Development of a predictive model to distinguish prostate cancer from benign prostatic hyperplasia by integrating serum glycoproteomics and clinical variables.

BACKGROUND: Prostate Cancer (PCa) represents the second leading cause of cancer-related death in men. Prostate-specific antigen (PSA) serum testing, currently used for PCa screening, lacks the necessary sensitivity and specificity. New non-invasive diagnostic tools able to discriminate tumoral from benign conditions and aggressive (AG-PCa) from indolent forms of PCa (NAG-PCa) are required to avoid unnecessary biopsies. METHODS: In this work, 32 formerly N-glycosylated peptides were quantified by PRM (parallel reaction monitoring) in 163 serum samples (79 from PCa patients and 84 from individuals affected by benign prostatic hyperplasia (BPH)) in two technical replicates. These potential biomarker candidates were prioritized through a multi-stage biomarker discovery pipeline articulated in: discovery, LC-PRM assay development and verification phases. Because of the well-established involvement of glycoproteins in cancer development and progression, the proteomic analysis was focused on glycoproteins enriched by TiO2 (titanium dioxide) strategy. RESULTS: Machine learning algorithms have been applied to the combined matrix comprising proteomic and clinical variables, resulting in a predictive model based on six proteomic variables (RNASE1, LAMP2, LUM, MASP1, NCAM1, GPLD1) and five clinical variables (prostate dimension, proPSA, free-PSA, total-PSA, free/total-PSA) able to distinguish PCa from BPH with an area under the Receiver Operating Characteristic (ROC) curve of 0.93. This model outperformed PSA alone which, on the same sample set, was able to discriminate PCa from BPH with an AUC of 0.79. To improve the clinical managing of PCa patients, an explorative small-scale analysis (79 samples) aimed at distinguishing AG-PCa from NAG-PCa was conducted. A predictor of PCa aggressiveness based on the combination of 7 proteomic variables (FCN3, LGALS3BP, AZU1, C6, LAMB1, CHL1, POSTN) and proPSA was developed (AUC of 0.69). CONCLUSIONS: To address the impelling need of more sensitive and specific serum diagnostic tests, a predictive model combining proteomic and clinical variables was developed. A preliminary evaluation to build a new tool able to discriminate aggressive presentations of PCa from tumors with benign behavior was exploited. This predictor displayed moderate performances, but no conclusions can be drawn due to the limited number of the sample cohort. Data are available via ProteomeXchange with identifier PXD035935.

Clinical Effects of Oral Supplementation of Gamma-Cyclodextrin Curcumin Complex in Male Patients with Moderate-To-Severe Benign Prostatic Hyperplasia-Related Lower Urinary Tract Symptoms.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms (LUTSs) in males. Curcumin exhibits anti-inflammatory and anti-tumor properties which may be effective for BPH. This multi-arm observational study evaluated the real-world efficacy of QURMIN® (Gamma-cyclodextrin-curcumin Complex-CAVACURMIN®) as single or combination therapy for BPH. METHODS: Men with moderate-severe LUTS/BPH, receiving a 6-month supplementation with QURMIN® alone or in combination with BPH-specific medication were propensity score matched with patients not taking curcumin and then divided into subgroups based on concomitant baseline treatment. Cohorts were compared in the 6-month variation of IPSS, quality of life (IPSS-QoL), Benign Prostatic Hyperplasia Impact Index (BII) and uroflowmetry parameters. Curcumin tolerability was evaluated in terms of discontinuations and adverse effects. RESULTS: The 1:1 propensity score matching resulted in a treatment-naïve (n = 152), an alpha-blocker only (AB) (n = 138) and AB + 5-alpha reductase inhibitors (5-ARIs) (n = 78) subgroup. After 6 months, drug-naïve patients taking curcumin reported significant improvement in IPSS-storage (-3.9, p < 0.001), IPSS-voiding (-2.0, p = 0.011), IPSS-total (-5.9, p < 0.001), IPSS-QoL (-3.9, p < 0.001), BII (-2.0, p < 0.001), Qmax (+3.1 mL/s, p < 0.001), Qmean (+1.9 mL/s, p = 0.005), post-void residual volume (-7.7 mL, p < 0.001), and PSA (-0.3 ng/mL, p = 0.003), compared to controls. Patients taking ABs and curcumin showed improvement in IPSS-storage (-2.7, p < 0.001), IPSS-voiding (-1.3, p = 0.033), IPSS-total (-3.5, p < 0.001), IPSS-QoL (-1.1, p = 0.004), BII (-1.7, p = 0.006), Qmax (+1.0 mL/s, p = 0.006), and PSA (-0.2 ng/mL, p = 0.01). Patients taking curcumin and AB + 5-ARI showed improvement in IPSS-storage (-1.3, p = 0.007), IPSS-total (-1.6, p = 0.034), IPSS-QoL (-1.1, p < 0.001), and BII (-2.0, p < 0.001). No adverse reactions were reported for curcumin supplementation. CONCLUSION: QURMIN® (CAVACURMIN®) led to significant improvements in symptom burden, uroflow parameters, and QoL, without significant additional side effects, thus proving to be a potential new treatment for BPH, either as a single therapy or in addition to standard treatment.

Extent of lymph node dissection and impact on survival in radical cystectomy for advanced bladder cancer.

PURPOSE OF REVIEW: In patients with muscle invasive bladder cancer (MIBC) or unresectable non-MIBC, radical cystectomy is routinely combined with bilateral pelvic lymph node dissection (LND) owing to the oncological benefits found in recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) compared with radical cystectomy alone. However, the optimal anatomic extent of LND is still unclear. RECENT FINDINGS: Retrospective studies were consistent in reporting oncological benefits of extended LND over nonextended LND. A recent RCT (the LEA trial) failed to demonstrate any benefit in terms of RFS, CSS and OS of super-extended LND over standard LND. Several confounding factors hindered the interpretation of the results, leaving the question of the right extent for LND still open. Results of a similar study, the SWOG S1011 are, therefore, highly anticipated. This study differed from the LEA study in several aspects but might also turn out to be a negative study. SUMMARY: There are still no firm data on the oncological benefit brought by more extended LND in patients with MIBC. Survival benefits seem limited, at least in the general population. Other factors could influence the impact of LND on survival, including the administration of adjuvant and neoadjuvant chemotherapies.

PSA and PSA Kinetics as Predictors for 18F-Fluciclovine PET/CT Positivity in Biochemically Recurrent Prostate Cancer.

INTRODUCTION: 18F-Fluciclovine PET/CT is one of the imaging techniques currently employed to restage prostate cancer (PCa). Due to the conflicting results reported in the literature, it is not yet known at what PSA threshold 18F-fluciclovine PET/CT could reliably demonstrate the presence of recurring disease. We explored the association between 18F-fluciclovine PET/CT positivity and prescan PSA, PSA doubling time, and PSA velocity in patients with biochemical recurrence (BCR) of PCa after curative-intent treatment. METHODS: Data from 59 patients who underwent 18F-fluciclovine PET/CT for BCR after radical prostatectomy or radiotherapy were retrieved from a single institution database. Patients already undergone salvage treatments at the time of PET/CT, with newly diagnosed PCa or with initial diagnosis of metastatic PCa were excluded. A 2-sided independent samples Bayesian t test and Bayesian Mann-Whitney U test were used to assess the association between PET/CT and prescan PSA, PSA doubling time, and PSA velocity. RESULTS: Evidence for no difference between PET/CT-positive and -negative patients for log-transformed PSA was found (BF01 3.61, % error: 0.01). Robustness check and sequential analysis showed stability across a wide range of prior distribution specifications. The hypothesis of no difference in terms of PSA-dt and for PSA-vel between groups was found to be more likely compared to the alternative hypothesis (BF01 of 3.44 and 3.48, respectively). CONCLUSION: PSA and PSA kinetics are unlikely to be associated with 18F-fluciclovine PET/CT positivity in patients with BCR, and none of these serum biomarkers might be used as single predictors of PET/CT detection. Larger studies might be needed to evaluate the role of different predictors.

Increased Body Mass Index Is a Risk Factor for Poor Clinical Outcomes after Radical Prostatectomy in Men with International Society of Urological Pathology Grade Group 1 Prostate Cancer Diagnosed with Systematic Biopsies.

INTRODUCTION: The association between obesity and clinically significant prostate cancer (PCa) is still a matter of debate. In this study, we evaluated the effect of body mass index (BMI) on the prediction of pathological unfavorable disease (UD), positive surgical margins (PSMs), and biochemical recurrence (BCR) in patients with clinically localized (≤cT2c) International Society of Urological Pathology (ISUP) grade group 1 PCa at biopsy. METHODS: 427 patients with ISUP grade group 1 PCa who have undergone radical prostatectomy and BMI evaluation were included. The outcome of interest was the presence of UD (defined as ISUP grade group ≥3 and pT ≥3a), PSM, and BCR. RESULTS: Statistically significant differences resulted in comparing BMI with prostate-specific antigen (PSA) and serum testosterone levels (both p < 0.0001). Patients with UD and PSM had higher BMI values (p < 0.0001 and p = 0.006, respectively). BCR-free survival was significantly decreased in patients with higher BMI values (p < 0.0001). BMI was an independent risk factor for BCR and PSM. Receiver-operating characteristic analysis testing PSA accuracy in different BMI groups, showed that PSA had a reduced predictive value (area under the curve [AUC] = 0.535; 95% confidence interval [CI] = 0.422-0.646), in obese men compared to overweight (AUC = 0.664; 95% CI = 0.598-0.725) and normal weight patients (AUC = 0.721; 95% CI = 0.660-0.777). CONCLUSION: Our findings show that increased BMI is a significant predictor of UD and PSM at RP in patients with preoperative low-to intermediate-risk diseases, suggesting that BMI evaluation may be useful in a clinical setting to identify patients with favorable preoperative disease characteristics harboring high-risk PCa.

Detection Rate of Prostate Specific Membrane Antigen Tracers for Positron Emission Tomography/Computerized Tomography in Prostate Cancer Biochemical Recurrence: A Systematic Review and Network Meta-Analysis.

PURPOSE: Restaging of prostate cancer in patients with biochemical recurrence after radical treatment remains a challenging clinical scenario as current imaging modalities are suboptimal. To date, prostate specific membrane antigen positron emission tomography/computerized tomography seems to represent a very promising diagnostic tool in this setting. Therefore, we evaluated the detection rate of several positron emission tomography/computerized tomography prostate specific membrane antigen based tracers in the restaging of prostate cancer in patients with biochemical recurrence. MATERIALS AND METHODS: According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement, a systematic search was performed across MEDLINE®, Embase® and Web of Science™. PICOS (Patient, Intervention, Comparator, Outcome, Study Type), criteria consisted of P: patients with biochemical recurrence after radical prostatectomy and/or radiation therapy as primary treatment; I: studies using gallium-68-prostate specific membrane antigen-11, gallium-68-prostate specific membrane antigen inhibitor for imaging and therapy, gallium-68-trishydroxypyridinone-prostate specific membrane antigen, copper-64-prostate specific membrane antigen-617, fluorine-18-DCFPyL or fluorine-18-prostate specific membrane antigen-1007; C: no control group or positron emission tomography/computerized tomography comparative studies; O: patient specific overall detection rate; and S: retrospective/prospective studies. A meta-analysis of proportions and a network meta-analysis were performed. Heterogeneity was assessed using Cochran Q and I2 statistics. Quality was assessed by QUADAS-2 (University of Bristol, Bristol, United Kingdom). Funnel plots and Egger test were used for publication biases. RESULTS: A total of 43 studies including 5,832 patients were identified and included in the analysis. An overall detection rate of 74.1% (95% CI 69.2%-78.5%) was found, with no differences between tracers. The overall detection rates were 33.7%, 50.0%, 62.8%, 73.1% and 91.7% % in prostate specific antigen subgroups of less than 0.2 ng/ml, 0.2 to 0.49 ng/ml, 0.50 to 0.99 ng/ml, 1.0 to 1.99 ng/ml, and 2.0 ng/ml or greater, respectively. No difference between tracers was found according to prostate specific antigen doubling time or prostate specific antigen velocity. No tracer proved superior to the others through network meta-analysis. High heterogeneity and inconsistency were found across all analyses. Included studies showed a low risk of bias. CONCLUSIONS: Prostate specific membrane antigen positron emission tomography/computerized tomography for prostate cancer restaging in patients with biochemical recurrence achieves best detection rates (over 70%) if prostate specific antigen is below 1 ng/ml. At lower prostate specific antigen levels the detection rate of prostate specific membrane antigen positron emission tomography/computerized tomography is lower (33.7% for levels below 0.2 ng/ml and 50% for levels 0.2 to 0.49 ng/ml), despite being better than "older" tracers such as choline based positron emission tomography or computerized tomography/bone scintigraphy. Furthermore, no prostate specific membrane antigen tracer can be currently considered superior to others. Further studies are needed to better define the diagnostic performance and role of these imaging techniques.

Circulating preoperative testosterone level predicts unfavourable disease at radical prostatectomy in men with International Society of Urological Pathology Grade Group 1 prostate cancer diagnosed with systematic biopsies.

PURPOSE: The association between circulating total testosterone (T) levels and clinically significant PCa is still a matter of debate. In this study, we evaluated whether serum testosterone levels may have a role in predicting unfavorable disease (UD) and biochemical recurrence (BCR) in patients with clinically localized (≤ cT2c) ISUP grade group 1 PCa at biopsy. METHODS: 408 patients with ISUP grade group 1 prostate cancer, undergone to radical prostatectomy and T measurement were included. The outcome of interest was the presence of unfavourable disease (UD) defined as ISUP grade group [Formula: see text] 3 and/or pT [Formula: see text] 3a. RESULTS: Statistically significant differences resulted between serum testosterone values and ISUP grade groups (P < 0.0001). Significant correlation was found analyzing testosterone values versus age (P < 0.0001), and versus PSA (P = 0.008). BCR-free survival was significantly decreased in patients with low levels of testosterone (P = 0.005). These findings were confirmed also in the ISUP 1-2 subgroups (P = 0.01). ROC curve analysis showed that T outperformed PSA in predicting UD (AUC 0.718 vs AUC 0.525; P < 0.001) and was and independent risk factor for BCR. CONCLUSION: Our findings suggested that circulating total T was a significant predictor of UD at RP in patients with preoperative low- to intermediate-risk diseases, confirming the potential role of circulating androgens in preoperative risk assessment of PCa patients.

A risk-group classification model in patients with bladder cancer under neoadjuvant cisplatin-based combination chemotherapy.

The objective of the current research was to explore the potential prognostic value of readily available clinical and pathologic variables in bladder cancer. The novel association found between cholesterol levels and prognosis may provide the rationale for exploring novel treatments. Patients included had histologically confirmed urothelial bladder cancer and were treated with at least 3 cycles of cisplatin-based neoadjuvant chemotherapy before radical cystectomy with lymphadenectomy. A total of 245 patients at low, intermediate and high risk, presenting with 0-1, 2 or 3-4 risk factors, including positive lymph nodes, Hb <12.8, NLR ≥2.7 and cholesterol levels ≥199, were included. Five-year cancer-specific survival rate was 0.67, 0.78 and 0.94 at high, intermediate and low risk, respectively. Total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and may be incorporated in a clinically meaningful risk-group classification model.

Lay abstract This present study assessed a large group of patients with urothelial bladder cancer treated with chemotherapy followed by radical cystectomy, to capture the predictive power of commonly collected clinical, pathological and biochemical factors. The design of the study highlighted that higher cholesterol levels at the time of cystectomy were associated with shorter cancer-specific survival. This finding suggests that high blood-cholesterol levels truly have a negative influence on surviving cancer. In conclusion, total cholesterol levels at the time of cystectomy may represent a commonly assessable prognostic factor and could be incorporated into a clinically meaningful and valuable risk-group classification model.

Mechanical and Ablative Minimally Invasive Techniques for Male LUTS due to Benign Prostatic Obstruction: A Systematic Review according to BPH-6 Evaluation.

The treatment of male lower urinary tract symptoms (LUTS) due to benign prostatic obstruction represents one of the major interesting aspects in urological clinical practice. Although transurethral resection of the prostate is still considered the surgical gold standard for treatment of benign prostatic hyperplasia with prostate volume <80 mL, various minimally invasive surgical treatments (MITs) have been developed to overcome the limitations of the "conventional" surgery. To date, there are no validated tools to evaluate the surgical outcomes of MITs; however, in the past, BPH-6 has been used for this purpose. In this systematic review, we evaluated the efficacy and safety of MITs according to BPH-6 score system. We focused our attention on MITs based on mechanical devices (prostatic urethral lift and the temporary implantable nitinol device) and techniques for prostate ablation (image guided robotic waterjet ablation and convective water vapor energy ablation). Evidence shows that MITs are capable of leading to an improvement in LUTS without having an overwhelming impact on complications and are a valid alternative to other treatments in patients who wish to preserve their sexual function or in case of inapplicability of conventional surgery. However, comparative studies between these techniques are still missing.

Beyond PSA: The Role of Prostate Health Index (phi).

BACKGROUND: Widespread use of prostate specific antigen (PSA) in screening procedures allowed early identification of an increasing number of prostate cancers (PCas), mainly including indolent cancer. Availability of different therapeutic strategies which have a very different impact on the patient's quality of life suggested a strong need for tools able to identify clinically significant cancer at diagnosis. Multi-parametric magnetic resonance showed very good performance in pre-biopsy diagnosis. However, it is an expensive tool and requires an experienced radiologist. In this context, a simple blood-based test is worth investigating. In this context, researchers focused their attention on the development of a laboratory test able to minimize overdiagnosis without losing the identification of aggressive tumors. RESULTS: Recent literature data on PCa biomarkers revealed a clear tendency towards the use of panels of biomarkers or a combination of biomarkers and clinical variables. Phi, the 4Kscore, and Stockholm3 as circulating biomarkers and the Mi-prostate score, Exo DX Prostate, and Select MD-X as urinary biomarker-based tests have been developed. In this scenario, phi is worthy of attention as a noninvasive test significantly associated with aggressive PCa. CONCLUSIONS: Literature data showed that phi had good diagnostic performance to identify clinically significant (cs) PCa, suggesting that it could be a useful tool for personalized treatment decision-making. In this review, phi potentialities, limitations, and comparisons with other blood- and urinary-based tests were explored.

Incidence of fatigue and low-dose corticosteroid use in prostate cancer patients receiving systemic treatment: a meta-analysis of randomized controlled trials.

BACKGROUND: Cancer-related fatigue (CRF) is a complex condition that is reported in > 50% of cancer patients. In men with castration-resistant prostate cancer (CRPC), CRF was reported in 12-21% of patients. Approved systemic therapy against CRPC is commonly administered in combination with androgen-deprivation treatment (ADT) and, in some cases, with daily, low-dose corticosteroids. Importantly, the use of low-dose corticosteroids is associated with multiple negative effects, including reduced muscle mass. On these grounds, we hypothesized that the chronic use of corticosteroids may increase the incidence of fatigue in patients with prostate cancer. METHODS: We reviewed all randomized trials published during the last 15 years conducted in patients with prostate cancer receiving systemic treatment and we performed a sub-group analysis to gather insights regarding the potential differences in the incidence of fatigue in patients receiving vs. not receiving daily corticosteroids as part of their systemic anti-neoplastic regimen. RESULTS: Overall, 22,734 men enrolled in prospective randomized phase II and III trials were evaluable for fatigue. Estimated pooled incidence of grade 1-2 fatigue was 30.89% (95% CI = 25.34-36.74), while estimated pooled incidence of grade 3-4 fatigue was reported in 3.90% (95% CI = 2.91-5.02). Sub-group analysis showed that grade 3-4 fatigue was approximately double in patients who received daily corticosteroids as part of their anti-neoplastic treatment (5.58; 95% CI = 4.33-6.98) vs. those who did not (2.67%; 95% CI = 1.53-4.11). CONCLUSION: Our findings highlight the need for ad hoc-designed prospective clinical trials to investigate whether the benefits associated with low-dose, daily corticosteroids outweigh the risks associated with corticosteroid-related adverse events such as fatigue.

An increased body mass index is associated with a worse prognosis in patients administered BCG immunotherapy for T1 bladder cancer.

PURPOSE: The body mass index (BMI) may be associated with an increased incidence and aggressiveness of urological cancers. In this study, we aimed to evaluate the impact of the BMI on survival in patients with T1G3 non-muscle-invasive bladder cancer (NMIBC). METHODS: A total of 1155 T1G3 NMIBC patients from 13 academic institutions were retrospectively reviewed and patients administered adjuvant intravesical Bacillus Calmette-Guérin (BCG) immunotherapy with maintenance were included. Multivariable Cox regression analysis was performed to identify factors predictive of recurrence and progression. RESULTS: After re-TURBT, 288 patients (27.53%) showed residual high-grade NMIBC, while 867 (82.89%) were negative. During follow-up, 678 (64.82%) suffered recurrence, and 303 (30%) progression, 150 (14.34%) died of all causes, and 77 (7.36%) died of bladder cancer. At multivariate analysis, tumor size (hazard ratio [HR]:1.3; p = 0.001), and multifocality (HR:1.24; p = 0.004) were significantly associated with recurrence (c-index for the model:55.98). Overweight (HR: 4; p < 0.001) and obesity (HR:5.33 p < 0.001) were significantly associated with an increased risk of recurrence. Addition of the BMI to a model that included standard clinicopathological factors increased the C-index by 9.9. For progression, we found that tumor size (HR:1.63; p < 0.001), multifocality (HR:1.31; p = 0.01) and concomitant CIS (HR: 2.07; p < 0.001) were significant prognostic factors at multivariate analysis (C-index 63.8). Overweight (HR: 2.52; p < 0.001) and obesity (HR: 2.521 p < 0.001) were significantly associated with an increased risk of progression. Addition of the BMI to a model that included standard clinicopathological factors increased the C-index by 1.9. CONCLUSIONS: The BMI could have a relevant role in the clinical management of T1G3 NMIBC, if associated with bladder cancer recurrence and progression. In particular, this anthropometric factor should be taken into account at initial diagnosis and in therapeutic strategy decision making.

High-throughput detection of low abundance sialylated glycoproteins in human serum by TiO2 enrichment and targeted LC-MS/MS analysis: application to a prostate cancer sample set.

Glycopeptide enrichment can be a strategy to allow the detection of peptides belonging to low abundance proteins in complex matrixes such as blood serum or plasma. Though several glycopeptide enrichment protocols have shown excellent sensitivities in this respect, few reports have demonstrated the applicability of these methods to relatively large sample cohorts. In this work, a fast protocol based on TiO2 enrichment and highly sensitive mass spectrometric analysis by Selected Reaction Monitoring (SRM) has been applied to a cohort of serum samples from prostate cancer and benign prostatic hyperplasia patients in order to detect low abundance proteins in a single LC-MS/MS analysis in nanoscale format, without immunodepletion or peptide fractionation. A peptide library of over 700 formerly N-glycosylated peptides was created by data dependent analysis. Then, 16 medium to low abundance proteins were selected for detection by single injection LC-MS/MS based on selected-reaction monitoring. Results demonstrated the consistent detection of the low-level proteins under investigation. Following label-free quantification, four proteins (Adipocyte plasma membrane-associated protein, Periostin, Cathepsin D and Lysosome-associated membrane glycoprotein 2) were found significantly increased in prostate cancer sera compared to the control group. Graphical abstract ᅟ.

High-Grade T1 on Re-Transurethral Resection after Initial High-Grade T1 Confers Worse Oncological Outcomes: Results of a Multi-Institutional Study.

INTRODUCTION: The aim of this multicenter study was to investigate the prognostic impact of residual T1 high-grade (HG)/G3 tumors at re-transurethral resection (TUR of bladder tumor) in a large multi-institutional cohort of patients with primary T1 HG/G3 bladder cancer (BC). PATIENTS AND METHODS: The study period was from January 2002 to -December 2012. A total of 1,046 patients with primary T1 HG/G3 and who had non-muscle invasive BC (NMIBC) on re-TUR followed by adjuvant intravesical Bacillus Calmette-Guerin (BCG) therapy with maintenance were included. Endpoints were time to disease recurrence, progression, and overall and cancer-specific death. RESULTS: A total of 257 (24.6%) patients had residual T1 HG/G3 tumors. The presence of concomitant carcinoma in situ, multiple and large tumors (> 3 cm) at first TUR were associated with residual T1 HG/G3. Five-year recurrence-free survival (RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) were 17% (CI 11.8-23); 58.2% (CI 50.7-65); 73.7% (CI 66.3-79.7); and 84.5% (CI 77.8-89.3), respectively, in patients with residual T1 HG/G3, compared to 36.7% (CI 32.8-40.6); 71.4% (CI 67.3-75.2); 89.8% (CI 86.6-92.3); and 95.7% (CI 93.4-97.3), respectively, in patients with NMIBC other than T1 HG/G3 or T0 tumors. Residual T1 HG/G3 was independently associated with RFS, PFS, OS, and CSS in multivariable analyses. CONCLUSIONS: Residual T1 HG/G3 tumor at re-TUR confers worse prognosis in patients with primary T1 HG/G3 treated with maintenance BCG. Patients with residual T1 HG/G3 for primary T1 HG/G3 are very likely to fail BCG therapy alone.

Safe introduction of laparoscopic and retroperitoneoscopic nephrectomy in clinical practice: impact of a modular training program.

PURPOSE: To describe and validate a novel modular training scheme (MTS) for trans-peritoneal laparoscopic nephrectomy (LN) and retroperitoneoscopic nephrectomy (RN). METHODS: Four consultant urologists attended a Masterclass in "Advanced Laparoscopic and Robotic Surgery," certified by the University of Turin (IT). The Masterclass was based on a supervised MTS, which involved progressive, proficiency-based training through nine and seven steps for LN and RN, respectively. After becoming proficient in all the steps, each trainee performed a minimum of five procedures as first operator under direct observation of the mentor in the training centre. Then, each trainee independently performed 10 LN and 10 RN at his home institution. The surgical outcomes were compared with those from a contemporary series of procedures performed by the mentor. RESULTS: All trainees successfully completed the 12-week MTS program. Median number of training cases to become competent in trans-peritoneal LN and RN was 13.0 (IQR 11.5-20.5) and 23.5 (IQR 19.5-32.0), respectively. A significantly higher rate of conversion to open surgery was observed for RNs independently performed by the trainees in their hospital compared to the mentor (p = 0.033). Failure to progress due to difficult anatomical orientation and abdominal wall bleeding during dissection of retroperitoneal space were the most frequent reasons of conversion. CONCLUSIONS: A 12-week intensive modular program allows to achieve proficiency in performing independently LN and a RN after a median of 13 and 23.5 cases, respectively. Therefore, these procedures can be safely introduced and implemented in clinical practice within a relatively short time.

The emerging role of obesity, diet and lipid metabolism in prostate cancer.

Obesity is associated with an increased risk of a number of serious medical conditions, including cancer. As far as prostate cancer is concerned, obesity is associated with an increased risk of high-grade tumors, which is possibly related to lower androgen levels. Diet may also affect prostate cancer risk since countries with a higher dietary fat intake also present higher prostate cancer mortality rates. Interestingly, prostate cancer is associated with a number of metabolic alterations that may provide valuable diagnostic and therapeutic targets. This review explores the available clinical as well as biological evidence supporting the relationship between obesity, diet, alteration in metabolic pathways and prostate cancer.

Impact of Prostate Involvement on Outcomes in Patients Treated with Radical Cystoprostatectomy for Bladder Cancer.

OBJECTIVE: The study aimed to evaluate the impact of the different types of prostate involvement at the time of radical cystoprostatectomy (RCP). METHODS: Data from 893 male patients treated with RCP at a referral center for bladder cancer (BCa) were assessed. Prostatic urothelial carcinoma (PUC) was stratified as stromal vs. urethral/duct involvements. Multivariable Cox regression analyses were built to test the impact of the presence of incidental prostate cancer (PCa) and PUC on survival outcomes. RESULTS: PCa was present in 319 (35.7%) RCP patients, of which 45 (14.1%) had significant PCa disease. PUC was identified in 181 patients (20%): 75 (41.1%) with urethral/duct involvement and 106 (58.6%) with stromal. Within a median follow-up of 72 months, stromal PUC, but not the other forms of PUC or PCa, was associated with worse survival outcomes. In multivariable analyses adjusted for the effects of standard features, stromal PUC remained associated with recurrence (hazards ratio [HR] 2.01, p = 0.03), cancer-specific mortality (HR 1.65, p = 0.01), and overall mortality (HR 1.45, p = 0.03). CONCLUSION: Prostatic stromal invasion with urothelial carcinoma confers a poor survival expectation to BCa patients after surgical treatment. Conversely, other type of urothelial prostatic invasions or the presence of concomitant PCa does not seem to be associated with differences in survival outcomes.

Epigenetic Signature: A New Player as Predictor of Clinically Significant Prostate Cancer (PCa) in Patients on Active Surveillance (AS).

Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low-risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and increase healthcare costs. Active surveillance (AS) has become an accepted alternative to immediate treatment in selected men with low-risk PCa. Despite much progress in recent years toward identifying the best candidates for AS in recent years, the greatest risk remains the possibility of misclassification of the cancer or missing a high-risk cancer. This is particularly worrisome in men with a life expectancy of greater than 10-15 years. The Prostate Cancer Research International Active Surveillance (PRIAS) study showed that, in addition to age and PSA at diagnosis, both PSA density (PSA-D) and the number of positive cores at diagnosis (two compared with one) are the strongest predictors for reclassification biopsy or switching to deferred treatment. However, there is still no consensus upon guidelines for placing patients on AS. Each institution has its own protocol for AS that is based on PRIAS criteria. Many different variables have been proposed as tools to enrol patients in AS: PSA-D, the percentage of freePSA, and the extent of cancer on biopsy (number of positive cores or percentage of core involvement). More recently, the Prostate Health Index (PHI), the 4 Kallikrein (4K) score, and other patient factors, such as age, race, and family history, have been investigated as tools able to predict clinically significant PCa. Recently, some reports suggested that epigenetic mapping differs significantly between cancer patients and healthy subjects. These findings indicated as future prospect the use of epigenetic markers to identify PCa patients with low-grade disease, who are likely candidates for AS. This review explores literature data about the potential of epigenetic markers as predictors of clinically significant disease.

Metabolic syndrome diagnosis and widespread high grade prostatic intraepithelial neoplasia significantly increase prostate cancer risk: results from a multicenter biopsy study.

BACKGROUND: To test in multicenter setting if patients affected of metabolic syndrome (MetS) and initial widespread high grade prostatic intraepithelial neoplasia (wHGPIN) diagnosis are at higher risk of prostate cancer (PCa) on repeat biopsy. METHODS: Patients clinical charts from three European Academic Hospital were reviewed in order to identify patients with initial diagnosis of HGPIN undergone to repeat biopsy. Inclusion and exclusion criteria were adopted to minimize patient heterogeneity. MetS was defined according to Word Heart Organization criteria while initial wHGPIN when ≥ 4 cores biopsy were involved. A multivariate logistic model was computed to assess the association between PCa and clinical-pathological variables. RESULTS: Overall 283 patients were scheduled. Median age was 67 years (IQR 62-72). MetS was diagnosed in 116/283 (41%) patients and PCa was detected in 84/283 (29.7%) patients. In particular, PCa was more frequently diagnosed in patients affected of wHGPIN and MetS (45/86, 52.3%) than in patients with wHGPIN and normal metabolic profile (28/95, 29.5%), p = 0.002. The multivariate logistic model confirmed that wHGPIN and MetS are independent risk factors for following PCa diagnosis, respectively OR 2.4 (95% CI 1.01-5.71, p = 0.04), OR 2.79 (95% CI 1.49-5.22, p = 0.01) while total PSA and DRE findings are not able to predict PCa at repeat biopsy, OR 1.05 (95% CI 0.98-1.03 p = 0.69) and OR 1.01 (95% CI 0.55-1.84, p = 0.96) respectively. CONCLUSIONS: wHGPIN is positively associated to PCa; assessing metabolic profile and repeat prostate biopsy is advisable in patients with initial diagnosis of wHGPIN.

In-parallel comparative evaluation between multiparametric magnetic resonance imaging, prostate cancer antigen 3 and the prostate health index in predicting pathologically confirmed significant prostate cancer in men eligible for active surveillance.

OBJECTIVE: To assess the performance capabilities of multiparametric magnetic resonance imaging (mpMRI), the prostate health index (PHI) and prostate cancer antigen 3 (PCA3) in predicting the presence of pathologically confirmed significant prostate cancer (PCSPCa), according to the European Randomized Study of Screening Prostate Cancer definition, in a single cohort of patients who underwent radical prostatectomy (RP) but who were eligible for active surveillance (AS). MATERIALS AND METHODS: An observational retrospective study was performed in 120 patients with prostate cancer (PCa), treated with robot-assisted RP but eligible for AS according to Prostate Cancer Research International: Active Surveillance criteria. Blood and urine specimens were collected before initial prostate biopsy for PHI and PCA3 measurements, respectively. In addition, all patients underwent mpMRI, preoperatively and 6-8 weeks after biopsy, with a 1.5T scanner using a four-to-five-channel phase array coil combined with an endorectal coin. mpMRI images were assessed and diagrams showing the prostate sextants were used to designate regions of abnormality within the prostate. Prostate findings were assigned to one of five categories according to Prostate Imaging-Reporting and Data System guidelines (PI-RADS) and considered positive for PCa if final PI-RADS score was >3 and negative if ≤3. RESULTS: Pathologically confirmed reclassification was observed in 55 patients (45.8%). mpMRI showed good specificity and negative predictive value (0.61 and 0.73, respectively) for excluding PCSPCa compared with the PHI and PCA3. On multivariate analyses and after 1 000 bootstrapping resampling, the inclusion of both mpMRI and the PHI significantly increased the accuracy of the base model in predicting PCSPCa. For the prediction of PCSPCa, in particular, the base model had an area under the curve (AUC) of 0.71 which significantly increased by 4% with the addition of the PHI (AUC = 0.75; P < 0.01) and by 7% with the addition of mpMRI (AUC = 0.78; P < 0.01). Decision-curve analysis showed that the multivariable model with mpMRI had the highest net benefit. CONCLUSION: In a single cohort of patients who underwent RP but who were eligible for AS, mpMRI and, to a lesser extent, the PHI, had an important role in discriminating the presence of PCSPCa; both measures could therefore be useful in the selection and monitoring of patients undergoing AS.