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Supplemental material, sj-pdf-1-cre-10.1177_02692155221091509 for Relaxation and related therapies for people with multiple sclerosis (MS): A systematic review by Ian I. Kneebone, Brooke E. Van Zanden, Diana S. Dorstyn, Rachel M. Roberts, Stephen R. Lord, Dawn Querstret, Alice Theadom, David S. Kennedy, Jay Raman and Roshan das Nair in Clinical Rehabilitation

Simple Summary Measuring the quality of care is important in health care to improve the treatment of patients. In this investigation, we sought to identify five indicators ("pentafecta") that reflect the quality of care of patients who have cancer of the upper urinary tract (kidney and/or ureter) and are treated with surgical removal of the affected kidney and ureter. Furthermore, we searched for conditions that can predict a failure to achieve these criteria during treatment. The five indicators that define the pentafecta are the complete removal of the tumor without residuals, the complete removal of the ureter and its bladder part, the absence of complications related to the blood, the absence of severe complications related to the surgery, and the absence of tumor recurrence 12 months after the surgery. Of the 1718 patients included, 844 (49%) achieved all pentafecta criteria. These patients had higher chances at 5 years after the surgery to be alive and not to die from any cause (A) or from cancer (B) compared to those who did not achieve the pentafecta criteria (A: 68.7 vs. 50.1% and B: 79.8 vs. 62.7%, respectively). There were no conditions related to the patient that were found to predict a failure to achieve the pentafecta. Using quality indicators such as the proposed pentafecta for the assessment of the treatment of cancer patients may help define prognosis and improve patient care. Background: Measuring quality of care indicators is important for clinicians and decision making in health care to improve patient outcomes. Objective: The primary objective was to identify quality of care indicators for patients with upper tract urothelial carcinoma (UTUC) and to validate these in an international cohort treated with radical nephroureterectomy (RNU). The secondary objective was to assess the factors associated with failure to validate the pentafecta. Design: We performed a retrospective multicenter study of patients treated with RNU for EAU high-risk (HR) UTUC. Outcome measurements and statistical analysis: Five quality indicators were consensually approved, including a negative surgical margin, a complete bladder-cuff resection, the absence of hematological complications, the absence of major complications, and the absence of a 12-month postoperative recurrence. After multiple imputations and propensity-score matching, log-rank tests and a Cox regression were used to assess the survival outcomes. Logistic regression analyses assessed predictors for pentafecta failure. Results: Among the 1718 included patients, 844 (49%) achieved the pentafecta. The median follow-up was 31 months. Patients who achieved the pentafecta had superior 5-year overall- (OS) and cancer-specific survival (CSS) compared to those who did not (68.7 vs. 50.1% and 79.8 vs. 62.7%, respectively, all p < 0.001). On multivariable analyses, achieving the pentafecta was associated with improved recurrence-free survival (RFS), CSS, and OS. No preoperative clinical factors predicted a failure to validate the pentafecta. Conclusions: Establishing quality indicators for UTUC may help define prognosis and improve patient care. We propose a pentafecta quality criteria in RNU patients. Approximately half of the patients evaluated herein reached this endpoint, which in turn was independently associated with survival outcomes. Extended validation is needed.

Supplemental material, sj-pdf-1-cre-10.1177_02692155221091509 for Relaxation and related therapies for people with multiple sclerosis (MS): A systematic review by Ian I. Kneebone, Brooke E. Van Zanden, Diana S. Dorstyn, Rachel M. Roberts, Stephen R. Lord, Dawn Querstret, Alice Theadom, David S. Kennedy, Jay Raman and Roshan das Nair in Clinical Rehabilitation

Additional file 4: Figure S1. Epigenetic landscape analysis of histone modifications in luminal and basal bladder cancers. a Genome-wide H3K27ac signals show that biological replicates and molecular subtypes (basal and luminal) cluster together. b Hierarchical clustering of genome-wide RNA-Seq results for 4 cell lines recapitulate the luminal and basal gene expression based molecular subtypes. c Integrated H3K27ac peaks at promoters and RNA-Seq gene expression association model identifies putative promoter and gene regulation. Top 10,000 most variable promoters (left heatmap) are plotted along with their corresponding gene expression (right heatmap). Luminal (cyan) and basal (magenta) genes are highlighted for their specific linked enhancers. d Corresponding enhancer H3K27ac and its linked RNA-Seq signals based on our predicted model for selected luminal and basal genes shows remarkable similarity. Figure S2. Epigenetic landscape analysis of open-chromatins in luminal and basal subtypes of bladder cancers. a Genome-wide overlap of ATAC-Seq peaks with H3K27ac ChIP-Seq is shown here for each cell line at either promoter, enhancer or all locations. b Genome-wide overlap of H3K27ac ChIP-Seq peaks with ATAC-Seq is shown here for each cell line at either promoter, enhancer or all locations. c Overlap between distal H3K27ac and ATAC-Seq peaks. d ATAC-Seq signal at distal enhancers compared with distal H3K27ac signal. e Genome-wide correlation of ATAC-Seq signals between cell lines recapitulate enhancer/promoter and RNA-Seq based clustering. f FOXA1 and GATA3 ChIP-Seq binding sites overlapped at promoters are shown here as genome-wide tag plot in three groups. g A comparison of top 3 motifs enriched p-values in each open-chromatins that does not overlap with any H3K27ac signals within its cell lines are shown. Figure S3. Hi-C maps of luminal and basal subtypes of bladder cancers and bladder tumors. Genome-wide chromosome view of Hi-C map is shown for RT4 (a), SW780 (b), SCABER (c), HT1376 (d), tumor T1 (e), tumor T2 (f), tumor T3 (G), tumor T4 (H) and tumor T5 (I) at 10 MB resolution. Figure S4. Copy number profiles for four bladder cancer cell lines (HT1376, RT4, SW780, and SCABER) and five tumor samples (Tumor T1, Tumor T2, Tumor T3, Tumor T4, and Tumor T5). CNVs were computed using Hi-C data. Figure S5. Intra- and inter-chromosome structure variation (SV) events. Circos plot showing intra- and inter-chromosome SVs in HT1376 (a), RT4 (b), Tumor T1 (c), Tumor T2 (d), Tumor T3 (e), Tumor T4 (f) and Tumor T5 (g).

Additional file 16. Computational data analysis methods.

Additional file 17. Review history.

Background Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. Methods This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary end point was the objective response rate (ORR). Secondary end points included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. Results Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had>10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with≤10% sarcomatoid histology ( P = 0.04). The most common grade 3 or higher treatment-related adverse events included neutropenia ( n = 20), anemia ( n = 10), and fatigue ( n = 7). Conclusions These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation.

Purpose We investigated structural hypertrophy and functional hyperfiltration as compensatory adaptations after radical nephrectomy in patients with renal cell carcinoma according to the preoperative chronic kidney disease stage. Materials and methods We retrospectively identified 543 patients who underwent radical nephrectomy for renal cell carcinoma between 1997 and 2012. Patients were classified according to preoperative glomerular filtration rate as no chronic kidney disease—glomerular filtration rate 90 ml/min/1.73 m 2 or greater (230, 42.4%), chronic kidney disease stage II—glomerular filtration rate 60 to less than 90 ml/min/1.73 m 2 (227, 41.8%), and chronic kidney disease stage III—glomerular filtration rate 30 to less than 60 ml/min/1.73 m 2 (86, 15.8%). Computerized tomography performed within 2 months before surgery and 1 year after surgery was used to assess functional renal volume for measuring the degree of hypertrophy of the remnant kidney, and the preoperative and postoperative glomerular filtration rate per unit volume of functional renal volume was used to calculate the degree of hyperfiltration. Results Among all patients (mean age = 56.0 y) mean preoperative glomerular filtration rate, functional renal volume, and glomerular filtration rate/functional renal volume were 83.2 ml/min/1.73 m 2 , 340.6 cm 3 , and 0.25 ml/min/1.73 m 2 /cm 3 , respectively. The percent reduction in glomerular filtration rate was statistically significant according to chronic kidney disease stage (no chronic kidney disease 31.2% vs. stage II 26.5% vs. stage III 12.8%, P P = 0.250). The change in glomerular filtration rate/functional renal volume was statistically significant (no chronic kidney disease 18.5% vs. stage II 20.1% vs. stage III 45.9%, P P = 0.012), diabetes mellitus ( P = 0.023), hypertension ( P = 0.015), and chronic kidney disease stage ( P Conclusions Patients with a lower preoperative glomerular filtration rate had a smaller reduction in postoperative renal function than those with a higher preoperative glomerular filtration rate due to greater degrees of functional hyperfiltration.

OBJECTIVE To describe a multicentre experience with preoperative platinum-based chemotherapy before radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) with loco-regional nodal metastases. PATIENTS AND METHODS We identified 313 patients from the UTUC Collaboration (over 1200 patients), who underwent RNU with concomitant retroperitoneal lymph node dissection between 1990 and 2007 and met the inclusion criteria for one of three groups. Group 1 comprised patients who received chemotherapy before RNU because of biopsy-proven loco-regional nodal metastases. Group 2 consisted of patients who underwent primary RNU and were found to have metastatic nodal disease on final pathological review (node-positive). Group 3 comprised a comparative cohort of patients treated with primary RNU for invasive or locally advanced (pT2/pT4) node-negative (N0) UTUC. RESULTS Groups 1, 2 and 3 included 18, 120 and 175 patients, respectively. The 5-year disease-free survival rates were 49%, 30% and 64%, whereas the 5-year cancer-specific survival rates were 44%, 36% and 69% in groups 1, 2 and 3, respectively. In group 1, on final pathological evaluation, nine patients were pN0, six patients were pT0 and five patients had pT0N0 disease. Kaplan-Meier survival analyses showed similar recurrence and survival rates in group 1 compared with group 3 (P = 0.14 and P = 0.06, respectively). Meanwhile, group 2 had significantly lower disease-free and cancer-specific survival rates compared with group 3 (P < 0.001 and P < 0.001, respectively) and compared with group 1 (P = 0.04 and P = 0.06, respectively). CONCLUSIONS Preoperative chemotherapy followed by aggressive surgical consolidation may yield favourable oncological outcomes in patients with UTUC with loco-regional nodal metastases. These data support further evaluation of neoadjuvant systemic therapy in patients at risk for locally advanced UTUC.

International audience; OBJECTIVE: *To assess the impact of differences in ethnicity on clinico-pathological characteristics and outcomes of patients with upper urinary tract urothelial carcinoma (UTUC) in a large multi-center series of patients treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: *We retrospectively collected the data of 2163 patients treated with RNU at 20 academic centres in America, Asia, and Europe. *Univariable and multivariable Cox regression models addressed recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: *In all, 1794 (83%) patients were Caucasian and 369 (17%) were Japanese. All the main clinical and pathological features were significantly different between the two ethnicities. *The median follow-up of the whole cohort was 36 months. At last follow-up, 554 patients (26%) developed disease recurrence and 461 (21%) were dead from UTUC. *The 5-year RFS and CSS estimates were 71.5% and 74.2%, respectively, for Caucasian patients compared with 68.8% and 75.4%, respectively, for Japanese patients. *On univariable Cox regression analyses, ethnicity was not significantly associated with either RFS (P= 0.231) or CSS (P= 0.752). *On multivariable Cox regression analyses that adjusted for the effects of age, gender, surgical type, T stage, grade, tumour architecture, presence of concomitant carcinoma in situ, lymphovascular invasion, tumour necrosis, and lymph node status, ethnicity was not associated with either RFS (hazard ratio [HR] 1.1; P= 0.447) or CSS (HR 1.0; P= 0.908). CONCLUSIONS: *There were major differences in the clinico-pathological characteristics of Caucasian and Japanese patients. *However, RFS and CSS probabilities were not affected by ethnicity and race was not an independent predictor of either recurrence or cancer-related death.

Lu DD, Raman JD. Infect Drug Resist. 2016;9:161–169On page 168, Reference section, an error occurred with some of the numbering, relating to:15. Berger AP, Gozzi C, Steiner H, et al. Complication Rate of transrectal ultrasound guided prostate biopsy: a comparison among 3 protocols with 6, 10 and 15 cores. J Urol. 2004;171(4):1478–1481.16. Jeon SS, Woo S-H, Hyun J-H, Choi HY, Chai SE. Bisacodyl rectal preparation can decrease infectious complications of transrectal ultrasound-guided prostate biopsy. Urology. 2003;62(3):461–466.17. Pepe P, Aragona F. Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. Urology. 2013;81(6):1142–1146.18. Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Is repeat prostate biopsy associated with a greater risk of hospitalization? Data from SEER-Medicare. J Urol. 2013;189(3):867–870.Read the original article

Purpose Percutaneous biopsy obtained from a single location is prone to sampling error in large heterogeneous renal masses, leading to nondiagnostic results or failure to detect poor prognostic features. We evaluated the accuracy of percutaneous biopsy for large renal masses using a modified multi-quadrant technique vs. a standard biopsy technique. Materials and methods Clinical and pathological data for all patients with cT2 or greater renal masses who underwent percutaneous biopsy from 2009 to 2014 were reviewed. The multi-quadrant technique was defined as multiple core biopsies from at least 4 separate solid enhancing areas in the tumor. The incidence of nondiagnostic findings, sarcomatoid features and procedural complications was recorded, and concordance between biopsy specimens and nephrectomy pathology was compared. Results A total of 122 biopsies were performed for 117 tumors in 116 patients (46 using the standard biopsy technique and 76 using the multi-quadrant technique). Median tumor size was 10 cm (IQR: 8–12). Biopsy was nondiagnostic in 5 of 46 (10.9%) standard and 0 of 76 (0%) multi-quadrant biopsies (P = 0.007). Renal cell carcinoma was identified in 96 of 115 (82.0%) tumors and nonrenal cell carcinoma tumors were identified in 21 (18.0%). One complication occurred using the standard biopsy technique and no complications were reported using the multi-quadrant technique. Sarcomatoid features were present in 23 of 96 (23.9%) large renal cell carcinomas studied. Sensitivity for identifying sarcomatoid features was higher using the multi-quadrant technique compared to the standard biopsy technique at 13 of 15 (86.7%) vs. 2 of 8 (25.0%) (P = 0.0062). Conclusions The multi-quadrant percutaneous biopsy technique increases the ability to identify aggressive pathological features in large renal tumors and decreases nondiagnostic biopsy rates.

Background: Improvement in postoperative risk stratification of upper tract urothelial carcinoma (UTUC) is required to better predict outcomes and counsel patients on adjuvant treatment. Objective: To validate the association between caveolin-1 and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for UTUC. Design, setting, and participants: Caveolin-1 expression was evaluated via immunochemistry on a tissue microarray from 621 patients. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positive. The median follow-up in this retrospective study was 35 mo (interquartile range 16-65). Intervention: Radical nephroureterectomy. Outcome measurements and statistical analysis: Univariate and multivariable Cox proportional hazards regression models were used to assess the association between caveolin-1 expression and recurrence and cancer-specific mortality (CSM). Results and limitations: Caveolin-1 was overexpressed in 150 patients (24%). Overexpression was associated with higher pathological stage (p< 0.001) and grade (p< 0.001). In univariate analyses, overexpression of caveolin-1 was significantly associated with lower recurrence (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2-2.6; p = 0.004) and CSM (HR 1.8, 95% CI 1.2-2.7; p = 0.005); however, multivariable analyses did not prove its independent association with outcomes. The study is limited by its retrospective nature. Conclusions: Despite overexpression in a quarter of UTUC patients, caveolin-1 was not independently associated with oncological outcomes. Its use could be evaluated to improve clinical staging of biopsy specimens and to help in clinical decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. Patient summary: Development of a panel of prognostic and predictive markers is mandatory for patient consultations in the era of personalized medicine. We evaluated the role of caveolin-1 in a large series of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma (UTUC) and found that it was not independently associated with oncological outcomes. Nevertheless, it was associated with adverse pathological features. Considering caveolin-1 in UTUC biopsy specimens could help in improving clinical staging and decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. Caveolin-1 is associated with worse oncological features among patients treated with radical nephroureterectomy for upper tract urothelial carcinoma (UTUC), but is not independently associated with oncological outcomes. Its clinical use could be explored in UTUC biopsy specimens for improving clinical staging and helping in decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment.

Objective: To analyse the outcomes of adjuvant chemotherapy vs observation in a multicentre cohort of patients with upper tract urothelial carcinoma (UTUC) in order to clarify whether such patients benefit from adjuvant chemotherapy after radical nephroureterectomy (RNU). Patients and Methods: Data from 15 centres were collected for a total of 1544 patients, treated between 2000 and 2015. Criteria for patient selection included pT2–4N0/x stage, or lymph node-positive disease, and prior RNU. The standardized difference approach was used to compare subgroup characteristics. Overall survival (OS) was the primary endpoint. The primary analysis used 1:1 propensity score matching, with inverse probability of treatment weighting in addition to this in the secondary analysis. The latter was also performed with the inclusion of covariates, i.e. with ‘doubly robust’ estimation. A 6-month landmark analysis was performed to exclude early events. Results: A total of 312 patients received adjuvant chemotherapy and 1232 underwent observation. Despite differences between the two groups, the standardized difference was generally

A few studies addressed predictive factors of cancer-specific mortality (CSM) in patients with recurrent renal cell carcinoma (RCC) following surgery. Time to recurrence (TTR) is an important predictor of CSM in various types of cancers. The aim of our study was to describe the course of RCC following disease recurrence and to identify prognostic factors that influence CSM with a special focus on TTR.Retrospective analysis of 331 patients who experienced disease recurrence after radical nephrectomy (n = 307) or partial nephrectomy (n = 24) with curative intent. A Cox proportional hazards regression model addressed the association between various clinicopathologic features and CSM after disease recurrence. TTR was defined as time from surgery to occurrence of disease recurrence.Of the 331 patients, 232 (70%) were male, and 99 (30%) were female. The median age at surgery was 62 years (interquartile range, 53-69 years). Median time from nephrectomy to disease recurrence was 1.2 years (interquartile range, 0.5-3.3 years). Of the recurrences, 63 (19%) were local, and 268 (81%) were distant. Shorter time to recurrence (P = .0008), female gender (P = .035), and distant versus local recurrence location (P .0001) were found to be independently associated with CSM following disease recurrence.In patients experiencing disease recurrence after nephrectomy for presumably localized RCC, shorter TTR, female gender, and distant recurrence were found to be associated with worse CSM. The inclusion of these factors into risk-stratification tools may help patient counseling and decision-making regarding type and regimen of salvage treatment.

Purpose: The aim of our study was to evaluate the expression pattern of HER2 overexpression in patients with upper tract urothelial carcinoma (UTUC) and to evaluate its association with clinical outcomes. Methods: This multicenter retrospective study included 732 patients treated with radical nephroureterectomy for UTUC. HER2 expression was assessed using immunohistochemistry and scored according to the HercepTest: Scores of 0 or 1 were considered negative and 2 or 3 as positive. To qualify for 2 scoring, complete membrane staining of more than 10Â % of tumor cells at a moderate intensity had to be observed. Results: HER2 was overexpressed in 262 (35.8Â %) patients. It was associated with pathologic characteristics such as more advanced T stage (pÂ

International audience; PURPOSE: We assessed the prognostic value of extranodal extension and other lymph node parameters in a large multicenter cohort of patients with lymph node metastasis after radical nephroureterectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of 222 patients with lymph node metastasis treated with radical nephroureterectomy for upper tract urothelial carcinoma without neoadjuvant therapy. Each lymph node metastasis was microscopically evaluated for extranodal extension. RESULTS: A median of 4 lymph nodes (IQR 8) was removed. Two lymph nodes (IQR 2) were positive. Lymph node density was 51.3% (IQR 71.7%). Overall 110 patients (49.5%) had extranodal extension, which was associated with more advanced pT stage (p = 0.026). On multivariable analysis extranodal extension was associated with disease recurrence (p = 0.01) and cancer specific mortality (p = 0.013). When stratified by a 30% cutoff, lymph node density was associated with disease recurrence and cancer specific mortality on univariable but not multivariable analysis (p = 0.048 and 0.049, respectively). Adding extranodal extension to a multivariable model including pT stage and tumor architecture improved predictive accuracy for disease recurrence from 70.3% to 74.5% (p

OBJECTIVES To determine whether a minimum number of lymph nodes (LNs) exist to detect lymph node invasion (LNI) in patients undergoing radical nephroureterectomy (RNU) for upper tract urothelial carcinoma. METHODS The study included 551 consecutive patients, from 13 centers worldwide, who underwent RNU and lymphadenectomy (LND) between 1992 and 2006. LND was performed at the discretion of the surgeon. All pathological slides were re-reviewed by uropathologists according to strict criteria. Receiver-operating characteristic curve coordinates were used to determine the probability of diagnosing LNI according to the total number of nodes removed. Additionally, the relationship between the number of nodes removed and the rate of positive LNs was tested in univariate and multivariate logistic regression models. RESULTS Median patient age was 68 years (range: 27-97). Of 551 patients, 140 (25.4%) had positive lymph nodes. Median number of lymph nodes removed was 5 (mean 6.7, range 1-41). The Receiver-operating characteristic coordinates plot indicated that the removal of 13 nodes yielded a 90% probability to detect >= 1 positive LNs. The removal of 8 nodes resulted in a 75% probability of finding >= 1 positive nodes. Removal of > 8 LNs (P = .03; odds ratio 1.49) was independently associated with LN1 after adjusting for pathological stage and grade. CONCLUSIONS Our data indicate that 8 LNs need to be removed at radical nephroureterectomy to achieve a 75% probability of finding >= 1 positive nodes. Further improvement of the specificity of LND will require the removal of more lymph nodes. UROLOGY 74: 1070-1077, 2009. (C) 2009 Elsevier Inc.

Background: The role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated. Objective: To establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC. Design, setting, and participants: The study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006. Intervention: Patients were treated with RNU and lymphadenectomy. Measurements: Univariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified. Results and limitations: in the entire population, the number of LNs removed was not associated with CSM. in univariable (hazard ratio [HR]: 0.99; p = 0.16) or in multi-variable (HR: 0.97; p = 0.12) analyses. In contrast, in the subgroup of pNO patients (n = 412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p = 0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p = 0.004). The inclusion of the variable defining dichotomously the number of removed LNs (= 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p < 0.001). Conclusions: The extension of the lymphadenectomy in pNO UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed. (C) 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Background: Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce. Objective: We compared recurrence and cause-specific mortality rates of ONU and LNU. Design, setting, and participants: Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC). Measurements: Univariable and multivariable survival models tested the effect of procedure type (ONU [n = 979] vs LNU [n = 270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, Ureteralcuff management, previous urothelial bladder cancer, and previous endoscopic treatment. Results and limitations: Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p < 0.001) and less lymphovascular invasion (14.8% vs 21.3%, p=0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p=0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p < 0.001] and 2.0 [p = 0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p = 0.1 for both). Conclusions: Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Longterm follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC. (C) 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Purpose: We created a prognostic tool for the accurate preoperative prediction of nonorgan confined upper tract urothelial carcinoma. Materials and Methods: A computerized data bank containing comprehensive information on 1,453 patients who underwent radical nephroureterectomy at 13 academic institutions was generated and continuously updated. This study comprised a subset of 659 patients in whom all appropriate preoperative prognostic variables (age, gender, race, symptoms, Eastern Cooperative Oncology Group performance status, primary tumor location, tumor architecture, tumor grade and history of previous bladder cancer) were available for statistical analysis. A multivariable logistic regression model containing relevant clinicopathological variables addressed the prediction of nonorgan confined stage disease (T3-4 and/or N+) at radical nephroureterectomy. A backward step-down selection process was applied to achieve the most informative and parsimonious model. Internal validation was performed using 200 bootstrap resamples. Results: Pathological nonorgan confined urothelial carcinoma was found in 40% of patients. Grade, architecture and location of the tumor were independently associated with nonorgan confined disease. A nomogram including these 3 variables achieved 76.6% accuracy in predicting nonorgan confined upper tract urothelial cancer. Conclusions: We developed a simple and accurate prognostic tool for the prediction of locally advanced upper tract urothelial cancer. This preoperative prediction model can be used for designing clinical trials, selecting patients for preoperative systemic therapy and guiding the extent of concomitant lymph node dissection at nephroureterectomy.

Objectives: To evaluate if preoperative symptom classification could refine prediction of outcomes for patients with clinically localized upper-tract urothelial carcinoma (UTUC) managed by radical nephroureterectomy (RNU). Methods: Data on 654 patients with localized UTUC who underwent RNU were reviewed. Preoperative symptoms were classified as incidental (S1), local (S2), and systemic (S3). Clinical and pathologic data were compared between the cohorts. Kaplan-Meier analyses and Cox proportional hazard modeling were used to determine recurrence-free and cancer-specific survival amongst the symptom cohorts. Results: Symptom classification was SI in 213 (33%) patients, S2 in 402 (61%), and S3 in 39 (6%). S3 symptoms were associated with advanced pathology, including higher stage, grade, and lymph node (LN) positivity. Five and 10-year recurrence-free and cancer-specific survival estimates were similar for patients with SI and S2 symptoms (P = 0.75 and 0.58, respectively), but was worse for patients with S3 symptoms (P < 0.001 for both). On multivariate analysis adjusting for final pathologic stage, grade, and LN status, S3 symptoms were not an independent predictor of recurrence (HR 1.44, P = 0.19) or death due to disease (HR 1.66, P = 0.07). Addition of symptom classification, however, increased the accuracy of a model consisting of stage, grade, and LNs for prediction of recurrence-free and cancer-specific survival by 1.4% and 1.3%, respectively (P < 0.001 for both). Conclusions: Local symptoms do not confer worse prognosis compared with patients with incidentally detected UTUC. However, systemic symptoms are associated with worse outcomes despite apparently effective RNU. Patients with systemic symptoms may harbor micrometastatic disease and could potentially benefit from a more rigorous metastatic evaluation or perioperative chemotherapy regimens. (C) 2011 Elsevier Inc. All rights reserved.

OBJECTIVE To determine the risk factors associated with clinical outcome in patients with lymph node (LN)-positive urothelial carcinoma of the upper urinary tract (UTUC) treated with radical nephroureterectomy (RNU) and lymphadenectomy, focusing on the concept of LN density (LND). PATIENTS AND METHODS Patients undergoing RNU with regional lymphadenectomy were identified through multi-institutional databases. All pathology slides were re-evaluated by genitourinary pathologists unaware of the clinical data. The exposure variable used was LND (continuously coded and that of all possible thresholds) with recurrence-free and disease-specific survival (DSS) serving as the outcome measures. RESULTS Of 432 patients undergoing RNU with lymphadenectomy, 135 (31%) had LN metastases. Within a median follow-up of 4.1 years, 90 of the 135 patients with LN metastases (68%) had disease recurrence and 76 (58%) died from UTUC. The mean (sem) 5-year recurrence-free and DSS probabilities were 27 (4)% and 33 (5)%, respectively. The median (range) LND was 50 (3–100)%. The most informative threshold for LND in relation to outcome was 30%. In multivariable analyses that adjusted for the effects of tumour stage and grade, patients with a LND of ≥30% were at greater risk of both cancer recurrence, with 5-year rates of 25 (5)% vs 38 (8)% (hazard ratio 1.8, P = 0.021) and mortality, with 5-year rates of 30 (6)% vs 48 (9)% (1.7, P = 0.032) compared to those with a LND of

Purpose: We examined the impact of lymphadenectomy on the clinical outcomes of patients with upper tract urothelial cancer treated with radical nephroureterectomy. Materials and Methods: Data were collected on 1,130 consecutive patients with pT1-4 upper tract urothelial cancer treated with radical nephroureterectomy at 13 centers worldwide. Patients were grouped according to nodal status (pN0 vs pNx vs pN+). The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were reevaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models measured the association of nodal status (pN0 vs pNx vs pN+) with cancer specific survival. Results: Overall 412 patients (36.5%) had pNO disease, 578 had pNx disease (51.1%) and 140 had pN+ disease (12.4%). The 5-year cancer specific survival estimate was lower in patients with pN+ compared to those with pNx disease (35% vs 69%, p

OBJECTIVES To assess the sex differences in the clinical and pathologic characteristics of upper tract urothelial carcinoma (UTUC) and to determine the effect on prognosis after radical nephroure-terectomy (RNU) in a large multicenter series. METHODS The records of 1363 patients who had undergone RNU were reviewed from the UTUC Collaboration database. The median follow-up was 47 months (range 0-250). The pathologic slides were re-evaluated by genitourinary pathologists unaware of the original findings from the slides and the clinical Outcomes. The endpoints were freedom from tumor recurrence and disease-specific survival. RESULTS The male-to-female ratio was 2.1:1. The women were older than the men at diagnosis (70 +/- 11 vs 68 +/- 11 years; P

Purpose: There is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival. Materials and Methods: Using an intemational collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pT3N0, pT4N0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts. Results: Of high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p

OBJECTIVE To assess whether tumour architecture can help to refine the prognosis of patients treated with nephroureterectomy (NU) for urothelial carcinoma (UC) of the upper urinary tract (UT), as the prognostic value of tumour architecture (papillary vs sessile) in UTUC remains elusive. PATIENTS AND METHODS The study included 1363 patients with UTUC and treated with radical NU at 12 centres worldwide. All slides were re-reviewed according to strict criteria by genitourinary pathologists who were unaware of the findings of the original pathology slides and clinical outcomes. Gross tumour architecture was categorized as sessile vs papillary. RESULTS Papillary growth was identified in 983 patients (72.2%) and sessile growth in 380 (27.8%). The sessile growth pattern was associated with higher tumour grade, more advanced stage, lymphovascular invasion, and metastasis to lymph nodes (all P

Purpose To assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). Patients and Methods Data were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space. Results LVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140). Conclusion LVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.