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Supplementary File 1 from Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression

Supplementary Table 2 from Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression

Supplementary Methods from Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression

Supplementary Table 1 from Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression

Supplementary Figure Legend 1, Table Legends 1-3 from Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression

Supplementary Table 3 from Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression

Integrative analysis of genomic aberrations in the context of trancriptomic alterations will lead to a more comprehensive perspective on prostate cancer progression. Genome-wide copy number changes were monitored using array comparative genomic hybridization of laser-capture microdissected prostate cancer samples spanning stages of prostate cancer progression, including precursor lesions, clinically localized disease, and metastatic disease. A total of 62 specific cell populations from 38 patients were profiled. Minimal common regions (MCR) of alterations were defined for each sample type, and metastatic samples displayed the most number of alterations. Clinically localized prostate cancer samples with high Gleason grade resembled metastatic samples with respect to the size of altered regions and number of affected genes. A total of 9 out of 13 MCRs in the putative precursor lesion, high-grade prostatic intraepithelial neoplasia (PIN), showed an overlap with prostate cancer cases (amplifications in 3q29, 5q31.3-q32, 6q27, and 8q24.3 and deletions in 6q22.31, 16p12.2, 17q21.2, and 17q21.31), whereas postatrophic hyperplasia (PAH) did not exhibit this overlap. Interestingly, prostate cancers that do not overexpress ETS family members (i.e., gene fusion–negative prostate cancers) harbor differential aberrations in 1q23, 6q16, 6q21, 10q23, and 10q24. Integrative analysis with matched mRNA profiles identified genetic alterations in several proposed candidate genes implicated in prostate cancer progression. [Cancer Res 2007;67(17):8229–39]

Modifiable lifestyle factors, such as following a healthy dietary pattern may delay or prevent prostate cancer (PCa) progression. However, few studies have evaluated whether following specific dietary patterns after PCa diagnosis impacts risk of disease progression among men with localized PCa managed by active surveillance (AS). 564 men enrolled in the Canary Prostate Active Surveillance Study, a protocol-driven AS study utilizing a pre-specified prostate-specific antigen monitoring and surveillance biopsy regimen, completed a food frequency questionnaire (FFQ) at enrollment and had ≥ 1 surveillance biopsy during follow-up. FFQs were used to evaluate adherence to the Dietary Guidelines for Americans (Healthy Eating index (HEI))-2015, alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns. Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models. During a median follow-up of 7.8 years, 237 men experienced an increase in Gleason score on subsequent biopsy (grade reclassification). Higher HEI-2015, aMED or DASH diet scores after diagnosis were not associated with significant reductions in the risk of grade reclassification during AS. However, these dietary patterns have well-established protective effects on chronic diseases and mortality and remain a prudent choice for men with prostate cancer managed by AS.

We assessed whether Prostate Health Index results improve prediction of grade reclassification for men on active surveillance.We identified men in Canary Prostate Active Surveillance Study with Grade Group 1 cancer. Outcome was grade reclassification to Grade Group 2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (RWe included 1,532 biopsies (n = 610 discovery; n = 922 validation) among 1,142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among the discovery set, at 95% sensitivity, RAmong active surveillance patients, using Prostate Health Index with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

We evaluated health related quality of life following robotic and open radical cystectomy as a treatment for bladder cancer.Using the Randomized Open versus Robotic Cystectomy (RAZOR) trial population we assessed health related quality of life by using the Functional Assessment of Cancer Therapy (FACT)-Vanderbilt Cystectomy Index and the Short Form 8 Health Survey (SF-8) at baseline, 3 and 6 months postoperatively. The primary objective was to assess the impact of surgical approach on health related quality of life. As an exploratory analysis we assessed the impact of urinary diversion type on health related quality of life.Analyses were performed in subsets of the per-protocol population of 302 patients. There was no statistically significant difference between the mean scores by surgical approach at any time point for any FACT-Vanderbilt Cystectomy Index subscale or composite score (p0.05). The emotional well-being score increased over time in both surgical arms. Patients in the open arm showed significantly better SF-8 sores in the physical and mental summary scores at 6 months compared to baseline (p0.05). Continent diversion (versus noncontinent) was associated with worse FACT-bladder-cystectomy score at 3 (p0.01) but not at 6 months, and the SF-8 physical component was better in continent-diversion patients at 6 months (p=0.019).Our data suggests lack of significant differences in the health related quality of life in robotic and open cystectomies. As robotic procedures become more widespread it is important to discuss this finding during counseling.

PurposeActive surveillance (AS) for grade group (GG) 2 patients is not yet well defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort.Materials and methodsParticipants were prospectively enrolled in an AS study with protocol-directed followup at 10 centers in the U.S. and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology and recurrence were also analyzed.ResultsAt diagnosis, 154 (9%) had GG2 and 1,574 (91%) had GG1. Five-year reclassification rates were similar between GG2 and GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p

No data exist on time to recovery of patient-reported and performance-related measures of functional independence after radical cystectomy (open or robotic).To determine recovery of functional independence after radical cystectomy and whether robot-assisted radical cystectomy (RARC) is associated with any advantage over open procedures.Data for this secondary analysis from the RAZOR (Randomized Open vs Robotic Cystectomy) trial were used. RAZOR was a phase 3 multicenter noninferiority trial across 15 academic medical centers in the US from July 1, 2011, to November 18, 2014, with a median follow-up of 2 years. Participants included the per-protocol population (n = 302). Data were analyzed from February 1, 2017, to May 1, 2021.Robot-assisted radical cystectomy or open radical cystectomy (ORC).Patient-reported (activities of daily living [ADL] and independent ADL [iADL]) and performance-related (hand grip strength [HGS] and Timed UpGo walking test [TUGWT]) measures of independence were assessed. Patterns of postoperative recovery for the entire cohort and comparisons between RARC and ORC were performed. Exploratory analyses to assess measures of independence across diversion type and to determine whether baseline impairments were associated with 90-day complications or 1-year mortality were performed.Of the 302 patients included in the analysis (254 men [84.1%]; mean [SD] age at consent, 68.0 [9.7] years), 150 underwent RARC and 152 underwent ORC. Baseline characteristics were similar in both groups. For the entire cohort, ADL, iADL, and TUGWT recovered to baseline by 3 postoperative months, whereas HGS recovered by 6 months. There was no difference between RARC and ORC for ADL, iADL, TUGWT, or HGS scores at any time. Activities of daily living recovered 1 month after RARC (mean estimated score, 7.7 [95% CI, 7.3-8.0]) vs 3 months after ORC (mean estimated score, 7.5 [95% CI, 7.2-7.8]). Hand grip strength recovered by 3 months after RARC (mean estimated HGS, 29.0 [95% CI, 26.3-31.7] kg) vs 6 months after ORC (mean estimated HGS, 31.2 [95% CI, 28.8-34.2] kg). In the RARC group, 32 of 90 patients (35.6%) showed a recovery in HGS at 3 months vs 32 of 88 (36.4%) in the ORC group (P = .91), indicating a rejection of the primary study hypothesis for HGS. Independent ADL and TUGWT recovered in 3 months for both approaches. Hand grip strength showed earlier recovery in patients undergoing continent urinary diversion (mean HGS at 3 months, 31.3 [95% CI, 27.7-34.8] vs 33.9 [95% CI, 30.5-37.3] at baseline; P = .09) than noncontinent urinary diversion (mean HGS at 6 months, 27.4 [95% CI, 24.9-30.0] vs 29.5 [95% CI, 27.2-31.9] kg at baseline; P = .02), with no differences in other parameters. Baseline impairments in any parameter were not associated with 90-day complications or 1-year mortality.The results of this secondary analysis suggest that patients require 3 to 6 months to recover baseline levels after radical cystectomy irrespective of surgical approach. These data will be invaluable in patient counseling and preparation. Hand grip strength and ADL tended to recover to baseline earlier after RARC; however, there was no difference in the percentage of patients recovering when compared with ORC. Further study is needed to assess the clinical significance of these findings.ClinicalTrials.gov Identifier: NCT01157676.

Altered adipose tissue (AT) metabolism in cancer-associated weight loss via inflammation, lipolysis, and white adipose tissue (WAT) browning is primarily implicated from rodent models; their contribution to AT wasting in cancer patients is unclear.Energy expenditure (EE), plasma, and abdominal subcutaneous WAT were obtained from men (aged 65 ± 8 years) with cancer, with (CWL, n = 27) or without (CWS, n = 47) weight loss, and weight-stable non-cancer patients (CON, n = 26). Clinical images were assessed for adipose and muscle area while plasma and WAT were assessed for inflammatory, lipolytic, and browning markers.CWL displayed smaller subcutaneous AT (SAT; P = 0.05) and visceral AT (VAT; P = 0.034) than CWS, and displayed higher circulating interleukin (IL)-6 (P = 0.01) and WAT transcript levels of IL-6 (P = 0.029), IL-1β (P = 0.042), adipose triglyceride lipase (P = 0.026), and browning markers (Dio2, P = 0.03; PGC-1a, P = 0.016) than CWS and CON. There was no difference across groups in absolute REE (P = 0.061), %predicted REE (P = 0.18), circulating free fatty acids (FFA, P = 0.13) or parathyroid hormone-related peptide (PTHrP; P = 0.88), or WAT protein expression of inflammation (IL-6, P = 0.51; IL-1β, P = 0.29; monocyte chemoattractant protein-1, P = 0.23) or WAT protein or gene expression of browning (uncoupling protein-1, UCP-1; P = 0.13, UCP-1, P = 0.14). In patients with cancer, FFA was moderately correlated with WAT hormone-sensitive lipase transcript (r = 0.38, P = 0.018, n = 39); circulating cytokines were not correlated with expression of WAT inflammatory markers and circulating PTHrP was not correlated with expression of WAT browning markers. In multivariate regression using cancer patients only, body mass index (BMI) directly predicted SAT (N = 25, RCancer-related weight loss was associated with elevated circulating IL-6 and elevations in some WAT inflammatory, lipolytic and browning marker transcripts. BMI, not weight loss, was associated with increased energy expenditure. The contribution of inflammation and lipolysis, and lack thereof for WAT browning, will need to be clarified in other tumour types to increase generalizability. Future studies should consider variability in fat mass when exploring the relationship between cancer and adipose metabolism and should observe the trajectory of lipolysis and energy expenditure over time to establish the clinical significance of these associations and to inform more mechanistic interpretation of causation.

Background Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort. Methods This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66). Conclusions A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions. Lay summary This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

Purpose:Smoking is the most common risk factor for bladder cancer and it is associated with adverse clinical outcomes. The bladder cancer diagnosis represents a teachable moment for smoking cessati...

e17009 Background: [68Ga]-PSMA-11 positron emission tomography (PSMA PET) detects sites of biochemically recurrent prostate cancer (BCR) at higher rates than conventional imaging. We hypothesized that PSMA PET would lead to high change in management (CIM) rates in this setting. Methods: We prospectively recruited patients (pts) with BCR, defined as confirmed PSA > 0.2 ng/mL > 6 weeks post-surgery or PSA ≥2 ng/mL above nadir post-radiation therapy, to undergo Ga-68 PSMA-11 PET. Some also had equivocal lesions on CT, MRI, bone scan, or fluciclovine PET obtained prior to PSMA PET. Pre-PET intended treatment, PSA (ng/mL), and PSA doubling time (PSAdt, months) from most recent 3 values were recorded prior to imaging. Post-PET treatment (intended or actual) was collected from medical record. CIM was categorized as major (change in or addition of treatment modality) vs minor (change within treatment modality, such as altered radiation field). Any lesion with uptake above blood pool was interpreted as positive for prostate cancer by an experienced PET reader (DLC). All values were represented as the median [interquartile range, IQR]. Kruskal Wallis analysis tested for significant differences among groups. Results: 44 pts with BCR age 71 [10] with Gleason scores (GS) at diagnosis of 6 (N = 2), 7 (N = 23), 8 (N = 5), and 9 (N = 13) enrolled, 14/44 with equivocal lesions on conventional imaging. 42 had post-PSMA PET treatment decisions available in medical records for CIM analysis. Time from PSA nadir to PSA at time of PSMA PET was 5 [7.25] months. PSMA PET was positive in 33 (8/33 with equivocal lesions on prior imaging; 7 local disease only; 11 regional nodal metastases, 2/11 also with local disease; and 15 with distant metastases, 4/15 also with local disease, 9/15 with regional nodal metastases), negative in 6, and equivocal in 5 pts. Of those with distant metastases, 8 had oligometastases, defined as 3 or fewer distinct sites (1 site = single nodal region or single bone lesion), 4 in bones and 4 in distant nodes. CIM rate was 71% (30/42) overall, 65.5% (16/29 major, 3/29 minor) in pts with BCR and negative conventional imaging; 84.6% (11/13, all major) in pts with equivocal lesions on conventional imaging. Of the patients with major CIM, a treatment modality was added in 21/27, modality switched in 3/27, and a modality removed in 3/27. PSA was significantly lower (p = 0.04) for those with negative or equivocal PSMA PET (0.5 [2.7]) than those with localized disease (4.1 [2.8]), regional nodal (1.1 [3.4]) or distant metastases (3.8 [5.3]), but not PSAdt (p = 0.2, negative/equivocal PET 5 [6.5], localized 15 [36], regional nodal metastases 11 [13], distant metastases 6 [6]). Conclusions: PSMA PET may impact decision making in pts with BCR after treatment of localized prostate cancer, particularly for those with equivocal findings on conventional imaging, regardless of clinical risk at diagnosis. Clinical trial information: NCT04777071.

Background: For men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification. Methods: Urine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short-term and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Results: 782 men contributed 2,069 urine specimens. After adjusting for PSA, prostate size and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR=1.3; 95% CI 1.0–1.7, p=0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker, nor marker kinetics, was associated with time to reclassification in subsequent biopsies. Conclusions: PCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy, but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies.

INTRODUCTION AND OBJECTIVE:The safety of Active Surveillance (AS) for grade group 2 (GG2) patients is debated. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergo...

PURPOSE The 17-gene Onco type DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort. MATERIALS AND METHODS Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models. RESULTS GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade ( P = .48). CONCLUSION In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1–75.3) and 65.4% (95% CI 56.8–72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5–80.5) and 68.5% (95% CI 59.8–75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Background There is a need to better understand the relationship between functional impairment and muscle mass in cancer cachexia. This study aimed to establish the relationship between computed tomography (CT)-derived muscle cross-sectional area (CSA), radiodensity, and skeletal muscle index (SMI) and dual energy X-ray absorptiometry (DXA) parameters with functional performance in cancer patients. Materials and methods Handgrip strength, stair climb power (SCP), one-repetition maximum (1RM) strength, and body composition (CT and DXA) were compared across cancer patients with cachexia (CAC; N = 28), without cachexia (CNC; N = 28), and non-cancer patients (CON; N = 19). Multivariate regression was performed to find predictors of function. Results CAC had lower CT muscle CSA and SMI and lower DXA appendicular lean mass (ALM) than CNC or CON (p ≤ 0.011). Muscle radiodensity was not different across groups despite larger proportion of low CT SMI in CAC, and CAC performed worse in SCP than CON (p = 0.018). In cancer patients, DXA ALM and CT muscle CSA each predicted physical function (p ≤ 0.05); muscle radiodensity did not, and DXA ALM explained more variability in SCP and 1RM than CT muscle CSA. Conclusions Stair climb power was reduced in cancer cachexia; muscle radiodensity was not. Muscle mass by CT or DXA, but not radiodensity, predicted functional performance in cancer patients.

Summary Background & aims There are currently no approved treatments for cancer cachexia. One of the main barriers to developing a treatment for this indication is the lack of consensus on clinically important tools for assessing functional impairment in this setting. This issue is of critical importance because functional improvement is likely to be required for approval by regulatory agencies. This cross-sectional study aimed to evaluate various functional performance measures and establish their association with body composition, energy expenditure, biomarkers, and patient-reported quality of life (QOL). Methods Physical function, body composition, energy expenditure, cytokines, testosterone, and patient-reported QOL were compared between men with solid tumors with cachexia (CAC; N = 48), without cachexia (CNC; N = 48), and weight-stable patients without cancer (CON; N = 37). Receiver Operator Characteristic curves and multivariate regression were performed to identify functional impairment cut-points and predictors of physical function, respectively. Results Patients with CAC displayed lower total lean and appendicular lean mass, stair climb power (SCP), upper body strength, and bioavailable testosterone, and displayed higher energy expenditure than CNC or CON (p ≤ 0.03); CAC showed lower handgrip, respiratory quotient, and appetite, and higher cytokines and fatigue than CON (p ≤ 0.032). A cut-point of 336 Watts for SCP provided 78% sensitivity and 77% specificity for classification of CAC (p = 0.001); SCP also performed better than other measures tested when compared to CON-derived normatives. Upper body strength exhibited moderate sensitivity and specificity for classification of CAC (p ≤ 0.02). Elevated relative energy expenditure and cytokines negatively predicted, and muscle mass positively predicted, various muscle strength outcomes. Conclusion Stair climb power and upper body strength may have potential as discriminatory tests for functional impairment in patients with cancer cachexia.

Summary Background Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy. Methods The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1–T4, N0–N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than −15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676. Findings Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI −9·6% to 10·9%; p non-inferiority =0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group). Interpretation In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types. Funding National Institutes of Health National Cancer Institute.

BACKGROUND: Many patients who are on active surveillance (AS) for prostate cancer will have surveillance prostate needle biopsies (PNBs) without any cancer evident. OBJECTIVE: To define the association between negative surveillance PNBs and risk of reclassification on AS. DESIGN, SETTING, AND PARTICIPANTS: All men were enrolled in the Canary Prostate Active Surveillance Study (PASS) between 2008 and 2016. Men were included if they had Gleason ≤3 + 4 prostate cancer and

Background Diagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease. Objective To evaluate the utility of a four kallikrein (4K) panel in predicting the presence of high-grade cancer in men on active surveillance. Design, setting, and participants Plasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA). Outcome measurements and statistical analysis The endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit. Results and limitations Significant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31–1.81) or PSA (OR 2.11, 95% CI 1.53–2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33–3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04–0.85), prostate volume (OR 0.47, 95% CI 0.31–0.70), and body mass index (OR 1.09, 95% CI 1.04–1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use. Conclusions The 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies. Patient summary Active surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed.

OBJECTIVE: To evaluate whether African American (AA) men are at higher risk of reclassification in a large, prospective multi-institutional active surveillance (AS) cohort. METHODS: The Canary Prostate Active Surveillance Study (PASS) is a protocol-driven active surveillance cohort with pre-specified prostate-specific antigen (PSA) and surveillance biopsies regimen. Men included in this study had Gleason Grade Group 1 or 2 at diagnosis, < 5 years between diagnosis and enrollment, and had undergone ≥ 1 surveillance biopsy. Risk of reclassification, defined as an increase in Gleason score on subsequent biopsy, was compared between AA and CA using cox proportional hazards models. For the subset of men undergoing delayed prostatectomy, rates of adverse pathology, defined as pT3a or greater or Gleason Grade Group 3 or greater, were compared for AA and CA. RESULTS: Of 1,315 men, there were 89 (7%) AA and 1,226 (93%) CA. There were no differences in the rate of treatment for AA and CA. In multivariate models, AA race was not associated with the risk of reclassification (HR=1.16, 95% CI: 0.78 – 1.72). Among 441 men who had a prostatectomy after a period of AS, rate of adverse pathology was similar for AA and CA (46% vs 47%, p=0.99). CONCLUSIONS: Among men on AS who follow a standardized protocol of regular PSA and biopsy, AA men were not at increased risk of pathologic reclassification on AS or adverse pathology at prostatectomy. AS appears to be an appropriate management strategy for AA men with favorable risk prostate cancer.

INTRODUCTION AND OBJECTIVES:In active surveillance (AS), disease progression as defined by pathology can only be ascertained at follow-up biopsy. However, clinical factors could also influence the ...

INTRODUCTION AND OBJECTIVES:The advantage of health-related quality of life (HRQoL) in continent (C) urinary diversions (UD) over non-continent (NC) UD remains controversial. We compared outcomes b...

INTRODUCTION AND OBJECTIVES:Health-related quality of life (HRQoL) can be significantly affected following radical cystectomy (RC) and factors affecting it have not been well studied in this popula...

To characterize morbidity of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testis cancer, we analyze a contemporary national database. PC-RPLND is the standard for residual radiographic masses ≥1 cm (nonseminoma) and positron emission tomography-avid masses ≥3 cm (seminoma). Morbidity for PC-RPLND is greater than primary RPLND, which may be mitigated by performing surgery at a high-volume cancer center.Current Procedural Terminology and International Classification of Diseases, Ninth Edition codes identified men with testis cancer undergoing PC- or primary RPLND in MarketScan (2007-2012). Multivariable logistic regression assessed factors associated with receiving adjunctive procedures (ie, nephrectomy, vascular reconstruction), prolonged hospitalization, and 90-day readmission. Geographic variables assessed regionalization of PC-RPLND.Of 559 men with claims for PC- or primary RPLND (206, 37% PC-RPLND), 19% of PC-RPLND underwent adjunctive procedures (vs 1% among RPLND, P .01). For PC-RPLND, the nephrectomy rate was 10% and the vascular reconstruction rate was 8%. On multivariable analysis, PC-RPLND was associated with undergoing adjunctive procedures (odds ratio 41.9; 95% confidence interval 11.7, 150) and prolonged hospitalization (odds ratio 3.75; 95% confidence interval 1.68, 8.42) compared to primary RPLND. PC-RPLND was not associated with 90-day readmission. Up to 29% of PC-RPLNDs are performed in centers, billing just a single case through MarketScan in the 6 years studied.PC-RPLND is associated with adjunctive procedures and longer hospitalizations. Given the morbidity of PC-RPLND in this young patient population, efforts are needed to establish quality benchmarks for, reduce the morbidity of, and to accurately discriminate risk during patient discussions prior to this complex, specialized surgery.

Purpose: Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multicenter study of active surveillance.Materials and Methods: We studied 905 men in the prospective Canary PASS enrolled between 2008 and 2013. We collected clinical data at study entry and at prespecified intervals, and determined associations with adverse reclassification, defined as increased Gleason grade or greater cancer volume on followup biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance.Results: At a median followup of 28 months 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued on active surveillance. Overall 19% of participants received treatment, 68% with adverse reclassification, while 32% opted for treatment w...

IMPORTANCE: Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost. OBJECTIVE: To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments. DESIGN, SETTING, AND PARTICIPANTS: The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data. EXPOSURES: Active surveillance for prostate cancer. MAIN OUTCOMES AND MEASURES: Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy. RESULTS: A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P = .004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P

Outcomes in patients who enroll in active surveillance programs for prostate cancer while receiving 5α-reductase inhibitors have not been well defined. We sought to determine the association of 5α-reductase inhibitor use with the risk of reclassification in the PASS (Canary Prostate Active Surveillance Study).Participants in the multicenter PASS were enrolled between 2008 and 2016. Study inclusion criteria were current or never 5α-reductase inhibitors use, Gleason score 3 + 4 or less prostate cancer at diagnosis, less than a 34% core involvement ratio at diagnosis and 1 or more surveillance biopsies. Included in study were 1,009 men, including 107 on 5α-reductase inhibitors and 902 who had never received 5α-reductase inhibitors. Reclassification was defined as increase in the Gleason score and/or an increase to 34% or greater in the ratio of biopsy cores positive for cancer. Adverse pathology at prostatectomy was defined as Gleason 4 + 3 or greater and/or nonorgan confined disease (pT3 or N1).On multivariable analysis there was no difference in reclassification between men who had received and those who had never received 5α-reductase inhibitors (HR 0.81, p = 0.31). Patients who had received 5α-reductase inhibitors were less likely to undergo radical prostatectomy (8% vs 18%, p = 0.01) or any definitive treatment (19% vs 24%, p = 0.04). In the 167 participants who underwent radical prostatectomy there was no suggestion of a difference in the rate of adverse pathology findings at prostatectomy between 5α-reductase inhibitor users and nonusers.Continued 5α-reductase inhibitor use after an initial diagnosis of prostate cancer was not associated with the risk of reclassification on active surveillance in men in the PASS cohort.