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.

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.

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.

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.

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.

Upper urinary tract and urethral recurrences following radical cystectomy: review of risk factors and outcomes between centres with different follow-up protocols.

PURPOSE: To examine which patient-related and tumour-related characteristics predict upper urinary tract recurrence (UUTR) and urethral recurrence (UR) of bladder cancer post-radical cystectomy (RC). Secondary objective is to evaluate whether or not recurrence patterns are similar between two centres with different post-RC follow-up (F/U) protocols. METHODS: A retrospective cohort study of 574 consecutive patients undergoing radical cystectomy for urothelial carcinoma of the bladder at two tertiary centres was performed. Clinicopathological factors associated with bladder cancer recurrence and patient-related outcomes, including time to recurrence and death, were collected. Risk factors for recurrences were examined using univariate and multivariable regression analyses. Likelihood of recurrence, time to recurrence, and survival were compared. RESULTS: There was a 3.7 % risk of UUTR (21/574) and a 3.6 % risk of UR (18/503) for the combined cohort at a median F/U of 45 months. When controlling for the effects of all variables modelled, female gender was a significant risk factor for UUT recurrence (OR 3.2, 95 % CI 1.0-9.5, p = 0.03) and prostatic urethral involvement was a significant risk factor for urethral recurrence (OR 7.8, 95 % CI 2.2-27.6, p = 0.001). UUTR were similar (p = 0.82) between Turku (8/205) and Toronto (12/369). Urethral recurrences trended (p = 0.06) towards being more common in Turku (9/151, 6.0 %) versus Toronto (9/352, 2.6 %), but no difference in overall survival was demonstrated between sites. CONCLUSION: The frequency of UUT and urethral recurrences post-cystectomy is relatively low and remained stable for the past 15 years. The ideal F/U protocol to maximize patient-survival remains unknown.

Platelet-adenovirus vs. inert particles interaction: effect on aggregation and the role of platelet membrane receptors.

Platelets are involved in host defense via clearance of bacteria from the circulation, interaction with virus particles, and uptake of various size particulates. There is a growing interest in micro- and nanoparticles for drug delivery and there is evidence that the properties of these particles critically influence their interaction and uptake by various tissues and cells including platelets. Virus mediated gene therapy applications are still challenged by the resultant thrombocytopenia and the mechanism(s) of platelet-foreign particles interaction remains unclear. We studied the specifics of platelet interaction with an active biological agent (adenovirus) and inert latex microspheres (MS) and investigated the role of platelet proteins in this interaction. We show that activated and not resting platelets internalize MS, without influencing platelet aggregation. In contrast, adenovirus induces and potentiates ADP-induced platelet aggregation and results in rapid expression of P-selectin. Platelets then internalize adenovirus and viral particles appear inside the open canalicular system. Inhibition of platelet αIIbß3, GPIbα, and P-selectin decreases both platelet aggregation and internalization of MS. Inhibition of αIIbß3 and αVß3 does not abolish adenovirus platelet internalization and adenovirus-induced platelet activation is maintained. Our study demonstrates that platelets react differentially with foreign particles and that αIIbß3 is a key player in platelet engulfing of foreign particles but not in mediating adenovirus internalization. Other platelet candidate molecules remain to be investigated as potential targets for management of adenovirus-induced thrombocytopenia.

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.

Does patient age affect survival after radical cystectomy?

UNLABELLED: What's known on the subject? and What does the study add? Elderly patients have more years to compound comorbidities and it has previously been shown that comorbidity is an important predictor of overall survival in patients with bladder cancer, including those treated with radical cystectomy (RC). Other studies have also demonstrated higher stage at diagnosis, higher rate of upstaging on final pathology and a longer delay to definitive therapy for older patients. Because of these findings, elderly patients are being offered RC less often than younger patients. Whether or not this practice is justified has come under recent scrutiny and there has been much conflicting data in the literature. While some studies have shown worse outcomes for elderly patients, others have shown similar results for both elderly and younger patients. Large population-based databases have recently been used to try to determine whether age effects outcome after RC but their conclusions may not be as generalizable as ours for several reasons: billing code data was used to build patient cohorts, patients were generally recipients of Medicare, lack of pathological review, and lack of available and accurate clinical data. Our series is unique in that it comprises a large group of patients from two major tertiary care academic institutions using a very robust dataset. Pathological specimens were reviewed by dedicated genitourinary pathologists, including those recovered from peripheral hospitals. Our sample size is one of the largest single- or multi-institutional studies. OBJECTIVE: • To analyse the impact of patient age on survival after radical cystectomy (RC). PATIENTS AND METHODS: • After ethics review board approval, two databases of patients with bladder cancer (BC) undergoing RC at the University Heath Network, Toronto, Canada (1992-2008) and the University of Turku, Turku, Finland (1986-2005) were retrospectively analysed. • A total of 605 patients who underwent this procedure between June 1985 and March 2010 were included. • Patients were divided into four age groups: ≤ 59, 60-69, 70-79 and ≥ 80 years. • Demographic, clinical and pathological data were compared, as well as recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OAS) rates. RESULTS: • Compared with younger patients (age ≤ 79 years), elderly patients (age ≥ 80 years) had higher American Society of Anesthesiologists scores (P < 0.001), a greater number of lymph nodes removed during surgical dissection (P < 0.001), and underwent less adjuvant treatment (P < 0.001). • Choice of urinary diversion differed among the groups, with ileal conduit being used for all patients ≥ 80 years (P < 0.001). • No differences were noted between age groups with respect to RFS (P= 0.3), DSS (P= 0.4) or OAS (P= 0.4). CONCLUSION: • Although RC is an operation with significant morbidity, it is a viable treatment option for carefully selected elderly patients. Senior patients (≥ 80 years) should not be denied RC if they are deemed fit to undergo surgery. • Senior adults do not suffer from adverse histopathological features as compared with younger patients.

Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome.

UNLABELLED: What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ-confined (OC) to non-organ-confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0-8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6-4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome. OBJECTIVES: To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres. To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC. PATIENTS AND METHODS: Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992-2010) and University of Turku, Turku, Finland (1986-2005) were analysed. RESULTS: Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ-confined (OC) to non-organ-confined (nOC) disease. During the study period, upstaging became more common in both centres. In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44-4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21-6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48-7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38-0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6-4.8) were associated with a risk of upstaging from OC to nOC disease. Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10-year disease-specific mortality, P < 0.001). CONCLUSIONS: Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades. LVI and the presence of histological variants are strong predictors of upstaging at the time of RC. Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

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.

Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guérin treatment.

OBJECTIVE: To report the long-term results of bacille Calmette-Guérin (BCG) intravesical therapy in relation to disease progression and recurrence in primary T1 high-grade (HG) bladder cancer (BC) confirmed by central pathological review. PATIENTS AND METHODS: In all, 136 patients from two university centres (Rotterdam, n = 49; Toronto, n = 87) were diagnosed with primary T1HG BC. One experienced uro-pathologist reviewed all slides, ensuring all cases were indeed HG and that muscle was present in all specimens. Patients were treated with BCG induction (six instillations) after transurethral resection (TUR) of the tumour and followed with cystoscopy and urinary cytology. Predictors for recurrence, progression and survival were assessed with multivariable Cox regression models. RESULTS: Mean (range) follow-up was 6.5 (0.3-21.6) years. There were no significant differences for recurrence (P = 0.52), progression (P = 0.35) and disease-specific survival (DSS) (P = 0.69) between the two centres. Among the cohort, 47 patients (35%) recurred and 42 (30.9%) progressed with a median time to progression of 2.1 years; 16 (38%) of these progressions occurred ≥ 3 years after the initial BCG course; 22 (16%) patients who progressed died from BC. Overall, 96 (71%) patients had no evidence of disease at the last follow-up. Carcinoma in situ was the only independent predictor for recurrence in multivariate analysis (P = 0.011). No independent predictors were found for progression. CONCLUSIONS: Conservative treatment with BCG is a valid option in primary T1HG BC. Nevertheless, the aggressive nature of T1HG BC is evident in the fact that 30% progressed, with a high proportion of these progression events occurring ≥ 3 years after BCG. Caution should be exercised when relying on the long-term effects of BCG, and close follow-up of these patients should not be neglected.

Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study.

OBJECTIVE: • To investigate androgen receptor (AR) expression in a large series of patients with bladder cancer (BC) because data on a limited number of patients showed that loss of AR expression was associated with invasive BC. PATIENTS AND METHODS: • A total of 472 patients with urothelial bladder carcinoma (UBC) from two institutional centres (Toronto and Dallas) were analysed. Tissue microarrays comprising both non-muscle-invasive UBC (n= 167) and muscle-invasive UBC (n= 305) were accrued and immunohistochemical staining for AR was performed. • We used bright-field microscopy imaging coupled with advanced colour detection software to detect, classify and count stained cellular objects and manual scoring. • Results obtained in Dallas were blindly reviewed and validated in Toronto and samples randomly chosen were further analysed in Rochester, NY, USA. RESULTS: • The AR were positively expressed in 61/472 (12.9%) bladder tumours. No statistically significant difference in AR expression between men and women was observed. • Only 9.0% of non-muscle-invasive BC expressed the AR compared with 15.1% of muscle-invasive tumours (P= 0.059). The highest percentage of AR positivity (28.9% of cases) was found in T2 tumours. • There was no statistically significant difference in death from BC, time to death, or time to recurrence between AR-positive and AR-negative cases. CONCLUSION: • In contrast to previous reports, based on our large BC series, we did not observe a decrease in AR protein expression in bladder tumours with increased pathological stage. Our data do not suggest that loss of AR expression is gender-related nor is it associated with invasive BC.

Mining the ovarian cancer ascites proteome for potential ovarian cancer biomarkers.

Current ovarian cancer biomarkers are inadequate because of their relatively low diagnostic sensitivity and specificity. There is a need to discover and validate novel ovarian cancer biomarkers that are suitable for early diagnosis, monitoring, and prediction of therapeutic response. We performed an in-depth proteomics analysis of ovarian cancer ascites fluid. Size exclusion chromatography and ultrafiltration were used to remove high abundance proteins with molecular mass >/=30 kDa. After trypsin digestion, the subproteome (

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.

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.

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.

Comprehensive analysis of conditioned media from ovarian cancer cell lines identifies novel candidate markers of epithelial ovarian cancer.

Ovarian cancer remains a deadly threat to women as the disease is often diagnosed in the late stages when the chance of survival is low. There are no good biomarkers available for early detection and only a few markers have shown clinical utility for prognosis, response to therapy and disease recurrence. We mined conditioned media of four ovarian cancer cell lines (HTB75, TOV-112D, TOV-21G and RMUG-S) by two-dimensional liquid chromatography-mass spectrometry. Each cell line represented one of the major histological types of epithelial ovarian cancer. We identified 2039 proteins from which 228 were extracellular and 192 were plasma membrane proteins. Within the latter list, we identified several known markers of ovarian cancer including three that are well established, namely, CA-125, HE4, and KLK6. The list of 420 extracellular and membrane proteins was cross-referenced with the proteome of ascites fluid to generate a shorter list of 51 potential biomarker candidates. According to Ingenuity Pathway Analysis, two of the top 10 diseases associated with the list of 51 proteins were cancer and reproductive diseases. We selected nine proteins for preliminary validation using 20 serum samples from healthy women and 10 from women with ovarian cancer. Of the nine proteins, clusterin (increase) and IGFBP6 (decrease) showed significant differences between women with or without ovarian cancer. We conclude that in-depth proteomic analysis of cell culture supernatants of ovarian cancer cell lines can identify potential ovarian cancer biomarkers that are worth further clinical validation.

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.