Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium.

PURPOSE: Our goal was to evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study. MATERIALS AND METHODS: We evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications. RESULTS: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep venous thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain. CONCLUSIONS: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.

Unexpected diversity in socially synchronized rhythms of shorebirds.

The behavioural rhythms of organisms are thought to be under strong selection, influenced by the rhythmicity of the environment. Such behavioural rhythms are well studied in isolated individuals under laboratory conditions, but free-living individuals have to temporally synchronize their activities with those of others, including potential mates, competitors, prey and predators. Individuals can temporally segregate their daily activities (for example, prey avoiding predators, subordinates avoiding dominants) or synchronize their activities (for example, group foraging, communal defence, pairs reproducing or caring for offspring). The behavioural rhythms that emerge from such social synchronization and the underlying evolutionary and ecological drivers that shape them remain poorly understood. Here we investigate these rhythms in the context of biparental care, a particularly sensitive phase of social synchronization where pair members potentially compromise their individual rhythms. Using data from 729 nests of 91 populations of 32 biparentally incubating shorebird species, where parents synchronize to achieve continuous coverage of developing eggs, we report remarkable within- and between-species diversity in incubation rhythms. Between species, the median length of one parent's incubation bout varied from 1-19 h, whereas period length-the time in which a parent's probability to incubate cycles once between its highest and lowest value-varied from 6-43 h. The length of incubation bouts was unrelated to variables reflecting energetic demands, but species relying on crypsis (the ability to avoid detection by other animals) had longer incubation bouts than those that are readily visible or who actively protect their nest against predators. Rhythms entrainable to the 24-h light-dark cycle were less prevalent at high latitudes and absent in 18 species. Our results indicate that even under similar environmental conditions and despite 24-h environmental cues, social synchronization can generate far more diverse behavioural rhythms than expected from studies of individuals in captivity. The risk of predation, not the risk of starvation, may be a key factor underlying the diversity in these rhythms.

A modified Delphi study to develop a practical guide for selecting patients with prostate cancer for active surveillance.

BACKGROUND: Active surveillance (AS) is a management option for men diagnosed with lower risk prostate cancer. There is wide variation in all aspects of AS internationally, from patient selection to investigations and follow-up intervals, and a lack of clear evidence on the optimal approach to AS. This study aimed to provide guidance for clinicians from an international panel of prostate cancer experts. METHODS: A modified Delphi approach was undertaken, utilising two rounds of online questionnaires followed by a face-to-face workshop. Participants indicated their level of agreement with statements relating to patient selection for AS via online questionnaires on a 7-point Likert scale. Factors not achieving agreement were iteratively developed between the two rounds of questionnaires. Draft statements were presented at the face-to-face workshop for discussion and consensus building. RESULTS: 12 prostate cancer experts (9 urologists, 2 academics, 1 radiation oncologist) participated in this study from a range of geographical regions (4 USA, 4 Europe, 4 Australia). Complete agreement on statements presented to the participants was 29.4% after Round One and 69.0% after Round Two. Following robust discussions at the face-to-face workshop, agreement was reached on the remaining statements. PSA, PSA density, Multiparametric MRI, and systematic biopsy (with or without targeted biopsy) were identified as minimum diagnostic tests required upon which to select patients to recommend AS as a treatment option for prostate cancer. Patient factors and clinical parameters that identified patients appropriate to potentially receive AS were agreed. Genetic and genomic testing was not recommended for use in clinical decision-making regarding AS. CONCLUSIONS: The lack of consistency in the practice of AS for men with lower risk prostate cancer between and within countries was reflected in this modified Delphi study. There are, however, areas of common practice and agreement from which clinicians practicing in the current environment can use to inform their clinical practice to achieve the best outcomes for patients.

Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

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.

Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.

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%; pnon-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.

Perioperative Oral Nutrition Supplementation Reduces Prevalence of Sarcopenia following Radical Cystectomy: Results of a Prospective Randomized Controlled Trial.

PURPOSE: We designed a prospective randomized, controlled pilot trial to investigate the effects of an enriched oral nutrition supplement on body composition and clinical outcomes following radical cystectomy. MATERIALS AND METHODS: A total of 61 patients were randomized to an oral nutrition supplement or a multivitamin multimineral supplement twice daily during an 8-week perioperative period. Body composition was determined by analyzing abdominal computerized tomography images at the L3 vertebra. Sarcopenia was defined as a skeletal muscle index of less than 55 cm/m in males and less than 39 cm/m in females. The primary outcome was the difference in 30-day hospital free days. Secondary outcomes included hospital length of stay, complications, readmissions and mortality. RESULTS: The oral nutrition supplement group lost less weight (-5 vs -6.5 kg, p = 0.04) compared to the multivitamin multimineral supplement group. The proportion of patients with sarcopenia did not change in the oral nutrition supplement group but increased 20% in the multivitamin multimineral supplement group (p = 0.01). Mean length of stay and 30-day hospital free days were similar in the groups. The oral nutrition supplement group had a lower rate of overall and major (Clavien grade 3 or greater) complications (48% vs 67% and 19% vs 25%, respectively) and a lower readmission rate (7% vs 17%) but the differences did not reach statistical significance. CONCLUSIONS: Patients who undergo radical cystectomy after consuming an oral nutrition supplement perioperatively have a reduced prevalence of sarcopenia and may also experience fewer and less severe complications and readmissions. A larger blinded, randomized, controlled trial is necessary to determine whether oral nutrition supplement interventions can improve outcomes following radical cystectomy.

An expressed retrogene of the master embryonic stem cell gene POU5F1 is associated with prostate cancer susceptibility.

Genetic association studies of prostate and other cancers have identified a major risk locus at chromosome 8q24. Several independent risk variants at this locus alter transcriptional regulatory elements, but an affected gene and mechanism for cancer predisposition have remained elusive. The retrogene POU5F1B within the locus has a preserved open reading frame encoding a homolog of the master embryonic stem cell transcription factor Oct4. We find that 8q24 risk alleles are expression quantitative trait loci correlated with reduced expression of POU5F1B in prostate tissue and that predicted deleterious POU5F1B missense variants are also associated with risk of transformation. POU5F1 is known to be self-regulated by the encoded Oct4 transcription factor. We further observe that POU5F1 expression is directly correlated with POU5F1B expression. Our results suggest that a pathway critical to self-renewal of embryonic stem cells may also have a role in the origin of cancer.

The Null Effect of Bladder Neck Size on Incontinence Outcomes after Radical Prostatectomy.

PURPOSE: We sought to determine whether bladder neck size is associated with incontinence scores after robot-assisted laparoscopic radical prostatectomy. MATERIALS AND METHODS: Consecutive eligible patients undergoing robot-assisted laparoscopic radical prostatectomy between July 19 and December 28, 2016 were enrolled in a prospective, longitudinal, observational cohort study. The primary outcome was patient reported urinary incontinence on the EPIC (Expanded Prostate Cancer Index Composite) scale 6 and 12 weeks postoperatively. The relationship between the EPIC score of urinary incontinence and bladder neck size was evaluated by multiple regression. Predicted EPIC scores for incontinence were displayed graphically after using restricted cubic splines to model bladder neck size. RESULTS: A total of 107 patients were enrolled. The response rate was 98% and 87% at 6 and 12 weeks, respectively. Bladder neck size was not significantly associated with incontinence scores at 6 and 12 weeks. Comparing the 90th percentile for bladder neck size (18 mm) with the 10th percentile (7 mm) revealed no significant difference in adjusted EPIC scores for incontinence at 6 weeks (ß coefficient 0.88, 95% CI -10.92-12.68, p = 0.88) or at 12 weeks (ß coefficient 5.80, 95% CI -7.36-18.97, p = 0.39). CONCLUSIONS: These findings question the merit of creating an extremely small bladder neck during robot-assisted laparoscopic radical prostatectomy. We contend that doing so increases the risk of positive margins at the bladder neck without facilitating early recovery of continence.

Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer.

We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression.

Oncologic Outcomes after Anterior Exenteration for Muscle Invasive Bladder Cancer in Women.

PURPOSE: We investigated oncologic and urinary outcomes after anterior exenteration for urothelial cell carcinoma in females, identifying tumor characteristics associated with female pelvic organ involvement. We hypothesized that a lack of trigonal or bladder floor tumor, intraoperative palpable posterior mass and clinical lymphadenopathy is associated with a lack of female pelvic organ involvement. MATERIALS AND METHODS: We retrospectively reviewed the charts of female patients who underwent radical cystectomy at our institution from 1999 to 2014. Patient and operative characteristics were extracted from the electronic medical record, and performance of hysterectomy was tested for association with disease recurrence. Categorical and continuous variables were analyzed with the chi-square and Student t-test, and Kaplan-Meier analysis was performed to determine recurrence-free survival according to hysterectomy performance. Women who had neobladder creation were additionally evaluated for an association between hysterectomy status, and nighttime wetting and catheter use. RESULTS: Of 322 eligible patients 160 with urothelial cancer did not have a hysterectomy before cystectomy. Mean followup was 2.2 years (SD 2.8). There were 22 patients (13.8%) who had recurrence during followup. No patient or surgical factor other than use of adjuvant chemotherapy or radiation (p <0.01) was associated with recurrence. Of 139 women 32 (23.0%) who underwent exenteration had female pelvic organ involvement. At least 1 of the 3 characteristics of interest were present in 28 of 99 (28.3%) women with any genitourinary organ involvement compared to only 4 of 40 (10.0%) of those who did not (p=0.01). Nighttime continence ranged between 21.9% and 48% but there was no significant association with continence and hysterectomy status. CONCLUSIONS: Lack of trigonal/bladder floor tumor, palpable posterior mass and clinical lymphadenopathy is associated with the absence of pelvic organ involvement. Individualized risk assessment using these factors along with patient preferences should be used to guide surgical planning.

Renal cell cancer histological subtype distribution differs by race and sex.

OBJECTIVES: To examine racial differences in the distribution of histological subtypes of renal cell carcinoma (RCC) and associations with established RCC risk factors by subtype. MATERIALS AND METHODS: Tumours from 1532 consecutive patients with RCC who underwent nephrectomy at Vanderbilt University Medical Center (1998-2012) were classified as clear-cell, papillary, chromophobe and other subtypes. In pairwise comparisons, we used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between race, sex, age, end-stage renal disease (ESRD) and body mass index at diagnosis according to histological subtype. RESULTS: The RCC subtype distribution was significantly different in black people from that in white people (P < 0.001), with a substantially higher proportion of patients with papillary RCC among black people than white people (35.7 vs 13.8%). In multivariate analyses, compared with clear-cell RCC, people with papillary RCC were significantly more likely to be black (OR 4.15; 95% CI 2.64-6.52) and less likely to be female (OR 0.60; 95% CI 0.43-0.83). People with chromophobe RCC were significantly more likely to be female (OR 2.32; 95% CI 1.44-3.74). Both people with papillary RCC (OR 6.26; 95% CI 2.75-14.24) and those with chromophobe RCC (OR 7.07; 95% CI 2.13-23.46) were strongly and significantly more likely to have ESRD, compared with those with clear-cell RCC. CONCLUSION: We observed marked racial differences in the proportional subtype distribution of RCCs diagnosed at a large tertiary care academic centre. To our knowledge, no previous study has examined racial differences in the distribution of RCC histologies while adjusting for ESRD, which was the factor most strongly associated with papillary and chromophobe RCC compared with clear-cell RCC.

Short term complications from transurethral resection of bladder tumor.

INTRODUCTION: The diagnosis and subsequent management of bladder cancer often involves transurethral resection of bladder tumor (TURBT). Risks of TURBT include perioperative complications such as bleeding, pain and perforation. We aimed to determine TURBT complication rates and risk factors in a contemporary series. MATERIALS AND METHODS: From 2002 to 2011, 505 patients underwent TURBT either for suspected bladder cancer or during follow up at a single institution. Baseline patient characteristics and complications within 2 weeks of surgery were extracted from the electronic medical record for all TURBTs. Patient and tumor characteristics were evaluated for associations with complication using univariate analysis. A multivariable logistic regression was fit to further examine associations between TURBT related characteristics and complication. RESULTS: A total of 910 TURBTs were performed on 505 patients. Overall complication rate was 8.1%. The most common complications were pain or spasm (3.0%), retention (2.8%), and infection (2.1%), and 0.5% of TURBTs had perforation. Over 85% of complications were Clavien-Dindo grade I or II. Forty-three patients had a complication after their first TURBT, while 25 had complications after subsequent TURBTs. Prior complication and single tumor, but not other patient or tumor-related characteristics, were associated with complication. Only prior complication (p < 0.01) was associated with subsequent complication after TURBT on multivariable analysis. CONCLUSIONS: Complication rate after TURBT is 8.1% and complications are generally not severe in nature. Prior short term complication is likely associated with subsequent complication. Further studies are needed to validate these results and determine patient groups most at risk for intraoperative and post TURBT complications.

The Impact of Health Literacy on Surgical Outcomes Following Radical Cystectomy.

Health literacy is the ability to obtain, comprehend, and act on medical information and is an independent predictor of health outcomes in patients with chronic health conditions. However, little has been reported regarding the potential association of health literacy and surgical outcomes. We hypothesized that patient complications after radical cystectomy would be associated with health literacy. In a sample of 368 patients, we found that higher health literacy scores (as determined by the Brief Health Literacy Screen) were associated with decreased odds of developing minor complications (odds ratio = 0.90, 95% confidence interval [0.83, 0.97]). Health literacy should be considered when caring for patients undergoing radical cystectomy and should serve as a potential indicator of the need for additional resources to improve postoperative outcomes.