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Objectives: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). Materials and Methods: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox’ regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as ‘organ-confined’ (≤pT2N0), ‘locally advanced’ (pT3-4N0) and ‘node-positive’ (pTanyN1-3). Results: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. Conclusions: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management.

OBJECTIVE To investigate the role of forkhead box protein M1 (FOXM1) mRNA expression and its prognostic value in stage pT1 non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS Clinical data and formalin-fixed paraffin-embedded tissues from transurethral resection of the bladder from patients with stage pT1 NMIBC, treated with an organ-preserving approach, were analysed retrospectively. Total RNA was isolated using commercial RNA extraction kits, and mRNA expression of FOXM1, MKI67, KRT20 and KRT5 was measured by single-step quantitative RT-PCR using RNA-specific TaqMan Assays. Statistical analysis was performed using Spearman's Rho, Wilcoxon or Kruskal-Wallis tests, Kaplan-Meier estimates of recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS) and Cox regression analysis. RESULTS Data from 296 patients (79.4% men, median age 72 years) were available for the final evaluation. Spearman correlation analysis showed that mRNA expression of FOXM1 was significantly correlated with MKI67 (ρ: 0.6530, P < 0.001) and with the luminal subtype, reflected by the positive correlation with KRT20 (ρ: 0.2113, P < 0.001). Furthermore, there was also a strong correlation of FOXM1 expression with adverse clinical and pathological variables, such as concomitant carcinoma in situ (P = 0.05), multifocal tumours (P = 0.005) and World Health Organization 1973 grade 3 disease (P < 0.001). Kaplan-Meier analysis showed overexpression of FOMX1 to be associated with worse PFS (P = 0.028) and worse CSS (P = 0.015). FOXM1 overexpression was also shown to be a predictive risk factor for CSS (hazard ratio 1.61 [1.13-2.34], L-R chi-squared: 7.19, P = 0.007). FOXM1 overexpression identified a subgroup of patients within the luminal subtype with worse RFS (P = 0.017), PFS (P < 0.001) and CSS (P = 0.015). Patients with low FOXM1 expression had better outcomes, irrespective of instillation therapy, whereas patients with high FOXM1 expression benefitted from intravesical chemotherapy with mitomycin C. CONCLUSION High FOXM1 expression was associated with adverse clinical and pathological features and worse outcomes, and predicted response to intravesical instillation therapy in patients with stage pT1 NMIBC.

Objectives To compare the prognostic value of the World Health Organization (WHO) 1973 and 2004 classification systems for grade in T1 bladder cancer (T1-BC), as both are currently recommended in international guidelines. Patients and methods Three uro-pathologists re-revised slides of 601 primary (first diagnosis) T1-BCs, initially managed conservatively (bacille Calmette-Guerin) in four hospitals. Grade was defined according to WHO1973 (Grade 1-3) and WHO2004 (low-grade [LG] and high-grade [HG]). This resulted in a lack of Grade 1 tumours, 188 (31%) Grade 2, and 413 (69%) Grade 3 tumours. There were 47 LG (8%) vs 554 (92%) HG tumours. We determined the prognostic value for progression-free survival (PFS) and cancer-specific survival (CSS) in Cox-regression models and corrected for age, sex, multiplicity, size and concomitant carcinoma in situ. Results At a median follow-up of 5.9 years, 148 patients showed progression and 94 died from BC. The WHO1973 Grade 3 was negatively associated with PFS (hazard ratio [HR] 2.1) and CSS (HR 3.4), whilst WHO2004 grade was not prognostic. On multivariable analysis, WHO1973 grade was the only prognostic factor for progression (HR 2.0). Grade 3 tumours (HR 3.0), older age (HR 1.03) and tumour size >3 cm (HR 1.8) were all independently associated with worse CSS. Conclusion The WHO1973 classification system for grade has strong prognostic value in T1-BC, compared to the WHO2004 system. Our present results suggest that WHO1973 grade cannot be replaced by the WHO2004 classification in non-muscle-invasive BC guidelines.

Objective To compare outcomes of patients with lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) treated with or without cisplatin-based combined adjuvant chemotherapy (AC) after radical cystectomy (RC). Patients and Methods We retrospectively analysed 1523 patients with LN-positive UCB, who underwent RC with bilateral pelvic LN dissection. All patients had no evidence of disease after RC. AC was administered within 3 months. Competing-risks models were applied to compare UCB-related mortality. Results Of the 1523 patients, 874 (57.4%) received AC. The cumulative 1-, 2- and 5-year UCB-related mortality rates for all patients were 16%, 36% and 56%, respectively. Administration of AC was associated with an 18% relative reduction in the risk of UCB-related death (subhazard ratio 0.82, P = 0.005). The absolute reduction in mortality was 3.5% at 5 years. The positive effect of AC was detectable in patients aged ≤70 years, in women, in pT3–4 disease, and in those with a higher LN density and lymphovascular invasion. This study is limited by its retrospective and non-randomised design, selection bias, the absence of central pathological review and lack in standardisation of LN dissection and cisplatin-based protocols. Conclusion AC seems to reduce UCB-related mortality in patients with LN-positive UCB after RC. Younger patients, women and those with high-risk features such as pT3–4 disease, a higher LN density and lymphovascular invasion appear to benefit most. Appropriately powered prospective randomised trials are necessary to confirm these findings.

To evaluate the effect of peri-operative blood transfusion (PBT) on recurrence-free survival, overall survival, cancer-specific mortality and other-cause mortality in patients undergoing radical cystectomy (RC), using a contemporary European multicentre cohort.The Prospective Multicentre Radical Cystectomy Series (PROMETRICS) includes data on 679 patients who underwent RC at 18 European tertiary care centres in 2011. The association between PBT and oncological survival outcomes was assessed using Kaplan-Meier, Cox regression and competing-risks analyses. Imbalances in clinicopathological features between patients receiving PBT vs those not receiving PBT were mitigated using conventional multivariable adjusting as well as inverse probability of treatment weighting (IPTW).Overall, 611 patients had complete information on PBT, and 315 (51.6%) received PBT. The two groups (PBT vs no PBT) differed significantly with respect to most clinicopathological features, including peri-operative blood loss: median (interquartile range [IQR]) 1000 (600-1500) mL vs 500 (400-800) mL (P0.001). Independent predictors of receipt of PBT in multivariable logistic regression analysis were female gender (odds ratio [OR] 5.05, 95% confidence interval [CI] 2.62-9.71; P0.001), body mass index (OR 0.91, 95% CI 0.87-0.95; P0.001), type of urinary diversion (OR 0.38, 95% CI 0.18-0.82; P = 0.013), blood loss (OR 1.32, 95% CI 1.23-1.40; P0.001), neoadjuvant chemotherapy (OR 2.62, 95% CI 1.37-5.00; P = 0.004), and ≥pT3 tumours (OR 1.59, 95% CI 1.02-2.48; P = 0.041). In 531 patients with complete data on survival outcomes, unweighted and unadjusted survival analyses showed worse overall survival, cancer-specific mortality and other-cause mortality rates for patients receiving PBT(P0.001, P = 0.017 and P = 0.001, respectively). After IPTW adjustment, those differences no longer held true. PBT was not associated with recurrence-free survival (hazard ratio [HR] 0.92, 95% CI 0.53-1.58; P = 0.8), overall survival (HR 1.06, 95% CI 0.55-2.05; P = 0.9), cancer-specific mortality (sub-HR 1.09, 95% CI 0.62-1.92; P = 0.8) and other-cause mortality (sub-HR 1.00, 95% CI 0.26-3.85; P0.9) in IPTW-adjusted Cox regression and competing-risks analyses. The same held true in conventional multivariable Cox and competing-risks analyses, where PBT could not be confirmed as a predictor of any given endpoint (all P values0.05).The present results did not show an adverse effect of PBT on oncological outcomes after adjusting for baseline differences in patient characteristics.

What's known on the subject? and What does the study add? Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between different Broders' grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet. Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders' grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of 82% for CSS. Objective To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically treated squamous cell carcinoma of the penis (SCCP). Patients and Methods A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. After conducting a central histopathological review, the staining profiles of Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin were evaluated for their correlation with conventional histopathological criteria and their prognostic relevance for predicting CSS in a multivariable Cox proportional hazards regression model (median [interquartile range] follow-up 33 [6–63] months). Results Staining evaluation showed high interobserver agreement (92–96%). Ki-67 and MCM2 displayed a significant positive correlation with histological tumour grade, lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade. The 5-year CSS for the entire study cohort was 62%. Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036). In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS. The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741–0.898). Conclusions At present, conventional histopathological criteria remain the most powerful predictors of CSS in surgically treated SCCP. Due to overlapping staining profiles, Ki-67, MCM2 and geminin, either singly or in various combinations, failed to immunohistochemically refine the boundaries between Broders' grading categories. Ki-67, MCM2 and geminin do not represent independent prognostic parameters but reflect a more aggressive behaviour in surgically treated SCCP. Further studies are needed to clarify the currently contradictory predictive role of proliferation-associated biomarkers in terms of predicting nodal involvement in SCCPs.

What's known on the subject? and What does the study add? Little is known on the association between obesity and urothelial carcinoma of the bladder (UCB). Most studies have shown that higher body mass index (BMI) is associated with higher rates of perioperative complications. Only one study specifically investigated obesity and bladder cancer-specific outcomes and reported no significant association between higher BMI and disease-specific survival in patients with UCB treated with radical cystectomy. However, that study was limited by its small sample size and a high rate of preoperative therapies. In contrast to the only previous study evaluating the association of BMI with oncological outcomes in UCB, we found that obesity (BMI ≥30 kg/m2) was associated with features of biologically aggressive UCB and clinical outcomes after radical cystectomy and, even when adjusting for the effects of standard clinicopathological features, obesity remained an independent predictor of cancer recurrence, cancer-specific mortality and overall mortality. Objective To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series. Patients and Methods Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded. Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality. BMI was analysed as a continuous and categorical variable (30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46–1.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.24–1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60–2.05, P < 0.001). Themain limitation is the retrospective design of the study. Conclusions Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB. Focusing on patient-modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB.

Study Type – Diagnosis (reliability) Level of Evidence 2b What's known on the subject? and What does the study add? Conventional sonography is the standard imaging technique used in patients with acute renal colic. A decreasing hydronephrosis index (HI) is associated with an increase in obstructive uropathy. Obstructive uropathy leads to an increase in the renal resistive index (RRI). The present study shows that both the RRI and HI methods are easily practicable in patients presenting with stone-related renal colic. The grade of hydronephrosis correlates positively with the HI but not with the RI. OBJECTIVE • To confirm the reliability of assessements of the renal resistive index (RRI) and the hydronephrosis index (HI) comprising two sonographic techniques providing additional information in patients with acute renal colic. PATIENTS AND METHODS • Sonographic measurement of hydronephrosis and assessment of common clinical criteria was performed in 22 consecutive patients presenting with unilateral stone-related renal colic. RRI and HI were separately recorded by two investigators within a prospective study. • Interobserver agreement and comparison of sonographic with computed tomography (CT) findings were assessed with the Cohen's kappa statistic (κ) for attributive ordinal characteristics and Spearman's rank correlation/rho (ρ) for attributive metric characteristics. RESULTS • There was a significant correlation between HI and the sonographically-evaluated grade of hydronephrosis, although not between RRI and the grade of hydronephrosis. • For all procedures (RRI, HI, sonography and CT), significant differences between the symptomatic and the asymptomatic kidney were assessed. • Interobserver agreement was excellent for the grade assessment of hydronephrosis by conventional sonography (κ= 0.82; P < 0.001), good to very good for HI (ρ= 0.60; P= 0.003) and acceptable to good for RRI (ρ= 0.49; P= 0.021). CONCLUSIONS • The RRI and HI methods are both easily practicable as stageless examination methods in patients presenting with stone-related renal colic, and both also reliably distinguish between obstruction and non-obstruction. • Exact thresholds for both methods must still be defined based on further successive studies. • Additionally, changes of values under medical expulsive therapy and correlation with the functional status of the obstructed kidney remain to be examined.

UNLABELLED What's known on the subject? and What does the study add? The degree of comorbidity significantly affects the course of patients with bladder cancer undergoing radical cystectomy (RC). To our knowledge this is the first study comparing four different comorbidity indices in patients undergoing RC for urothelial carcinoma to assess the best clinical predictors for 90-day perioperative mortality. We concluded that the ASA score should be the method of choice, as it showed a predictive ability superior to that of ECOG and CCI, and is much easier to generate than the ACE-27. OBJECTIVE To evaluate which of the following among the Adult Comorbidity Evaluation-27 (ACE-27), the Charlson Comorbidity Index (CCI), the Eastern Cooperative Oncology Group performance status (ECOG) and the American Society of Anesthesiologists (ASA) comorbidity scores correlate best with perioperative mortality after radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder. PATIENTS AND METHODS A study was carried out on 555 unselected consecutive patients without neoadjuvant chemotherapy who underwent RC for UC of the bladder from 2000 to 2010 at one of two institutions. Patients' medical records were reviewed retrospectively. We established a defined binary linear progression model based on clinical variables to predict perioperative mortality

UNLABELLED What's known on the subject? and What does the study add? Several sets of comprehensive treatment guidelines (national and international) exist for managing male lower urinary tract symptoms (LUTS), but these are not widely adopted in primary and secondary care, and are not consistently applied across Europe. This paper will improve the consistency of treatment approaches for adult males with LUTS by providing a clear, concise summary of existing treatment guidelines that can be easily adopted by urologists and primary care specialists. OBJECTIVE To review current treatment guidelines (international and national) on managing male lower urinary tract symptoms (LUTS) and to summarize them for easy application in clinical practice. METHODS A group of European urology specialists from primary and secondary care reviewed current treatment guidelines for male LUTS. RESULTS The most appropriate recommendations for managing male LUTS were identified from existing international and national guidelines, and were summarized and simplified for use as a quick reference guide for healthcare professionals managing LUTS in adult males. CONCLUSIONS Current guidelines for managing male LUTS were developed by urologists and are too complex for easy application in routine practice. This brief summary of current guidance should help to achieve consistent adoption of recommendations for best practice, improve working relationships between primary care specialists and urologists and clarify which patients' treatments should be managed entirely by urology specialists.

OBJECTIVE •To evaluate the characteristics and long-term outcome of patients with pT0 stage after radical cystectomy (RC) for urothelial carcinoma of the urinary bladder (UCB). PATIENTS AND METHODS •Clinical and pathological records of 2403 patients treated with RC for UCB were collected in a multi-institutional database. •The patients met the following criteria: clinical tumour stage cTa-cT2, cN0, cM0, no neoadjuvant chemotherapy or radiotherapy. •Overall (OS) and cancer-specific survival rates (CSS) were calculated for the various clinical tumour stages in relation to their corresponding pathological tumour stage in the RC sample. •Further to this, a multivariable prediction model was developed based on the available clinical data to estimate the probability of tumour stage pT0. RESULTS •The mean follow-up was 53 months and 132 patients (5.5%) were stage pT0. •Patients with stage cT2-pT0 had a 5-year CSS of 87% vs 69% for cT2-pT2 (P= 0.012) and 57% for cT2-pT+ (P < 0.001). •In a multivariable Cox-model, stage pT0 led to a significant reduction of cancer-specific mortality (hazard ratio0.27; 95% confidence interval 0.12-0.61). •A logistical regression model identified clinical tumour stage (advantage for non-invasive stages) and transurethral resection of the urinary bladder (TURB) time frame (advantage for more recent surgery) as independent predictors for stage pT0. CONCLUSIONS •In muscle-invasive clinical tumour stages, patients with pathological tumour stage pT0 form a subgroup showing a significantly better CSS. •A radical TURB is, assumedly, not causative of this improved survival rate, but rather it is that individual tumour characteristics allow for complete tumour eradication through the TURB procedure. •A TURB with R0 resection is, as such, only a sign of a better tumour prognosis.

OBJECTIVE • To compare oncological outcomes in patients undergoing open radical nephroureterectomy (ONU) with those in patients undergoing laparoscopic radical nephroureterectomy (LNU). PATIENTS AND METHODS • A total of 773 patients underwent radical nephroureterectomy at nine centres worldwide; 703 patients underwent ONU and 70 underwent LNU. • Demographic, perioperative and oncological outcome data were collected retrospectively. • Statistical analysis of data was performed using chi-squared, Mann-Whitney U- and log-rank tests, and Cox regression analyses. • The median (interquartile range) follow-up for the cohort was 34 (15-65) months. RESULTS • The two groups were well matched for tumour stage, presence of lymphovascular invasion (LVI) and concomitant carcinoma in situ (CIS). • There were more high-grade tumours (77.1% vs. 56.3%; P < 0.001) but fewer lymph node positive patients (2.9% vs. 6.8%; P= 0 . 041 ) in the LNU group. • Estimated 5-year recurrence-free survival (RFS) was 73.7% and 63.4% for the ONU and LNU groups, respectively (P = 0.124) and estimated 5-year cancer-specific survival (CSS) was 75.4% and 75.2% for the ONU and LNU groups, respectively (P= 0.897). • On multivariable analyses, which included age, gender, race, previous endoscopic treatment for bladder cancer, technique for distal ureter management, tumour location, pathological stage, grade, lymph node status, LVI and concomitant CIS, the procedure type (LNU vs. ONU) was not predictive of RFS (Hazard ratio [HR] 0.80; P=0 . 5 34 ) or CSS (HR 0.96; P= 0 . 907 ). CON • The present study is the second large, independent, multicentre cohort to show oncological equivalence between ONU and LNU for well selected patients with upper urinary tract urothelial cancer, and the first to suggest parity for the techniques in patients with unfavourable disease.

Objective To ascertain which of the currently defined World Health Organization (WHO) grading classifications of pT1 urothelial bladder cancer (BC), published in 1973 and 2004, is more suitable for predicting outcome. Patients and methods Transurethral resection of the bladder (TURB) specimens of 310 patients with first diagnosis of initial pT1 BC were reassessed by three urological pathologists according to the WHO classifications of 1973 and 2004. The TURB procedure was followed by either immediate cystectomy or adjuvant bacille Calmette-Guerin (BCG) instillations. Kaplan-Meier analysis was used to compare survival rates of the different tumour grades (mean follow-up was 57 months). Results According to the 1973 WHO classification, none of the pT1 BC specimens were graded as G1, while 36% were graded as G2 and 64% were graded as G3. Histological reassessment according to the 2004 WHO classification highlighted only 4% low-grade and 96% high-grade tumours. The 10-year cancer-specific survival rates of high-grade tumours (85%) were intermediate between G2 (96%) and G3 (78%). Conclusions The results of the present study support the presumption that the 1973 WHO classification is more suitable for predicting outcome for pT1 tumours, by defining at least two prognostic groups. A new classification should revise the definition of low- and high-grade pT1 BC to preserve the prognostic value of tumour grading.

Study Type – Prognosis (inception cohort) Level of Evidence 1b OBJECTIVES To validate the association of lymphovascular invasion (LVI) with disease recurrence and cancer-specific survival (CSS) in a multicentre cohort of patients treated with radical cystectomy (RC) for urothelial bladder cancer (UBC). PATIENTS AND METHODS We collected pathological and clinical data on 1099 lymph node-negative patients treated with RC at six German institutions. LVI was defined as the presence of tumour cells within an unequivocal endothelium-lined space in haematoxylin and eosin-stained sections. RESULTS LVI was present in 295 (26.8%) patients; the presence of LVI correlated significantly with increasing tumour stage, i.e. pT1, 65 (29.4%); pT2, 88 (31.5%); pT3 110 (31.8%); and pT4 32 (38.1%) (P= 0.002) and grade (P 75 vs ≥75 years; P= 0.018) and LVI (P < 0.001) were identified as independent predictors of CSS. CONCLUSIONS Our large multicentre study confirms the independent prognostic value of LVI in patients with node-negative UBC. LVI can be regarded as a surrogate variable for lymphatic micrometastasis in node-negative UBC. Assessment of LVI might improve the selection of patients who are likely to benefit from adjuvant therapy after RC. The identification of factors involved in the process of LVI could reveal new therapeutic targets for UBC.

OBJECTIVE To determine whether published nomograms, i.e. The International Bladder Cancer Nomogram Consortium (IBCNC) and the Bladder Cancer Research Consortium (BCRC) statistical models for predicting disease recurrence and survival of patients after radical cystectomy, are feasible for routine use in intermediate-volume institutions in Europe, as although these nomograms had high accuracy by internal validation tests, they stem from high-volume centres and have not been validated elsewhere and thus their general applicability remains unproven. PATIENTS AND METHODS We externally validated the published nomograms. Information about treatments, pathological details, and recurrence and survival status was retrospectively collected from 246 patients. The expected survival according to the nomograms was calculated. The predictive accuracy of the proposed models was calculated by Harrell's concordance indices. To assess the independent prognostic value of the variables proposed by IBCNC and BCRC, stepwise multivariable Cox regressions based on Akaike's Information Criterion (AIC) for the different endpoints were used. A best model for prediction was created on the basis of our data. RESULTS The IBCNC and the BCRC nomograms showed an improvement in the predictive accuracy of recurrence, all-cause and bladder-cancer-specific survival after radical cystectomy of up to 4% compared to Tumour-Node-Metastasis stage-based predictions. According to the calculated AIC values for the different models, all nomograms performed better than the TNM classification. CONCLUSIONS The BCRC and IBCNC nomograms provided accurate predictions when they were applied to an external cohort of patients from low- to intermediate-volume centres. The prediction of recurrence and survival based on the addressed nomograms is better than TNM stage-based prediction. The application of such nomograms can be supported on a sound basis, but further amendments are warranted.

Objective To externally validate the pT4a-specific risk model for cancer-specific survival (CSS) proposed by May et al. (Urol Oncol 2013;31: 1141-1147) and to develop a new pT4a-specific nomogram predicting CSS in an international multicentre cohort of patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) Patients and Methods Data from 856 patients with pT4a UCB treated with RC at 21 centres in Europe and North-America were assessed. The risk model proposed by May et al., which includes female gender, presence of positive lymphovascular invasion (LVI) and lack of adjuvant chemotherapy administration as adverse predictors for CSS, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver-operating characteristic-derived area under the curve. A nomogram for predicting CSS in pT4a UCB after RC was developed after internal validation based on multivariable Cox proportional hazards regression analysis evaluating the impact of clinicopathological variables on CSS. Decision-curve analyses were applied to determine the net benefit derived from the two models. Results The estimated 5-year-CSS after RC was 34% in our cohort. The risk model devised by May et al. predicted individual 5-year-CSS with an accuracy of 60.1%. In multivariable Cox proportional hazards regression analysis, female gender (hazard ratio [HR] 1.45), LVI (HR 1.37), lymph node metastases (HR 2.54), positive soft tissue surgical margins (HR 1.39), neoadjuvant (HR 2.24) and lack of adjuvant chemotherapy (HR 1.67, all P < 0.05) were independent predictors of an adverse CSS rate and formed the features of our nomogram with a predictive accuracy of 67.1%. Decision-curve analyses showed higher net benefits for the use of the newly developed nomogram in our cohort over all thresholds. Conclusions The risk model devised by May et al. was validated with moderate discrimination and was outperformed by our newly developed pT4a-specific nomogram in the present study population. Our nomogram might be particularly suitable for postoperative patient counselling in the heterogeneous cohort of patients with pT4a UCB.

To compare outcomes of patients with lymph node (LN)-positive urothelial carcinoma of the bladder (UCB) treated with or without cisplatin-based combined adjuvant chemotherapy (AC) after radical cystectomy (RC).We retrospectively analysed 1523 patients with LN-positive UCB, who underwent RC with bilateral pelvic LN dissection. All patients had no evidence of disease after RC. AC was administered within 3 months. Competing-risks models were applied to compare UCB-related mortality.Of the 1523 patients, 874 (57.4%) received AC. The cumulative 1-, 2- and 5-year UCB-related mortality rates for all patients were 16%, 36% and 56%, respectively. Administration of AC was associated with an 18% relative reduction in the risk of UCB-related death (subhazard ratio 0.82, P = 0.005). The absolute reduction in mortality was 3.5% at 5 years. The positive effect of AC was detectable in patients aged ≤70 years, in women, in pT3-4 disease, and in those with a higher LN density and lymphovascular invasion. This study is limited by its retrospective and non-randomised design, selection bias, the absence of central pathological review and lack in standardisation of LN dissection and cisplatin-based protocols.AC seems to reduce UCB-related mortality in patients with LN-positive UCB after RC. Younger patients, women and those with high-risk features such as pT3-4 disease, a higher LN density and lymphovascular invasion appear to benefit most. Appropriately powered prospective randomised trials are necessary to confirm these findings.

What's known on the subject? and what does the study add?: Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between different Broders' grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet. Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders' grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of 82% for CSS.To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically treated squamous cell carcinoma of the penis (SCCP).A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. After conducting a central histopathological review, the staining profiles of Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin were evaluated for their correlation with conventional histopathological criteria and their prognostic relevance for predicting CSS in a multivariable Cox proportional hazards regression model (median [interquartile range] follow-up 33 [6-63] months).Staining evaluation showed high interobserver agreement (92-96%). Ki-67 and MCM2 displayed a significant positive correlation with histological tumour grade, lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade. The 5-year CSS for the entire study cohort was 62%. Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036). In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS. The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741-0.898).At present, conventional histopathological criteria remain the most powerful predictors of CSS in surgically treated SCCP. Due to overlapping staining profiles, Ki-67, MCM2 and geminin, either singly or in various combinations, failed to immunohistochemically refine the boundaries between Broders' grading categories. Ki-67, MCM2 and geminin do not represent independent prognostic parameters but reflect a more aggressive behaviour in surgically treated SCCP. Further studies are needed to clarify the currently contradictory predictive role of proliferation-associated biomarkers in terms of predicting nodal involvement in SCCPs.

To confirm the reliability of assessements of the renal resistive index (RRI) and the hydronephrosis index (HI) comprising two sonographic techniques providing additional information in patients with acute renal colic.Sonographic measurement of hydronephrosis and assessment of common clinical criteria was performed in 22 consecutive patients presenting with unilateral stone-related renal colic. RRI and HI were separately recorded by two investigators within a prospective study. Interobserver agreement and comparison of sonographic with computed tomography (CT) findings were assessed with the Cohen's kappa statistic (κ) for attributive ordinal characteristics and Spearman's rank correlation/rho (ρ) for attributive metric characteristics.There was a significant correlation between HI and the sonographically-evaluated grade of hydronephrosis, although not between RRI and the grade of hydronephrosis. For all procedures (RRI, HI, sonography and CT), significant differences between the symptomatic and the asymptomatic kidney were assessed. Interobserver agreement was excellent for the grade assessment of hydronephrosis by conventional sonography (κ = 0.82; P0.001), good to very good for HI (ρ = 0.60; P = 0.003) and acceptable to good for RRI (ρ = 0.49; P = 0.021).The RRI and HI methods are both easily practicable as stageless examination methods in patients presenting with stone-related renal colic, and both also reliably distinguish between obstruction and non-obstruction. Exact thresholds for both methods must still be defined based on further successive studies. Additionally, changes of values under medical expulsive therapy and correlation with the functional status of the obstructed kidney remain to be examined.

What's known on the subject? and What does the study add? The degree of comorbidity significantly affects the course of patients with bladder cancer undergoing radical cystectomy (RC). To our knowledge this is the first study comparing four different comorbidity indices in patients undergoing RC for urothelial carcinoma to assess the best clinical predictors for 90-day perioperative mortality. We concluded that the ASA score should be the method of choice, as it showed a predictive ability superior to that of ECOG and CCI, and is much easier to generate than the ACE-27.To evaluate which of the following among the Adult Comorbidity Evaluation-27 (ACE-27), the Charlson Comorbidity Index (CCI), the Eastern Cooperative Oncology Group performance status (ECOG) and the American Society of Anesthesiologists (ASA) comorbidity scores correlate best with perioperative mortality after radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder.A study was carried out on 555 unselected consecutive patients without neoadjuvant chemotherapy who underwent RC for UC of the bladder from 2000 to 2010 at one of two institutions. Patients' medical records were reviewed retrospectively. We established a defined binary linear progression model based on clinical variables to predict perioperative mortality90 days after RC (90PM). To this model we added, individually, the comorbidity indices ACE-27, CCI, ECOG, and ASA to assess their predictive capacity regarding 90PM.The overall 90PM was 7.9%. Age (P = 0.01) and clinical distant metastatic tumour stage (P = 0.002) were independent predictors for 90PM in the multivariate analysis. Each of the four investigated comorbidity indices was able to significantly increase the predictive capacity of the basic model: ECOG +13.5%, (odds ratio [OR]: 1.61, P = 0.036; area under the curve [AUC] 74.7), ASA Score +28.3% (OR: 2.19, P = 0.004; AUC 76.1), Charlson Index +12.3% (OR: 1.31, P = 0.047; AUC 73.8) and ACE-27 + 29.8% (OR: 1.72, P = 0.004; AUC 76.1).ASA and ACE-27 show a nearly identical clinical predictive value for perioperative mortality. Both scores could be considered for clinical practice. With regard to ease of generation and availability, the ASA score can be regarded as the best instrument.

What's known on the subject? and What does the study add? Several sets of comprehensive treatment guidelines (national and international) exist for managing male lower urinary tract symptoms (LUTS), but these are not widely adopted in primary and secondary care, and are not consistently applied across Europe. This paper will improve the consistency of treatment approaches for adult males with LUTS by providing a clear, concise summary of existing treatment guidelines that can be easily adopted by urologists and primary care specialists.To review current treatment guidelines (international and national) on managing male lower urinary tract symptoms (LUTS) and to summarize them for easy application in clinical practice.A group of European urology specialists from primary and secondary care reviewed current treatment guidelines for male LUTS.The most appropriate recommendations for managing male LUTS were identified from existing international and national guidelines, and were summarized and simplified for use as a quick reference guide for healthcare professionals managing LUTS in adult males.Current guidelines for managing male LUTS were developed by urologists and are too complex for easy application in routine practice. This brief summary of current guidance should help to achieve consistent adoption of recommendations for best practice, improve working relationships between primary care specialists and urologists and clarify which patients' treatments should be managed entirely by urology specialists.

•To evaluate the characteristics and long-term outcome of patients with pT0 stage after radical cystectomy (RC) for urothelial carcinoma of the urinary bladder (UCB).•Clinical and pathological records of 2403 patients treated with RC for UCB were collected in a multi-institutional database. •The patients met the following criteria: clinical tumour stage cTa-cT2, cN0, cM0, no neoadjuvant chemotherapy or radiotherapy. •Overall (OS) and cancer-specific survival rates (CSS) were calculated for the various clinical tumour stages in relation to their corresponding pathological tumour stage in the RC sample. •Further to this, a multivariable prediction model was developed based on the available clinical data to estimate the probability of tumour stage pT0.•The mean follow-up was 53 months and 132 patients (5.5%) were stage pT0. •Patients with stage cT2-pT0 had a 5-year CSS of 87% vs 69% for cT2-pT2 (P= 0.012) and 57% for cT2-pT+ (P0.001). •In a multivariable Cox-model, stage pT0 led to a significant reduction of cancer-specific mortality (hazard ratio0.27; 95% confidence interval 0.12-0.61). •A logistical regression model identified clinical tumour stage (advantage for non-invasive stages) and transurethral resection of the urinary bladder (TURB) time frame (advantage for more recent surgery) as independent predictors for stage pT0.•In muscle-invasive clinical tumour stages, patients with pathological tumour stage pT0 form a subgroup showing a significantly better CSS. •A radical TURB is, assumedly, not causative of this improved survival rate, but rather it is that individual tumour characteristics allow for complete tumour eradication through the TURB procedure. •A TURB with R0 resection is, as such, only a sign of a better tumour prognosis.

To ascertain which of the currently defined World Health Organization (WHO) grading classifications of pT1 urothelial bladder cancer (BC), published in 1973 and 2004, is more suitable for predicting outcome.Transurethral resection of the bladder (TURB) specimens of 310 patients with first diagnosis of initial pT1 BC were reassessed by three urological pathologists according to the WHO classifications of 1973 and 2004. The TURB procedure was followed by either immediate cystectomy or adjuvant bacille Calmette-Guérin (BCG) instillations. Kaplan-Meier analysis was used to compare survival rates of the different tumour grades (mean follow-up was 57 months).According to the 1973 WHO classification, none of the pT1 BC specimens were graded as G1, while 36% were graded as G2 and 64% were graded as G3. Histological reassessment according to the 2004 WHO classification highlighted only 4% low-grade and 96% high-grade tumours. The 10-year cancer-specific survival rates of high-grade tumours (85%) were intermediate between G2 (96%) and G3 (78%).The results of the present study support the presumption that the 1973 WHO classification is more suitable for predicting outcome for pT1 tumours, by defining at least two prognostic groups. A new classification should revise the definition of low- and high-grade pT1 BC to preserve the prognostic value of tumour grading.

To validate the association of lymphovascular invasion (LVI) with disease recurrence and cancer-specific survival (CSS) in a multicentre cohort of patients treated with radical cystectomy (RC) for urothelial bladder cancer (UBC).We collected pathological and clinical data on 1099 lymph node-negative patients treated with RC at six German institutions. LVI was defined as the presence of tumour cells within an unequivocal endothelium-lined space in haematoxylin and eosin-stained sections.LVI was present in 295 (26.8%) patients; the presence of LVI correlated significantly with increasing tumour stage, i.e. pT1, 65 (29.4%); pT2, 88 (31.5%); pT3 110 (31.8%); and pT4 32 (38.1%) (P= 0.002) and grade (P0.001). In univariable analysis the presence of LVI was significantly associated with reduced recurrence-free survival (P= 0.008) and reduced CSS (P= 0.039). On multivariable Cox regression analysis tumour stage (P0.001), age (75 vsor=75 years; P= 0.018) and LVI (P0.001) were identified as independent predictors of CSS.Our large multicentre study confirms the independent prognostic value of LVI in patients with node-negative UBC. LVI can be regarded as a surrogate variable for lymphatic micrometastasis in node-negative UBC. Assessment of LVI might improve the selection of patients who are likely to benefit from adjuvant therapy after RC. The identification of factors involved in the process of LVI could reveal new therapeutic targets for UBC.

To determine whether published nomograms, i.e. The International Bladder Cancer Nomogram Consortium (IBCNC) and the Bladder Cancer Research Consortium (BCRC) statistical models for predicting disease recurrence and survival of patients after radical cystectomy, are feasible for routine use in intermediate-volume institutions in Europe, as although these nomograms had high accuracy by internal validation tests, they stem from high-volume centres and have not been validated elsewhere and thus their general applicability remains unproven.We externally validated the published nomograms. Information about treatments, pathological details, and recurrence and survival status was retrospectively collected from 246 patients. The expected survival according to the nomograms was calculated. The predictive accuracy of the proposed models was calculated by Harrell's concordance indices. To assess the independent prognostic value of the variables proposed by IBCNC and BCRC, stepwise multivariable Cox regressions based on Akaike's Information Criterion (AIC) for the different endpoints were used. A best model for prediction was created on the basis of our data.The IBCNC and the BCRC nomograms showed an improvement in the predictive accuracy of recurrence, all-cause and bladder-cancer-specific survival after radical cystectomy of up to 4% compared to Tumour-Node-Metastasis stage-based predictions. According to the calculated AIC values for the different models, all nomograms performed better than the TNM classification.The BCRC and IBCNC nomograms provided accurate predictions when they were applied to an external cohort of patients from low- to intermediate-volume centres. The prediction of recurrence and survival based on the addressed nomograms is better than TNM stage-based prediction. The application of such nomograms can be supported on a sound basis, but further amendments are warranted.

OBJECTIVE To compare the clinical outcome and prognostic power of the former and current World Health Organization (WHO) grading system in patients with early vs regular onset of noninvasive urothelial bladder cancer (UBC), as little is known of the natural history of early onset UBC and in how far it is reflected by histopathological grading and staging in guiding clinical decisions. PATIENTS AND METHODS The medical records of 69 consecutive patients presenting with initial UBC of early onset (≥45 years old, EO) and of 100 randomly chosen patients with regular onset (RO) were reviewed. There were no significant differences in gender distribution, risk factors or tumour stage. All histopathological specimens were re-staged and re-graded according to the former and current WHO grading. RESULTS In all, 51 EO and 63 RO patients with tumours staged pTa and complete follow-up information were analysed. Recurrence-free survival (RFS) was prolonged in patients with EO. In EO neither the former nor the current WHO grading system was significantly related to RFS or to progression to muscle-invasive disease. In RO, while both WHO grading systems were significantly related to RFS, only the current WHO grading system was related to progression. CONCLUSION While larger studies are needed, UBC in patients with EO and RO do not seem to differ in risk factors and oncological outcome. The current WHO classification reflects the outcome more accurately than the former classification in patients with RO. However, for EO no grading system has sufficient prognostic power and novel methods, i.e. molecular markers, need to be evaluated for clinical use.