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Purpose To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC). Materials and methods We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age. Results pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6–37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p p = 0.002) compared to those with luminal papillary subtype. Conclusions While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.

Objective: To evaluate the role of incomplete metastasectomy (IM) for patients with metastatic renal cell carcinoma (mRCC) on overall survival (OS) and time to introduction of first-line systemic therapy. Methodology: Patients diagnosed with mRCC between Jan 2011 and Apr 2019 in 16 centers were selected from the Canadian Kidney Cancer information system database. We included mRCC patients who had prior nephrectomy and had received an IM (resection of at least 1 metastasis) or no metastasectomy (NM). A propensity score matching was performed to minimize selection bias. Cox proportional hazards analysis was used to assess the impact of the metastasectomy while adjusting for potential confounders. OS was assessed by Kaplan-Meier analysis. Results: A total of 138 patients with mRCC underwent IM, while 1221 patients did not. On multivariate analysis, IM did not improve OS (hazard ratio [HR] 0.96, 95% CI 0.63 to 1.45, P = 0.836) However, subgroup analyses revealed IM improved OS compared with NM when lungs were the only site involved (median time to OS not reached versus 66 months, respectively; P = 0.014). Additionally, lung metastasectomy delayed the systemic therapy compared with NM (median 41 and 13 months, respectively, P = 0.014). IM of endocrine organs (thyroid, pancreas, adrenals) or bone metastases did not impact OS. Conclusion: The role of IM for mRCC is limited. Incomplete resection of lung metastases was associated with improved OS and delayed time to introduction of systemic therapy when lungs were the sole location of metastatic disease. Despite case-matching, unknown unadjusted confounders may explain the relationship between IM and survival in this analysis.

IntroductionNon-muscle invasive bladder cancer (NMIBC) accounts for about 75% of newly diagnosed bladder cancers. The treatment for NMIBC involves surgical removal of the tumour followed by 6 weekly instillations of immunotherapy or chemotherapy directly into the bladder (ie, intravesical therapy). NMIBC has a high rate of recurrence (31%–78%) and progression (15%). Moreover, bladder cancer and its treatment may affect patient functioning and quality of life. Exercise is a safe and effective intervention for many patient with cancer groups, however, no studies have examined exercise during intravesical therapy for NMIBC. The primary objective of the Bladder cancer and exeRcise trAining during intraVesical thErapy (BRAVE) trial is to examine the safety and feasibility of an exercise intervention in patients with bladder cancer undergoing intravesical therapy. The secondary objectives are to investigate the preliminary efficacy of exercise on health-related fitness and patient-reported outcomes; examine the social cognitive predictors of exercise adherence; and explore the potential effects of exercise on tumour recurrence and progression.Methods and analysisBRAVE is a phase II randomised controlled trial that aims to include 66 patients with NMIBC scheduled to receive intravesical therapy. Participants will be randomly assigned to the exercise intervention or usual care. The intervention consists of three supervised, high-intensity interval training sessions per week for 12 weeks. Feasibility will be evaluated by eligibility, recruitment, adherence and attrition rates. Preliminary efficacy will focus on changes in cardiorespiratory fitness and patient-reported outcomes from baseline (prior to intravesical therapy) to pre-cystoscopy (3 months). Cancer outcomes will be tracked at 3 months, and 1-year follow-up by cystoscopy. Analysis of covariance will compare between-group differences at post-intervention (pre-cystoscopy) for all health-related fitness and patient-reported outcomes.Ethics and disseminationThe study was approved by the Health Research Ethics Board of Alberta-Cancer Committee (#20–0184). Dissemination will include publication and presentations at scientific conferences and public channels.Trial registration numberNCT04593862; Pre-results.

INTRODUCTION AND OBJECTIVE:Surgical morbidity after radical cystectomy (RC) is significant, particularly in patients with an above-normal body mass index (BMI). Prehabilitation is a multi-modal, pr...

ObjectivesRectus sheath blocks are an established option for analgesia following abdominal surgery, but pharmacokinetic data are limited. This study sought to characterise the absorption of lidocaine injectate and the pharmacokinetics of lidocaine after rectus sheath injection.MethodsBilateral rectus sheath single-injection blocks were given to 10 patients undergoing general or urological surgery. Afterwards, serial lidocaine serum levels and ultrasound measurements of the rectus sheath injectate reservoir were collected.Key findingsInjectate within the rectus sheath was visible with ultrasound up to 12 h after injection. However, the rate of drug absorption exceeded that of injectate disappearance. Peak serum concentration occurred within 30 min with average peak concentrations of 1.65 μg/ml. Lidocaine clearance was lower than reported in young healthy subjects. The body mass index positively correlated with lidocaine terminal phase half-life, and clearance negatively correlated with age.ConclusionsThe study provides the first data describing lidocaine pharmacokinetics after rectus sheath injection. Peak serum concentrations transiently achieved systemic levels associated with pain relief after a single bolus injection. The data from this study could be used to develop a regime using single shot rectus sheath blockade with a bolus of lidocaine followed by infusion using bilateral rectus sheath catheters.

Introduction: The impact of paraneoplastic syndromes (PNS) on survival in patients with renal cell carcinoma (RCC) is uncertain. This study was conducted to analyze the association of PNS with recurrence and survival of patients with non-metastatic RCC undergoing nephrectomy. Methods: The Canadian Kidney Cancer information system is a multi-institutional cohort of patients started in January 2011. Patients with nephrectomy for non-metastatic RCC were identified. PNS included anemia, polycythemia, hypercalcemia, and weight loss. Associations between PNS and recurrence or death were assessed using Kaplan-Meier curves and multivariable analysis. Results: Of 4337 patients, 1314 (30.3%) had evidence of one or more PNS. Patients with PNS, were older, had higher comorbidity, and had more advanced clinical and pathological tumor characteristics as compared to patients without PNS (all p

Objective To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC). Methods Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses. Results A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75–1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71–1.58, P = 0.77). Conclusion Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.

Background Testicular cancer survivors (TCS) are at increased risk of cancer-related fatigue (CRF), psychosocial impairment, and poor mental health-related quality of life (HRQoL). Here, we examine the effects of high-intensity interval training (HIIT) on patient-reported outcomes (PROs) in TCS. Secondarily, we explore cardiorespiratory fitness as a mediator of intervention effects and select baseline characteristics as moderators of intervention effects. Methods TCS (n = 63) were randomly assigned to 12 weeks of supervised HIIT or usual care (UC). PROs included CRF, depression, anxiety, stress, self-esteem, sleep quality, and HRQoL assessed at baseline, post-intervention, and 3-month follow-up. Results TCS (median 7 years postdiagnosis) completed 99% of training sessions and achieved 98% of target training intensity. ANCOVA revealed that, compared to UC, HIIT significantly improved post-intervention CRF (p = 0.003), self-esteem (p = 0.029), and multiple HRQoL domains (ps ≤ 0.05). Effects on CRF (p = 0.031) and vitality (p = 0.015) persisted at 3-month follow-up. Cardiorespiratory fitness changes mediated CRF and HRQoL improvements. CRF effects were larger for TCS with an inactive lifestyle, lower fitness, higher testosterone, and clinical fatigue at baseline. Conclusions HIIT significantly improves CRF and HRQoL in TCS. Mediation by cardiorespiratory fitness and moderation by clinical characteristics suggests opportunities for targeted exercise interventions to optimise PROs in TCS.

Key Points Question Does the implementation of multiple Enhanced Recovery After Surgery (ERAS) pathways across 1 health care system affect ERAS guideline adherence, length of stay, complications, readmissions, and mortality? Findings In this quality improvement study, comparison of pre-post–ERAS cohorts found that pathway implementation was associated with increased guideline adherence, from 52% to 76%; decreased unadjusted length of stay, from a mean of 9.4 to 7.8 days; and decreased adjusted length of stay by 0.71 days, with no differences in serious complications or 30-day mortality. Meaning These results suggest that implementation of multiple ERAS pathways could provide system-level improvement in ERAS guidelines adherence and length of stay., Importance Engaging multidisciplinary care teams in surgical practice is important for the improvement of surgical outcomes. Objective To evaluate the association of multiple Enhanced Recovery After Surgery (ERAS) pathways with ERAS guideline adherence and outcomes. Design, Setting, and Participants This quality improvement study compared a pre-ERAS cohort (2013-2017) with a post-ERAS cohort (2014-2018). All patients were from Alberta Health Services in Alberta, Canada, and had available ERAS and up to 1-year postsurgery administrative data. Data collected included age, sex, body mass index, tobacco and alcohol use, diabetes, comorbidity index, and surgical characteristics. Data analysis was performed from May 7, 2020, to February 1, 2021. Interventions Implementation of 5 ERAS pathways (colorectal, liver, pancreas, gynecologic oncology, and radical cystectomy) across 9 sites. Main Outcomes and Measures Adherence to ERAS guidelines was measured by the percentage of patients whose care met the common ERAS pathway care element criteria. Surgical procedures were grouped by complexity; complications were classified by severity. Outcome measures for the pre-post–ERAS cohorts included length of stay (LOS), readmission, complications, and mortality. Results A total of 7757 patients participated in the study, including 984 in the pre-ERAS cohort (median [interquartile range] age, 62 [53-71] years; 526 [53.5%] female) and 6773 in the post-ERAS cohort (median [interquartile range] age, 62 [53-71] years; 3470 [51.2%] male). In the total cohort, care-element adherence improved from 52% to 76% (P, This quality improvement study evaluates the implementation of Enhanced Recovery After Surgery pathways to examine the association with guideline adherence, length of stay, complications, readmissions, and mortality.

BACKGROUND Testicular cancer survivors (TCS) have an increased risk of treatment-related cardiovascular disease (CVD), which may limit their overall survival. We evaluated the effects of high-intensity aerobic interval training (HIIT) on traditional and novel CVD risk factors and surrogate markers of mortality in a population-based sample of TCS. METHODS This phase 2 trial (ClinicalTrials.gov identifier NCT02459132) randomly assigned 63 TCS to usual care (UC) or 12 weeks of supervised HIIT (ie, alternating periods of vigorous-intensity and light-intensity aerobic exercise). The primary outcome was peak aerobic fitness (VO2peak) assessed via a treadmill-based maximal cardiorespiratory exercise test. Secondary endpoints included CVD risk (eg, Framingham Risk Score), arterial health, parasympathetic nervous system function, and blood-based biomarkers. RESULTS Postintervention VO2peak data were obtained for 61 participants (97%). HIIT participants attended 99% of the exercise sessions and achieved 98% of the target exercise intensity. Analysis of covariance demonstrated that HIIT was superior to UC for improving VO2peak (adjusted between-group mean difference, 3.7 mL O2/kg/min; 95% confidence interval, 2.4-5.1 [P

Active surveillance instead of active treatment (at) is preferred for patients with low-risk prostate cancer (lr-pca), but practice varies widely. We conducted a population-based study to assess the proportion of patients who underwent at between January 2011 and December 2014, and to evaluate factors associated with at. The provincial cancer registry was linked to administrative health datasets to identify patients with lr-pca and to acquire demographic, tumour, and treatment data. The primary outcome was receipt of at during the first 12 months after diagnosis, defined as any receipt of external-beam radiotherapy, brachytherapy, radical prostatectomy, cryotherapy, or androgen deprivation. Univariate and multivariate logistic regression were used to analyze the correlation between patient and tumour factors and at. Of 1565 patients with lr-pca, 554 (35.4%) underwent at within 12 months of diagnosis. Radical prostatectomy was the most common treatment (58%), followed by brachytherapy (29.6%). Younger age [odds ratio (or) 0.92, 95% confidence interval (ci): 0.91 to 0.94], lower score (&ge, 3) on the Charlson comorbidity index (OR: 0.36, 95% ci: 0.19 to 0.68), T2 stage (or: 3.05, 95% ci: 2.03 to 4.58), higher prostate-specific antigen (psa) at diagnosis (or: 1.13, 95% ci: 1.06 to 1.21), radiation oncologist consultation (or: 3.35, 95% ci: 2.55 to 4.39), and earlier diagnosis year (2012 or: 0.46, 95% ci: 0.34 to 0.63, 2013 or: 0.45, 95% ci: 0.32 to 0.63, 2014 or: 0.33, 95% ci: 0.23 to 0.47) were associated with a higher probability of at. This contemporary population-based study demonstrates that approximately one third of patients with lr-pca undergo at. Patients of younger age, with less comorbidity, a higher tumour stage, higher psa, earlier year of diagnosis, and radiation oncologist consultation were more likely to undergo at. Further investigation is needed to identify strategies that could minimize overtreatment.

The choice of urinary diversion at cystectomy is a life altering decision. Patient decision aids are clinical tools that promote shared decision making by providing information about management options and helping patients communicate their values. We sought to develop and evaluate a patient decision aid for individuals undergoing cystectomy with urinary diversion.We used the IPDAS (International Patient Decision Aids Standards) to guide a systematic development process. A literature review was performed to determine urinary diversion options and the incidence of outcomes. We created a prototype using the Ottawa Decision Support Framework. A 10-question survey was used to assess patient decision aid acceptability among patients, allied health professionals and urologists. The primary outcome was acceptability of the patient decision aid.Ileal conduit and orthotopic neobladder were included as primary urinary diversion options because they had the most evidence and are most commonly performed. Continent cutaneous diversion was identified as an alternative option. Outcomes specific to ileal conduit were stomal stenosis and parastomal hernia. Outcomes specific to neobladder were daytime and nighttime urinary incontinence and urinary retention. Acceptability testing was completed by 8 urologists, 9 patients and 1 advanced practice nurse. Of the respondents 94% reported that the language was appropriate, 94% reported that the length was adequate and 83% reported that option presentation was balanced. The patient decision aid met all 6 IPDAS defining criteria, all 6 certification criteria and 21 of 23 quality criteria.We created a novel patient decision aid to improve the quality of decisions made by patients when deciding among urinary diversion options. Effectiveness testing will be performed prospectively.

INTRODUCTION AND OBJECTIVES:We conducted a whole human genome short hairpin RNA (shRNA) screen on highly motile human squamous cell carcinoma (Hep3) cells and identified a panel of novel functional...

INTRODUCTION AND OBJECTIVES:Metastatic RCC is incurable, and the current therapeutic paradigm is centered around controlling the disease burden to prolong overall survival. We conducted a whole hum...

To evaluate outcomes of surgically treated patients with clinically localized papillary renal cell carcinoma (RCC) and determine if papillary RCC subtype is associated with recurrence and survival.This is a historical cohort study using the prospectively maintained Canadian Kidney Cancer Information System database between January 2011 and September 2018. All patients underwent partial or radical nephrectomy. Patient, tumor, treatment, and outcomes were compared between papillary RCC type 2 and type 1 cohorts.During the study period, 509 patients had clinically localized papillary RCC type 2 (n = 172) or type 1 (n = 337) histology. Sex, race, and comorbidities were similar between groups. Pathologic stage (pT3 or pT4), nuclear grade (3 or 4), and tumor diameter were higher in the type 2 papillary RCC cohort (P0.0001). A greater proportion of type 2 papillary RCC patients received radical nephrectomy (42.4% vs. 24.6%, P0.0001). More type 2 papillary RCC patients underwent lymph node dissection (19.6% vs. 5.5%, P0.0001) and had lymph node metastases removed during surgery (6.4% vs. 0.6%, P= 0.103). Overall, adjusting for age, grade, pathologic stage, positive nodes, and tumor size, type 2 papillary RCC had worse outcomes compared to type 1, as demonstrated by elevated all-cause mortality (hazard ratio = 7.7 [95% confidence interval: 2.0-28.9]), P=0.0027) and worse recurrence-free survival (hazard ratio = 8.2 [95% confidence interval: 3.6-19.0], P0.0001).Patients with clinically localized type 2 papillary RCC present with higher risk disease and have worse prognosis compared to patients with clinically localized type 1 papillary RCC. To the best of our knowledge, this is the largest cohort study comparing papillary RCC subtypes.

Background Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence. Methods Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth. Results Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. Conclusions Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies. Prostate © 2016 Wiley Periodicals, Inc.

PurposeThe Alberta Prostate Cancer Research Initiative (APCaRI) Registry and Biorepository was established in 2014 by the APCaRI to facilitate the collection of clinical and patient-reported data, biospecimen, to measure prostate cancer outcomes and to support the development and clinical translation of innovative technologies to better diagnose and predict outcomes for patients with prostate cancer.ParticipantsMen suspected with prostate cancer and referred to Urology centres in Alberta were enrolled in the APCaRI 01 study, while men with a prior prostate cancer diagnosis participated in the APCaRI 03 study from 1 July 2014 to 30 June 2019. The APCaRI Registry and Biorepository links biospecimens and data from a wide representation of patients drawn from an Alberta population of more than 4 million.Findings to dateFrom 1 July 2014 to 30 June 2019, total APCaRI 01 and 03 study recruitment was 3754 men; 142 (4%) of these men withdrew in full, 65 men (2%) withdrew biospecimens and 123 men (3%) died of any cause. Over this same time, 8677 patient-reported outcome measure (PROM) surveys and 7368 biospecimens were collected and are available from the registry and biorepository, respectively. The data entry error rate was 0.8% and 0.95% for critical and non-critical values, respectively, and 1.8% for patient-reported surveys.Future plansThe APCaRI Registry and Biorepository will collect longitudinal data and PROM surveys until 2024, patient outcomes up to 25 years after recruitment and biospecimen storage for up to 25 years. The APCaRI cohorts will continue to provide data and samples to researchers conducting retrospective studies. The richness of the data and biospecimens will complement many different research questions, ultimately to improve the quality of care for men with prostate cancer.

Microflow cytometry (µFCM) has recently emerged as a viable technology to enumerate and quantify individual EVs from complex biologic fluids. This method is a promising alternative to biopsy collection because it is highly sensitive and allows for longitudinal assessment of patients. EVs are highly abundant and analysis by µFCM allows for sophisticated multiparametric analysis of organ-specific, disease-specific, and outcome-specific proteins, genes, or metabolites. Detection of EVs with µFCM requires very little sample yet provides exceptional specificity and sensitivity for low abundance events. By combining µFCM analysis of EVs with advanced machine learning approaches, we have developed a platform technology called ClarityDX to generate EV fingerprints that significantly improve the diagnosis of diseases such as prostate cancer using a few drops of blood. Here I will discuss the development and clinical validation of new blood tests for prostate cancer that utilize the ClarityDX platform. Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer deaths in men. Screening has enabled the early detection of many latent prostate cancers, and it is estimated that up to 50% of new prostate cancer diagnoses detect a tumor that was unlikely to surface clinically in the absence of PSA screening. In the majority of cases, the treatment of indolent cancer causes a patient more harm than good. Consequently, there is an urgent need for a noninvasive test to detect clinically significant prostate cancer, or perhaps even more importantly, to detect metastatic disease. ClarityDX Prostate is a µFCM-based test to predict clinically significant prostate cancer prior to a prostate biopsy. A prospective clinical validation of ClarityDX Prostate was performed in a cohort of 377 Albertan men. The overall average AUC for ClarityDX Prostate in this population was 0.83, which was significantly higher than PSA alone. While PSA alone provided only 17% specificity for aggressive prostate cancer at a 95% sensitivity, ClarityDX Prostate was 56% specific for aggressive prostate cancer. We are now conducting a pivotal clinical validation study, in which up to 2,800 men will be enrolled to assess the performance of ClarityDX Prostate in a “real-world” clinical environment. Overall, we have established a robust µFCM EV platform for the development of novel and clinically viable diagnostic tests. Incorporating ClarityDX Prostate into routine prostate cancer screening could reduce the number of unnecessary biopsies by up to 40%. This abstract is also being presented as Poster B57. Citation Format: John D. Lewis, Robert J. Paproski, Desmond B. Pink, Catalina Vasquez, Eric Hyndman, Adrian Fairey, APCaRI. Detection of EV-based signatures in prostate cancer using microflow cytometry and machine learning [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR12.

To determine the association of micropapillary urothelial carcinoma (MUC) variant histology with bladder cancer outcomes after radical cystectomy.Information on MUC patients treated with radical cystectomy was obtained from five academic centers. Data on 1,497 patients were assembled in a relational database. Tumor histology was categorized as urothelial carcinoma without any histological variants (UC; n = 1,346) or MUC (n = 151). Univariable and multivariable models were used to analyze associations with recurrence-free (RFS) and overall (OS) survival.Median follow-up was 10.0 and 7.8 years for the UC and MUC groups, respectively. No significant differences were noted between UC and MUC groups with regard to age, gender, clinical disease stage, and administration of neoadjuvant and adjuvant chemotherapy (all, P ≥ 0.10). When compared with UC, presence of MUC was associated with higher pathologic stage (organ-confined, 60% vs. 27%; extravesical, 18% vs. 23%; node-positive, 22% vs. 50%; P0.01) and lymphovascular invasion (29% vs. 58%; P0.01) at cystectomy. In comparison with UC, MUC patients had poorer 5-year RFS (70% vs. 44%; P0.01) and OS (61% vs. 38%; P0.01). However, on multivariable analysis, tumor histology was not independently associated with the risks of recurrence (P = 0.27) or mortality (P = 0.12).This multi-institutional analysis demonstrated that the presence of MUC was associated with locally advanced disease at radical cystectomy. However, clinical outcomes were comparable to those with pure UC after controlling for standard clinicopathologic predictors.

Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70). In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

BACKGROUND: Sequential bacillus Calmette-Guerin (BCG) and electromotive mitomycin (sequential therapy) have been shown in a randomized prospective trial to be superior to therapy with BCG alone in patients with high-risk non–muscle-invasive bladder cancer. The objective of the current study was to compare the costs and benefits of these 2 treatment strategies by performing a 5-year and 10-year cost-effectiveness study. METHODS: A Markov model was developed to estimate the incremental cost-effectiveness ratio over a 5-year and 10-year period. Estimates of disease progression, death, and treatment efficacy were obtained from what to the authors’ knowledge is the only randomized trial comparing the 2 therapies. Costs included: 1) medical costs (physician fees); 2) drug costs (preparation and instillation); and 3) hospital costs (procedure fees, admission fees, and tests and procedures done during surveillance). Patients were allowed a second course of induction therapy. RESULTS: Sequential therapy was found to be associated with a higher initial material cost for induction and maintenance. The average effectiveness for the patients treated with therapy with BCG alone was 4.39 years with a mean cost of $9236 (95% confidence interval, $9118-$9345) per patient. The sequential group resulted in an average effectiveness of 4.65 years, with a mean cost of $16,468 (95% confidence interval, $16,371-$16,527). The 5-year incremental cost-effectiveness ratio of sequential versus BCG-alone therapy was $27,815 per life-year gained. The corresponding figure over a 10year period was $8618 per life-year gained. CONCLUSIONS: The results of the current study suggest that sequential therapy is a cost-effective treatment for patients with high-risk non–muscle-invasive bladder cancer. Cancer 2014;000:000-000. V C 2014 American Cancer Society.

IntroductionActive surveillance (AS) is the preferred primary treatment strategy for men with low-risk clinically localised prostate cancer (PCa); however, the majority of these men still receive radical treatment within 10 years due to disease progression and/or fear of cancer progression. Interventions designed to suppress tumour growth, mitigate fear of cancer progression and precondition men for impending radical treatments are an unmet clinical need. Exercise has been shown to delay the progression of prostate tumours in animal models, improve physical and functional health and manage psychological outcomes in cancer patients; however, these outcomes have not been demonstrated in PCa patients undergoing AS.Methods and analysisThis phase II randomised controlled trial will randomise 66 men undergoing AS to either an exercise group or a usual care group. The exercise group will perform a 12-week, supervised, high-intensity interval training programme, consisting of 3 sessions/week for 28–40 min/session. The primary outcome will be cardiorespiratory fitness. Secondary outcomes will include immunosurveillance and cancer-related biomarkers, psychosocial outcomes including fear of cancer progression and quality of life and physical function. Exploratory outcomes will include clinical indicators of disease progression. The trial has 80% power to detect a significant between-group difference in VO2peakof 3.5 mL/kg/min with a two-tailed alpha level Ethics and disseminationThe study has received full ethical approval from the Health Research Ethics Board of Alberta – Cancer Committee (Protocol Number: HREBA.CC-17–0248). The findings of the study will be disseminated through public and scientific channels.Trial registration numberNCT03203460; Pre-results.

characteristics consisted of age, Charlson Comorbidity Index, surgical approach (retropubic vs. robot-assisted vs. laparoscopic vs. perineal), status of lymph node dissection (LND) and nerve-sparing procedure, hospital district, hospital region and hospital volume. We examined the rate of blood transfusion, intraand postoperative complications, inhospital mortality, length of stay (LOS) and hospital charges using validated methodology. RESULTS: Overall, 25,333 men underwent RP. Of these, 16,372 (64.6%) men were treated by retropubic, 5,657 (22.3%) by robot-assisted, 2,730 (10.8%) by laparoscopic and 574 (2.3%) by perineal RP. The rate of LND and nerve-sparing procedure was 84.1 and 52.8%, respectively. The rate of autologous and allogeneic blood transfusion was 0.3 and 8.8%, respectively. Intraoperative complications were recorded in 2.7%. Specifically, rectal laceration, ureteral injury and nerveor vessel injury were recorded in 1.5, 0.7 and 1.1%, respectively. Postoperative complications were recorded in 26.7%. Specifically, 2.7% of patients suffered from cardial, 1.1% from respiratory, 4.0% from wound, 1.6% from vascular, 8.6% from genitourinary, 7.5% from miscellaneous medical and 13.2% from miscellanoeous surgical complications. In-hospital mortality was 0.2%. Mean LOS was 10.8 days. Mean hospital charges were 7,409 Euro. Results from multivariable logistic regression analyses will be presented at the congress. CONCLUSIONS: Institutional results should ideally be compared to nationally representative data. In 2012, RP in Germany was performed in 33% in a minimally-invasive fashion, the most temporal overall postoperative complication rate was 27%.

BACKGROUND. Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence. METHODS. Radical prostatectomy (RP) specimens (±disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth. RESULTS. Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. CONCLUSIONS. Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies.

INTRODUCTION AND OBJECTIVES: Better biomarkers are needed in prostate cancer (PCa) to predict disease recurrence and guide optimal therapy. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and clinical outcomes in localized disease. METHODS: Radical prostatectomy (RP) specimens (þ/disease recurrence) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Univariable and multivariable associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts and in-silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa proliferation, invasion and tumor growth. RESULTS: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. In external cohorts and in silico, low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. In vitro and in vivo, low AXIN2 expression was associated with a cancer stem-like cell-surface signature, and siRNA knockdown of AXIN2 resulted in significantly greater invasiveness. Conversely, ectopic overexpression of AXIN2 significantly reduced cell proliferation and tumor growth in mice (Figure). CONCLUSIONS: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. Based on these novel roles in PCa, AXIN2 may represent a new putative biomarker and potential therapeutic target in this disease.

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.

Objective To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC. Patients and methods We retrospectively analysed data of 263 patients with LN-positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC-related mortality was evaluated using competing-risks regression models. Results In all patients (Tall N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3–4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC-related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non-randomised design, selection bias, absence of a central pathological review and different AC protocols. Conclusions AC seems to reduce mortality in patients with pT3–4 LN-positive UTUC after RNU. This subgroup of LN-positive patients could serve as target population for an AC prospective randomised trial.

INTRODUCTION AND OBJECTIVES: The safety and feasibility of salvage robot-assisted radical prostatectomy (sRARP) for recurrent prostate cancer is unclear. Herein we report short-term cancer control, functional, and perioperative outcomes in a multi-institutional cohort. METHODS: Between July 2007 and October 2011, 38 consecutive men underwent sRARP for recurrent prostate cancer at the University of Southern California (n 14) or Global Robotics Institute (n 24). Failed primary therapy was varied (external beam radiotherapy [EBRT; n 14]; interstitial brachytherapy [IBT; n 11]; EBRT IBT [n 5]; high-intensity focused ultrasound [n 3]; cryoablation [n 3]; other [n 2]). The main outcomes were immediate biochemical failure (IBF), positive surgical margins (PSM), urinary continence and erectile function at 3 months, and complications within 90 days of surgery. Immediate biochemical failure was defined as a PSA 0.2 ng/ml. Urinary continence was defined as the use of no pads and erectile function was defined as a SHIM score 21. Complications were classified and graded using the Clavien system. RESULTS: The median age was 68 years (50-83 years) and median preoperative PSA was 4.1 ng/ml (0.4-15.2 ng/ml). Preoperative biopsy Gleason score was 6 (n 7), 7 (n 18), and 8 (n 12). All procedures were completed without the need for open conversion. No patient experienced an intra-operative complication. Median estimated blood loss was 100 ml (30-300 ml) and operative time was 1.5 h (1-6h). Median length of hospital stay was 1 day (1-7 days). The median duration of urethral catheterization was 12 days (4-48 days). IBF occurred in 9 (29%) patients and PSM occurred in 7 (18%) patients. Urinary continence and erectile function occurred in 9 (34%) and 0 patients, respectively. One or more postoperative complications occurred in 12 (31%) patients. Low grade (I-II) and high grade (III-IV) complications occurred in 8 (21%) and 4 (10%) patients, respectively. No patient died. CONCLUSIONS: Salvage robot-assisted radical prostatectomy is safe and feasible. Short-term cancer control and perioperative morbidity were acceptable.

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.