PDF file - 425K, Clusters of genes with coordinated expression across samples

PDF file - 1.8MB, Detailed description of gene expression signatures

PDF file - 392K, Expression of cell adhesion genes

XLS file - 22K, Summary of patient and sample data

Supplementary Tables S1-S2 from Distinct Mitotic Segregation Errors Mediate Chromosomal Instability in Aggressive Urothelial Cancers

XLS file - 193K, Patient and sample data

Supplementary Figures 1-6 from Combined Gene Expression and Genomic Profiling Define Two Intrinsic Molecular Subtypes of Urothelial Carcinoma and Gene Signatures for Molecular Grading and Outcome

PDF file - 519K, Preprocessing of expression data, Identification of molecular subtypes in urothelial carcinoma, validation of MS subtypes in independent datasets, sample classification

PDF file - 1.8MB, Validation of tumor clusters in external data sets

Supplementary Figure S1 from Distinct Mitotic Segregation Errors Mediate Chromosomal Instability in Aggressive Urothelial Cancers

Objectives To investigate the long‐term functional outcomes and complications after continent cutaneous diversion with the Lundiana pouch. Patients and Methods Complications, re‐operations, renal function, and continence were ascertained from patient charts. Outcome variables were validated by a second and independent review of the patient files. Results A complication of Clavien–Dindo grade ≥ III , including unscheduled re‐admissions, occurred in 45/193 patients (23%) at ≤90 days of surgery. At a median follow‐up of 13 years, 105/193 patients (54%) had undergone at least one re‐operation, with uretero‐intestinal stricture being the most prevalent cause [28 patients (15%)]. Re‐operations were more prevalent in patients operated during the first half of the study period than during the second half (2000–2007; 62% vs 47%; P = 0.03), and they were also more frequent in patients who underwent surgery for benign causes than in patients who underwent surgery for malignancy (60% vs 51%; P = 0.04). Continence was achieved in 172/188 patients (91%). In all, 16% of all patients required revisional surgery of the outlet to remain continent with an easily catheterisable pouch or to address stomal stenosis. The mean decrease in estimated glomerular filtration rate was more pronounced in patients with benign indications for urinary diversion than in those with malignancies, even after adjusting for younger age at surgery and longer follow‐up in the former group (22 vs 11 mL /min/1.73 m 2 ; P < 0.006). A disinterested third‐party assessment revealed 10 postoperative complications, 17 re‐operations during follow‐up, and seven occasions of hospitalisation due to pyelonephritis (included in data above) not recorded at the primary data review. Conclusions The Lundiana pouch is associated with a high risk of re‐operation, although the functional results are good. Independent review by a third party increased the validity of the outcome data.

Background: One third of patients with stage T1 urothelial carcinoma (UC) progress to muscle-invasive disease requiring radical surgery. Thus, reliable tools are needed for risk stratification of stage T1 UC.Objective: To investigate the extent to which stratification of stage T1 tumours into previously described molecular pathologic UC subtypes can provide improved information on tumour progression.Design, setting, and participants: A population-based cohort of 167 primary stage T1 UCs was characterised by immunohistochemistry and classified into the molecular subtypes urobasal (Uro, 32%), genomically unstable (GU, 58%), and squamous-cellcarcinoma- like (SCCL, 10%).Outcome measurements and statistical analysis: Progression-free survival using univariate and multivariate models.Results and limitations: Subtype classification was validated using nine additional markers with known subtype-specific expression. Analysis of mRNA expression of progression biomarkers revealed a strong association with molecular subtype. Kaplan-Meier analyses showed that the risk of progression was low for Uro tumours and high for GU/SCCL tumours. High progression risk scores were found only for GU/SCCL tumours. Clinical risk factors such as multifocality, concomitant carcinoma in situ, invasion depth, lymphovascular invasion, and high CD3(+) lymphocyte infiltration were observed almost exclusively in GU/SCCL cases.Conclusions: Molecular subtypes Uro, GU, and SCCL were identified in an independent population-based cohort of stage T1 UCs. Biomarkers and clinical risk factors for progression were associated with molecular subtype. Rapidly progressing T1 tumours were of subtype GU or SCCL and had either a high progression risk score or an elevated CD3+ cell count.Patient summary: We show that classification of stage T1 urothelial carcinoma into molecular subtypes can improve the identification of patients with progressing tumours. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

OBJECTIVES:Urothelial carcinoma (UC) aggressiveness is determined by tumor inherent molecular characteristics, such as molecular subtypes, as well as by host reactions directed toward the tumor. Cell types responsible for the host's response include tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). The aim of the present investigation was to explore the immunological response in relation to UC molecular subtypes and to evaluate the prognostic effect of TIL and TAM counts in tissue sections from muscle-invasive (MI) tumors. METHODS AND MATERIALS:Tissue microarrays with 296 tumors spanning all pathological stages and grades were analyzed with antibodies for CD3, CD8, FOXP3, CD68, and CD163. Cases were classified into the following molecular subtypes: urobasal, genomically unstable, and squamous cell carcinoma-like using a combination of immunohistochemistry and histology. The Cox regression and Kaplan-Meier analyses were performed with progression-free survival and disease-specific survival as end points. RESULTS:UC molecular subtypes demonstrate different degrees of immunological responses; the urobasal subtype induces a weak response, the genomically unstable subtype induces an intermediate response, and the squamous cell carcinoma-like subtype induces a strong response. These subtype specific responses are independent of tumor stage and include both TILs and TAMs. The presence of infiltrating CD3(+) TILs was significantly associated with good prognosis in the MI cases (P<0.01). This positive association was modulated by the presence of CD68(+) TAMs. The strongest association with poor survival was observed for a high ratio between CD68 and CD3 (P = 7×10(-5)). CONCLUSION:UC molecular subtypes induce immunological responses at different levels. A high CD68/CD3 ratio identifies a bad prognosis group among MI UC cases.

OBJECTIVE:To determine the rates of the available urinary diversion options for patients treated with radical cystectomy for bladder cancer in different settings (pioneering institutions, leading urologic oncology centers, and population based). METHODS:Population-based data from the literature included all patients (n = 7608) treated in Sweden during the period 1964-2008, from Germany (n = 14,200) for the years 2008 and 2011, US patients (identified from National Inpatient Sample during 1998-2005, 35,370 patients and 2001-2008, 55,187 patients), and from Medicare (n = 22,600) for the years 1992, 1995, 1998, and 2001. After the International Consultation on Urologic Diseases-European Association of Urology International Consultation on Bladder Cancer 2012, the urinary diversion committee members disclosed data from their home institutions (n = 15,867), including the pioneering institutions and the leading urologic oncology centers. They are the coauthors of this report. RESULTS:The receipt of continent urinary diversion in Sweden and the United States is <15%, whereas in the German high-volume setting, 30% of patients receive a neobladder. At leading urologic oncology centers, this rate is also 30%. At pioneering institutions up to 75% of patients receive an orthotopic reconstruction. Anal diversion is <1%. Continent cutaneous diversion is the second choice. CONCLUSION:Enormous variations in urinary diversion exist for >2 decades. Increased attention in expanding the use of continent reconstruction may help to reduce these disparities for patients undergoing radical cystectomy for bladder cancer. Continent reconstruction should not be the exclusive domain of cystectomy centers. Efforts to increase rates of this complex reconstruction must concentrate on better definition of the quality-of-life impact, technique dissemination, and the centralization of radical cystectomy.

OBJECTIVE:This study aimed to reveal the late results of rediversion after urinary diversion.MATERIAL AND METHODS:From 1985 to 2009, 28 patients underwent rediversion at the Department of Urology, Lund University Hospital, Sweden. Median follow-up after rediversion was 147 months (range 7-300 months, interquartile range 63-214). The following rediversions were performed: ileal conduit, cutaneous ureterostomy, ureterosigmoidostomy and rectal bladder to continent cutaneous diversion (group I, n = 17); cutaneous ureterostomy to neobladder (group II, n = 1); ileal conduit and cutaneous ureterostomy to gastric conduit (group III, n = 2); and continent cutaneous diversion and neobladder to ileal conduit (group IV, n = 8).RESULTS:In group I, reoperations were necessary after rediversion in nine of the 17 patients. Excellent functional results were obtained in 14 patients. Two patients, both with Kock pouches, underwent multiple operations and finally required rediversion to an ileal conduit. The sole patient in group II had a ureteric reimplantation owing to ureterointestinal stricture and is now continent but performs clean intermittent catheterization. Both patients in group III underwent reoperations owing to ureteric strictures and renal stones. In group IV, one patient had ureteric stenosis, and one died owing to complications related to later surgery for small bowel obstruction.CONCLUSIONS:Complications are common after urinary rediversion, and several of the present patients required reoperations for a variety of reasons. Modern techniques for continent cutaneous diversion can provide excellent functional results. Patients with difficulties in accepting a urostomy bag pose special problems and need extensive information and counselling.

Objective. Urinary diversion may be an option in patients with disabling lower urinary tract dysfunction (DLUTD), refractory to conservative and minor invasive treatment. The aim of this study was to evaluate whether urostomy improves quality of life and cost of surgery, in terms of complications, loss of kidney function and hospital stay, in these patients. Material and methods. This prospective study included 52 consecutive patients (nine men and 43 women) with various benign disorders. Twenty-six patients received an ileal conduit and 26 a continent cutaneous diversion. The patients completed the general health-related quality of life instrument WHOQOL-BREF and a urinary problem-specific quality of life instrument preoperatively and 6 and 12 months after surgery. Length of hospital stay and complications were registered. Intravenous urography and determination of glomerular filtration rate (GFR) were performed preoperatively and 12 months postoperatively. Results. Disease-specific and health-related quality of life improved significantly (p < 0.0005 and p < 0.05) in all domains except for social relationship, from preoperative to 12 months after surgery. There was no difference in improvement between patients with continent and those with incontinent diversion. Mean hospital stay was 14 days. Early and late complications required open surgery in 12 patients (23%). GFR was unchanged postoperatively. Conclusions. Urinary diversion improves health-related and disease-specific quality of life in patients with DLUTD refractory to conservative and minor invasive treatments. The burden of surgery is acceptable. Urinary diversion could be recommended more often in such patients.

Objective. The aim of this study was to evaluate enterocystometry, voiding pattern and urine leakage of four types of orthotopic bladder substitute. Material and methods. At eight urological departments, 78 consecutive men were studied: 66 with an ileal neobladder [30 Studer pouches (S), 24 Hautmann pouches (H) and 12 T-pouches (T)] and 12 with a right colonic [Goldwasser type (G)] neobladder. Enterocystometry, determination of residual urine, micturition protocol and 24 h pad weight test were performed 6 and 12 months postoperatively. Results. Colonic neobladders had higher pouch pressure at first desire, normal desire and strong desire than ileal neobladders (except at first and normal desire at 12 months) (p < 0.02) and contraction was present more often at both 6 and 12 months (p < 0.01 and p < 0.01). Compliance was good in all types of pouch. Intermittent self-catheterization was more common in H patients at 6 months (p = 0.033). All patients with colonic neobladders used pads during the day and night. In patients with ileal pouches 32% used pads during the day and 70% during the night at 12 months. Urine leakage was higher in patients with colonic bladders at 6 and 12 months during the day (mean/median of 98/31 ml and 82/16 ml versus 10/0 ml and 4/0 ml, p < 0.001). T-pouches had excellent day-time continence, but nocturnal leakage was high. Conclusions. The Hautmann pouch and the Studer pouch behaved similarly at enterocystometry and clinically, and continence was good in the majority of patients. The low number of patients with the other two types of pouch precludes definitive statements.

Context: A summary of the 2nd International Consultation on Bladder Cancer recommendations on the reconstructive options after radical cystectomy (RC), their outcomes, and their complications. Objective: To review the literature regarding indications, surgical details, postoperative care, complications, functional outcomes, as well as quality-of-life measures of patients with different forms of urinary diversion (UD). Evidence acquisition: An English-language literature review of data published between 1970 and 2012 on patients with UD following RC for bladder cancer was undertaken. No randomized controlled studies comparing conduit diversion with neobladder or continent cutaneous diversion have been performed. Consequently, almost all studies used in this report are of level 3 evidence. Therefore, the recommendations given here are grade C only, meaning expert opinion delivered without a formal analysis. Evidence synthesis: Indications and patient selection criteria have significantly changed over the past 2 decades. Renal function impairment is primarily caused by obstruction. Complications such as stone formation, urine outflow, and obstruction at any level must be recognized early and treated. In patients with orthotopic bladder substitution, daytime and nocturnal continence is achieved in 85-90% and 60-80%, respectively. Continence is inferior in elderly patients with orthotopic reconstruction. Urinary retention remains significant in female patients, ranging from 7% to 50%. Conclusions: RC and subsequent UD have been assessed as the most difficult surgical procedure in urology. Significant disparity on how the surgical complications were reported makes it impossible to compare postoperative morbidity results. Complications rates overall following RC and UD are significant, and when strict reporting criteria are incorporated, they are much higher than previously published. Fortunately, most complications are minor (Clavien grade 1 or 2). Complications can occur up to 20 yr after surgery, emphasizing the need for lifelong monitoring. Evidence suggests an association between surgical volume and outcome in RC; the challenge of optimum care for elderly patients with comorbidities is best mastered at high-volume hospitals by high-volume surgeons. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones to achieve good long-term results. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.