Role of Renin-Angiotensin System Blockers on BCG Response in Nonmuscle Invasive, High Risk Bladder Cancer.

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.

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy.

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.

Proof of Concept: Microinvasive AngioVac Approach in Renal Cell Carcinoma With Atrial Thrombosis.

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.

Morbidity, mortality, and quality assessment following open radical cystectomy in elderly patients with bladder cancer.

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.

Spermatic Cord Sarcoma: A 20-Year Single-Institution Experience.

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.

Urological Care and COVID-19: Looking Forward.

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.

Efficacy of topical photodynamic therapy in the treatment of Erythroplasia of Queyrat.

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.

Metabolic Plasticity in Chemotherapy Resistance.

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.

Recommendations for surveillance and follow-up of men with testicular germ cell tumors: a multidisciplinary consensus conference by the Italian Germ cell cancer Group and the Associazione Italiana di Oncologia Medica.

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.

Does 1.5 T mpMRI play a definite role in detection of clinically significant prostate cancer? Findings from a prospective study comparing blind 24-core saturation and targeted biopsies with a novel data remodeling model.

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.

MALDI-TOF peptidomic analysis of serum and post-prostatic massage urine specimens to identify prostate cancer biomarkers.

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 log2 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.

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.

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 of diagnostic accuracy of Fagan's two-step nomogram in increasing the value of predictive tools for prostate cancer: application of specific spatial distribution of positive/negative bioptic cores to predict extracapsular extension.

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.

PCA3 score of 20 could improve prostate cancer detection: results obtained on 734 Italian individuals.

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.

Spermatic cord sarcoma: our experience and review of the literature.

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.

Effectiveness of the combined evaluation of KLK3 genetics and free-to-total prostate specific antigen ratio for prostate cancer diagnosis.

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.

Prognostic value of renal vein and inferior vena cava involvement in renal cell carcinoma.

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

Detection of prostate-specific antigen coupled to immunoglobulin M in prostate cancer 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.