Carcinoma In Situ (CIS): Is There a Difference in Efficacy between Various BCG Strains? A Comprehensive Review of the Literature.

Introduction: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is the standard of care for high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC) as well as for Carcinoma in situ (CIS). Evidence supports that the different BCG strains, despite genetic variability, are equally effective clinically for preventing the recurrence and progression of papillary NMIBC. The available evidence regarding possible differences in clinical efficacy between various BCG strains in CIS is lacking. Methods: We reviewed the literature on the efficacy of different BCG strains in patients with CIS (whether primary, secondary, concomitant, or unifocal/multifocal), including randomized clinical trials (RCTs), phase II/prospective trials, and retrospective studies with complete response rates (CRR), recurrence-free survival (RFS), or progression-free survival (PFS) as endpoints. Results: In most studies, being RCTs, phase II prospective trials, or retrospective studies, genetic differences between BCG strains did not translate into meaningful differences in clinical efficacy against CIS, regardless of the CIS subset (primary, secondary, or concurrent) or CIS focality (unifocal or multifocal). CRR, RFS, and PFS were not statistically different between various BCG strains. None of these trials were designed as head-to-head comparisons between BCG strains focusing specifically on CIS. Limitations include the small sample size of many studies and most comparisons between strains being indirect rather than head-to-head. Conclusions: This review suggests that the clinical efficacy of the various BCG strains appears similar, irrespective of CIS characteristics. However, based on the weak level of evidence available and underpowered studies, randomized studies in this space should be encouraged as no definitive conclusion can be drawn at this stage.

Long-term outcomes and cost savings of office fulguration of papillary Ta low-grade bladder cancer.

OBJECTIVES: To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia. PATIENTS AND METHODS: Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings. RESULTS: In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up. CONCLUSIONS: This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely.

Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis.

BACKGROUND: Previous randomised controlled trials comparing bladder preservation with radical cystectomy for muscle-invasive bladder cancer closed due to insufficient accrual. Given that no further trials are foreseen, we aimed to use propensity scores to compare trimodality therapy (maximal transurethral resection of bladder tumour followed by concurrent chemoradiation) with radical cystectomy. METHODS: This retrospective analysis included 722 patients with clinical stage T2-T4N0M0 muscle-invasive urothelial carcinoma of the bladder (440 underwent radical cystectomy, 282 received trimodality therapy) who would have been eligible for both approaches, treated at three university centres in the USA and Canada between Jan 1, 2005, and Dec 31, 2017. All patients had solitary tumours less than 7 cm, no or unilateral hydronephrosis, and no extensive or multifocal carcinoma in situ. The 440 cases of radical cystectomy represent 29% of all radical cystectomies performed during the study period at the contributing institutions. The primary endpoint was metastasis-free survival. Secondary endpoints included overall survival, cancer-specific survival, and disease-free survival. Differences in survival outcomes by treatment were analysed using propensity scores incorporated in propensity score matching (PSM) using logistic regression and 3:1 matching with replacement and inverse probability treatment weighting (IPTW). FINDINGS: In the PSM analysis, the 3:1 matched cohort comprised 1119 patients (837 radical cystectomy, 282 trimodality therapy). After matching, age (71·4 years [IQR 66·0-77·1] for radical cystectomy vs 71·6 years [64·0-78·9] for trimodality therapy), sex (213 [25%] vs 68 [24%] female; 624 [75%] vs 214 [76%] male), cT2 stage (755 [90%] vs 255 [90%]), presence of hydronephrosis (97 [12%] vs 27 [10%]), and receipt of neoadjuvant or adjuvant chemotherapy (492 [59%] vs 159 [56%]) were similar between groups. Median follow-up was 4·38 years (IQR 1·6-6·7) versus 4·88 years (2·8-7·7), respectively. 5-year metastasis-free survival was 74% (95% CI 70-78) for radical cystectomy and 75% (70-80) for trimodality therapy with IPTW and 74% (70-77) and 74% (68-79) with PSM. There was no difference in metastasis-free survival either with IPTW (subdistribution hazard ratio [SHR] 0·89 [95% CI 0·67-1·20]; p=0·40) or PSM (SHR 0·93 [0·71-1·24]; p=0·64). 5-year cancer-specific survival for radical cystectomy versus trimodality therapy was 81% (95% CI 77-85) versus 84% (79-89) with IPTW and 83% (80-86) versus 85% (80-89) with PSM. 5-year disease-free survival was 73% (95% CI 69-77) versus 74% (69-79) with IPTW and 76% (72-80) versus 76% (71-81) with PSM. There were no differences in cancer-specific survival (IPTW: SHR 0·72 [95% CI 0·50-1·04]; p=0·071; PSM: SHR 0·73 [0·52-1·02]; p=0·057) and disease-free survival (IPTW: SHR 0·87 [0·65-1·16]; p=0·35; PSM: SHR 0·88 [0·67-1·16]; p=0·37) between radical cystectomy and trimodality therapy. Overall survival favoured trimodality therapy (IPTW: 66% [95% CI 61-71] vs 73% [68-78]; hazard ratio [HR] 0·70 [95% CI 0·53-0·92]; p=0·010; PSM: 72% [69-75] vs 77% [72-81]; HR 0·75 [0·58-0·97]; p=0·0078). Outcomes for radical cystectomy and trimodality therapy were not statistically different among centres for cancer-specific survival and metastasis-free survival (p=0·22-0·90). Salvage cystectomy was done in 38 (13%) trimodality therapy patients. Pathological stage in the 440 radical cystectomy patients was pT2 in 124 (28%), pT3-4 in 194 (44%), and 114 (26%) node positive. The median number of nodes removed was 39, the soft tissue positive margin rate was 1% (n=5), and the perioperative mortality rate was 2·5% (n=11). INTERPRETATION: This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option. FUNDING: Sinai Health Foundation, Princess Margaret Cancer Foundation, Massachusetts General Hospital.

Development, multi-institutional external validation, and algorithmic audit of an artificial intelligence-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA) for patients undergoing radical prostatectomy: a retrospective cohort study.

BACKGROUND: Accurate prediction of side-specific extraprostatic extension (ssEPE) is essential for performing nerve-sparing surgery to mitigate treatment-related side-effects such as impotence and incontinence in patients with localised prostate cancer. Artificial intelligence (AI) might provide robust and personalised ssEPE predictions to better inform nerve-sparing strategy during radical prostatectomy. We aimed to develop, externally validate, and perform an algorithmic audit of an AI-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA). METHODS: Each prostatic lobe was treated as an individual case such that each patient contributed two cases to the overall cohort. SEPERA was trained on 1022 cases from a community hospital network (Trillium Health Partners; Mississauga, ON, Canada) between 2010 and 2020. Subsequently, SEPERA was externally validated on 3914 cases across three academic centres: Princess Margaret Cancer Centre (Toronto, ON, Canada) from 2008 to 2020; L'Institut Mutualiste Montsouris (Paris, France) from 2010 to 2020; and Jules Bordet Institute (Brussels, Belgium) from 2015 to 2020. Model performance was characterised by area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), calibration, and net benefit. SEPERA was compared against contemporary nomograms (ie, Sayyid nomogram, Soeterik nomogram [non-MRI and MRI]), as well as a separate logistic regression model using the same variables included in SEPERA. An algorithmic audit was performed to assess model bias and identify common patient characteristics among predictive errors. FINDINGS: Overall, 2468 patients comprising 4936 cases (ie, prostatic lobes) were included in this study. SEPERA was well calibrated and had the best performance across all validation cohorts (pooled AUROC of 0·77 [95% CI 0·75-0·78] and pooled AUPRC of 0·61 [0·58-0·63]). In patients with pathological ssEPE despite benign ipsilateral biopsies, SEPERA correctly predicted ssEPE in 72 (68%) of 106 cases compared with the other models (47 [44%] in the logistic regression model, none in the Sayyid model, 13 [12%] in the Soeterik non-MRI model, and five [5%] in the Soeterik MRI model). SEPERA had higher net benefit than the other models to predict ssEPE, enabling more patients to safely undergo nerve-sparing. In the algorithmic audit, no evidence of model bias was observed, with no significant difference in AUROC when stratified by race, biopsy year, age, biopsy type (systematic only vs systematic and MRI-targeted biopsy), biopsy location (academic vs community), and D'Amico risk group. According to the audit, the most common errors were false positives, particularly for older patients with high-risk disease. No aggressive tumours (ie, grade >2 or high-risk disease) were found among false negatives. INTERPRETATION: We demonstrated the accuracy, safety, and generalisability of using SEPERA to personalise nerve-sparing approaches during radical prostatectomy. FUNDING: None.

The impact of grading scheme on non-muscle invasive bladder cancer progression: potential utility of hybrid grading schemes.

Non-muscle invasive bladder cancer (NMIBC) grade is a major determinant of progression risk. The most widely utilised grading systems are the World Health Organization (WHO) 1973 and 2004 schemes. Recent publications suggest the utility of combining both into a four-tier or a hybrid three-tier system, subdividing WHO 2004 high grade into two separate categories while maintaining low grade as a single group. We identified two retrospective cohorts of bladder resections/biopsies of papillary urothelial NMIBC with long term clinical follow-up. The sentinel specimen was assessed for WHO 2004 and 1973 grade, along with pathological stage and carcinoma in situ. Each case was additionally stratified into a hybrid three-tier system (low grade; high grade, grades 2 and 3) and a four-tier system (low grade, grades 1 and 2; high grade, grades 2 and 3). Uni- and multivariable analysis for progression and event free survival (PFS/EFS) were calculated along with the time dependent area under the curve (AUC) for each grading scheme. There were 609 cases (Cohort A, n=343; Cohort B, n=266), including 449 (74%) pTa, 156 pT1 (26%) and four pTx with 338 (56%) low grade (177, grade 1; 161, grade 2) and 271 (44%) high grade (137, grade 2; 134, grade 3). A total of 108 patients progressed (17.7%): 97 high grade, (grade 3, n=59; grade 2, n=38). Multivariable analyses of PFS with the hybrid 3- and 4-tier systems showed higher Harrell's concordance indices (0.851 and 0.853, respectively) than WHO 1973 (0.844) and WHO 2004 (0.846). In both cohorts AUC values were higher (0.77-0.85) for the two hybrid grading systems compared to WHO 1973 or WHO 2004 (0.72-0.82). Similar results were seen on analysis of EFS. The data support the use of a hybrid three-tier or four-tier grading system to improve stratification of NMIBC patients.

Trimodal therapy in muscle invasive bladder cancer management.

INTRODUCTION: Radical cystectomy (RC) is the current mainstay for muscle-invasive bladder cancer (MIBC). Concerns regarding morbidity, mortality and quality of life have favored the introduction of bladder sparing strategies. Trimodal therapy, combining transurethral resection, chemotherapy and radiotherapy is the current standard of care for bladder preservation strategies in selected patients with MIBC. EVIDENCE ACQUISITION: A comprehensive search of the Medline and Embase databases was performed. A total of 19 studies were included in a systematic review of bladder sparing strategies in MIBC management was carried out following the preferred reporting items for systematic reviews and meta-analysis (PRISMA). EVIDENCE SYNTHESIS: The overall median complete response rate after trimodal therapy (TMT) was 77% (55-93). Salvage cystectomy rate with TMT was 17% on average (8-30). For TMT, the 5-year cancer-specific survival and overall survival rates range from 42-82% and 32-74%, respectively. Currently data supporting neoadjuvant or adjuvant chemotherapy in bladder sparing approaches are emerging, but robust definitive conclusions are still lacking. Gastrointestinal toxicity rates are low around 4% (0.5-16), whereas genitourinary toxicity rates reached 8% (1-24). Quality of life outcomes are still underreported. CONCLUSIONS: Published data and clinical experience strongly support trimodal therapy as an acceptable bladder sparing strategy in terms of oncological outcomes and quality of life in selected patients with MIBC. A strong need exists for specialized centers, to increase awareness among urologists, to discuss these options with patients and to stress the increased participation of patients and their families in treatment path decision-making.

Sequential administration of Bacillus Calmette-Guerin (BCG) and Electromotive Drug Administration (EMDA) of mitomycin C (MMC) for the treatment of high-grade nonmuscle invasive bladder cancer after BCG failure.

BACKGROUND: There is a need for effective nonsurgical treatment options in patients with nonmuscle invasive bladder cancer (NMIBC) in whom Bacillus Calmette-Guerin (BCG) therapy has failed. OBJECTIVE: We aimed to determine the efficacy of Electromotive Drug Administration (EMDA) of mitomycin C (MMC) with NMIBC after BCG failure. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 26 NMIBC patients in whom BCG therapy failed who received BCG/EMDA-MMC between 2013 and 2017 was performed. All but 4 patients fulfilled the FDA criteria for BCG unresponsive disease. Progression and recurrence-free survival (RFS)were calculated using Kaplan-Meier curves. Progression was defined as development of muscle invasive disease, presence of metastasis on imaging or treatment. We used FDA-defined criteria as complete response (CR) for single-arm trials of BCG-unresponsive patients. RESULTS AND LIMITATIONS: Twenty-six patients were included. Initial pathology was carcinoma in situ (CIS) in 53.8% (14/26), pT1 in 34.6% (9/26), and pTa HG disease in 11.6% (3/26). Twelve of 26 patients progressed (46.2%). Following BCG/EMDA-MMC treatment, progression-free survival rates were 58.3% (95% confidence interval [CI] 41.1-82.1) at 1 year and 48.9% (95% CI 48.9) at 2 years from the date of induction of BCG/EMDA-MMC, respectively. RFS was 41.9% (95% CI 25.9-67.8) at 1 year and 27.2% (95% CI 13.6-54.4) at 2 years. CR at 6, 12, and 18 months was observed in 16 (61.5%), 11 (44.0%), and 7 patients (30.4%), respectively. Side effects included dysuria (19.2%), hematuria (19.2%), and frequency (11.5%). Three patients were admitted for side effects but managed conservatively. Four patients (15.4%) died of bladder cancer over the course of the study. CONCLUSIONS: EMDA-MMC BCG represents a viable option in patients with BCG unresponsive NMIBC with close to 50% progression-free survival at 2 years. However, these patients have a high risk of death from bladder cancer (15% in our cohort at 2 years) thus warranting extremely close surveillance.

A noninvasive urine-based methylation biomarker panel to detect bladder cancer and discriminate cancer grade.

BACKGROUND: Highly sensitive and specific urinary biomarkers for the early detection of bladder cancer (BC) to improve the performance of urinary cytology are needed. OBJECTIVE: To investigate the usefulness of methylation markers in voided urine to identify BC presence and grade. DESIGN, SETTINGS, AND PARTICIPANTS: Using genome-wide methylation strategies in Toronto, Canada and Liège, Belgium, we have identified differentially methylated genes (TWIST1, RUNX3, GATA4, NID2, and FOXE1) in low-grade vs. high-grade BC tissue and urine. We accrued urine samples from 313 patients using a 2:1 ratio in a case-control setting from Toronto, Canada, Halifax, Canada, and Zurich, Switzerland. We studied the usefulness of these 5 methylated genes to identify BC and discriminate cancer grade in voided urine specimens. Urinary cell sediment DNA was evaluated using qPCR-based MethyLight assay. Multivariable logistic regression prediction models were created. RESULTS AND LIMITATIONS: We included 211 BC patients (180 nonmuscle invasive) and 102 controls. In univariate analyses, all methylated genes significantly predicted BC vs. no BC, and high grade vs. low grade (all P < 0.05). In multivariable analysis, NID2, TWIST1, and age were independent predictors of BC (all P < 0.05). Sensitivity of NID2 and TWIST1 to predict BC and BC grade was 76.2% and 77.6%, respectively, whereas specificity was 83.3% and 61.1%, respectively. Multivariable models predicting BC overall and discriminating between high-grade and low-grade BC reached area under the receiver operating characteristics curves of 0.89 and 0.78, respectively. CONCLUSIONS: This multi-centric study in a real life scenario (different countries, techniques, and pathologists) supports the promise of epigenetic urinary markers in noninvasively detecting BC. With sensitivities and specificities in the range of 80%, the overall performance characteristics of this panel of methylated genes probably does not allow such signature to significantly alter clinical care at this stage but is worth further studying for instance in BC surveillance or screening in high-risk populations.

Germline Mutations in the Kallikrein 6 Region and Predisposition for Aggressive Prostate Cancer.

Background: There is a need for markers that can specifically identify individuals at increased risk of harboring aggressive forms of prostate cancer (PCa). Methods: We surveyed the Kallikrein ( KLK ) region ( KLK 1-15) for single-nucleotide polymorphisms (SNPs) associated with aggressive PCa (Gleason Score ≥ 8) in 1858 PCa patients. Discovery cohorts (Swiss arm of the European Randomized Study of Screening for PCa, n = 379; Toronto, Canada, n = 540) and a validation cohort (Prostate, Lung, Colorectal and Ovarian [PLCO] screening trial, n = 939) were analyzed. Fine-mapping within the KLK region was carried out by genotyping and imputation in the discovery cohort, whereas PLCO data were provided through database of Genotypes and Phenotypes ( dbGaP ). The influence of SNPs of interest on biochemical-free survival was evaluated in a cohort of localized PCa from the International Cancer Genome Consortium (ICGC; n = 130) analyzed with next-generation sequencing. Single- and multi-SNP association studies, as well as haplotype analyses, were performed. All statistical tests were two-sided. Results: Several SNPs in very strong linkage disequilibrium in the KLK 6 region and located within the same haplotype (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287), identified individuals at increased risk of aggressive PCa in both discovery (odds ratio [OR] = 3.51-3.64, 95% confidence interval [CI] = 2.01 to 6.36, P = 1.0x10 -5 -8.4x10 -6 ) and validation (OR = 1.89-1.96, 95% CI = 0.99 to 3.71, P = .04-.05) cohorts. The overall test of haplotype association was highly statistically significant in each cohort ( P = 3.5x10 -4 and .006, respectively) and in the three data sets combined ( P = 2.3x10 -5 ). These germline SNPs independently predicted relapse in the ICGC cohort (hazard ratio = 3.15, 95% CI = 1.57 to 6.34, P = .001). Conclusions: Our fine-mapping study has identified novel loci in the KLK 6 region strongly associated with aggressive PCa.

Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic.

Purpose Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. Although radical cystectomy (RC) currently is viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) that combines transurethral resection of bladder tumor, chemotherapy for radiation sensitization, and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, this study compared the oncologic outcomes between patients treated with RC or TMT by using a propensity score matched-cohort analysis. Methods Data from patients treated in a multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were reviewed retrospectively. Those who received TMT for MIBC were identified and matched (for sex, cT and cN stage, Eastern Cooperative Oncology Group status, Charlson comorbidity score, treatment date, age, carcinoma in situ status, and hydronephrosis) with propensity scores to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox proportional hazards modeling and a competing risk analysis, respectively. Results A total of 112 patients with MIBC were included after matching (56 who had been treated with TMT, and 56 who underwent RC). The median age was 68.0 years, and 29.5% had stage cT3/cT4 disease. At a median follow-up of 4.51 years, there were 20 deaths (35.7%) in the RC group (13 as a result of BC) and 22 deaths (39.3%) in the TMT group (13 as a result of BC). The 5-year DSS rate was 73.2% and 76.6% in the RC and TMT groups, respectively ( P = .49). Salvage cystectomy was performed in 6 (10.7%) of 56 patients who received TMT. Conclusion In the setting of a MDBCC, TMT yielded survival outcomes similar to those of matched patients who underwent RC. Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options, including organ-sparing TMT.

Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts.

Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. Using tumorgraft models, we previously showed that AS is sensitive to small-molecule inhibitors that target mitogen-activated/extracellular-signal-regulated protein kinase kinases 1 and 2 (MEK). The objective of this study was to identify drugs that combine with MEK inhibitors to more effectively inhibit AS growth. We examined the in vitro synergy between the MEK inhibitor PD0325901 and inhibitors of eleven common cancer pathways in melanoma cell lines and canine angiosarcoma cell isolates. Combination indices were calculated using the Chou-Talalay method. Optimized combination therapies were evaluated in vivo for toxicity and efficacy using canine angiosarcoma tumorgrafts. Among the drugs we tested, rapamycin stood out because it showed strong synergy with PD0325901 at nanomolar concentrations. We observed that angiosarcomas are insensitive to mTOR inhibition. However, treatment with nanomolar levels of mTOR inhibitor renders these cells as sensitive to MEK inhibition as a melanoma cell line with mutant BRAF. Similar results were observed in B-Raf wild-type melanoma cells as well as in vivo, where treatment of canine AS tumorgrafts with MEK and mTOR inhibitors was more effective than monotherapy. Our data show that a low dose of an mTOR inhibitor can dramatically enhance angiosarcoma and melanoma response to MEK inhibition, potentially widening the field of applications for MEK-targeted therapy.

Not all gleason pattern 4 prostate cancers are created equal: A study of latent prostatic carcinomas in a cystoprostatectomy and autopsy series.

BACKGROUND: The Gleason grading system represents the cornerstone of the management of prostate cancer. Gleason grade 4 (G4) is a heterogeneous set of architectural patterns, each of which may reflect a distinct prognostic value. METHODS: We determined the prevalence of the various G4 architectural patterns and intraductal carcinoma (IDC) in latent prostate cancer in contemporary Russian (n = 220) and Japanese (n = 100) autopsy prostates and in cystoprostatectomy (CP) specimens (n = 248) collected in Italy. We studied the association of each G4 pattern with extraprostatic extension (EPE) and tumor volume to gain insight into their natural history. Presence of IDC and nine architectural features of Gleason grade 4 and 5 cancer were recorded. RESULTS: The prevalence of Gleason score ≥ 7 PC was higher in the autopsy series (11%) compared to the CP series (6.5%, P = 0.04). The prevalence of IDC and carcinoma with a cribriform architecture was 2.2% and 3.4% in the autopsy series and 0.8% and 3.6% in the cystoprostatectomy series, respectively. In multivariable analysis, cribriform architecture was significantly associated with increased tumor volume (P < 0.001) and EPE (OR:11.48, 95%CI:2.30-57.16, P = 0.003). IDC was also significantly associated with EPE (OR:10.08, 95%CI:1.58-64.28, P = 0.014). Small fused glands had a strong negative association with EPE in the autopsy series (OR:0.06, 95%CI:0.01-0.58, P = 0.015). DISCUSSION: Our study revealed that in latent prostate cancer both cribriform architecture and IDC are uniquely associated with poor pathological outcome features. In contrast, Gleason score 7 (3 + 4) cancers with small-fused gland pattern might possibly include some prostate cancers with a more indolent biology.

Next-generation RNA sequencing of archival formalin-fixed paraffin-embedded urothelial bladder cancer.

UNLABELLED: Molecular profiling of individual cancers is key to personalised medicine. While sequencing technologies have required stringent sample collection and handling, recent technical advances offer sequencing from tissues collected in routine practice and tissues already stored in archives. In this paper, we establish methods for whole-transcriptome RNA sequencing (RNA-seq) from formalin-fixed paraffin-embedded tissues. We obtain average RNA-seq reads of >100 million per sample using the Illumina HiSeq2000 platform. We find high concordance with results from matching fresh frozen samples (>0.8 Spearman correlation). For validation, we compared low- and high-grade bladder cancer transcriptomes in 49 tumour samples after transurethral resection of bladder tumour. We found 947 differentially expressed protein-coding genes. While high-grade lesions exhibited distinct intertumour transcriptome heterogeneity, the transcriptome of low-grade tumours was homogeneous. PATIENT SUMMARY: In this report, we show that it is now possible to use universally available bladder cancer samples that have been fixed in formalin to perform high-quality transcriptome analysis. This ability will facilitate the development of transcriptome-wide tests based on gene expression correlated with clinical outcome.

Prevalence of inflammation and benign prostatic hyperplasia on autopsy in Asian and Caucasian men.

UNLABELLED: Inflammation has been suggested to be involved in the pathogenesis of benign prostatic hyperplasia (BPH). We studied the prevalence of inflammation and BPH in Asian and Caucasian men on prostate glands (n=320) obtained during autopsy in Moscow, Russia (Caucasian men, n=220), and Tokyo, Japan (Asian men, n=100). We correlated the presence and grade of acute inflammation (AI) or chronic inflammation (CI) and BPH. AI, CI, and histologic BPH were analyzed in a blinded fashion using a grading system (0-3). We used the Cochran-Armitage test for associations between the degree of BPH and clinical variables and proportional odds logistic regression models in multivariable analysis. Histologic BPH was observed in a similar proportion of Asian and Caucasian men (p=0.94). CI was found in>70% of men in both the Asian and Caucasian groups (p>0.05). Higher BPH scores were associated with more CI (p<0.001). In multivariate analyses, individuals with CI were 6.8 times more likely to have a higher BPH score than individuals without (p<0.0001). Men included in this study presented at the hospital and their symptomatic status was not known. The prevalence of CI and BPH on autopsy is similar in Asian and Caucasian men despite very different diet and lifestyle. CI is strongly associated in both groups with BPH. PATIENT SUMMARY: In this study, we looked at the prevalence of inflammation and benign prostatic hyperplasia (BPH) on autopsy in Asian and Caucasian men. We found chronic inflammation in>70% of men on autopsy. More chronic inflammation was associated with more BPH.

Prevalence of prostate cancer across the globe: what can autopsy studies teach us about this peculiar disease?

Prostate cancer (PCa) represents a major public health burden in the western world. It is a peculiar disease as more men die with it than from it. Also interestingly, PCa was virtually unknown for centuries until the 20th century. Randomized trials on PCa screening have outlined the risks of over-diagnosis and over-treatment of latent cancers. Significant geographical differences in PCa incidence and mortality exist, being supposedly low among Asian men compared to Caucasians. In some areas like Korea and Japan, changes have been observed that cannot be explained easily by changing diagnostic procedures and increases in mortality may be due to lifestyles and dietary changes. We have recently studied and compared the prevalence of PCa in Caucasian (CAU) from Moscow, Russia and Asian (ASI) men from Tokyo, Japan. We chose a specific Cau population in Russia with little sun exposure and high fat diet but without widespread PSA screening. Autopsy data in western countries (North America and Europe) would have been heavily contaminated due to opportunistic PSA screening. Screening in Asi men in Japan is uncommon. Prostates were removed en-block with the seminal vesicles within 24 hours of death and analyzed in toto (perpendicular sections at 4 mm intervals) by an experienced uro-pathologist in Toronto. PCa was found on autopsy in a similar proportion of Russian Caucasian and Japanese men. Over 50% of cancers are Gleason ≥7 in Japanese and nearly 25% in Russian Caucasian men raising questions about 1) previous assumptions related to Asian PCa and 2) the notion of significant vs. insignificant cancers. Autopsy studies are key to improve our understanding of this very curious cancer.

Prevalencia global del cáncer de próstata: ¿Qué nos pueden enseñar los estudios de autopsias sobre esta peculiar enfermedad? / Prevalence of prostate cancer across the globe: what can autopsy studies teach us about this peculiar disease

El cáncer de próstata (CaP) representa una gran carga para la salud pública en el mundo occidental. Es una enfermedad peculiar porque mueren más hombres con él que por él. También es interesante que el CaP fue virtualmente desconocido durante siglos hasta el siglo XX. Los estudios aleatorizados de cribado del CaP han delineado los riesgos de sobrediagnóstico y sobretratamiento del cáncer latente. Existen diferencias geográficas significativas en la incidencia y mortalidad, siendo supuestamente menor entre los varones asiáticos en comparación con los caucasianos. En algunas áreas como Corea y Japón, se han observado cambios que no pueden explicarse fácilmente por el cambio de los procedimientos diagnósticos y los aumentos en la mortalidad pueden ser debidos a cambios en estilos de vida y dieta. Recientemente hemos estudiado y comparado la prevalencia de CaP entre varones caucasianos (CAU) de Moscú, Rusia, y asiáticos (ASI) de Tokio, Japón. Elegimos una población caucasiana específica en Rusia, con poca exposición al sol y una dieta rica en grasas, pero sin cribado de PSA generalizado. Los datos de autopsias en los países occidentales (Norteamérica y Europa) habrían sido contaminados ampliamente debido al cribado de PSA oportunista. El cribado en varones asiáticos es poco frecuente. Se extrajeron las próstatas en bloque con las vesículas seminales en las primeras 24 horas después de la muerte y fueron analizadas completamente (secciones perpendiculares con intervalos de 4 mm) por una uropatólogo experto en Toronto. Se encontró CaP en autopsia en una proporción similar de varones rusos caucasianos y japoneses. Más del 50% de los cánceres son Gleason ≥ 7 en japoneses y cerca del 25% en rusos caucasianos planteando interrogantes sobre 1) asunciones previas relacionadas con el CaP en asiáticos y 2) la noción de cáncer significativo frente a no significativo. Los estudios en autopsias son la llave para mejorar nuestra comprensión de este cáncer tan curioso

Prostate cancer (PCa) represents a major public health burden in the western world. It is a peculiar disease as more men die with it than from it. Also interestingly, PCa was virtually unknown for centuries until the 20th century. Randomized trials on PCa screening have outlined the risks of over-diagnosis and over-treatment of latent cancers. Significant geographical differences in PCa incidence and mortality exist, being supposedly low among Asian men compared to Caucasians. In some areas like Korea and Japan, changes have been observed that cannot be explained easily by changing diagnostic procedures and increases in mortality may be due to lifestyles and dietary changes. We have recently studied and compared the prevalence of PCa in Caucasian (CAU) from Moscow, Russia and Asian (ASI) men from Tokyo, Japan. We chose a specific Cau population in Russia with little sun exposure and high fat diet but without widespread PSA screening. Autopsy data in western countries (North America and Europe) would have been heavily contaminated due to opportunistic PSA screening. Screening in Asi men in Japan is uncommon. Prostates were removed en-block with the seminal vesicles within 24 hours of death and analyzed in toto (perpendicular sections at 4 mm intervals) by an experienced uro-pathologist in Toronto. PCa was found on autopsy in a similar proportion of Russian Caucasian and Japanese men. Over 50% of cancers are Gleason ≥7 in Japanese and nearly 25% in Russian Caucasian men raising questions about 1) previous assumptions related to Asian PCa and 2) the notion of significant vs. insignificant cancers. Autopsy studies are key to improve our understanding of this very curious cancer

The importance of surgeon characteristics on impacting oncologic outcomes for patients undergoing radical cystectomy.

PURPOSE: Given that the urologist has a major influence on outcomes of radical cystectomy, it is of interest to patients, trainees, urologists and administrators to understand the provider characteristics associated with favorable outcomes. Therefore, we assessed associations between various surgeon characteristics and long-term oncologic outcomes for patients undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS: A retrospective cohort treated with radical cystectomy for muscle invasive or nonmuscle invasive bladder cancer at University Health Network (Toronto) was assembled. The characteristics studied included years of experience in independent practice, surgical radical cystectomy volume, subspecialized focus in bladder cancer and uro-oncology fellowship training. The outcomes were overall survival, bladder cancer specific survival and recurrence-free survival. Kaplan-Meier analyses and multivariate Cox proportional hazards models adjusting for patient, tumor and treatment related parameters were used. RESULTS: The final cohort included 410 patients treated by 11 urologists (median followup 57 months). Bladder cancer focused and uro-oncology fellowship trained urologists performed more extensive lymphadenectomies and more often performed continent diversions, but there was no difference in the use of neoadjuvant chemotherapy. In Kaplan-Meier and univariate Cox analyses, subspecialized bladder cancer focus and uro-oncology fellowship were associated with improved survival outcomes. However, in multivariate Cox models only subspecialized bladder cancer focus was independently associated with improved overall survival (HR 0.68, 95% CI 0.55-0.85, p <0.001), bladder cancer specific survival (HR 0.63, 95% CI 0.41-0.96, p = 0.032) and recurrence-free survival (HR 0.63, 95% CI 0.42-0.95, p = 0.027). CONCLUSIONS: While radical cystectomy volume, experience and uro-oncology fellowship are all likely important, we found that subspecialized focus in bladder cancer was independently associated with improved long-term oncologic outcomes. Our data support disease site differentiation among uro-oncologists at large institutions.