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Background: Patients with urothelial carcinoma (UC) often develop multifocal metachronous tumors throughout the genitourinary tract. In the present study, we evaluated the prognostic value of prior history of UC of the bladder (UCB) in patients with upper tract urothelial carcinoma (UTUC) in an international multi-institutional cohort. Patients and methods: Data from 785 patients who underwent radical nephroureterectomy (RNU) with ipsilateral bladder cuff resection at nine academic institutions in Europe and the USA between 1987 and 2008 were reviewed. Log-rank tests and Cox proportional hazards regression models were used for univariable and multivariable analyses. Results: The median follow-up of the whole cohort was 34 months (interquartile range 15-66 months). Five hundred and fifty-eight (72 %) patients had no UCB before the diagnosis of UTUC; a prior history of non-muscle-invasive and muscle-invasive UCB before the UTUC was found in 179 (23 %) and 36 (5 %), respectively. History of UCB before RNU was an independent predictor of both recurrence-free survival ( p = 0.012; no UCB vs. non-muscle-invasive UCB: hazard ratio (HR) 1.4, p = 0.082; no UCB vs. muscle-invasive UCB: HR 2.1, p = 0.007) and cancer-specific survival ( p = 0.008; no UCB vs. non-muscle-invasive UCB: HR 1.2, p = 0.279; no UCB vs. muscle-invasive UCB: HR 2.3, p = 0.008) on multivariable Cox regression analyses that included age, gender, surgical type, stage, grade, presence of concomitant carcinoma in situ, presence of lymphovascular invasion, and lymph node status. Conclusions: Prior history of muscle-invasive UCB was significantly associated with an increased risk of disease recurrence and cancer-specific death in patients with UTUC. [ABSTRACT FROM AUTHOR]

Study Type - Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Tumour stage is a powerful predictor of clinical outcomes and the most important factor driving clinical decision-making after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). It has been suggested that renal pelvic pT3 subclassification into microscopic infiltration of the renal parenchyma (pT3a) versus macroscopic infiltration or invasion of peripelvic adipose tissue (pT3b) has strong prognostic value. This is an external validation study of the prognostic value of pT3 subclassification of renal pelvic UTUC in a large international cohort of patients treated with RNU. pT3b UTUC is associated with features of aggressive tumour biology, disease recurrence and cancer-specific mortality. However, pT3 subclassification is not an independent predictor of clinical outcomes. OBJECTIVE To externally validate the prognostic value of subclassification of pT3 renal pelvic upper tract urothelial carcinoma (UTUC) in a large international cohort of patients treated with radical nephroureterectomy (RNU)., PATIENTS AND METHODS The RNU specimens with pT3 UTUC of the renal pelvis from 284 patients at 11 centres located in Asia, North America and Europe were retrospectively evaluated. All specimens were reviewed by genitourinary pathologists at each institution. Tumours were categorized as pT3a (microscopic infiltration of the renal parenchyma) or pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue)., RESULTS Overall, 148 (52%) tumours were classified as pT3a and 136 (48%) as pT3b. Patients with pT3b disease were more likely to have high-grade tumours and sessile tumour architecture (all P≤ 0.02). Patients with pT3b tumours were at increased risk of disease recurrence (5-year estimates: 55% versus 42%, P= 0.012) and cancer-specific mortality (CSM) (5-year estimates: 48% versus 40%, P= 0.04). Lymph node status, tumour architecture and tumour grade were independently associated with disease recurrence, whereas lymph node status, tumour architecture and lymphovascular invasion were independently associated with CSM. Subclassification of pT3 tumours was not associated with recurrence or CSM in multivariable analyses., CONCLUSION Patients with pT3b UTUC were more likely to have tumours with aggressive pathological features and were at higher risk of disease recurrence and CSM after RNU compared with patients with pT3a disease. However, the pT3 subclassification did not remain an independent predictor of disease recurrence or CSM after controlling for tumour grade, lymph node status, tumour architecture and lymphovascular invasion. [ABSTRACT FROM AUTHOR]

Study Type - Prognosis (retrospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Lymphadenectomy is the most accurate lymph node staging procedure in patients with prostate cancer. We presented the first formal validation of the 2010 European Association of Urology guidelines for lymphadenectomy in prostate cancer patients. OBJECTIVE • To assess the 2010 European Association of Urology (EAU) guidelines for prostate cancer, which recommend a pelvic lymph node dissection (PLND) at radical prostatectomy in all individuals with a nomogram-predicted lymph node invasion (LNI) risk of >7%. PATIENTS and methods • We focused on 1520 patients treated with radical prostatectomy and PLND, between 2006 and 2010, at a single European institution. We examined the ability of the EAU proposed threshold to correctly predict histologically confirmed LNI. Moreover, we tested the ability of a range of nomogram thresholds between 1 and 14% to correctly predict histologically confirmed LNI. Finally, we externally validated the EAU PLND guideline nomogram. RESULTS • Overall, 10.6% of patients had LNI. The use of the 7% limit would have allowed the avoidance of 49% of PLNDs, at the cost of missing 11% of patients with LNI. The use of thresholds of 6% and 8% would have allowed the avoidance of respectively 46% and 52% of PLNDs, at the cost of missing respectively 9% and 11% of patients with LNI. Overall, the accuracy of the EAU guideline nomogram according to the receiver operating characteristics derived area under curve was 81% CONCLUSION • Our observations indicate that the EAU guideline nomogram is highly accurate. The recommended threshold of 7%, above which a PLND should be performed, is associated with a favourable compromise between avoidable PLNDs and potentially missed LNI cases. [ABSTRACT FROM AUTHOR]

To examine the rate of Gleason sum upgrading (GSU) from a sum of 6 to a Gleason sum of ≥7 in patients undergoing radical prostatectomy (RP), who fulfilled the recommendations for low dose rate brachytherapy (Gleason sum 6, prostate-specific antigen ≤10 ng/mL, clinical stage ≤T2a and prostate volume ≤50 mL), and to test the performance of an existing nomogram for prediction of GSU in this specific cohort of patients. The analysis focused on 414 patients, who fulfilled the European Society for Therapeutic Radiation and Oncology and American Brachytherapy Society criteria for low dose rate brachytherapy (LD-BT) and underwent a 10-core prostate biopsy followed by RP. The rate of GSU was tabulated and the ability of available clinical and pathological parameters for predicting GSU was tested. Finally, the performance of an existing GSU nomogram was explored. The overall rate of GSU was 35.5%. When applied to LD-BT candidates, the existing nomogram was 65.8% accurate versus 70.8% for the new nomogram. In decision curve analysis tests, the new nomogram fared substantially better than the assumption that no patient is upgraded and better than the existing nomogram. GSU represents an important issue in LD-BT candidates. The new nomogram might improve patient selection for LD-BT and cancer control outcome by excluding patients with an elevated probability of GSU. [ABSTRACT FROM AUTHOR]

Purpose: To test the validity of an updated version of the preoperative Kattan nomogram for prediction of recurrence after radical prostatectomy (RP), published by Stephenson et al. Methods and Materials: We relied on clinical and postoperative prostate-specific antigen follow-up data of 1978 patients treated with open RP at our institution between 1992 and 2006. The accuracy of the nomogram-derived recurrence-free survival predictions were separately tested at 1 to 10 years after RP. Moreover, the relationship between the nomogram-predicted recurrence-free survival rate and the observed recurrence-free survival rate was graphically explored in calibration plots. Results: Median follow-up of censored patients was 32 months. For nomogram-derived recurrence-free survival predictions at 1 to 10 years, the accuracy of the nomogram ranged from 70% to 76%. The calibration between the predicted and observed recurrence-free survival rates was good at 1 and 2 years after RP. However, at all other examined time points, departures from ideal predictions were recorded. Conclusions: Our findings indicate that the preoperative biochemical recurrence nomogram reported by Stephenson et al. can be applied to European patients with good accuracy. However, its calibration was only suboptimal for predictions made 3 or more years after RP, with a tendency to overestimate the probability of recurrence-free survival. This potential limitation should be considered when this tool is applied to European patients. [Copyright &y& Elsevier]

OBJECTIVE To examine cancer-specific and non-cancer-related mortality rates in 451 patients with T1a–bN0M0 renal cell carcinoma (RCC) treated with either radical or partial nephrectomy (RN or PN) in Europe. PATIENTS AND METHODS Between 1987 and 2007, 451 patients with T1a–bN0M0 RCC were treated for histologically confirmed RCC with RN or PN at one of seven participating European institutions. The preoperative American Society of Anesthesiology (ASA) score was available for all patients and was used to control for baseline comorbidities. The preoperative glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease study group equation. We used univariate and multivariate competing-risks regression analyses to test the effect of the ASA score, GFR, T stage (T1a vs T1b) and nephrectomy type (RN or PN) on RCC-specific mortality and non-RCC-related mortality. RESULTS In patients with T1a–b RCC cancer- specific mortality was unaffected by stage, nephrectomy type or GFR. Conversely, non-RCC-related mortality was strongly affected by the ASA score and GFR. Unlike in a previous report, nephrectomy type did not affect non-RCC-related mortality. This lack of significance relative to RN may stem from the relatively high rate of PN use in the present series. CONCLUSION PN or RN virtually eliminate the risk of cancer-specific mortality in patients with T1a–b RCC. Poor preoperative ASA score and impaired renal function appear to represent relative contra-indications to surgical management of T1a–b lesions. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the rate of pathologic stages misclassification on the use of the clinical criteria for active surveillance (AS) among patients with low-risk prostate cancer (PCa) in Europe. The study utilized five different clinical criteria wherein the misclassification rates are associated with high grade Gleason scores. It states that the use of more selective clinical criteria for AS decreases the risk of misclassification.

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. First-line oral therapy for ED includes the use of phosphodiesterase type 5 inhibitors (sildenafil, tadalafil and vardenafil) and sublingual apomorphine. Apomorphine is a dopamine D1 and D2 receptor agonist that has been approved for marketing in Europe.Different apomorphine formulations have been tested, such as sublingual, subcutaneous and intranasal. However, the sublingual formulation has shown the best results in terms of efficacy, safety and tolerability, especially the 2mg and 3mg doses. Although clinical studies of the efficacy and tolerability of apomorphine sublingual (SL) have included older patients, who are more likely to have ED, no study has specifically assessed the efficacy and tolerability of different doses of apomorphine SL in aging men. Therefore, a MEDLINE search was conducted from January 1987 to November 2005 to identify studies of the efficacy, safety (in particular cardiovascular safety) and tolerability of different apomorphine formulations and doses as treatments for ED in the subcohort of aging men.On the basis of the most recent peer-reviewed publications, the first part of this article critically evaluates data regarding the epidemiology of ED in the aging population. The second part of the article focuses on the mechanism of action and pharmacokinetics of apomorphine both in the general and the elderly population. Finally, a critical analysis of the efficacy and safety of different apomorphine formulations and doses for the treatment of ED is reported.Apomorphine represents a first-line oral treatment for ED. Available formulations include only sublingual administration. Few studies have assessed the efficacy and safety of apomorphine in the elderly population. However, in clinical practice, older patients with multiple vascular risk factors and systematic vascular damage show poor overall response to apomorphine SL for the treatment of ED. [ABSTRACT FROM AUTHOR]

Abstract: Background: The Bladder Cancer Research Consortium (BCRC) created nomograms to predict all-cause mortality (ACM), cancer-specific mortality (CSM), and recurrence after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). Objective: To perform a formal validation of the BCRC nomograms in a large multi-institutional patient cohort from Europe. Design, setting, and participants: Records of 2501 patients who underwent RC for UCB at eight European centers were reviewed. Complete information for external validation was available in 2404 patients for the ACM and CSM nomograms and in 2243 patients for the recurrence nomogram. Measurements: For the purpose of external validation, model discrimination was measured using the receiver operating characteristics derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities at 2 yr, 5 yr, and 8 yr. Decision curve analyses were applied to assess the net benefit derived from the three models. Results and limitations: The discrimination accuracies of the BCRC nomograms for ACM and CSM at 2 yr, 5 yr, and 8 yr after RC were 71.0%, 69.1%, and 68.2%, and 74.9%, 73.1%, and 72.4%, respectively. The accuracy of discrimination for the recurrence nomogram at the same time points was 76.5%, 75.3%, and 74.9%, respectively. Calibration plots revealed slight underestimations from ideal predictions. Decision curve analyses showed an increased net benefit for the use of the BCRC nomograms in this cohort. Limitations include the retrospective study design, potential surgeon bias, and lack of a central pathologic review. Conclusions: The ACM, CSM, and recurrence nomograms showed acceptable predictive accuracies and could thus be adopted into clinical practice in UCB patients treated in Europe. [Copyright &y& Elsevier]

Abstract: Background: Lymphovascular invasion (LVI) identified following pathologic slide review has been shown to be an independent predictor of recurrence-free survival (RFS) and cancer-specific survival (CSS) in a multicenter series of patients undergoing radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). However, the validity of LVI in everyday practice, where pathologic re-review of all slides is uncommon, has not been assessed. Objective: Our aim was to evaluate the prognostic role of LVI in an international cohort of patients treated with RNU for UTUC without pathologic slide review. Design, setting, and participants: Data from 762 patients treated with RNU for UTUC without neoadjuvant chemotherapy were collected at nine centers located in Europe, Asia, and Canada. Measurements: We evaluated patients’ characteristics, RFS, and CSS. Results and limitations: LVI was present in 148 patients (19.4%). At a median follow-up of 34 mo, 23.5% of the patients developed disease recurrence and 19.8% died of UTUC. The 5-yr RFS and CSS rates were 79.3% and 82.1%, respectively, in the absence of LVI compared with 45.1% and 45.8%, respectively, in the presence of LVI (p values <0.0001). On multivariable Cox regression analyses, LVI was an independent predictor of RFS (hazard ratio [HR]: 3.3; p =0.005) and CSS (HR: 5.9; p <0.0001). Similarly, among patients with pN0/Nx disease, LVI was an independent predictor of RFS (HR: 2.1; p =0.001) and CSS (HR: 2.3; p <0.0001). Conclusions: In a large multicenter series of patients treated with RNU for UTUC and for which no pathologic slide review was performed, LVI was present in approximately 20% and was an independent predictor of both RFS and CSS. LVI status should always be included in the pathologic report of RNU specimens, and patients with LVI should be considered for adjuvant therapy studies. [Copyright &y& Elsevier]

Objective: To test the ability of the 2015 modified version of the European Network for the Study of Adrenal Tumors staging system (mENSAT) in predicting cancer-specific mortality (CSM), as well as overall mortality (OM) in adrenocortical carcinoma (ACC) patients of all stages, in a large-scale, and contemporary United States cohort., Methods: We relied on the Surveillance, Epidemiology, and End Results (SEER) database (2004-2020) to test the accuracy and calibration of the mENSAT and subsequently compared it to the 8th edition of the American Joint Committee on Cancer staging system (AJCC)., Results: In 858 ACC patients, mENSAT accuracy was 74.7% for 3-year CSM predictions and 73.8% for 3-year OM predictions. The maximum departures from ideal predictions in mENSAT were +17.2% for CSM and +11.8% for OM. Conversely, AJCC accuracy was 74.5% for 3-year CSM predictions and 73.5% for 3-year OM predictions. The maximum departures from ideal predictions in AJCC were -6.7% for CSM and -7.1% for OM., Conclusion: The accuracy of mENSAT is virtually the same as that of AJCC in predicting CSM (74.7% vs 74.5%) and OM (73.7% vs 73.5%). However, calibration is lower for mENSAT than for AJCC. In consequence, no obvious benefit appears to be associated with the use of mENSAT relative to AJCC in US ACC patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We validated the current NCCN (National Comprehensive Cancer Network®) classification of very high risk patients, and compared the pathological, functional and oncologic outcomes between surgically treated high risk and very high risk patients., Materials and Methods: We retrospectively analyzed 4,041 patients stratified into high risk or very high risk groups who underwent radical prostatectomy between 1992 and 2016. Kaplan-Meier as well as multivariable logistic and Cox regression analyses were used to compare outcomes between the groups., Results: After radical prostatectomy the rate of adverse pathological features was higher in 1,369 very high risk vs 2,672 high risk cases. Functional outcomes were similar between the groups, with 1-year continence and potency rates of 81.0% and 43.6% in the very high risk compared to 81.9% and 45.2% in the high risk group, respectively (p = 0.7 and p = 0.9). In a subset of 1,835 patients who underwent radical prostatectomy between 1992 and 2011 (median followup 58.8 months, IQR 36.5-84.6), those with very high risk disease had significantly worse 5 and 8-year biochemical recurrence-free survival, metastatic progression-free survival, prostate cancer specific mortality-free survival and overall survival rates compared to those with high risk disease., Conclusions: Despite the relatively poor prognosis of patients with high risk prostate cancer, radical prostatectomy results in favorable 5 and 8-year metastatic progression-free survival, prostate cancer specific mortality-free survival and overall survival rates. Relative to high risk cases, their very high risk counterparts have significantly worse pathological and oncologic outcomes, and more frequently require additional therapies. These observations validate the stratification between high risk and very high risk in European patients with prostate cancer. Interestingly, very high risk patients treated with radical prostatectomy did not have a worse functional outcome than their high risk counterparts., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Lymph node metastasis (LNM) is the most powerful pathologic predictor of disease recurrence after radical cystectomy (RC). However, the outcomes of patients with LNM are highly variable., Objective: To assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters., Design, Setting, and Participants: A retrospective analysis of 748 patients with urothelial carcinoma of the bladder and LNM treated with RC and lymphadenectomy without neoadjuvant therapy at 10 European and North American centers (median follow-up: 27 mo)., Intervention: All subjects underwent RC and bilateral pelvic lymphadenectomy., Outcome Measurements and Statistical Analysis: Each LNM was microscopically evaluated for the presence of ENE. The number of LNs removed, number of positive LNs, and LN density were recorded and calculated. Univariable and multivariable analyses addressed time to disease recurrence and cancer-specific mortality after RC., Results and Limitations: A total of 375 patients (50.1%) had ENE. The median number of LNs removed, number of positive LNs, and LN density were 15, 2, and 15, respectively. The rate of ENE increased with advancing pT stage (p<0.001). In multivariable Cox regression analyses that adjusted for the effects of established clinicopathologic features and LN parameters, ENE was associated with disease recurrence (hazard ratio [HR]: 1.89; 95% confidence interval [CI], 1.55-2.31; p<0.001) and cancer-specific mortality (HR: 1.90; 95% CI, 1.52-2.37; p<0.001). The addition of ENE to a multivariable model that included pT stage, tumor grade, age, gender, lymphovascular invasion, surgical margin status, LN density, number of LNs removed, number of positive LNs, and adjuvant chemotherapy improved predictive accuracy for disease recurrence and cancer-specific mortality from 70.3% to 77.8% (p<0.001) and from 71.8% to 77.8% (p=0.007), respectively. The main limitation of the study is its retrospective nature., Conclusions: ENE is an independent predictor of both cancer recurrence and cancer-specific mortality in RC patients with LNM. Knowledge of ENE status could help with patient counseling, clinical decision making regarding inclusion in clinical trials of adjuvant therapy, and tailored follow-up scheduling after RC., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Previous randomised trials demonstrated that adjuvant radiation therapy (aRT) improves cancer control in patients with pT3 prostate cancer (PCa). However, there is currently no evidence supporting early salvage radiation therapy (eSRT) as equivalent to aRT in improving freedom from biochemical recurrence (BCR) after radical prostatectomy (RP)., Objective: To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0, R0-R1 PCa., Design, Setting, and Participants: Using a European multi-institutional cohort, 890 men with pT3pN0, R0-R1 PCa were identified., Intervention: All patients underwent RP. Subsequently, patients were stratified into two groups: aRT versus initial observation followed by eSRT in cases of relapse. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Propensity-matched analysis was employed, and patients were stratified into two groups: aRT versus observation and eventual eSRT, defined as RT given at a postoperative serum prostate-specific antigen (PSA) ≤ 0.5 ng/ml at least 6 mo after RP. BCR, defined as PSA >0.20 ng/ml and rising after administration of RT, was compared between aRT and initial observation followed by eSRT in cases of relapse using Kaplan-Meier and Cox regression methods., Results and Limitations: Overall, 390 (43.8%) and 500 (56.2%) patients were treated with aRT and initial observation, respectively. Within the latter group, 225 (45.0%) patients experienced BCR and underwent eSRT. In the postpropensity-matched cohort, the 2- and 5-yr BCR-free survival rates were 91.4% and 78.4% in aRT versus 92.8% and 81.8% in patients who underwent initial observation and eSRT in cases of relapse, respectively (p=0.9). No differences in the 2- and 5-yr BCR-free survival rates were found, even when patients were stratified according to pT3 substage and surgical margin status (all p ≥ 0.4). These findings were also confirmed in multivariable analyses (p=0.6). Similar results were achieved when the cut-off to define eSRT was set at 0.3 ng/ml (all p ≥ 0.5)., Conclusions: The current study suggests that timely administration of eSRT is comparable to aRT in improving BCR-free survival in the majority of pT3pN0 PCa patients. Therefore, eSRT may not compromise cancer control but significantly reduces overtreatment associated with aRT., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Macroscopic sessile tumor architecture was associated with adverse outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Before inclusion in daily clinical decision-making, the prognostic value of tumor architecture needs to be validated in an independent, external dataset. We tested whether macroscopic tumor architecture improves outcome prediction in an international cohort of patients., Material and Methods: We retrospectively studied 754 patients treated with RNU for UTUC without neoadjuvant chemotherapy at 9 centers located in Asia, Canada, and Europe. Tumor architecture was macroscopically categorized as either papillary or sessile. Univariable and multivariable Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates., Results: Macroscopic sessile architecture was present in 20% of the patients. Its prevalence increased with advancing pathologic stage and it was significantly associated with established features of biologically aggressive UTUC, such as tumor grade, lymph node metastasis, lymphovascular invasion, and concomitant CIS (all P values < 0.02). The median follow-up for patients who were alive at last follow-up was 40 months (IQR: 18-75 months, range: 1-271 months). Two-year RFS and CSS for tumors with papillary architecture were 85% and 90%, compared with 58% and 66% for those with macroscopic sessile architecture, respectively (P values < 0.0001). On multivariable Cox regression analyses, macroscopic sessile architecture was an independent predictor of both RFS (hazard ratio {HR}: 1.5; P = 0.036) and CSS (HR: 1.5; P = 0.03)., Conclusion: We confirmed the independent prognostic value of macroscopic tumor architecture in a large, independent, multicenter UTUC cohort. It should be reported in every pathology report and included in post-RNU predictive models in order to refine current clinical decision making regarding follow-up protocol and adjuvant therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described., Objective: We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU., Design, Setting, and Participants: Our study included 2244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant carcinoma in situ (CIS). The cohort was randomly split for development (12 centers, n=1273) and external validation (11 centers, n=971)., Interventions: All patients underwent RNU., Measurements: Univariable and multivariable models addressed RFS, CSS, and comparison of discrimination and calibration with American Joint Committee on Cancer (AJCC) stage grouping., Results and Limitations: At a median follow-up of 45 mo, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p for trend <0.001), lymph node metastasis (hazard ratio [HR]: 1.98; p=0.002), lymphovascular invasion (HR: 1.66; p<0.001), sessile tumor architecture (HR: 1.76; p<0.001), and concomitant CIS (HR: 1.33; p=0.035) were associated with disease recurrence. Similarly, T classification (p for trend<0.001), lymph node metastasis (HR: 2.23; p=0.001), lymphovascular invasion (HR: 1.81; p<0.001), and sessile tumor architecture (HR: 1.72; p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination., Conclusions: Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be used for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study is to assess the association of concomitant carcinoma in situ (CIS) with disease recurrence and cancer-related death in a multi-institutional series of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC)., Methods: We collected retrospectively the data of 772 patients treated with RNU and ipsilateral bladder cuff excision at 9 international institutions in Asia, Europe, and Northern America from 1987 to 2008. Surgical specimens were processed according to standard pathologic procedures at each institution. Univariable and multivariable Cox regression models addressed time to recurrence and cancer-specific mortality., Results: Concomitant CIS was present in 88 patients (11.4%); it was associated with more advanced pathologic stage, higher tumor grade, and presence of lymphovascular invasion (all P-values < 0.05). The five-year recurrence-free (RFS) and cancer-specific survival (CSS) estimates were 74.4 and 76.3%, respectively, in the absence of CIS compared with 56.4 and 59.9%, respectively, in the presence of CIS (P-values < 0.0001 for RFS and 0.002 for CSS, respectively). On multivariable Cox regression analyses, concomitant CIS was an independent predictor of both RFS (hazard ratio (HR): 1.9; P = 0.007) and CSS (HR: 1.7, P = 0.048). Similar findings were reconfirmed in subgroups analyses limited to T2, organ confined, and N0/Nx UTUC, or patients who did not receive adjuvant chemotherapy., Conclusions: Presence of concomitant CIS is an independent predictor of both RFS and CSS in patients treated with RNU for UTUC. This information may be useful in risk stratification of UTUC patients for follow-up and additional therapy.

Objective: The aim of this study was to externally validate the prognostic value of concomitant urothelial carcinoma in situ (CIS) in radical cystectomy (RC) specimens using a large international cohort of bladder cancer patients., Methods: The records of 3,973 patients treated with RC and bilateral lymphadenectomy for urothelial carcinoma of the bladder (UCB) at nine centers worldwide were reviewed. Surgical specimens were evaluated by a genitourinary pathologist at each center. Uni- and multivariable Cox regression models addressed time to recurrence and cancer-specific mortality after RC., Results: 1,741 (43.8%) patients had concomitant CIS in their RC specimens. Concomitant CIS was more common in organ-confined UCB and was associated with lymphovascular invasion (p < 0.001). Concomitant CIS was not associated with either disease recurrence or cancer-specific death regardless of pathologic stage. The presence of concomitant CIS did not improve the predictive accuracy of standard predictors for either disease recurrence or cancer-specific death in any of the subgroups., Conclusions: We could not confirm the prognostic value of concomitant CIS in RC specimens. This, together with the discrepancy between pathologists in determining the presence of concomitant CIS at the morphologic level, limits the clinical utility of concomitant CIS in RC specimens for clinical decision-making., (Copyright © 2011 S. Karger AG, Basel.)

Background: Prognostic factors after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) are inconclusive, because most data in the literature have been obtained from small series., Objective: To assess the association of tumour necrosis with cancer recurrence and survival in a large international series of patients treated with RNU., Design, Setting, and Participants: Data were collected from 1425 patients treated with RNU at 13 centres and combined into a relational database. Pathologic slides were re-reviewed by genitourinary pathologists according to strict criteria. Extensive tumour necrosis was scored as >10% of the tumour area., Intervention: Patients underwent either open or laparoscopic RNU. Lymph node dissection was performed in the presence of enlarged nodes., Measurements: Recurrence was defined as tumour relapse in the operative field, lymph node (LN) metastasis, and/or distant metastases. Bladder recurrences were not considered. Associations of extensive tumour necrosis with recurrence-free survival and cancer-specific survival were evaluated by univariate and multivariate analyses., Results and Limitations: Extensive tumour necrosis was observed in 364 patients (25.5%) and was associated with advanced tumour stage, high tumour grade, sessile architecture, lymphovascular invasion (LVI), concomitant carcinoma in situ, and LN metastasis (p<0.0001 each). Extensive tumour necrosis was independently associated with disease recurrence and survival (p=0.037 and p=0.046, respectively) after adjusting for the effects of pathologic stage, grade, LVI, and LN status. The addition of extensive tumour necrosis to a base model comprising standard pathologic predictors marginally improved its predictive accuracy for both cancer-specific recurrence (1.5%) and survival (1.4%)., Conclusions: Extensive tumour necrosis is an independent predictor of clinical outcomes in patients who undergo RNU for UTUC. Assessment of tumour necrosis may help to identify patients who could benefit from multimodal therapy after RNU in the future. Evaluation of extensive tumour necrosis should be part of standard pathologic reporting., (Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To determine whether an increased body mass index (BMI) is a predictor of advanced pathologic findings in European men undergoing radical prostatectomy (RP). The relationship between obesity and prostate cancer is controversial. Studies, predominantly derived from the United States, have suggested that an increased BMI is a significant predictor of adverse pathologic findings in patients treated with open RP., Methods: From April 2005 to June 2008, 1538 consecutive patients were treated with open RP at a single tertiary referral center. We tested the effect of BMI on the rate of extracapsular extension, seminal vesicle invasion, lymph node invasion, and positive surgical margins in univariate and multivariate logistic regression models. The covariates consisted of clinical stage, prostate-specific antigen, biopsy Gleason score, age, prostate volume, and rate of nerve-sparing surgery., Results: On multivariate analysis, both continuously coded and categorically coded BMI was unrelated to the rate of extracapsular extension (odds ratio [OR] 1.02, P = .5), seminal vesicle invasion (OR 1.03, P = .3), lymph node invasion (OR 0.98, P = .7), or positive surgical margins (OR 1.03, P = .3)., Conclusions: Obese patients who are candidates for open RP should not expect to have worse pathologic findings after surgery than their nonobese counterparts. Differences in patients' weight and height between North America and Europe might explain the lack of adverse effects of an elevated BMI in this European cohort.

Objectives: The Epstein criteria represent the most widely used scheme for prediction of clinically insignificant prostate cancer (PCa). However, they were never validated in European men. We assessed the rate of unfavorable prostate cancer (Gleason 7-10 or non-organ-confined disease) in a cohort of 366 men who fulfilled the Epstein clinically insignificant PCa criteria., Methods: Between 1996 and 2006, 2580 men underwent radical prostatectomy at a single academic European institution. Of those, 366 fulfilled the contemporary Epstein clinically insignificant PCa criteria. Analyses targeted the rate of pathologically unfavorable prostate cancer, defined as either Gleason sum 7-10 or non-organ-confined disease, or a combination of these characteristics in patients with clinically insignificant PCa., Results: Gleason 7-10 prostate cancer at radical prostatectomy was found in 88 patients (24%) with clinically insignificant PCa. In addition, 30 (34.1%) of the 88 patients harboured non-organ-confined disease. Consequently, the contemporary Epstein criteria for clinically insignificant PCa were inaccurate in 24% of patients., Conclusions: The Epstein clinical insignificant PCa criteria may underestimate the true nature of prostate cancer in as many as 24% of European patients. Therefore, caution is advised when treatment decisions are based solely on these criteria.

Objective: To examine the stage migration patterns in patients treated with radical prostatectomy (RP) for prostate cancer in Europe and in the USA in the last 20 years., Patients and Methods: Between 1988 and 2005, RP was performed in 11 350 men: 5739 from Europe and 5611 from the USA. Independent-samples t-test and the chi-square test were, respectively, used for comparisons of means and proportions. The trend test was used to test the statistical significance of trends in proportions over time. RESULTS; Temporal patterns in patients' age, stage and PSA level at presentation were similar on both continents. Conversely, temporal patterns in Gleason sum distribution differed. In the USA, the rate of biopsy Gleason sums of 2-5 decreased from 32.8% to 0.2% (P < 0.001), while the rate of Gleason sums of 7 and 8-10 increased (P < 0.001). Conversely, in Europe the rate of Gleason sums of 6 increased from 40% to 64% (P < 0.001) at the expense of all other Gleason sums. At RP, the rate of Gleason sums of 2-5 decreased on both continents and the rate of a Gleason sum of 7 increased in the USA. Moreover, no important differences in pathological stage trends (organ confinement, extracapsular extension and seminal vesicle invasion) distinguished either population. Finally, the rate of lymph node involvement increased in the USA but remained stable in Europe., Conclusions: Stage and grade migration affected the USA and Europe to different extents. These differences should be accounted for when prediction tools or comparisons between the USA and Europe are considered.

Objective: To compare the performance and discriminant properties of two instruments (a tree-structured regression model and a logistic regression-based nomogram), recently developed to predict lymph node invasion (LNI) at radical prostatectomy (RP), in a contemporary cohort of European patients., Patients and Methods: The cohort comprised 1525 consecutive men treated with RP and bilateral pelvic LN dissection (PLND) in two tertiary academic centres in Europe. Clinical stage, pretreatment prostate-specific antigen (PSA) level and biopsy Gleason sum were used to test the ability of the regression tree and the nomogram to predict LNI. Accuracy was quantified by the area under the receiver operating characteristic curve (AUC). All analyses were repeated for each participating institution., Results: The AUC for the nomogram was 81%, vs 77% for the regression tree (P = 0.007). When data were stratified according to institution, the nomogram invariably had a higher AUC than the regression tree (Hamburg cohort: nomogram 82.1% vs regression tree 77.0%, P = 0.002; Milan cohort: 82.4% vs 75.9%, respectively; P = 0.03)., Conclusions: Nomogram-based predictions of LNI were more accurate than those derived from a regression tree; therefore, we recommend the use of nomogram-derived predictions.

Background: C-reactive protein (CRP) represents a promising prognostic variable in patients with sporadic renal cell carcinoma (RCC). It was hypothesized that CRP can improve the prognostic ability of standard RCC-specific mortality (RCC-SM) predictors in patients treated with nephrectomy for all stages of RCC., Methods: Radical nephrectomy was performed in 314 patients from 2 European centers. Life table, Kaplan-Meier, and Cox regression analyses addressed RCC-SM. Covariates included age, gender, TNM stage, tumor size, Fuhrman grade, and histologic subtype., Results: The median survival of the cohort was 19.9 years. Age ranged from 10 to 77 years. Most patients were male (69%). T-stages were distributed as follows: T1-121 (38.7%), T2-45 (14.4%), T3-140 (44.7%), T4-7 (2.2%). CRP values ranged from 1.0 to 358.0 mg/L (mean 40.9, median 11.0 mg/L). In multivariable analyses, CRP was an independent predictor of RCC-SM (P = .003). The consideration of CRP in the multivariable model increased the predictive accuracy by 3.7% (P < .001). Moreover, the model with CRP performed 2.4% and 4.6% better than the UCLA Integrated Staging System (UISS) at, respectively, 2 and 5 years., Conclusions: CRP represents an informative predictor of RCC-SM. Its routine use could allow better risk stratification and risk-adjusted follow-up of RCC patients., ((c) 2007 American Cancer Society.)

Objective: To test whether the rate of lymph node invasion (LNI) differs between patients treated with radical prostatectomy (RP) at a European or a North American centre., Patients and Methods: In all, 1385 men had RP with bilateral lymphadenectomy for clinically localized prostate cancer (587 from Dallas, Texas and 798 from Milan, Italy). Univariate and multivariate analyses focused on the association between the continent of origin and the rate of LNI, after controlling for prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum and the number of examined and removed lymph nodes., Results: European men had higher PSA levels (9.1 vs 7.8 ng/mL), a higher proportion of palpable cancers (44.5 vs 32.8%), more nodes removed (mean 14.9 vs 7.8) and a higher rate of LNI (9.0% vs 1.2%; all differences P < 0.001). In multivariate analyses that controlled for PSA level and clinical variables, European men had an 8.9-fold higher risk of LNI (P < 0.001) than their counterparts from the USA. Among preoperative variables, the continent of origin was the third most informative predictor of LNI (67.5%), after biopsy Gleason sum (74.3%) and the number of examined lymph nodes (71.0%), and improved the ability to predict LNI by 4.7%., Conclusion: Men treated at a European centre had a 7.3-8.9-fold higher rate of LNI, despite adjusting for all clinical and pathological variables. It remains to be shown what predisposes European men to a higher rate of LNI.

Objective: To determine whether health-insurance status might result in more localized stage at presentation, more favourable stage at surgery and in a lower rate of biochemical recurrence (BCR), in patients diagnosed with prostate cancer and treated with radical prostatectomy (RP), as despite uninhibited access to healthcare, private and public health insurance are available in most European countries., Patients and Methods: In all, 4442 consecutive men had RP in two large European centres, of whom 2372 had public and 2070 had private health insurance. The groups were compared for several variables according to insurance status (private vs public). Means and proportions tests were complemented with logistic regression or Kaplan-Meier analyses., Results: Serum prostate-specific antigen level (P < 0.001), clinical stage (P < 0.001), pathological Gleason sum (P = 0.02), positive surgical margin rate (18.4% vs 25.4%, P < 0.001), extracapsular extension rate (17.7% vs 20.0%, P = 0.047) and seminal vesicle invasion rate (9.6% vs 11.6%, P = 0.04) were more favourable in privately insured patients. Conversely, the rate of lymph-node involvement was higher in those with private than public insurance (4.4% vs 3.3%, P = 0.045). In univariate analyses addressing pathological variables, private insurance was invariably protective (all P < 0.05). The Kaplan-Meier analyses showed that privately insured patients had a lower rate of BCR after RP (log-rank P = 0.017)., Conclusion: Despite uninhibited access to healthcare, insurance status represents a rate-limiting variable, which affects stage at presentation and the outcome of cancer control.

Objective: To assess the association between surgical volume (SV) and the rate of positive surgical margins (PSM) after radical prostatectomy (RP) in a large single-institution European cohort of patients., Patients and Methods: In all, 2402 men had a RP by a group of 11 surgeons, all of whom were trained by the surgeon with the highest SV; all surgeons used the same surgical technique. Variables assessed before RP were prostate-specific antigen (PSA) level, clinical stage and biopsy Gleason sum; variables assessed after RP were PSA level, extracapsular extension, seminal vesicle invasion, lymph node invasion and pathological Gleason sum. These were used to predict the rate of PSM in models before or after RP. Multivariate models were complemented with SV to test its independent and multivariate statistical significance and to quantify its impact on the model's overall (and 200 bootstrap-corrected) predictive accuracy., Results: The mean (range) SV was 201 (1-1293) RPs; the mean (median, range) rate of PSM was 20.2 (21.4, 0-32.9)%. In multivariate models, SV was a highly statistically significant independent predictor of PSM (P < 0.001) and increased the predictive accuracy in multivariate models both before (2.0%) and after RP (1.5%, both P < 0.001). However, when the surgeon with the highest SV, who contributed to 1293 cases, was removed from the analyses, the multivariate independent prediction and the gains in predictive accuracy related to adding SV, disappeared in the models both before (P = 0.9, accuracy gain 0.1%) and after (P = 0.4, accuracy gain - 0.3%) RP., Conclusions: These results indicate that patients treated by surgeons with a very high volume can expect to have a significantly lower rate of PSM, after accounting for clinical and pathological case-mix differences. However, SV is not a predictor of PSM when analyses are restricted to intermediate- and low-volume surgeons.

Introduction: We examined the prognostic value of AJCC pT2 substages in prediction of biochemical recurrence (BCR) after radical prostatectomy (RP), in European patients., Methods: A cohort of 1726 RP patients with pT2N0 prostate cancer (PCa) was studied. Multivariate Cox regression models addressed the association between either the 1997 or 1992/2002 pT2 substages after controlling for total PSA, primary and secondary pathologic Gleason scores and surgical margin status and time to PSA recurrence (PSA >0.1 and rising) after RP. Regression coefficients were then used to test the predictive accuracy of multivariate models in a nomogram setting., Results: PSA recurrence occurred in 80 (4.6%) patients. Mean and median times to recurrence were respectively 28.9 and 24.4 months. In univariate analyses, neither the 1997 (p = 0.48) nor the 1992/2002 pT2 substages (p = 0.054) were predictive of recurrence. In multivariate analyses the lack of significance persisted (1997 p = 0.709; 1992/2002 p = 0.124). When either the 1997 or 1992/2002 pT2 substages were added to a multivariate nomogram without pT2 substage information, its accuracy respectively decreased by 0.8% and 1.1%., Conclusion: Our data indicate that pT2 substages offer no incremental value relative to pre-treatment total PSA, surgical margin status and pathologic Gleason scores. Therefore, it might be postulated that it is sufficient to confirm organ confinement according to Partin's pathologic staging.

Objectives: Prostate cancer patients in the US and Europe differ due to selection and treatment differences. Accuracy of predictive tools derived in the US might therefore suffer when applied to European patients. We tested the validity of the widely accepted Partin tables for their ability to predict pathologic stage in German patients., Methods: Clinical and pathological characteristics were obtained from 1,298 consecutive men with clinically localized prostate cancer undergoing radical prostatectomy at the University Hospital Hamburg between January 1992 and February 2000. Receiver operating characteristic (ROC) curve analysis was performed to compare observed and predicted Partin rates for each pathologic stage., Results: The rate for organ confinement was 56% in Hamburg patients compared to 48% in the Partin study. The rates of Hamburg patients for extracapsular extension without seminal vesicle or lymph node involvement were 25%, for seminal vesicle without lymph node involvement 14% and for lymph node metastases 5%. The corresponding rates of the Partin study were 40, 7 and 5%, respectively. The accuracy of Partin table derived probability was high with an area under the ROC curve of 0.817 (95% CI, 0.757-0.876) for organ confinement and 0.807 (95% CI, 0.781-0.833) for lymph node involvement., Conclusion: Our study demonstrated that predictive tools for prostate cancer developed in the US could be applied to European patients with comparable accuracy to that reported for validation studies performed with US patients.