience in the treatment of these tumors and a review of the literature., Patients and Methods: A review of the literature was performed using the Medline database with no restriction on language and date of published papers. The literature search used the following terms: epidemiology, surgery, chemotherapy, radiotherapy and spermatic cord sarcomas. Four cases treated from December 2009 to May 2010 are described., Results: All patients were treated with radical orchiectomy. The final pathological report showed different types of sarcomas. Two of the patients were treated with adjuvant chemotherapy. 12 months after surgery, 2/4 patients were alive without signs of relapse., Conclusion: SCS are very rare tumors with a poor prognosis. SCS's prognostic factors have been identified in grading, size, depth of invasion and surgical margin status. Age and performance status of the patient are however very important. Lymphatic and hematogenous dissemination is uncommon. Surgery is the most important treatment both in the first approach and in local relapse. The role of adjuvant chemotherapy and radiation therapy is still debated., (Copyright © 2012 S. Karger AG, Basel.)

Purpose: Of serum prostate specific antigen variability 40% depends on inherited factors. We ascertained whether the knowledge of KLK3 genetics would enhance prostate specific antigen diagnostic performance in patients with clinical suspicion of prostate cancer., Materials and Methods: We studied 1,058 men who consecutively underwent prostate biopsy for clinical suspicion of prostate cancer. At histology prostate cancer was present in 401 cases and absent in 657. Serum total prostate specific antigen and the free-to-total prostate specific antigen ratio were determined. Four polymorphisms of the KLK3 gene (rs2569733, rs2739448, rs925013 and rs2735839) and 1 polymorphism of the SRD5A2 gene (rs523349) were studied. The influence of genetics on prostate specific antigen variability was evaluated by multivariate linear regression analysis. The performance of total prostate specific antigen and the free-to-total prostate specific antigen ratio alone or combined with a genetically based patient classification were defined by ROC curve analyses., Results: For prostate cancer diagnosis the free-to-total prostate specific antigen ratio index alone (cutoff 11%) was superior to total prostate specific antigen (cutoff 4 ng/ml) and to free-to-total prostate specific antigen ratio reflex testing (positive predictive value 61%, 43% and 54%, respectively). Prostate specific antigen correlated with KLK3 genetics (rs2735839 polymorphism p = 0.001, and rs2569733, rs2739448 and rs925013 haplotype combination p = 0.003). In patients with different KLK3 genetics 2 optimal free-to-total prostate specific antigen ratio cutoffs (11% and 14.5%) were found. For free-to-total prostate specific antigen ratio values between 11% and 14.5% the prostate cancer probability ranged from 30.0% to 47.4% according to patient genetics., Conclusions: The free-to-total prostate specific antigen ratio is superior to total prostate specific antigen for prostate cancer diagnosis, independent of total prostate specific antigen results. Free-to-total prostate specific antigen ratio findings below 11% are positively associated with prostate cancer and those above 14.5% are negatively associated with prostate cancer, while the interpretation of those between 11% and 14.5% is improved by patient KLK3 genetic analysis., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic significance of venous tumor thrombus extension in patients with renal cell carcinoma (RCC) is a matter of many controversies in the current literature., Objective: To evaluate the prognostic role of inferior vena cava (IVC) involvement in a large series of pT3b and pT3c RCCs., Design, Setting, and Participants: A total of 1192 patients from 13 European institutions underwent a radical nephrectomy for pT3b and pT3c RCC between 1982 and 2003. The patients were evaluated in a retrospective manner. Age, gender, clinical symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, TNM stage, tumor size, adrenal invasion, perinephric fat invasion, histological type, and Fuhrman grade were reviewed. The log-rank and Cox uni- and multivariate regression analyses were used to evaluate prognostic factors for overall survival., Measurements: Overall survival and prognostic factors for overall survival in patients with RCC extending to the renal vein (RV) or to the IVC., Results and Limitations: The median follow-up was 61.4 mo (56.3-66.5 mo). The mean age was 63.2 yr. The mean tumor size was 8.9 cm. Group 1 (Gr 1) included 933 patients with a renal vein tumor thrombus (78.3%), Group 2 (Gr 2) included 196 patients with a subdiaphragmatic IVC tumor thrombus (16.4%), and Group 3 (Gr 3) included 63 patients with a supradiaphragmatic IVC tumor thrombus (5.3%). Median survival was 52 mo for Gr 1, 25.8 mo for Gr 2, and 18 mo for Gr 3. In univariate analysis, Gr 1 had a significantly better overall survival than Gr 2 (p<0.001) and Gr 3 (p

Objective: To assess the feasibility and activity of a neoadjuvant treatment combining a luteinizing hormone-releasing hormone (LHRH)-analogue, estramustine and docetaxel before radical retropubic prostatectomy (RRP) in patients with high-risk prostate cancer., Patients and Methods: High-risk patients were defined as clinical stage > or =T3 and/or a prostate-specific antigen (PSA) level of > or =15 ng/mL, and/or biopsy a Gleason sum of > or =8. Patients received LHRH analogue treatment until the PSA nadir (a stable PSA level for two consecutive determinations) and then, continuing hormone therapy, a combined regimen of estramustine and docetaxel. Patients had RRP within a month of completing the neoadjuvant regimen. All patients were assessed for toxicity and surgical complications. A clinical response was defined as complete (CR, the disappearance of all palpable and radiological abnormalities and a decline in PSA level of > or =90%) or partial (PR, a decline in PSA level of half or more with stable or improved palpable and/or radiological abnormalities). A pathological response was defined as 'complete' (undetectable cancer), 'substantial' (residual cancer in < or =10% of the surgical specimen) or 'minimal' (residual cancer in >10% of the surgical specimen). The biomarkers p53, bcl-2, MIB1, erbB2 and factor VIII were also evaluated., Results: Of 22 patients enrolled between March 1999 and January 2002, 21 (mean age 63 years; mean PSA level 61 ng/mL; median biopsy Gleason sum 8) completed the neoadjuvant therapy. The clinical stage was organ-confined in three patients (15%); five (25%) had pelvic lymphadenopathy on computed tomography. The neoadjuvant treatment was well tolerated, with only one grade 2 toxicity (Eastern Cooperative Oncology Group grading). All PSA values decreased by >90% from baseline after hormonal therapy only, and the mean reduction from before to after chemotherapy was statistically significant (P = 0.001). Three patients (15%) had a CR, 16 (80%) had a PR and one (5%), with sarcomatoid tumour, had progression; 19 had non-nerve-sparing RRP and there were no major complications during or after RRP. The pathological assessment showed that one patient (5%) had no tumour (pT0) and six (32%) had a 'substantial' response. The overall rate of organ-confined disease was 58%, vs a mean 8% predicted likelihood from the Kattan nomogram. Five patients (26%) had positive surgical margins and four (21%) had positive lymph nodes. At a median follow-up of 53 months, eight patients (42%) were disease-free. Organ-confined disease (P = 0.022), residual cancer at pathology in < or =10% of the surgical specimen (P = 0.007) and no seminal vesicle invasion (P = 0.001) correlated with disease-free survival., Conclusion: A neoadjuvant chemohormonal regimen before RRP is feasible and active in patients with high-risk prostate cancer. The rate of pathological organ-confined disease was higher than expected and responding patients had an 85% disease-free survival rate at 5 years.

Objective: To evaluate the prognostic role of tumour size in pathological stage T3a renal cell carcinoma (RCC) with fat invasion only and to assess whether this subgroup maintains its relevance over the other pathological stages., Methods: We retrospectively studied 2113 patients from eight international institutions who were treated by surgical resection for T2-4 RCC. Disease-specific survival (DSS) was evaluated with univariate and multivariate analyses., Results: Univariate analysis of patients with T3a RCC showed that tumour size was significantly associated with DSS (HR: 1.09, 95% CI: 1.05-1.12, p<0.001). An ideal cut-off of 7 cm for these patients was identified with a scatter plot of Martingale residuals and tumour size. The two T3a groups were distinctly different with respect to clinicopathologic parameters (performance status, metastases, grade, histological subtype) and survival (p<0.001). Median survival time was not reached for patients with T2 and T3a< or =7 cm disease with a 5- and 10-yr DSS rate of 70% and 59% and 63% and 53%, respectively. Median survival time for patients with T3a>7 cm, T3b, T3c, and T4 disease was 54, 46, 21, and 11 mo, respectively, with 5- and 10-yr DSS rates of 46% and 36%, 46% and 36%, 34% and 0%, and 16% and 14%, respectively., Conclusions: Our data indicate that tumour size is an important factor for predicting outcome of patients with T3a RCC with fat invasion only. Our findings should merit consideration during the next revision of the TNM classification.

Purpose: The current tumor classification for renal cell carcinoma classifies pT2 tumors as larger than 7 cm in greatest dimension and limited to the kidney. We examined the current pT2 tumor classification of renal cell carcinoma and determined whether a tumor size cutoff exists that would improve prognostic accuracy., Materials and Methods: We studied 706 patients with pT2 renal cell carcinoma treated with surgical extirpation at 9 international academic centers. Data collected from each patient included age at diagnosis, gender, 2002 TNM (tumor, node, metastasis) stage, tumor size, nuclear grade, performance status, histological subtype and disease specific survival. Disease specific survival was evaluated with univariate and multivariate analysis., Results: Median followup was 52 months. Univariate Cox regression analysis showed a significant association of tumor size with disease specific survival (HR 1.11, p<0.001). An ideal tumor size cutoff of 11 cm was identified, which led to the stratification of 2 groups with respect to disease specific survival (p<0.0001) with 5 and 10-year survival rates of 73% and 65% for pT2 11 cm or less, and 57% and 49% for pT2 larger than 11 cm, respectively. The incidence of metastases was significantly greater in the larger than 11 cm group, while Eastern Cooperative Oncology Group performance status, Fuhrman grade and histological subtype were similar. Multivariate Cox regression analysis retained tumor size as an independent prognostic factor and as the strongest prognostic factor for patients with pT2N0M0 disease., Conclusions: Our data suggest that the current pT2 classification can be improved by subclassification into pT2a and pT2b based on a tumor size cutoff of 11 cm. Patients in the proposed pT2bN0M0 group are at higher risk for death from renal cell carcinoma and should be considered for adjuvant therapies. External validation is warranted before suggesting change to the TNM classification.

Objective: To evaluate features and clinical outcome of patients with clinically localized prostate cancer graded pT0 following radical retropubic prostatectomy (RRP)., Study Design: Between 1974 and 2001 we performed 1,135 RRPs for cT1-T2 prostate cancer, of which 386 (34%) underwent 3-6 months of neoadjuvant endocrine treatment (NHT) before RRP. Median clinical follow-up was 53.8 months (range 24-251). Estimation of likelihood events for biochemical relapse was calculated according to the Kaplan-Meier method. Statistical differences between curves were calculated using the log-rank test., Results: In 24 cases (2.12%) routine histologic workup failed to detect residual tumor. The pT0 group contained a higher proportion of cTla-b patients and a biopsy Gleason score < or =6. A tendency toward lower pre-operatory PSA levels in the pT0 group compared to the pT2-3 group was shown. PSA progression was observed in 3 pT0 patients, all of whom previously underwent NHT., Conclusion: Patients pT0 at RRP presented with lower preoperative PSA values and low preoperative Gleason score compared to the pT+ group. Absence of tumor at pathology examination has a different clinical meaning when it occurs following NHT or in untreated patients. Patients pT0 after NHT may have a worse clinical outcome than pT0 untreated patients.

Background: Several reports indicate that the main biomarkers for liver and colorectal cancer circulating in the blood stream associate with immunoglobulin M (IgM) to form stable complexes that show increased diagnostic relevance compared to circulating free biomarkers., Methods: To further investigate the association between cancer biomarkers and IgM, we assessed the presence of prostate-specific antigen (PSA) as IgM complexes in sera of patients with prostate cancer (PC) or benign prostatic hyperplasia (BPH) in comparison with PSA measurements., Results: PSA-IgM levels were significantly elevated in 40% (20/50) and 12% (6/51) of PC and BPH patients, respectively, compared to 22% (11/50) and 29% (15/51) of PSA positive patients in the same groups. Detection of cancer markedly increased from 22 to 60% by co-determination of both markers (30/50 patients). Significantly elevated levels of PSA-IgM were found in 13 out of 30 patients affected by PC with a PSA value between 4 and 10 ng/mL and only in 4 out of 34 BPH patients in the same PSA range., Conclusions: The results are the first evidence of the occurrence of PSA-IgM complexes in patients with prostate cancer. The gain achieved in cancer detection by using the combination of PSA and PSA-IgM suggests that PSA-IgM could be a complementary serological marker of prostate cancer.

We review the role of prostate-specific antigen (PSA) and the importance of patient education in the management of prostate cancer, based on discussions held at a European symposium on managing prostate cancer. Although PSA is the most widely used serum marker for detecting prostate cancer and for monitoring treatment responses, its use as a diagnostic marker is controversial due to concerns of over-diagnosis and low specificity. PSA isoforms, as well as PSA doubling time, might improve the specificity for earlier prostate cancer detection and can be used as surrogate markers for treatment efficacy. Patients can differ considerably in the importance they place on health-related quality of life aspects and fear of cancer progression. Consequently, there needs to be active, educated discussion of risk and outcomes between physicians and patients. Risk assessment tools, e.g. validated nomograms, enable clinicians to improve their decision analysis and form the basis for subsequent discussion of treatment options between the physician and patient, thereby enabling informed consent and appropriate decision-making.

We review the effectiveness of androgen-deprivation therapy (ADT) in the management of prostate cancer, and the effect that this treatment has on a patient's quality of life (QoL), based on discussions held at a European symposium on the management of prostate cancer. The overall QoL is reduced in asymptomatic men, and there are known decreases in cognitive function, self-esteem, libido and sexual function. Hot flashes are also a frequent problem. Prolonged ADT can lead to osteoporosis and subsequently fractures. Various effective methods exist to manage and minimize these side-effects; some are specific to the side-effect, whereas other more general methods include lifestyle changes, specific drugs and added hormonal manipulations. Intermittent ADT for patients taking luteinizing hormone-releasing hormone agonists offers a promising method to reduce adverse effects, and possibly increases the time to androgen independence. Initial studies indicate that prostate-specific antigen-based progression with intermittent ADT is similar to that seen with continuous ADT, but there is a reduction in side-effects, leading to an improvement in QoL.

Objectives: To investigate the incidence of urinary incontinence and its development over time, to compare the effects of alternative definitions on the incontinence rate and to explore risk factors for incontinence after radical retropubic prostatectomy (RRP) for clinically localized prostate cancer., Patients and Methods: Urinary continence was assessed using a questionnaire administered by a third party in 1144 consecutive patients after undergoing RRP at our department from January 1986 to December 2001. Overall, 985 men (86%) were suitable for evaluation (mean age 64.5 years, mean follow-up 95.5 months). We compared the effects of three definitions on the actuarial rate of continence: (1) no or occasional pad use; (2) 0 or 1 pads used daily, but for occasional dribbling only; (3) 0-1 pads daily. The time to recovery of continence was defined as the date on which the patient met the continence definitions. The impact of incontinence on health-related quality of life (HRQoL) was also evaluated. Univariate and multivariate analyses were used to identify predictors of incontinence, using data gathered prospectively., Results: At the last follow-up at 24 months after RRP, 83%, 92.3% and 93.4% of men achieved continence according to definitions 1, 2 and 3, respectively. The difference in time to recovering continence was significant for definition 1 compared to the others (P < 0.001). Most men using 1 pad/day complained of occasional dribbling only (89.3%), considered themselves continent (98%) and their HRQoL was not as seriously affected as those requiring > or = 2 pads/day. Men continent (by definition 3) at 2 years had an actuarial probability of preserving continence of 72.2% at the last follow-up. On multivariate analysis the age at surgery (P = 0.009), anastomotic stricture and follow-up interval (both P < 0.001) were independent prognostic factors. Bilateral neurovascular bundle resection was another independent predictive factor (P = 0.03) in the subset of the last 560 men with available data on surgical technique. The reduction in the incidence of incontinence over time was as high as 86%., Conclusions: Continence improves progressively until 2 years from RRP but some patients can become incontinent later. The criterion of pad use discriminates well between men with a limited reduction in their QoL (no or one pad used) and those with a markedly affected QoL (> or =2 pads/day). It could be clinically valid to consider users of 1 pad/day as continent. Age, bilateral neurovascular bundle resection and anastomotic stricture are significant risk factors for incontinence. There was a marked trend for the incidence of incontinence and anastomotic stricture to decrease with time.

Objectives: Our aim was to verify whether the quantitative determination of PSA mRNA in circulating cells is helpful in diagnosing and scoring localized prostate cancer (PC)., Design and Methods: The study included 145 patients with benign prostatic hyperplasia (BPH), 138 with localized PC and 28 healthy controls (CS). PSA cDNA was amplified by real-time PCR from circulating mononuclear cells. Serum total and free PSA were determined. Prostate cancers were histologically scored according to the Gleason criteria., Results: The most sensitive index of PC was tPSA (70%), and the most specific was f/t PSA (80%). High PSA mRNA was found more frequently in PC patients with poorly differentiated (23.1%) than in those with well (4.5%) or moderately (4.3%) differentiated tumors., Conclusions: tPSA and f/t PSA are the best available tools for discriminating between localized PC and BPH. The quantitative assessment of PSA mRNA in blood might be helpful in the biochemical grading of prostate cancer.

Objective: The efficacy and safety of using alpha(1)-adrenergic blockers for treating primary bladder neck obstruction in young and middle-aged men was assessed as the first therapeutic step, before surgery, in a symptomatic non-neurogenic selected group of patients., Materials and Methods: From January 1995 to December 2001, primary bladder neck obstruction was diagnosed in 41 men whose average age was 43 years. All of them were evaluated by a complete clinical history, American Urological Association (AUA) symptom score index, physical examination, uroflowmetry, transabdominal ultrasound prostatic volume determination, ultrasound post-void residual determination, videourodynamics including pressure-flow analysis and upper urinary tract screening with renal ultrasound or an excretory urogram. A full daily dose of alpha(1)-adrenergic blockers (alfuzosin or tamsulosin) was administered for at least 6 months. Successful treatment was defined as improved symptoms, voiding diary, maximum flow rate and pressure-flow parameters. Patients who did not gain improvement of symptoms with pharmacological treatment were offered surgery., Results: Overall, pharmacological treatment was successful in 29/41 patients (70.7%) whereas bladder neck endoscopic incision was mandatory in 12/41 (29.3%)., Conclusions: alpha(1)-Blockers were effective and safe for treating young and middle-aged men with symptomatic bladder neck obstruction.

Prostate carcinoma, with about 190,000 new cases occurring each year (15% of all cancers in men), is the most frequent cancer among men in northern and western Europe. Causes of the disease are essentially unknown, although hormonal factors are involved, and diet may exert an indirect influence; some genes, potentially involved in hereditary prostate cancer (HPC) have been identified. A suspect of prostate cancer may derive from elevated serum prostate-specific antigen (PSA) values and/or a suspicious digital rectal examination (DRE) finding. For a definitive diagnosis, however, a positive prostate biopsy is requested. Treatment strategy is defined according to initial PSA stage, and grade of the disease and age and general conditions of the patient. In localized disease, watchful waiting is indicated as primary option in patients with well or moderately differentiated tumours and a life expectancy <10 years, while radical prostatectomy and radiotherapy (with or without hormone-therapy) could be appropriate choices in the remaining cases. Hormone-therapy is the treatment of choice, combined with radiotherapy, for locally advanced or bulky disease and is effective, but not curative, in 80-85% of the cases of advanced disease. Patients who develop a hormone-refractory prostate cancer disease (HRPC) have to be evaluated for chemotherapy because of the recent demonstration of improved overall survival (2-2.5 months) and quality of life with docetaxel in more than 1,600 cases.

Background: The current study defined an optimal tumor size breakpoint to stratify localized renal cell carcinoma (RCC) into groups with significantly different cancer-related outcomes and proposed a revision of the TNM classification system., Methods: The authors analyzed the data from 1138 patients who had undergone partial or radical nephrectomy for localized RCC at 7 European urologic centers. The optimal pathologic size breakpoint was calculated using the martingale residuals from a Cox proportional hazards regression model., Results: The mean follow-up time was 87 months. The scatterplot of tumor size versus expected risk of death per patient suggested that an interval of 5-6 cm was appropriate. A total of 720 (63.3%) and 418 (36.7%) patients had tumors measuring < or = 5.5-cm and tumors measuring > 5.5-cm, respectively. Significant cancer-specific survival differences between the two groups of patients were reported in the series by all the centers participating in the study. On univariate analysis, the other variables found to be associated with cancer-specific survival were the patient's age, symptomatic tumor presentation, and the Fuhrman nuclear grade. On multivariate analysis, the pathologic stage of the primary tumor defined according to the 5.5-cm breakpoint was found to be an independent predictor of cancer-specific survival, as well as age, mode of presentation, and nuclear grade. According to the multivariate analysis, the authors clustered patients into 3 groups with statistically significant outcome differences: 1) patients with < or = 5.5-cm incidentally detected RCC; 2) patients with < or = 5.5-cm symptomatic RCC; and 3) patients with > 5.5-cm RCC. This cancer-related outcome stratification was valid regardless of the patient's age., Conclusions: The 5.5-cm breakpoint was found to be the optimal tumor size breakpoint with which to stratify patients with organ-confined RCC. The study supported the upgrade of the TNM classification system according to this breakpoint., (Copyright 2005 American Cancer Society)

Background: The current study validated the 2002 edition of the TNM staging system in a multicenter, multinational European series of localized renal cell carcinoma (RCC)., Methods: The authors analyzed the clinical data of 2217 patients who had undergone radical or partial nephrectomy for localized RCC in 7 urologic centers., Results: In the current study, 1065 patients (48%) were classified as having pT1a disease, 771 (34.8%) were classified as having pT1b disease, and 381 (17.2%) were classified as having pT2 disease. Tumor histotype was conventional RCC in 1886 patients (85%), papillary in 182 (8.2%) patients, chromophobe in 64 (2.9%) patients, and unclassified in 85 (3.8%) patients. The mean follow-up time was 65.36 +/- 52.09 months. The 5 and 10-year disease-specific survival probabilities were 95.3% and 91.4% in patients with pT1a disease, 91.4% and 83.4% in patients with pT1b disease, and 81.6% and 75.2% in patients with pT2 disease (log-rank test P value = 0.0000). The disease-specific survival rates of patients with pT1a RCC were significantly higher than those recorded in patients with pT1b and pT2 RCC. Similarly, the disease-specific survival probabilities of patients with pT1b RCC were significantly better than those of patients with pT2 RCC. Analyzing the seven series individually, the 2002 TNM staging system provided appropriate stratification for only one series. The 2002 TNM staging system allowed significant stratification of the cancer-related outcomes in the subgroup of patients with conventional RCC but not in those with papillary carcinomas., Conclusions: The application of the 2002 TNM staging system in the current multicenter series enabled the authors to demonstrate optimal stratification of patients with localized RCC. Stratifying by tumor histotype, the data coming from the whole group analysis were reconfirmed for clear cell RCC only.

Objective: To evaluate the clinical impact of different definitions of hereditary prostate cancer (PCa), the relative risk (RR) of relatives of PCa cases and differences in clinical-pathological features and outcome as function of a family history in a surgical series exposed to Mediterranean diet., Methods: We classified as Sporadic (SPC), Familial (FPC) or Hereditary (HPC) 606 consecutive PCa cases, 65 years old or less at diagnosis, underwent radical retropubic prostatectomy between January 1, 1987 and December 31, 2002 (mean follow-up: 6.4 years). The disease-free, overall and PCa-specific survival were also compared between SPC and non-SPC (NSPC) cases., Results: Overall 12.5% of cases had a positive family history. We found 14 (2.3%) HPC cases versus 16 (2.6%) taking account of X-linked transmission. Relatives of early-onset PCa cases had a higher RR to PCa (4.3) compared to late-onset PCa cases. NSPC cases had a lower frequency of positive margins status (p=0.011), perineural infiltration (p=0.028) and positive lymph nodes (p=0.005) than SPC cases, but no differences were found in major prognostic factors (preoperative PSA, Gleason sum, pathological stage) and outcome endpoints as function of a family history., Conclusions: A positive family history is an important risk factor to PCa. HPC frequency is probably underestimated because of exclusion of X-linked transmission. We support the similarity between SPC and NSPC with respect to biological aggressiveness.

Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix-supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

Objectives: To identify an optimal tumor-size breakpoint to distinguish between two groups with different prognoses in a large cohort of patients with localized renal cell carcinoma (RCC)., Methods: We reviewed the clinical records of 813 patients who had undergone surgical treatment for localized RCC from 1976 to 2000. The optimal breakpoint for the pathologic size was calculated by receiver operating characteristic curve analysis., Results: The receiver operating characteristic curve analysis identified 5.5 cm as the optimal breakpoint to predict cancer-specific survival rates. The pathologic size was 5.5 cm or less in 565 neoplasms (69.5%) and more than 5.5 cm in 248 (30.5%). In the multivariate analysis, the more predictive model included the 5.5-cm-or-less pathologic size breakpoint. The pathologic size of 7 cm or less was not an independent variable in this cohort of patients., Conclusions: In a large cohort of patients with localized RCC, 5.5 cm was the optimal breakpoint to classify patients with localized RCC into two subgroups with different prognoses; the 7-cm-or-less cutoff value was not an independent variable. The data obtained by analyzing a large cohort of consecutive patients should be validated by other large series with the prospective of redefining the TNM staging system.