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Background: Androgen inactivation occurs mainly through the glucuronidation conjugative reaction mediated by UDP-glucuronosyltransferases (UGTs). This metabolic process is involved in the control of systemic and local androgen bioavailability., Objective: To examine the relationship among expression of the androgen-inactivating UGT2B28 enzyme, circulating steroid hormone levels, and clinical phenotype in prostate cancer (PCa)., Design, Setting, and Participants: We conducted an analysis of a high-density prostate tumor tissue microarray consisting of 239 localized PCa cases. The study of 51 additional PCa patients with no copies of UDP glucuronosyltransferase 2B subfamily, polypeptide B28 (UGT2B28) in their genomes was performed to confirm the importance of the enzyme on circulating hormone levels., Outcome Measurements and Statistical Analysis: Steroid hormones were measured by mass spectrometry. Multivariate Cox proportional hazard models assessed the influence of UGT2B28 on progression, and general linear model regression evaluated variations in hormone levels., Results and Limitations: Tumor overexpression of UGT2B28 was associated with lower prostate-specific antigen levels at diagnosis, higher Gleason scores, margin and nodal invasion status, and it was shown to be an independent prognostic factor associated with progression. Enzyme overexpression correlated with 30% higher circulating levels of testosterone (T) and dihydrotestosterone (DHT). Patients with no copies of UGT2B28 in their genomes have lower levels of T (19%), DHT (17%), its glucuronide metabolites (18-38%), and enhanced levels of the adrenal precursor androstenedione (36%)., Conclusions: The UGT2B28 steroid-inactivating pathway modifies circulating T and DHT levels, and UGT2B28 overexpression is associated with high-grade PCa. Our work has uncovered the role of UGT2B28 as a regulator of steroidogenesis and underscores the interconnectivity among the steroid-inactivation capacity of cancer cells, hormone levels, disease characteristics, and the risk of cancer progression., Patient Summary: The androgen-inactivating UGT2B28 enzyme influences hormone levels, clinical and pathologic factors, and the risk of cancer progression., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.) more...

Cigarette smoking is the most important known risk factor for urinary bladder cancer. Selected arylamines in cigarette smoke are recognized human bladder carcinogens and undergo biotransformation through several detoxification pathways, such as the glutathione S-transferases (GST), and uridine-diphospho-glucuronosyltransferases (UGT) pathways. GSTM1 deletion status and UGT1A1*28 rs8175347 genotypes were assessed in 189 non-muscle-invasive bladder cancers (NMIBC) patients with pTa (77.2%) and pT1 (22.8%) tumors and a mean follow-up of 5.6 years, to investigate whether two common functional polymorphisms in GSTM1 and UGT1A1 genes and smoking history are associated with recurrence-free survival of patients with NMIBC. Most patients were current (48.7%) or previous (35.4%) cigarette smokers and 15.9% never smoked. Tumor recurrence occurred in 65.1% of patients, at a median time of 12.9 months. Upon multivariate analysis, previous and current smokers approximately tripled their risk of recurrences [HR = 2.76; 95% confidence interval (CI), 1.03-7.40 and HR = 2.93; 95% CI, 1.08-7.94, respectively]. When adjusted for age, smoking status, stage, grade, gender, and presence of carcinoma in situ, carriers of GSTM1 (+/- and -/-) and UGT1A1*28/*28 alleles were significantly at risk of NMIBC recurrence (HR = 10.05; 95% CI, 1.35-75.1 and HR = 1.91; 95% CI, 1.01-3.62, respectively). Compared with nonsmokers with UGT1A1*1/*1 and *1/*28 genotypes, previous and current smokers homozygous for the UGT1A1*28 allele demonstrated a risk of recurrence of 4.95 (95% CI, 1.02-24.0) and 5.32 (95% CI, 2.07-13.7), respectively. This study establishes a connection between GSTM1, UGT1A1, and tobacco exposure as prognostic markers of NMIBC recurrence in bladder cancer patients. These findings warrant validation in larger cohorts., (©2015 American Association for Cancer Research.) more...

Background: The tumor proliferative index marker Ki-67 was shown to be associated with clinically significant outcomes in prostate cancer, but its clinical application has limitations due to lack of uniformity and consistency in quantification. Our objective was to compare the measurements obtained with digital image analysis (DIA) versus virtual microscopy (visual scoring (VS))., Methods: To do so, we compared the measurement distributions of each technique and their ability to predict clinically useful endpoints. A tissue microarray series from a cohort of 225 men who underwent radical prostatectomy was immunostained for Ki-67. The percentage of Ki-67 positive nuclei in malignant cells was assessed both by VS and DIA, and a H-score was calculated. The distribution and predictive ability of these scoring methods to predict biochemical recurrence (BCR) and death from prostate cancer (DPCa) were compared using Mann-Whitney test and C-index., Results: The measurements obtained with VS were similar to the DIA measurements (p = 0.73) but dissimilar to the H-score (p < 0.001). Cox regression models showed that Ki-67 was associated with BCR (HR 1.46, 95 % CI 1.10-1.94) and DPCa (HR 1.26, 95 % CI 1.06-1.50). C-indexes revealed that Ki-67 was a better predictor of DPCa (0.803, 0.8059 and 0.789; VS, DIA and H-score, respectively) than of BCR (0.625, 0.632 and 0.604; VS, DIA and H-score, respectively)., Conclusion: The measurement distributions and the predictive abilities of VS and DIA were similar and presented the same predictive behaviour in our cohort, supporting the role of Ki-67 proliferative index as an important prognostic factor of BCR and DPCa in prostate cancer post RP., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6656878501536663. more...

Background: Conditional survival (CS) provides better estimates of the survival probability at each follow-up time, and its usefulness has been proven in several solid malignancies., Objective: To assess the changes in 5-yr CS rates after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) and to determine how well-established prognostic factors evolve over time., Design, Setting, and Participants: We analysed data from 3544 patients treated with RNU at 15 international academic centres between 1989 and 2012., Intervention: RNU., Outcomes Measurements and Statistical Analysis: Conditional intravesical recurrence-free (IVRFS), cancer-specific survival (CSS), and overall survival (OS) estimates were calculated using the Kaplan-Meier method. A multivariable Cox regression model was used to calculate proportional hazard ratios for the prediction of mortality., Results and Limitations: The 5-yr bladder cancer recurrence-free survival, CSS, and OS rates were 54.9%, 72.2%, and 62.6%, respectively. Given a 1-, 2-, 3-, and 4-yr survivorship, the 5-yr conditional OS rates improved to 65.2%, 69.3%, 71.5%, and 73.0%, respectively. The 5-yr CS improvement was primarily noted among surviving patients with advanced-stage disease. The impact of pathologic parameters on CS estimates decreased over time for both CSS and OS, whereas the impact of age and gender increased with survivorship. No survival benefit was noted regarding the adjuvant chemotherapy status. Findings were confirmed upon multivariable analyses. Tumour location, the presence of carcinoma in situ, and the type of bladder cuff excision were continuously predictive for IVRFS whatever the survivorship. A limitation is the retrospective design., Conclusions: CS analysis demonstrates that the patient risk profile evolves during the post-RNU follow-up. The probability of survival markedly increases over time in patients having high-stage disease. The impact of prognostic pathologic features decreases over time and can disappear for long-term CS., Patient Summary: In this study, we found that the risk of intravesical recurrence, cancer-specific survival, and overall mortality evolves over the follow-up after surgery. Taking into account the survivorship provides better estimates of the survival probability at each follow-up time., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.) more...

Growing evidence suggests that tumor-associated macrophages (TAM) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling, and immunosuppression. In this study, prostate cancer under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to prostate cancer disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF1 or CSF1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF1 signaling through its receptor, CSF1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared with ABT alone., (©2015 American Association for Cancer Research.) more...

Background: The role of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in prostate cancer (PCa) has not been well defined yet. Because high-grade PCa tends to exhibit increased glycolytic rate, FDG-PET/CT could be useful in this setting. The aim of this study was to assess the value of FDG-PET/CT for pre-operative staging and prognostic stratification of patients with high-grade PCa at biopsy., Methods: Fifty-four patients with a Gleason sum≥8 PCa at biopsy underwent FDG-PET/CT as part of the staging workup. Thirty-nine patients underwent radical prostatectomy (RP) and pelvic lymph node (LN) dissection, 2 underwent LN dissection only, and 13 underwent non-surgical treatments. FDG-PET/CT findings from clinical reports, blinded reading and quantitative analysis were correlated with clinico-pathological characteristics at RP., Results: Suspicious foci of increased FDG uptake were found in the prostate, LNs and bones in 44, 13 and 6% of patients, respectively. Higher clinical stage, post-RP Gleason sum and pattern, and percentage of cancer involvement within the prostate were significantly associated with the presence of intraprostatic FDG uptake (IPFU) (P<0.05 in all cases). Patients without IPFU who underwent RP were downgraded to Gleason≤7 in 84.6% of cases, as compared to 30.8% when IPFU was reported (P=0.003). Qualitative and quantitative IPFU were significantly positively correlated with post-RP Gleason pattern and sum, and pathological T stage. Absence and presence of IPFU were associated with a median 5-year cancer-free survival probability of 70.2 and 26.9% (P=0.0097), respectively, using the CAPRA-S prognostic tool., Conclusion: These results suggest that, among patients with a high-grade PCa at biopsy, FDG-PET/CT could improve pre-treatment prognostic stratification by predicting primary PCa pathological grade and survival probability following RP. more...

Introduction: The proportion of patients with stage 1 renal tumours receiving partial nephrectomy is considered a quality of care indicator. The objective of this study was to characterize surgical practice patterns at Canadian academic institutions for the treatment of these tumours., Methods: The Canadian Kidney Cancer Information System (CKCis) is a multicentre collaboration of 13 academic institutions in Canada. All patients with pathologic stage T1 renal tumours in CKCis were identified. Descriptive statistics were performed to characterize practice patterns over time. Associations between patient, tumour, and treatment factors with the use of partial nephrectomy were determined., Results: From 1988 to April 2014, 1453 patients with pathologic stage 1 renal tumours were entered in the CKCis database. Of these, 977 (67%) patients had pT1a tumours; of these, 765 (78%) received partial nephrectomy. Of the total number of patients (1453), 476 (33%) had pT1b tumours; of these, 204 (43%) received partial nephrectomy. The use of partial nephrectomy increased over time from 60% to 90% for pT1a tumours and 20% to 60% for pT1b tumours. Stage pT1b (relative risk [RR] 0.56, 95% confidence interval [CI] 0.50-0.63) and minimally invasive surgical approach (RR 0.78, 95% CI 0.73-0.84 for pT1a and RR 0.23, 95% CI 0.17-0.30 for pT1b) were associated with decreased use of partial nephrectomy. Most patient factors including age, gender, body mass index, hypertension, and renal function were not significantly associated with use of partial nephrectomy (p > 0.05)., Conclusion: Almost all pT1a and most pT1b renal tumours managed surgically at academic centres in Canada receive partial nephrectomy. The use of partial versus radical nephrectomy appears to occur independently of patient age and comorbid status, which may indicate that urologists are performing partial nephrectomy whenever technically feasible based on tumour factors. Although the ideal proportion patients receiving partial nephrectomy cannot be determined, treatment distribution observed in this cohort may indicate an achievable case distribution among experienced surgeons. more...

The prognostic significance of common deletions in uridine diphospho-glucuronosyltransferase 2B (UGT2B) genes encoding sex steroid metabolic enzymes has been recently recognized in localized prostate cancer (PCa) after radical prostatectomy (RP). However, the role of germline variations at the UGT1 locus, encoding half of all human UGTs and primarily involved in estrogen metabolism, remains unexplored. We investigated whether variants of UGT1 are potential prognostic markers. We studied 526 Caucasian men who underwent RP for clinically localized PCa. Genotypes of patients for 34 haplotype-tagged single-nucleotide polymorphisms (htSNPs) and 11 additional SNPs across the UGT1 locus previously reported to mark common variants including functional polymorphisms were determined. The risk of biochemical recurrence (BCR) was estimated using adjusted Cox proportional hazards regression and Kaplan-Meier analysis. We further investigated whether variants are associated with plasma hormone levels by mass spectrometry. In multivariable models, seven htSNPs were found to be significantly associated with BCR. A greater risk was revealed for four UGT1 intronic variants with hazard ratios (HRs) of 1.59-1.88 (P<0.002) for htSNPs in UGT1A10, UGT1A9, and UGT1A6. Conversely, decreased BCR was associated with three htSNPs in introns of UGT1A10 and UGT1A9 (HR=0.56-058; P≤0.01). An unfavorable UGT1 haplotype comprising all risk alleles, with a frequency of 14%, had a HR of 1.68 (95% CI=1.13-2.50; P=0.011). Significant alteration in circulating androsterone levels was associated with this haplotype, consistent with changes in hormonal exposure. This study provides the first evidence, to our knowledge, that germline polymorphisms of UGT1 are potential predictors of recurrence of PCa after prostatectomy., (© 2015 Society for Endocrinology.) more...

Aim: We determined whether the Y-box binding protein-1 (YB-1) and its binding partner, the X-linked ribosomal protein S4 (RPS4X), are associated with clinical outcome in bladder cancer., Materials &amp; Methods: A population of 167 patients with muscle-invasive bladder tumor without evidence of metastasis at time of cystectomy was analyzed retrospectively. YB-1 and RPS4X expressions were evaluated immunohistochemically in tumors and analyzed for association with clinical variables and survival., Results: Kaplan-Meier and multivariate Cox regression analyses indicated that low expression of RPS4X was associated with a higher risk of death or disease recurrence. In contrast, YB-1 was not significantly associated with either recurrence-free or overall survival., Conclusion: Low RPS4X expression is associated with poor disease-specific and recurrence-free survival in bladder cancer. more...

Recent evidence indicates that microRNAs might participate in prostate cancer initiation, progression and treatment response. Germline variations in microRNAs might alter target gene expression and modify the efficacy of prostate cancer therapy. To determine whether genetic variants in microRNAs and microRNA target sites are associated with the risk of biochemical recurrence (BCR) after radical prostatectomy (RP). We retrospectively studied two independent cohorts composed of 320 Asian and 526 Caucasian men with pathologically organ-confined prostate cancer who had a median follow-up of 54.7 and 88.8 months after RP, respectively. Patients were systematically genotyped for 64 single-nucleotide polymorphisms (SNPs) in microRNAs and microRNA target sites, and their prognostic significance on BCR was assessed by Kaplan-Meier analysis and Cox regression model. After adjusting for known clinicopathologic risk factors, two SNPs (MIR605 rs2043556 and CDON rs3737336) remained associated with BCR. The numbers of risk alleles showed a cumulative effect on BCR [perallele hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.16-2.21, p for trend = 0.005] in Asian cohort, and the risk was replicated in Caucasian cohort (HR 1.55, 95% CI 1.15-2.08, p for trend = 0.004) and in combined analysis (HR 1.57, 95% CI 1.26-1.96, p for trend <0.001). Results warrant replication in larger cohorts. This is the first study demonstrating that SNPs in microRNAs and microRNA target sites can be predictive biomarkers for BCR after RP., (© 2014 UICC.) more...

Introducton: Radical nephroureterectomy for upper tract urothelial carcinoma (UTUC) must include some form of distal ureter management to avoid high rates of tumour recurrence. It is uncertain which distal ureter management technique has the best oncologic outcomes. To determine which distal ureter management technique resulted in the lowest tumour recurrence rate, we analyzed a multi-institutional Canadian radical nephroureterectomy database., Methods: We retrospectively analyzed patients who underwent radical nephroureterectomy with distal ureter management for UTUC between January 1990 and June 2010 at 10 Canadian tertiary hospitals. Distal ureter management approaches were divided into 3 categories: (1) extravesical tenting for ureteric excision without cystotomy (EXTRAVESICAL); (2) open cystotomy with intravesical bladder cuff excision (INTRAVESICAL); and (3) extravesical excision with endoscopic management of ureteric orifice (ENDOSCOPIC). Data available for each patient included demographic details, distal ureter management approach, pathology and operative details, as well as the presence and location of local or distant recurrence. Clinical outcomes included overall recurrence-free survival and intravesical recurrence-free survival. Survival analysis was performed with the Kaplan-Meier method. Multivariable Cox regression analysis was also performed., Results: A total of 820 patients underwent radical nephroureterectomy with a specified distal ureter management approach at 10 Canadian academic institutions. The mean patient age was 69.6 years and the median follow-up was 24.6 months. Of the 820 patients, 406 (49.5%) underwent INTRAVESICAL, 316 (38.5%) underwent EXTRAVESICAL, and 98 (11.9%) underwent ENDOSOPIC distal ureter management. Groups differed significantly in their proportion of females, proportion of laparoscopic cases, presence of carcinoma in situ and pathological tumour stage (p < 0.05). Recurrence-free survival at 5 years was 46.3%, 35.6%, and 30.1% for INTRAVESICAL, EXTRAVESICAL and ENDOSCOPIC, respectively (p < 0.05). Multivariable Cox regression analysis confirmed that INTRAVESICAL resulted in a lower hazard of recurrence compared to EXTRAVESICAL and ENDOSCOPIC. When looking only at intravesical recurrence-free survival (iRFS), a similar trend held up with INTRAVESICAL having the highest iRFS, followed by ENDOSCOPIC and then EXTRAVESICAL management (p < 0.05). At last follow-up, 406 (49.5%) patients were alive and free of disease., Conclusion: Open intravesical excision of the distal ureter (INTRAVESICAL) during radical nephroureterectomy was associated with improved overall and intravesical recurrence-free survival compared with extravesical and endoscopic approaches. These findings suggest that INTRAVESICAL should be considered the gold standard oncologic approach to distal ureter management during radical nephroureterectomy. Limitations of this study include its retrospective design, heterogeneous cohort, and limited follow-up. more...

Introduction and Objectives: Mortality due to AKI has not changed significantly over the past 50 years. This is due in part to failure to detect early AKI and to initiate appropriate therapeutic measures. There is therefore a need to identify biomarkers that would improve the early detection of AKI. The objective of this study was to assess whether cystatin C levels obtained at specific timepoints during laparoscopic partial nephrectomy (PN) could be early predictors of AKI., Materials and Methods: Twenty-five patients underwent laparoscopic PN for organ-confined tumors. All procedures were performed by two surgeons in a single institution. Plasma samples were collected preoperatively, and post-unclamping at 5, 20, 120 min and on the day following surgery. Plasma cystatin C was measured by enzyme-linked immunosorbent assay. Correlation between levels of cystatin C and other parameters of interest were assessed in order to define cystatin C ability to predict AKI and loss of renal function following laparoscopic PN., Results: The mean baseline eGFR was 93 ml/min/1.73 m(2). Warm ischemia time varied between 16 and 44 min. Post-operative day 1 (POD1) cystatin C levels compared to baseline were increased in 13 (52%) of the patients. There was a high correlation between the difference of POD 1 and baseline value, and eGFR in the immediate postoperative period (r = -0.681; P = 0.0002) and at 12-month follow-up (r = -0.460, P = 0.048). However, the variation in cystatin C levels at earlier timepoints were not associated to AKI nor renal function., Conclusions: High increase in POD 1 cystatin C levels from baseline may help identify patients with AKI and those at higher risk of chronic kidney disease, following laparoscopic PN. more...

Purpose: To evaluate the impact of concomitant carcinoma in situ (CIS) on upstaging and outcome of patients treated with radical cystectomy with pelvic lymph node dissection., Methods: We collected and pooled a database of 1,968 patients who have undergone radical cystectomy between 1998 and 2008 in eight academic centers across Canada. Collected variables included patient's age, gender, tumor grade, histology and the presence of concomitant CIS with either cTa-1 or cT2 disease, dates of recurrence and death., Results: In the presence of concomitant CIS, upstaging following radical cystectomy occurred in 48 and 55 % of patients with cTa-1 and cT2 disease, respectively. On univariate analysis, the presence of concomitant CIS with cT2 disease was associated with upstaging (p < 0.0001), and the presence of concomitant CIS with cTa-1 disease was also associated with upstaging but did not reach statistical significance (p = 0.0526). On multivariate analyses, the presence of concomitant CIS with either cTa-1 or cT2 tumors was independently prognostic of disease upstaging (p = 0.0001 and 0.0186, respectively). However, on multivariate analysis that incorporates pathologic stage, concomitant CIS was not significantly associated with worse overall, recurrence-free or disease-specific survival., Conclusion: These results demonstrate that while the presence of concomitant CIS on cystectomy specimens does not independently affect outcomes, its presence is significantly predictive of a higher rate of upstaging at radical cystectomy. more...

Objective: To evaluate risk factors for bladder cancer recurrence in a cohort of patients treated with radical nephroureterectomy (RNU)., Patients and Methods: At 10 Canadian University Centers, we retrospectively evaluated data, between 1990 and 2010, from 743 patients who were free from bladder cancer and were previously treated with RNU for upper tract urothelial cancer., Results: Of 743 patients, 167 (22.5%) developed bladder tumors after a median time of 17.2 months after RNU. Multivariable analysis detected age (hazard ratio [HR] = 1.028; 95% CI: 1.010-1.046; P = 0.0018), tumor location in both the renal pelvis and the ureter (HR = 2.205; 95% CI: 1.355-3.589; P = 0.0015), the use of adjuvant systemic chemotherapy (HR = 2.309; 95% CI: 1.439-3.705; P = 0.0005), and laparoscopic surgery (HR = 1.876; 95% CI: 1.226-2.87; P = 0.0037) as risk factors for bladder cancer recurrence. Open excision of a bladder cuff (HR = 0.661; 95% CI: 0.453-0.965; P = 0.0319) and transurethral resection of the intramural ureter (HR = 0.548; 95% CI: 0.306-0.981; P = 0.0429) on comparison with extravesical resection decreased the risk of bladder cancer recurrence significantly. Major limitations were the retrospective design and partially missing data, although the significance of variables did not change in the imputation analysis., Conclusion: Older patients, those with tumor location in both the renal pelvis and the ureter, and those treated with adjuvant systemic chemotherapy were found at higher risk for intravesical recurrence, as were those having undergone extravesical ureterectomy or laparoscopic RNU., (Copyright © 2014 Elsevier Inc. All rights reserved.) more...

Purpose: Reliable biomarkers that predict prostate cancer outcomes are urgently needed to improve and personalize treatment approaches. With this goal in mind, we individually and collectively appraised common genetic polymorphisms related to estradiol metabolic pathways to find prostate cancer prognostic markers., Methods: The genetic profiles of 526 men with organ-confined prostate cancer were examined to find common genetic polymorphisms related to estradiol metabolic pathways and these findings were replicated in a cohort of 213 men with more advanced disease (follow-up time for both cohorts, >7.4 years). Specifically, we examined 71 single-nucleotide polymorphisms (SNP) in SULT2A1, SULT2B1, CYP1B1, COMT, CYP3A4, CYP3A5, CYP3A43, NQO1, and NQO2 and assessed the impact of the SNPs alone and in combination on prostate cancer progression and on circulating hormone levels., Results: According to a multivariate analysis, CYP1B1 (rs1800440), COMT (rs16982844), and SULT2B1 (rs12460535, rs2665582, rs10426628) were significantly associated with prostate cancer progression and hormone levels. Remarkably, by combining the SNP information with previously identified HSD17B2 markers, the patients could be stratified into four distinct prognostic subgroups. The most prominent association was observed for the eight-marker combination [CYP1B1 (rs1800440), SULT2B1 (rs12460535, rs2665582, and rs10426628), and HSD17B2 (rs4243229, rs1364287, rs2955162, and rs1119933)]., Conclusion: This study identified specific germline variations in estradiol metabolism-related pathways, namely CYP1B1, SULT2B1, and HSD17B2, as novel prognostic markers that are cumulatively associated with increased risk of prostate cancer progression. This panel of markers warrants additional investigation and validation to help stratify patients according to their risk of progression. Clin Cancer Res; 20(11); 2971-83. ©2014 AACR., (©2014 American Association for Cancer Research.) more...

Objective: To evaluate the effect of body mass index (BMI) on the outcomes of patients with urinary tract carcinoma treated with radical surgery., Materials and Methods: Data were collected from 10 Canadian centers on patients who underwent radical cystectomy (RC) (1998-2008) or radical nephroureterectomy (RNU) (1990-2010). Various parameters among subsets of patients (BMI < 25, 25 ≤ BMI < 30, and BMI ≥ 30 kg/m(2)) were analyzed. Kaplan-Meier and multivariate analyses were performed to assess the effect of BMI on overall survival, disease-specific survival, and recurrence-free survival (RFS)., Results: Among the 847 RC and 664 RNU patients, there was no difference in histology, stage, grade, and margin status among the 3 patient subsets undergoing either surgery. However, RC patients with lower BMIs (< 25 kg/m(2)) were significantly older (P = 0.004), had more nodal metastasis (P = 0.03), and trended toward higher stage (P = 0.052). RNU patients with lower BMIs (< 25 kg/m(2)) were significantly older (P = 0.0004) and fewer received adjuvant chemotherapy (P = 0.04) compared with those with BMI ≥ 30 kg/m(2); however, there was no difference in tumor location (P = 0.20), stage (P = 0.48), and management of distal ureter among the groups (P = 0.30). On multivariate analysis, BMI was not prognostic for overall survival, disease-specific survival, and RFS in the RC group. However, BMI ≥ 30 kg/m(2) was associated with more bladder cancer recurrences and worse RFS in the RNU group (HR = 1.588; 95% CI: 1.148-2.196; P = 0.0052)., Conclusions: Increased BMI did not influence survival among RC patients. BMI ≥ 30 kg/m(2) is associated with worse bladder cancer recurrences among RNU patients; whether this is related to difficulty in obtaining adequate bladder cuff in patients with obesity requires further evaluation., (© 2013 Published by Elsevier Inc.) more...

Purpose: Polymorphisms in the genes SRD5A1 and SRD5A2 encoding androgen biosynthetic 5α-reductase enzymes have been associated with an altered risk of biochemical recurrence after radical prostatectomy in localized prostate cancer., Experimental Design: To gain potential insights into SRD5A biologic effects, we examined the relationship between SRD5A prognostic markers and endogenous sex-steroid levels measured by mass spectrometry in plasma samples and corresponding prostatic tissues of patients with prostate cancer., Results: We report that five of the seven SRD5A markers differentially affect sex-steroid profiles of dihydrotestosterone and its metabolites in both the circulation and prostatic tissues of patients with prostate cancer. Remarkably, a 32% increase in intraprostatic testosterone levels was observed in the presence of the high-risk SRD5A rs2208532 polymorphism. Moreover, SRD5A2 markers were associated predominantly with circulating levels of inactive glucuronides. Indeed, the rs12470143 SRD5A2 protective allele was associated with high circulating androstane-3α, 17β-diol-17-glucuronide (3α-diol-17G) levels as opposed to lower levels of both 3α-diol-17G and androsterone-glucuronide observed with the rs2208532 SRD5A2 risk allele. Moreover, SRD5A2 rs676033 and rs523349 (V89L) risk variants, in strong linkage disequilibrium, were associated with higher circulating levels of 3α-diol-3G. The SRD5A2 rs676033 variant further correlated with enhanced intraprostatic exposure to 5α-reduced steroids (dihydrotestosterone and its metabolite 3β-diol). Similarly, the SRD5A1 rs166050C risk variant was associated with greater prostatic exposure to androsterone, whereas no association was noted with circulating steroids., Conclusions: Our data support the association of 5α-reductase germline polymorphisms with the hormonal milieu in patients with prostate cancer. Further studies are needed to evaluate if these variants influence 5α-reductase inhibitor efficacy., (©2013 AACR.) more...

Penile necrosis is a rare condition that has been mostly described in association with diabetes mellitus and end-stage renal disease. We report an unusual case of acute penile necrosis because of heparin-induced thrombocytopenia. A 75-year-old man presented with acute renal failure and experienced cardiac complications during the hospitalization. The patient was treated twice with intravenous heparin. He developed symptoms of penile necrosis 4 days after the reintroduction of heparin. At that moment, the platelet count dropped by 61%, and the analysis of heparin-pf4 antibodies was positive for heparin-induced thrombocytopenia. The patient underwent a total penectomy and a perineal urethrostomy. more...

Objectives: Upper-tract urothelial carcinoma (UTUC) is associated with poor outcomes. Our aim was to assess adequacy of renal function and evaluate the role of adjuvant chemotherapy (AC) in patients with UTUC treated by radical nephroureterectomy (RNU) in a universal health care system., Materials and Methods: Retrospective data from 1,029 patients treated with RNU across 10 Canadian academic centers were collected. Tested variables included various clinico-pathological parameters, the use of perioperative chemotherapy, preoperative and postoperative creatinine values, and estimated glomerular filtration rates (eGFR). Univariable and multivariable Cox regression models addressed overall survival and disease-specific survival after surgery. Kaplan-Meier survival curves were used to compare outcomes in patients who received or did not receive AC., Results: Median age of patients was 70 years with a median follow-up of patients who were alive of 26 months. The median preoperative and postoperative eGFR rates were 59 mL/min/1.73 m(2) and 47 mL/min/1.73 m(2), respectively. Using a cutoff eGFR of 60, 49% of all the patients and 48% of the patients with ≥ pT3 or pTxN+ or both diseases would have been eligible for cisplatin-based chemotherapy preoperatively and only 18% and 21% of the patients, respectively remained eligible postoperatively. Of the patients who received AC, 75% had an eGFR<60. On multivariate analysis, AC was not prognostic for improved overall survival or disease-specific survival., Conclusions: Chronic kidney disease is common in patients with UTUC. Following RNU, 57% of the high-risk patients with good preoperative renal function became ineligible for cisplatin-based chemotherapy. Use of AC did not translate into improved survival. Whether this is due to inherent biases of retrospective analysis, limited efficacy of AC in patients with UTUC, or use of suboptimal regimen or dose because of poor postoperative renal function requires further evaluation., (Copyright © 2014 Elsevier Inc. All rights reserved.) more...

Introduction: Our objective is to assess differences in practice patterns and outcomes across 3 regions in bladder cancer patients treated with radical cystectomy under a universal healthcare system., Methods: In total, we included 2287 patients treated with radical cystectomy at 8 Canadian centres from 1998 to 2008. Variables included various clinico-pathologic parameters, recurrence, and death stratified into different regions., Results: In total, 1105 patients were from the east region (group 1), 601 from the centre region (group 2), and 581 from the west region of Canada (group 3). The median follow-up of groups 1, 2, and 3 was 22.1, 17.1, and 28.6 months, respectively. Although the overall rate of neoadjuvant chemotherapy was low (3.1%), rates were higher in group 2 compared with groups 1 and 3 (p = 0.07). Continent diversions and extended lymphadenectomy were performed in 23.5%, 8.5%, 23.9% and 39.7%, 27.7%, 12.6% across groups 1, 2, and 3, respectively. There were statistically significant differences in gender distribution, performance of lymphadenectomy, presence of concomitant carcinoma in situ and lymphovascular invasion across the 3 groups. There were no differences among the 3 geographical locations in terms of stage, surgical margin status, and use of adjuvant chemotherapy. The mean number of days from the transurethral resection of the bladder tumour to cystectomy was 50, 79, 69 days for groups 1, 2, 3, respectively (p = 0.0006). The 5-year overall survival was 53.6%, 66.8%, and 52.4% for groups 1, 2 and 3, respectively (p < 0.0001)., Conclusions: Significant variations in practice patterns were noted across different geographic regions in a universal healthcare system. Use of continent diversions, extended lymphadenectomy, and neoadjuvant chemotherapy remains low across all 3 regions. Treatment delays are significant. more...

Well-characterized, high-quality fresh-frozen prostate tissue is required for prostate cancer research. As part of the PROCURE Prostate Cancer Biobank launched in 2007, four University Hospitals in Quebec joined to bank fresh frozen prostate tissues from radical prostatectomies (RP). As the biobank progressed towards allocation, the nature and quality of the tissues were determined. RP tissues were collected by standardized alternate mirror-image or biopsy-based targeted methods, and frozen for banking. Clinical/pathological parameters were captured. For quality control, two presumed benign and two presumed cancerous frozen, biobanked tissue blocks per case (10/site) were randomly selected during the five years of collection. In a consensus meeting, 4 pathologists blindly evaluated slides (n=160) and graded quality, Gleason score (GS), and size of cancer foci. The quality of tissue RNA (37/40 cases) was assessed using the RNA Integrity Number. The biobank included 1819 patients of mean age: 62.1 years; serum PSA: 8 ng/ml; prostate weight: 47.8 g; GS: 7; and pathological stage: T2 in 64.5%, T3A in 25.5% and T3B in 10% of cases. Of the 157 evaluable slides, 79 and 78 had benign and cancer tissue, respectively. GS for the 37 cancer-positive cases were: 6 in 9, 7 in 18 and >7 in 10 and, in most instances, in concordance with final GS. In 40% of slides containing cancer, foci occupied ≥50% of block surface and 42% had a diameter ≥1 cm. Tissue was well preserved and consistently yielded RNA of very good quality with RNA Integrity Number (RIN) >7 for 97% of cases (mean=8.7 ± 0.7) during the five-year collection period. This study confirms the high quality of randomly selected benign and cancerous fresh-frozen prostate tissues of the PROCURE Quebec Prostate Cancer Biobank. These results strengthen the uniqueness of this large prospective resource for prostate cancer research. more...

Objectives: Whether a patient has urothelial carcinoma located within the renal pelvis or ureter remains a controversial prognostic indicator in clinical urology. We wished to evaluate whether tumor location is associated with recurrence in patients undergoing nephroureterectomy for upper tract urothelial cancer in a large volume patient cohort., Subjects and Methods: We created a retrospective database of patients from 7 academic centers throughout Canada who underwent nephroureterectomy for upper tract urothelial carcinoma. Patient demographics as well as pathologic and surgical factors were analyzed to evaluate any statistical association between tumor location and overall survival, disease-free survival, and disease-specific survival., Results: A total of 1,029 patients had data available for analysis with a mean follow up of 3.2 years. Kaplan Meier 5-year disease-free survivals (DFS) were 46%, 37%, and 19% for renal pelvis tumors, ureteric tumors, and multifocal tumors respectively. There was no association between the location of the tumor and the DFS, however, disease involving both the ureter and renal pelvis was associated with lower DFS and overall survival (OS) (P < 0.001)., Conclusions: Tumor location does not appear to have any influence on the risk of recurrence of disease following nephroureterectomy in this large patient cohort. However, multifocal tumors involving both the ureter and renal pelvis had a significantly worse prognosis and should be considered for more aggressive management., (Copyright © 2013. Published by Elsevier Inc.) more...

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?Open radical nephroureterectomy (ORNU) with excision of the ipsilateral bladder cuff is a standard treatment for upper tract urothelial carcinoma (UTUC). However, over the past decade laparoscopic RNU (LRNU) has emerged as a minimally invasive surgical alternative. Data comparing the oncological efficacy of ORNU and LRNU have reported mixed results and the equivalence of these surgical techniques have not yet been established. We found that surgical approach was not independently associated with overall or disease-specific survival; however, there was a trend toward an independent association between LRNU and poorer recurrence-free survival (RFS). To our knowledge, this is the first large, multi-institutional analysis to show a trend toward inferior RFS in patients with UTUC treated with LRNU., Objective: To examine the association between surgical approach for radical nephroureterectomy (RNU) and clinical outcomes in a large, multi-institutional cohort, as there are limited data comparing the oncological efficacy of open RNU (ORNU) and laparoscopic RNU (LRNU) for upper urinary tract urothelial carcinoma (UTUC)., Patients and Methods: Institutional RNU databases containing detailed information on patients with UTUC treated between 1994 and 2009 were obtained from 10 academic centres in Canada. Data were collected on 1029 patients and combined into a relational database formatted with patient characteristics, pathological characteristics, and survival status. Surgical approach was classified as ORNU (n = 403) or LRNU (n = 446). The clinical outcomes were overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS). The Kaplan-Meier method and Cox proportional regression analysis were used to analyse survival data., Results: Data were evaluable for 849 of 1029 (82.5%) patients. The median (interquartile range) follow-up duration was 2.2 (0.6-5.0) years. The predicted 5-year OS (67% vs 68%, log-rank P = 0.19) and DSS (73% vs 76%, log-rank P = 0.32) rates did not differ between the ORNU and LRNU groups; however, there was a trend toward an improved predicted 5-year RFS rate in the ORNU group (43% vs 33%, log-rank P = 0.06). Multivariable Cox proportional regression analysis showed that surgical approach was not significantly associated with OS (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.63-1.27, P = 0.52) or DSS (HR 0.90, 95% CI 0.60-1.37, P = 0.64); however, there was a trend toward an independent association between surgical approach and RFS (HR 1.24, 95% CI 0.98-1.57, P = 0.08)., Conclusion: Surgical approach was not independently associated with OS or DSS but there was a trend toward an independent association between LRNU and poorer RFS. Further prospective evaluation is needed., (© 2012 BJU International.) more...

Background: Positive surgical margins (PSMs) increase the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), but their impact on hard clinical end points is a topic of ongoing discussion., Objective: To evaluate the influence of solitary PSMs (sPSMs) and multiple PSMs (mPSMs) on important clinical end points., Design, Setting, and Participants: Data from 1712 patients from the Centre Hospitalier Universitaire de Québec with pT2-4 N0 prostate cancer (PCa) and undetectable prostate-specific antigen after RP were analyzed., Intervention: RP without neoadjuvant or adjuvant treatment., Outcome Measurements and Statistical Analysis: Kaplan-Meier analysis estimated survival functions, and Cox proportional hazards models addressed predictors of clinical end points., Results and Limitations: Median follow-up was 74.9 mo. A total of 1121 patients (65.5%) were margin-negative, 281 patients (16.4%) had sPSMs, and 310 patients (18.1%) had mPSMs. A total of 280 patients (16.4%) experienced BCR, and 197 patients (11.5%) were treated with salvage radiotherapy (SRT). Sixty-eight patients (4.0%) received definitive androgen deprivation therapy, 19 patients (1.1%) developed metastatic disease, and 15 patients (0.9%) had castration-resistant PCa (CRPC). Thirteen patients (0.8%) died from PCa, and 194 patients (11.3%) died from other causes. Ten-year Kaplan-Meier estimates for BCR-free survival were 82% for margin-negative patients, 72% for patients with sPSMs, and 59% for patients with mPSMs (p<0.0001). Time to metastatic disease, CRPC, PCa-specific mortality (PCSM), or all-cause mortality did not differ significantly among the three groups (p=0.991, p=0.988, p=0.889, and p=0.218, respectively). On multivariable analysis, sPSMs and mPSMs were associated with BCR (hazard ratio [HR]: 1.711; p=0.001 and HR: 2.075; p<0.0001), but sPSMs and mPSMs could not predict metastatic disease (p=0.705 and p=0.242), CRPC (p=0.705 and p=0.224), PCSM (p=0.972 and p=0.260), or all-cause death (p=0.102 and p=0.067). The major limitation was the retrospective design., Conclusions: In a cohort of patients who received early SRT in 70% of cases upon BCR, sPSMs and mPSMs predicted BCR but not long-term clinical end points. Adjuvant radiotherapy for margin-positive patients might not be justified, as only a minority of patients progressed to end points other than BCR. PCSM was exceeded 15-fold by competing risk mortality., (Copyright © 2012. Published by Elsevier B.V.) more...

Purpose: To analyze time in relation to biochemical recurrence (BCR) and antiandrogen therapy (ADT) in patients with node metastasis at retropubic prostatectomy (RRP) and to identify prognostic factors of BCR- and ADT-free survival., Methods: Positive node patients at RRP and extended pelvic lymph node dissection (ePLND) were recruited retrospectively. Neoadjuvant and adjuvant therapy were exclusion criteria. BR was defined as PSA ≥ 0.3 ng/ml or the beginning of salvage radiotherapy or, ADT., Results: Between 1995 and 2008, 70 node-positive patients after RRP were followed without ADT. Overall, BCR-free survival was 77.9% at 2 years and 29.7% at 8 years. The median time to BCR was 59.2 months for patients with only one node compared to 27.7 months for those with ≥2 nodes. The number of positive nodes was the only independent predictor of BCR in Cox regression multivariable analysis. ADT-free survival was 78% at 2 years and 39% at 8 years. The median time to ADT for patients with only one positive node was 115 months, and the 5 years ADT-free survival was 68.8%. Gleason score and the number of positive nodes were the only independent prognostic factors of time to ADT in the Cox regression multivariable analysis., Conclusions: The prognosis of patients with positive nodes after RRP and ePNLD is good in terms of BCR- and ADT-free survival. After 8 years, 29.7% were still free from BCR, and 39% did not receive ADT. The number of positive nodes was the most important predictor of BCR- and ADT-free survival. more...

Purpose: Prostate cancer is a heterogeneous genetic disease, and molecular methods for predicting prognosis in patients with aggressive form of the disease are urgently needed to better personalize treatment approaches. The objective was to identify host genetic variations in candidate steroidogenic genes affecting hormone levels and prostate cancer progression., Experimental Design: The study examined two independent cohorts composed of 526 Caucasian men with organ-confined prostate cancer and 601 Taiwanese men on androgen-deprivation therapy. Caucasians were genotyped for 109 haplotype-tagging single-nucleotide polymorphisms (SNP) in CYP17A1, ESR1, CYP19A1, and HSD3B1, and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings, including previously identified SRD5A1, SRD5A2, HSD17B2, HSD17B3, and HSD17B12 polymorphisms, were then explored in Taiwanese men (n = 32 SNPs). The influence of positive markers on the circulating hormonal levels was then appraised in Caucasians using specific and sensitive mass spectrometry-based methods., Results: After adjusting for known risk factors, variants of CYP17A1 (rs6162), HSD17B2 (rs4243229 and rs7201637), and ESR1 (rs1062577) were associated with progressive disease in both cohorts. Indeed, the presence of these variations was significantly associated with progression in Caucasians (HR, 2.29-4.10; P = 0.0014-2 × 10(-7)) and survival in Taiwanese patients [HR = 3.74; 95% confidence interval (CI): 1.71-8.19, P = 0.009]. Remarkably, the CYP17A1 rs6162 polymorphism was linked to plasma dehydroepiandrosterone-sulfate (DHEA-S) levels (P = 0.03), HSD17B2 rs7201637 with levels of dihydrotestosterone (P = 0.03), and ESR1 rs1062577 with levels of estrone-S and androsterone-glucuronide (P ≤ 0.05)., Conclusion: This study identifies, in different ethnic groups and at different disease stages, CYP17A1, HSD17B2, and ESR1 as attractive prognostic molecular markers of prostate cancer progression. more...

Introduction: : We delineated Canadian regional differences in practice patterns in the management of upper tract urothelial carcinoma (UTUC) after nephroureterectomy and relate these to patient outcomes., Methods: : A database was created with 1029 patients undergoing radical nephroureterectomy for UTUC between 1994 and 2009 at 10 Canadian centres. Demographic, clinical and pathological variables were collected from chart review. Practice pattern variables were defined as: open versus laparoscopic nephroureterectomy, management strategy for the distal ureter, performance of lymphadenectomy and administration of chemotherapy and/or radiation therapy. The outcome measures were overall (OS), disease-specific (DSS) and recurrence-free survival (RFS). The centres were divided into three regions (West, Central, East). Cox proportional multivariable linear regression analysis was used to determine the association between regional differences in practice patterns and clinical outcomes., Results: : There was a significant difference in practice patterns between regions within Canada for: time from diagnosis to surgery (p = 0.001), type of surgery (open vs. laparoscopic, p < 0.01) and method of management of the distal ureter (p = 0.001). As well, there were significant differences in survival between regions across Canada: 5-year OS (West 70%, Central 81% and East 62%, p < 0.0001) and DSS (West=79%, Central=85%, East=75%, p = 0.007) were significantly different, but there was no difference in RFS (West 47%, Central 48%, East 46%, p = 0.88). Multivariable linear regression analysis demonstrated that the differences in survival were independent of region OS (p = 0.78), DSS (p = 0.30) or RFS (p = 0.43)., Conclusion: : There is significant disparity in practice patterns between regions within Canada, but these do not appear to have an effect on survival. We believe that the variability in practice is a reflection of the lack of standardized treatments for UTUC and underlines the need for multi-institutional studies in this disease. more...

Background: The present study documents the natural history and outcomes of high-risk bladder cancer after radical cystectomy (RC) in patients who did not receive neoadjuvant chemotherapy during a contemporary time period., Methods: We analyzed 1180 patients from 1993 to 2008 with >pT3N0 or pT0-4N+ bladder cancer who underwent RC ± standard (sLND) or extended (eLND) lymph node dissection from 8 Canadian centres., Results: Of the 1180 patients, 55% (n = 643) underwent sLND, 34% (n = 402) underwent ePLND and 11% did not undergo a formal LND. Of the total number of patients, 321 (27%) received adjuvant chemotherapy. The median follow-up was 2.1 years (range: 0.6 to 12.9). Overall 30-day mortality was 3.2%. Clinical and pathological stages T3-4 were present in 6.1% and 86.7% of the patients, respectively; this demonstrates a dramatic understaging. Overall survival (OS) at 2 and 5 years was 60% and 43%, respectively. Patients who received adjuvant chemotherapy had a 2- and 5-year disease-specific survival (DSS) of 72% and 57% versus 64% and 51% for those who did not (log-rank p = 0.0039). The 2- and 5-year OS for high-risk node-negative disease was 67% and 52%, respectively, whereas for node-positive patients, the OS was 52% and 32%, respectively (p < 0.001). The OS, DSS and RFS for patients with pN0 were significantly improved compared to those who did not undergo a LND (log-rank p = 0.0035, 0.0241 and 0.0383, respectively)., Interpretation: This series suggests that bladder cancer outcomes in advanced disease have improved in the modern era. The need for improved staging investigations, use of neoadjuvant chemotherapy and performance of complete LND is emphasized. more...

We evaluated the value of the 'alternative slices mirror image method' used in prostate tissue banking in terms of predicting the sampling of cancerous tissue while preserving the pathological prognostic information. The concordance of diagnosis between banked sections and their mirror image paraffin- sections was studied using 50 cases corresponding to 400 H&E sections taken from 400 banked frozen blocks (two presumed benign and two presumed cancer for each case). The mean number of paraffin blocks in each case was 21. On average 29% of the prostate gland was banked and banked tissue contained cancer in 47 cases (94%). There was no difference between the concordant and discordant groups in terms of the final Gleason score, pathological stage, prostate size, number of banked blocks and the percentage of the prostate submitted for banking. However, concordant cases had larger foci of cancer in the mirror image paraffin block (P = 0.0088). In addition, the surgical margins sections which are not banked using this method provided important information about the pathological stage, surgical margins status and the final Gleason score in 2.6, 2.6, and 1.3% of cases, respectively. The 'alternative slices mirror image method' is a straightforward method that is highly efficient in banking prostatic cancerous tissue. Overall, tumor volume and especially size of tumor foci in the image paraffin block are the most important factors in dictating the success rate of banking frozen cancerous tissue. Including 'surgical margins' sections for histology provides additional important prognostic information in a minority of cases. more...

Purpose: To compare clinical and pathologic outcomes of radical cystectomy for muscle invasive bladder cancer in relation to prior history of non-invasive urothelial carcinoma., Materials and Methods: Retrospective data collected from 1,150 patients managed by radical cystectomy for urothelial carcinoma of the bladder from the Canadian Bladder Cancer Network were analysed. Patients with clinical stage T2 or more were included and divided into two groups: (Group 1) patients with prior history of non-invasive urothelial carcinoma (N = 365) and (Group 2) patients with clinical muscle invasive cancer de novo (N = 785). Variables analysed included patient age, gender, pathologic stage, adjuvant chemotherapy, recurrence and mortality., Results: Both groups were nearly equal in mean age and gender distribution, with mean ages of 67.2 and 66.7 years, and 79.7 and 79.5%, respectively (P = 0.4 and 0.9, respectively). The presence of preoperative hydronephrosis was 20.8 and 32.6% (P = 0.0007) for groups 1 and 2, respectively. The rate of higher pathological stage (T3 or T4) was 36.3 and 58% (P < 0.0001), positive lymph nodes were 20.1 and 28.8% (P = 0.002), and lymphovascular invasion was 31.7 and 46.2% (P = 0.0001) for groups 1 and 2, respectively. The rate of adjuvant chemotherapy was 15.5 and 23.3% (P = 0.002) for groups 1 and 2, respectively. None of the sampled patients received neoadjuvant chemotherapy. The overall survival (OS) and disease-specific survival (DSS) rates at 5 years were 62 and 70% for group 1 and 51 and 60% for group 2, respectively, while at 10 years, OS and DSS were 46 and 66% for group 1 and 35 and 49% for group 2, respectively (P = 0.0001 and 0.0002, respectively). Using multivariate analysis examining factors affecting recurrence and survival, we found that previous non-invasive bladder tumour history was associated with a significantly reduced risk of mortality and recurrence (Hazard ratio of 0.7 for all risks, P = 0.0002)., Conclusion: Our retrospective study suggests that patients with non-invasive urothelial carcinoma of the bladder that progress to muscle invasion and require radical cystectomy appear to have better pathologic and clinical outcome than patients presenting with clinical muscle invasive disease de novo. more...

Unlabelled: Study Type - Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Radical cystectomy with pelvic lymph node dissection is recognized as the standard of care for carcinoma invading bladder muscle and for refractory non-muscle-invasive bladder cancer. Owing to high recurrence and progression rates, a two-pronged strict surveillance regimen, consisting of both functional and oncological follow-up, has been advocated. It is also well recognized that more aggressive tumours with extravesical disease and node-positive disease recur more frequently and have worse outcomes. This study adds to the scant body of literature available regarding surveillance strategies after radical cystectomy for bladder cancer. In the absence of any solid evidence supporting the role of strict surveillance regimens, this extensive examination of recurrence patterns in a large multi-institutional project lends further support to the continued use of risk-stratified follow-up and emphasizes the need for earlier strict surveillance in patients with extravesical and node-positive disease., Objectives: • To review our data on recurrence patterns after radical cystectomy (RC) for bladder cancer (BC). • To establish appropriate surveillance protocols., Patients and Methods: • We collected and pooled data from a database of 2287 patients who had undergone RC for BC between 1998 and 2008 in eight different Canadian academic centres. • Of the 2287 patients, 1890 had complete recurrence information and form the basis of the present study., Results: • A total of 825 patients (43.6%) developed recurrence. • According to location, 48.6% of recurrent tumours were distant, 25.2% pelvic, 14.5% retroperitoneal and 11.8% to multiple regions such as pelvic and retroperitoneal or pelvic and distant. • The median (range) time to recurrence for the entire population was 10.1 (1-192) months with 90 and 97% of all recurrences within 2 and 5 years of RC, respectively. • According to stage, pTxN+ tumours were more likely to recur than ≥pT3N0 tumours and ≤pT2N0 tumours (5-yr RFS 25% vs. 44% vs. 66% respectively, P < 0.001). Similarly, pTxN+ tumours had a shorter median time to recurrence (9 months, range 1-72 months) than ≥pT3N0 tumours (10 months, range 1-70 months) or ≤pT2N0 tumours (14 months, range 1-192 months, P < 0.001)., Conclusions: • Differences in recurrence patterns after RC suggest the need for varied follow-up protocols for each group. • We propose a stage-based protocol for surveillance of patients with BC treated with RC that captures most recurrences while limiting over-investigation., (© 2012 BJU INTERNATIONAL.) more...

Background: The relationship between polymorphisms in the hydroxysteroid (17-beta) dehydrogenase (HSD17B) family of genes, which are involved in steroid hormone biotransformation, and the risk of prostate cancer (PCa) progression remains unexplored., Objective: Determine whether inherited variations in HSD17B genes are associated with PCa progression., Design, Setting, and Participants: We studied two independent Caucasian cohorts composed of 526 men with organ-confined PCa and 213 men with advanced disease who had a median follow-up of 7.4 yr and 7.8 yr after surgery, respectively., Measurements: Patients with localised PCa were genotyped for 88 haplotype-tagging single nucleotide polymorphisms in HSD17B type 1 (HSD17B1), type 2 (HSD17B2), type 3 (HSD17B3), type 4 (HSD17B4), type 5 (HSD17B5), and type 12 (HSD17B12), and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings were then investigated in advanced disease., Results and Limitations: After adjusting for known risk factors, 12 SNPs distributed across HSD17B2, HSD17B3, and HSD17B12 were significantly associated with risk of biochemical recurrence (BCR) in localised PCa (for variants in HSD17B2: hazard ratio [HR]: 1.92-2.93; p=0.025-0.004). In addition, four variants of HSD17B2 (rs1364287, rs2955162, rs1119933, rs9934209) were significantly associated with progression-free survival (HR: 2.96-4.69; p=0.004-0.00005) and overall survival in advanced disease (HR: 3.98-8.14; p=0.003-0.00002). Four variants of HSD17B3 and HSD17B12 were associated with a reduced risk of BCR (HR: 0.51-0.65; p=0.020-0.036) but not with progression in advanced disease. These results were generated mainly in Caucasians and should be studied in other ethnic groups., Conclusions: This study suggests a prominent role for common genetic variants in the HSD17B2 pathway in PCa progression., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.) more...

Introduction: : Radical cystectomy is the standard treatment for muscle invasive bladder cancer. We assessed clinical outcomes in patients found to have no evidence of disease (i.e., pT0N0) following radical cystectomy., Methods: : We collected and pooled a database of 2287 patients who underwent radical cystectomy between 1993 and 2008 in eight centres across Canada. Of this number, 135 patients were found to have pT0N0 bladder cancer at the time of cystectomy. Survival data and prognostic variables were analyzed using Kaplan-Meier method and Cox proportional hazard regression analysis., Results: : Median patient age was 66 years with a mean follow-up of 42 months. Clinical stage distribution was Tis 8.9%, Ta 1.5%, T1 20.7%, T2 45.2%, T3 5.2%, and T4 5.2%. The five-year recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were 83%, 96%, and 88%, respectively. The 10-year RFS, DSS and OS were 66%, 92%, and 70%, respectively. On Cox proportional regression analysis, no variables were associated with disease recurrence and only patient age was associated with overall survival., Interpretation: : Patients with pT0N0 pathology after cystectomy have excellent outcomes with high five- and 10-year RFS, DSS and OS. However, there is still a risk of tumour recurrence in this patient population and thus postoperative surveillance is still required. more...

Background: The relationship between inherited germ-line variations in the 5α-reductase pathways of androgen biosynthesis and the risk of biochemical recurrence (BCR) after radical prostatectomy (RP) remains an unexplored area., Objective: To determine the link between germ-line variations in the steroid-5α-reductase, α-polypeptide 1 (SRD5A1) and steroid-5α-reductase, α-polypeptide 2 (SRD5A2) genes and BCR., Design, Settings, and Participants: We studied retrospectively two independent cohorts composed of 526 white (25% BCR) and 320 Asian men (36% BCR) with pathologically organ-confined prostate cancer who had a median follow-up of 88.8 and 30.8 mo after surgery, respectively., Measurements: Patients were genotyped for 19 haplotype-tagging single nucleotide polymorphisms (htSNPs) in SRD5A1 and SRD5A2 genes, and their prognostic significance on prostate-specific antigen recurrence was assessed using Kaplan-Meier analysis and the Cox regression model., Results and Limitations: After adjusting for all clinicopathologic risk factors, four SNPs (rs2208532, rs12470143, rs523349, and rs4952197) were associated with BCR in both whites and Asians. The strongest effect was conferred by the SRD5A2 V89L nonsynonymous SNP (rs523349C) with a hazard ratio (HR) of 2.87 (95% confidence interval [CI], 2.07-4.00; p = 4 × 10⁻¹⁰; 48% BCR). In addition, in whites, the combination of two SNPs, rs518673T in SRD5A1 and rs12470143A in SRD5A2, was associated with a reduced BCR rate for carriers of three or four alleles (HR: 0.37; 95% CI, 0.19-0.71; p=0.003;16% BCR) compared with noncarriers (38% BCR), whereas the SRD5A2 rs12470143A was significant in Asians (HR: 0.46; 95% CI, 0.28-0.73; p=0.001). Limitations of our study include few events of androgen-deprivation resistance or cancer-specific death., Conclusions: Our study is the first to show positive associations of several SRD5A1 and SRD5A2 variations as independent predictors of BCR after RP., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.) more...

Context: The prognostic relevance of inherited variations in hormone-related genes in the context of prostate cancer (PCa) progression has not been well studied. Of these, UDP-glucuronosyltransferase (UGT) gene products lead to inactivation of steroids., Objective: Our objective was to determine whether polymorphisms in five UGT genes, involved in steroid metabolism, are associated with the risk of biochemical recurrence after radical prostatectomy (RP) and to examine their relationship with hormonal exposure., Design: The study included 526 Caucasian and 320 Asian men who underwent RP for clinically localized PCa. The relationship between genotypes and biochemical recurrence were assessed with multivariate Cox proportional hazard models. Plasma steroids were measured using specific and sensitive mass spectrometry-based methods., Results: The presence of at least two deleted copies of UGT2B17 and UGT2B28 genes resulted in a hazard ratio of 2.26 (95% confidence interval = 1.41-3.61; P = 0.0007) for Caucasians and 2.16 (95% confidence interval = 1.24-3.73; P = 0.006) for Asians. A positive association was observed only between UGT2B17 deletion and the Gleason score in Asians, whereas no other interaction was shown with prostate-specific antigen, Gleason score, and TNM (tumor node metastasis) staging. Patients carrying UGT2B17 deletions and those with three deleted UGT2B copies had significantly lower androgen glucuronides, in support of an altered androgen metabolism., Conclusion: This study is the first to recognize the prognostic significance of common deletions in steroid inactivation pathways in localized PCa after RP. Alteration of circulating steroid levels associated with UGT2B gene deletions further support the notion that such inherited genomic deletions have the potential to modify hormonal exposure and risk of recurrence. more...

Unlabelled: Study Type - Prognosis (case series)., Level of Evidence: 4 OBJECTIVE: To determine whether the expression of cyclo-oxygenase (COX)-2 has an influence on survival and on the response to chemotherapy in invasive bladder cancer., Patients and Methods: A population of 266 patients from a tertiary university centre with carcinoma invading bladder muscle without evidence of metastasis at time of cystectomy was analyzed retrospectively. COX-2 expression was evaluated immunohistochemically with a monoclonal anti-COX-2 antibody. All pertinent clinical and pathological parameters were reviewed and correlated with risk factors influencing outcome, including disease-specific and overall survival, as well as COX-2 expression. Immunoreactivity was categorized as positive if COX-2 staining was present in >5% tumour cells., Results: The expression of COX-2 was not influenced by tumour stage, grade or nodal status, nor any other parameters. The risk factors that influenced disease-specific survival in carcinoma invading bladder muscle on multivariate analysis were lymph node status (hazards ratio, HR = 2.46 for N1, P = 0.001, HR = 2.90 for N2, P < 0.001, HR = 5.19 for N3, P = 0.012), use of neoadjuvant chemotherapy (HR = 3.54; P= 0.004) or adjuvant chemotherapy (HR = 0.57, P = 0.014) and COX-2 expression (HR = 0.64 if >5% cells had positive expression; P = 0.025). Kaplan-Meier analysis showed an increased disease-specific survival (P = 0.0063), as well as longer recurrence-free survival (P = 0.003), in patients with muscle-invasive bladder tumours expressing COX-2 in >5% of the cells. A tendency was also observed in a subgroup with positive nodes treated with adjuvant chemotherapy (P = 0.093)., Conclusions: The overexpression of COX-2 is associated with a better recurrence-free and disease-specific survival in a large cohort of 266 patients with carcinoma invading bladder muscle treated by cystectomy. A trend for increased disease-specific survival was also observed for patients with COX-2 overexpression and positive nodes who received adjuvant chemotherapy. Potential of COX-2 as a prognostic marker in bladder cancer should be considered., (© 2010 THE AUTHORS; BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.) more...

Unlabelled: Study Type -Therapy (case series)., Level of Evidence: 4., Objective: To evaluate data obtained from a large, multi-institutional, contemporary series of patients who underwent radical cystectomy (RC) in a universal healthcare system aiming to assess outcome and identify novel prognostic variables., Materials and Methods: Data were collected and pooled from 2287 patients treated with RC between 1998 and 2008 by urological oncologists from eight Canadian academic centres. Collected variables included various clinicopathological parameters, recurrence and death. Survival and prognostic variables were analyzed using the Kaplan-Meier method and Cox regression analysis., Results: The median age of patients was 68 years with a mean (median) follow-up time of 35 (29) months. The 30, 60 and 90-day postoperative mortality rates were 1.3%, 2.6% and 3.2%, respectively. The 5-year overall, recurrence-free and cancer-specific survival was 57%, 48% and 67%, respectively, with a local recurrence rate of 6%. Pathological stage distribution was more...

Purpose: High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor of invasive prostate cancer (PCa). Preclinical evidence suggests vitamin E, selenium, and soy protein may prevent progression of HGPIN to PCa. This hypothesis was tested in a randomized phase III double-blind study of daily soy (40 g), vitamin E (800 U), and selenium (200 μg) versus placebo., Patients and Methods: Three hundred three men in 12 Canadian centers were analyzed. The main eligibility criterion was confirmed HGPIN in at least one of two biopsies within 18 months of random assignment. Treatment was administered daily for 3 years. Follow-up prostate biopsies occurred at 6, 12, 24, and 36 months postrandomization. The primary end point was time to development of invasive PCa. Kaplan-Meier plots and log-rank tests were used to compare two treatment groups for this end point., Results: For all patients, the median age was 62.8 years. The median baseline prostate-specific antigen (PSA; n = 302) was 5.41 ug/L; total testosterone (n = 291) was 13.4 nmol/L. Invasive PCa developed among 26.4% of patients. The hazard ratio for the nutritional supplement to prevent PCa was 1.03 (95% CI, 0.67 to 1.60; P = .88). Gleason score distribution was similar in both groups with 83.5% of cancers graded Gleason sum of 6. Baseline age, weight, PSA, and testosterone did not predict for development of PCa. The supplement was well tolerated with flatulence reported more frequently (27% v 17%) among men receiving micronutrients., Conclusion: This trial does not support the hypothesis that combination vitamin E, selenium, and soy prevents progression from HGPIN to PCa. more...

Background: Radical cystectomy may provide optimal survival outcomes in the management of clinical T1 bladder cancer. We present our data from a large, multi-institutional, contemporary Canadian series of patients who underwent radical cystectomy for clinical T1 bladder cancer in a single-payer health care system., Methods: We collected a pooled database of 2287 patients who underwent radical cystectomy between 1993 and 2008 in 8 different centres across Canada; 306 of these patients had clinical T1 bladder cancer. Survival data were analyzed using Kaplan-Meier method and Cox regression analysis., Results: The median age of patients was 67 years with a mean follow-up time of 35 months. The 5-year overall, disease-specific and disease-free survival was 71%, 77% and 59%, respectively. The 10-year overall and disease-specific survival were 60% and 67%, respectively. Pathologic stage distribution was p0: 32 (11%), pT1: 78 (26%), pT2: 55 (19%), pT3: 60 (20%), pT4: 27 (9%), pTa: 16 (5%), pTis: 28 (10%), pN0: 215 (74%) and pN1-3: 78 (26%). Only 12% of patients were given adjuvant chemotherapy. On multivariate analysis, only margin status and pN stage were independently associated with overall, disease-specific and disease-free survival., Interpretation: These results indicate that clinical T1 bladder cancer may be significantly understaged. Identifying factors associated with understaged and/or disease destined to progress (despite any prior intravesical or repeat transurethral therapies prior to radical cystectomy) will be critical to improve survival outcomes without over-treating clinical T1 disease that can be successfully managed with bladder preservation strategies. more...

Objectives: To evaluate the rate and duration of prostate-specific antigen (PSA) response to high-dose bicalutamide (150 mg) in nonmetastatic castration-resistant prostate cancer patients and its impact on metastasis-free survival., Methods: This single center, prospective study included 38 prostate cancer patients surgically or medically castrated who had PSA increases above their nadir after previous antiandrogen manipulation and in absence of bone metastases. Patients were given daily dose of bicalutamide 150 mg. Clinical evaluations and serum PSA testing were performed every 3 months. Response was defined according to PSA decline from baseline as if ≥ 50% or ≥ 85%. The duration of response was the time from entering into study until PSA increased ≥ 25% or ≥ 2 ng/ml from the nadir. Bone scintigraphy was repeated at PSA increase or at symptom appearance., Results: The mean follow-up was 34.5 months (range, 3-75.2). A PSA decline was observed in 17 of 38 patients (44.7%): 7 (18.4%) ≥ 85% and 10 (26.3%) ≥ 50 but < 85% responders. The median duration of response was 18.5 months for partial and 37.4 months for complete responders. The median time to metastasis was 52.5 months for responders and 15.7 months for nonresponders (Log-Rank test 9.3, P = .002)., Conclusions: High-dose bicalutamide can induce a second response in almost half of castration-resistant prostate cancer patients without metastasis. The duration of response is more than 1.5 years on average and responders have prolonged metastasis-free survival., (Copyright © 2010 Elsevier Inc. All rights reserved.) more...

Objective: To investigate the role of (18) F-fluorodeoxyglusose positron-emission tomography (FDG-PET), combined with computed tomography (CT) and forced diuresis, in the staging and follow-up of urothelial carcinoma (UC)., Patients and Methods: We recruited 44 patients with muscle-invasive urothelial bladder cancer (UBC) before radical cystectomy (RC), 19 under follow-up after RC and seven after systemic chemotherapy. For those who had RC, histopathology was used as the reference standard to compare the sensitivity and specificity of FDG-PET/CT and standard CT in detecting UBC and pelvic lymph node metastasis. Furthermore, 36 patients with ≥ 6 months of follow-up imaging were considered to describe the progression of UC and extrapelvic positive FDG-PET/CT images., Results: For the detection of primary UBC, FDG-PET/CT was slightly more sensitive than CT (85% vs 77%) but less specific (25% vs 50%). For the detection of pelvic node metastasis FDG-PET/CT was more sensitive than CT (57% vs 33%) with a specificity of 100% for both imaging techniques. In 20 patients, extrapelvic FDG-PET/CT images showed suspected disease at the first evaluation. UC progressed in nine of the 10 patients who had synchronous multiple PET-positive retroperitoneal or mediastinal lymph nodes, and in only two of the nine with unique hyperactive lesions in the lung. FDG-PET/CT also detected a pT1G3 UC of the renal pelvis and all bone metastases detected by bone scintigraphy., Conclusions: FDG-PET/CT could replace standard CT and bone scintigraphy in the presurgical staging and monitoring of patients with UC after surgery or chemotherapy., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.) more...

Cancer-testis (CT) genes encode proteins that are ideal targets for cancer immunotherapy because of their restricted expression in normal tissues and frequent expression in cancers. We previously observed that MAGE-A9 was one of the CT genes most frequently expressed in bladder tumors. To confirm that observation and evaluate the potential prognostic value of MAGE-A9 protein, we analyzed its expression by immunohistochemistry in 493 primary bladder tumors and 33 lymph node metastases, in comparison with MAGE-A4 protein, also frequently expressed in bladder tumors. Overall, MAGE-A4 and MAGE-A9 were observed, respectively, in 38% and 63% of nonmuscle-invasive tumors, 48% and 57% of muscle-invasive tumors, 65% and 84% of carcinomas in situ and in 73% and 85% of lymph node metastases. Expression was associated with higher grade (MAGE-A4, p = 0.007; MAGE-A9, p = 0.012). In multivariate Cox regression analyses, expression of MAGE-A9 in pTa tumors was associated with recurrence (HR = 1.829; p = 0.010). In univariate analyses, MAGE-A4 expression in these same tumors was associated with progression to muscle-invasive cancer (HR = 7.417, p = 0.013). MAGE-A9 expression was even more predictive of progression as all tumors that progressed expressed this antigen. In muscle-invasive bladder tumors, no association was found between expression of either MAGE and bladder cancer-specific death. In conclusion, MAGE-A9 is a target of choice for bladder cancer immunotherapy as it is expressed in 60% of bladder tumors, predominantly high-grade tumors, and at higher frequency in pTis and metastatic tumors. Moreover, in pTa tumors, an immunotherapy targeting MAGE-A9 could be protective against recurrence and progression to more advanced cancer., (2009 UICC) more...

Background: Carcinomas of the upper urinary tract are uncommon tumors that usually occurred in elderly patients. Competing causes of mortality should be considered when treating these patients., Methods: All patients with upper urinary tract tumors who were treated surgically at Centre Hospitalier Universitaire de Québec and affiliated hospitals from 1978 to 2001 were retrospectively reviewed. Clinical and pathologic variables were assessed from both the preoperative and postoperative periods of management, and clinical outcomes were tracked. Competing risks regression, Cox proportional hazards modeling, and multiple imputation were used to assess predictors of cancer-related and competing risks-related mortality in both preoperative and postoperative settings., Results: Competing risks were responsible for 46% of deaths in this cohort of 168 patients. Preoperatively, the most important predictor of cancer-related mortality was a clinically invasive tumor (hazards ratio [HR], 3.97; P < .001), whereas increasing age (HR, 1.07; P < .001) was found to be the most important predictor of competing mortality. Postoperatively, tumor grade was the most important predictor of cancer-related mortality (HR, 3.92; P < .001) whereas constitutional symptoms (HR, 1.91; P = .015) and increasing age (HR, 1.06; P < .001) were found to be predictive of competing mortality., Conclusions: In the current study, stage and grade were found to be the 2 most important independent predictors of survival in patients with tumors of the upper urinary tract and were highly correlated. Pain or weight loss was found to be a novel predictor of survival in this cancer. Although a survival disadvantage was not noted for women, nephron-sparing surgery, ureteral tumors, or older patients with respect to cancer, competing causes of mortality were found to be responsible for greater than one-third of observed deaths and age was the best predictor of this occurrence. more...

Purpose: We assessed the role of urinary prostate-specific antigen (uPSA) in the follow-up of prostate cancer after retropubic radical prostatectomy (RRP) for the early detection of local recurrences., Methods: We recruited 50 patients previously treated for prostate cancer with RRP and who had not experienced a prostate-specific antigen (PSA) recurrence within their first postoperative year into a cross-sectional laboratory assessment and prospective 6-year longitudinal follow-up study. We defined biochemical failure as a serum PSA (sPSA) of 0.3 μg/L or greater. Patients provided blood samples and a 50-mL sample of first-voided urine. We performed Wilcoxon rank-sum and Fisher exact tests for statistical analysis., Results: The median sPSA was 0.13 μg/L. The median uPSA was 0.8 μg/L, and was not significantly different when comparing Gleason scores or pathological stages. Of the 50 patients, 27 initially had a nondetectable sPSA but a detectable uPSA, and 11 patients experienced sPSA failure after 6 years. Six patients had detectable sPSA and uPSA initially. Fifteen patients were negative for both sPSA and uPSA, and 13 remained sPSA-free after 6 years. The odds ratio (OR) of having sPSA failure given a positive uPSA test was 4.5 if sPSA was undetectable, but was reduced to 2.6 if sPSA was detectable. The pooled Mantel-Haenszel OR of 4.2 suggested that a detectable uPSA quadrupled the risk of recurrence, independent of whether sPSA was elevated or not. The sensitivity of uPSA for detecting future sPSA recurrences was 81% and specificity was 45%., Conclusion: Urinary PSA could contribute to an early detection of local recurrences of prostate cancer after a radical prostatectomy. more...

Background: The clinical significance of tumor-infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs) as markers of immune response has been reported for many cancers., Objective: To measure tumor infiltration by CD83(+) dendritic cells (DCs) and CD68(+) macrophages in non-muscle-invasive urothelial cancer (NMIUC) prior to bacillus Calmette-Guérin (BCG) immunotherapy and to evaluate their significance in the response to immunotherapy., Design, Setting, and Participants: Patients with NMIUC at high risk of recurrence and progression were recruited for a study on markers of the response to BCG., Intervention: Patients were treated by transurethral resection followed by maintenance BCG., Measurements: Immunohistochemical staining with anti-CD83 and anti-CD68 monoclonal antibodies on 53 and 46 NMIUC tumors, respectively, prior to BCG treatment. A scoring index was calculated based on the average density of positive cells within the papillary axis, the stroma, lymphoid aggregates, and infiltration into tumors., Results and Limitations: CD83(+) TIDCs were observed mostly within lymphoid aggregates. Multivariate Cox regression analysis showed that maintenance BCG (more than one maintenance cycle) was highly effective in patients with a low level of CD83(+) TIDCs at time of resection (hazard ratio [HR]: 0.035; p=0.002) but showed reduced efficacy in patients with a high level of CD83(+) TIDCs (HR: 0.87; p=0.810). A high level of infiltration by CD83(+) TIDCs slightly decreased the risk of recurrence in patients treated with one or no maintenance BCG cycle (HR: 0.4; p=0.117). In the same population, a strong infiltration of CD68(+) TAMs was associated with an increased risk of recurrence (HR: 3.8; p=0.013)., Conclusions: These results suggest that patients with a high level of infiltration by CD83(+) TIDCs or CD68(+) TAMs do not respond as well to BCG immunotherapy. If confirmed in larger cohorts, the pretreatment level of infiltration by these cells may be useful to influence the choice of treatment strategy. more...