Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial.

BACKGROUND: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. METHODS: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. FUNDING: Merck Sharp & Dohme.

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

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

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

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

Obesity and Complication Risk From Radical Cystectomy: Identifying a Body Mass Index Threshold.

PURPOSE: There are conflicting reports regarding radical cystectomy complication risk from obesity subcategories, and a BMI threshold below which complication risk is notably reduced is undefined. A BMI threshold may be helpful in prehabilitation to aid patient counseling and inform weight loss strategies to potentially mitigate obesity-associated complication risk. This study aims to identify such a threshold and further investigate the association between BMI subcategories and perioperative complications from radical cystectomy. MATERIALS AND METHODS: Data were extracted from the Canadian Bladder Cancer Information System, a prospective registry across 14 academic centers. Five hundred and eighty-nine patients were analyzed. Perioperative (≤90 days) complications were compared between BMI subcategories. Unconditional multivariable logistic regression and cubic spline analysis were performed to determine the association between BMI and complication risk and identify a BMI threshold. RESULTS: Perioperative complications were reported in 51 (30%), 97 (43%), and 85 (43%) normal, overweight, and obese patients (P = .02). BMI was independently associated with developing any complication (OR 1.04 95% CI 1.01, 1.07). Predicted complication risk began to rise consistently above a BMI threshold of 34 kg/m2. Both overweight (OR 2.00 95% CI 1.26-3.17) and obese (OR 1.98 95% CI 1.24-3.18) patients had increased risk of complications compared to normal BMI patients. CONCLUSIONS: Complication risk from radical cystectomy is independently associated with BMI. Both overweight and obese patients are at increased risk compared to normal BMI patients. A BMI threshold of 34 kg/m2 has been identified, which may inform prehabilitation treatment strategies.

Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline.

PURPOSE: The purpose of this guideline is to provide a useful reference on the effective evidence-based diagnoses and management of non-metastatic upper tract urothelial carcinoma (UTUC). MATERIALS/METHODS: The Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU) team conducted searches in Ovid MEDLINE (1946 to March 3rd, 2022), Cochrane Central Register of Controlled Trials (through January 2022), and Cochrane Database of Systematic Reviews (through January 2022). The searches were updated August 2022. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (Table 1).[Table: see text]Results:This Guideline provides updated, evidence-based recommendations regarding diagnosis and management of non-metastatic UTUC including risk stratification, surveillance and survivorship. Treatments discussed include kidney sparing management, surgical management, lymph node dissection (LND), neoadjuvant/adjuvant chemotherapy and immunotherapy. CONCLUSION: This standardized guideline seeks to improve clinicians' ability to evaluate and treat patients with UTUC based on available evidence. Future studies will be essential to further support these statements for improving patient care. Updates will occur as the knowledge regarding disease biology, clinical behavior and new therapeutic options develop.

Robotic Versus Open Cystectomy for Bladder Cancer: Synthesizing the Data from Current Systematic Reviews and Meta-Analyses.

This is a summary of existing systematic reviews comparing robotic assisted radical cystectomy (RARC) with open radical cystectomy (ORC). Our aim was to compare operative approaches with respect to perioperative, postoperative, oncologic, and health-related quality of life (QOL) outcomes. We performed a systematic review of MEDLINE, Medline-in-Process and Medline Epubs Ahead of Print, and the Cochrane Library on 22 February 2022. We included reviews of adult patients with bladder cancer undergoing RARC or ORC for muscle invasive or high-risk non-muscle invasive bladder cancer. Nonrandomized studies were excluded to minimize confounding and selection bias. The GRADE approach was used to determine the confidence in estimates. We assessed the quality of identified systematic reviews using AMSTAR 2 checklist. Six well-conducted, systematic reviews and meta-analyses were included. RARC was consistently associated with lower estimated blood loss (EBL) and transfusion rates, and longer operative time. There was inconsistent evidence for the impact of RARC on hospital length of stay (LOS). There was no significant difference in overall complication rate or major complication rate, or oncologic outcomes between groups. Comparison of QOL outcomes between studies was limited by statistical and methodological heterogeneity. RARC is associated with improvement in EBL and transfusion risk. There does not appear to be differences in oncologic outcomes or complications between approaches. Prospective studies are needed to assess the impact of diversion type, technique, and recovery pathways on patient outcomes and to assess the impact of operative approach on cost and patient-reported QOL.

Surgical Site Infections During the Pandemic: The Impact of the "COVID Bundle".

BACKGROUND: A reduction in surgical site infections (SSIs) has been reported in several discrete patient populations during the COVID-19 pandemic. Herein, this study evaluates the impact of the COVID-19 pandemic on SSI in a large patient cohort incorporating multiple surgical disciplines. We hypothesize that enhanced infection control and heightened awareness of such measures is analogous to an SSI care bundle, the hypothetical "COVID bundle", and may impact SSI rates. METHOD: Data collected for the American College of Surgeons National Surgical Quality Improvement Program between January 1, 2015, and April 1, 2021, were retrospectively analyzed. SSI rates were compared among time-dependent patient cohorts: Cohort A (pre-pandemic, N = 24,060, 87%) and Cohort B (pandemic, N = 3698, 13%). Time series and multivariable analyses predicted pre-pandemic and pandemic SSI trends and tested for association with timing of surgery. RESULTS: The overall SSI incidence was reduced in Cohort B versus Cohort A (2.8% vs. 4.5%, p < 0.001). Multivariable analysis indicated a downward SSI trend before pandemic onset (IRR 0.997, 95% CI 0.994, 1). At pandemic onset, the trend reduced by a relative factor of 39% (IRR 0.601, 95% CI 0.338, 1.069). SSI then trended upward during the pandemic (IRR 1.035, 95% CI 0.965, 1.111). SSI rates significantly trended downward in general surgical patients at pandemic onset (IRR 0.572, 95% CI 0.353, 0.928). CONCLUSION: Although overall SSI incidence was reduced during the pandemic, a statistically significant decrease in the predicted SSI rate only occurred in general surgical patients at pandemic onset. This trend may suggest a positive impact of the "COVID bundle" on SSI rates in these patients.

Association Between Surgeon and Anesthesiologist Sex Discordance and Postoperative Outcomes: A Population-based Cohort Study.

OBJECTIVE: The aim of this study was to examine the effect of surgeon-anesthesiologist sex discordance on postoperative outcomes. SUMMARY BACKGROUND DATA: Optimal surgical outcomes depend on teamwork, with surgeons and anesthesiologists forming two key components. There are sex and sex-based differences in interpersonal communication and medical practice which may contribute to patients' perioperative outcomes. METHODS: We performed a population-based, retrospective cohort study among adult patients undergoing 1 of 25 common elective or emergent surgical procedures from 2007 to 2019 in Ontario, Canada. We assessed the association between differences in sex between surgeon and anesthesiologists (sex discordance) on the primary endpoint of adverse postoperative outcome, defined as death, readmission, or complication within 30 days following surgery using generalized estimating equations. RESULTS: Among 1,165,711 patients treated by 3006 surgeons and 1477 anesthesiologists, 791,819 patients were treated by sex concordant teams (male surgeon/male anesthesiologist: 747,327 and female surgeon/female anesthesiologist: 44,492), whereas 373,892 were sex discordant (male surgeon/female anesthesiologist: 267,330 and female surgeon/male anesthesiologist: 106,562). Overall, 12.3% of patients experienced >1 adverse postoperative outcomes of whom 1.3% died. Sex discordance between surgeon and anesthesiologist was not associated with a significant increased likelihood of composite adverse postoperative outcomes (adjusted odds ratio 1.00, 95% confidence interval 0.97-1.03). CONCLUSIONS: We did not demonstrate an association between intraoperative surgeon and anesthesiologist sex discordance on adverse postoperative outcomes in a large patient cohort. Patients, clinicians, and administrators may be reassured that physician sex discordance in operating room teams is unlikely to clinically meaningfully affect patient outcomes after surgery.

Factors Associated with Re-Resection in T1 Bladder Cancer: Identifying Patients Who Do Not Receive Guideline-Concordant Care at the Population Level.

PURPOSE: Prior research has shown that concordance with the guideline-endorsed recommendation to re-resect patients diagnosed with primary T1 bladder cancer (BC) is suboptimal. Therefore, the aim of this population-based study was to identify factors associated with re-resection in T1 BC. MATERIALS AND METHODS: We linked province-wide BC pathology reports (January 2001 to December 2015) with health administrative data sources to derive an incident cohort of patients diagnosed with T1 BC in the province of Ontario, Canada. Re-resection was ascertained by a billing claim for transurethral resection within 2 to 8 weeks after the initial resection, accounting for system-related wait times. Multivariable logistic regression analysis accounting for the clustered nature of the data was used to identify various patient-level and surgeon-level factors associated with re-resection. P values <0.05 were considered statistically significant (2-sided). RESULTS: We identified 7,373 patients who fulfilled the inclusion criteria. Overall, 1,678 patients (23%) underwent re-resection. Patients with a more aggressive tumor profile and individuals without sufficiently sampled muscularis propria as well as younger, healthier and socioeconomically advantaged patients were more likely to receive re-resection (all p <0.05). In addition, more senior, lower volume and male surgeons were less likely to perform re-resection for their patients (all p <0.05). CONCLUSIONS: Only a minority of all patients received re-resection within 2 to 8 weeks after initial resection. To improve the access to care for potentially underserved patients, we suggest specific knowledge translation/exchange interventions that also include equity aspects besides further promotion of evidence-based instead of eminence-based medicine.

Oncological benefit of re-resection for T1 bladder cancer: a comparative effectiveness study.

OBJECTIVES: To quantify the real-world survival benefit of re-resection vs no re-resection in patients diagnosed with T1 bladder cancer (BC) at the population level. PATIENTS AND METHODS: Retrospective population-wide observational cohort study based on pathology reports linked to health administrative data. We identified patients who were diagnosed with T1 BC in the province of Ontario (01/2001-12/2015) and used billing claims to ascertain whether they received re-resection within 2-10 weeks. The time-dependent effect of re-resection on survival outcomes was modelled by Cox proportional hazards regression (unadjusted and adjusted for numerous assumed patient- and surgeon-level confounding variables). Effect measures were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 7666 patients of which 2162 (28.7%) underwent re-resection after a median (interquartile range) time of 45 (35-56) days. Patients who received re-resection were less likely to die from any causes (HR 0.68, 95% CI 0.63-0.74, P < 0.001) and from BC (HR 0.66, 95% CI 0.57-0.76, P < 0.001) during any time of follow-up. After adjusting for all assumed confounding variables, re-resection was still significantly associated with a lower overall mortality (HR 0.88, 95% CI 0.81-0.95, P < 0.001), while the association with cancer-specific survival marginally lost its statistical significance (HR 0.87, 95% CI 0.75-1.02, P = 0.08). CONCLUSIONS: A second transurethral resection within 2-6 weeks after the initial resection (i.e. re-resection) is recommended for patients diagnosed with primary T1 BC as prior studies suggest therapeutic, diagnostic, and prognostic benefits. However, results on survival endpoints are sparse, conflicting, and often affected by various biases. To the best of our knowledge, the present population-wide study represents the largest cohort of patients diagnosed with T1 BC and provides real-world evidence supporting the utilisation of re-resection in this group of patients.

"Bring the Hoses to Where the Fire Is!": Differential Impacts of Marginalization and Socioeconomic Status on COVID-19 Case Counts and Healthcare Costs.

OBJECTIVES: Local health leaders and the Director General of the World Health Organization alike have observed that COVID-19 "does not discriminate." Nevertheless, the disproportionate representation of people of low socioeconomic status among those infected resembles discrimination. This population-based retrospective cohort study examined COVID-19 case counts and publicly funded healthcare costs in Ontario, Canada, with a focus on marginalization. METHODS: Individuals with their first positive severe acute respiratory syndrome coronavirus 2 test from January 1, 2020 to June 30, 2020, were linked to administrative databases and matched to negative/untested controls. Mean net (COVID-19-attributable) costs were estimated for 30 days before and after diagnosis, and differences among strata of age, sex, comorbidity, and measures of marginalization were assessed using analysis of variance tests. RESULTS: We included 28 893 COVID-19 cases (mean age 54 years, 56% female). Most cases remained in the community (20 545, 71.1%) or in long-term care facilities (4478, 15.5%), whereas 944 (3.3%) and 2926 (10.1%) were hospitalized, with and without intensive care unit, respectively. Case counts were skewed across marginalization strata with 2 to 7 times more cases in neighborhoods with low income, high material deprivation, and highest ethnic concentration. Mean net costs after diagnosis were higher for males ($4752 vs $2520 for females) and for cases with higher comorbidity ($1394-$7751) (both P < .001) but were similar across levels of most marginalization dimensions (range $3232-$3737, all P ≥ .19). CONCLUSIONS: This study suggests that allocating resources unequally to marginalized individuals may improve equality in outcomes. It highlights the importance of reducing risk of COVID-19 infection among marginalized individuals to reduce overall costs and increase system capacity.

Diagnostic Accuracy of MRI in Local Staging (T Category) of Penile Cancer and the Value of Artificial Erection: A Systematic Review and Meta-Analysis.

BACKGROUND. Treatment recommendations of penile cancers are determined primarily by the local extent of the primary tumor. Clinical palpation is used for local staging. OBJECTIVE. We reviewed diagnostic performance of MRI in local staging of penile cancer in three clinical scenarios (questions [Qs] 1 through 3, Q1-Q3) and one imaging scenario (Q4). Q1 asked whether MRI reliably distinguishes ≤ T1 from ≥ T2 disease. Q2 asked whether clinical staging reliably identifies ≤ T1 versus ≥ T2 disease and how clinical staging compares to MRI. Q3 asked if MRI is accurate for diagnosis of T3 disease. Q4 asked if artificial erection (by intracavernosal injection of prostaglandin E1) improved accuracy of MRI in T categorization. EVIDENCE ACQUISITION. MEDLINE, EMBASE, and Cochrane Library databases were searched through September 13, 2021, for studies evaluating local staging of penile cancer using MRI with surgical pathology as the reference standard. Diagnostic accuracy was calculated using a bivariate random-effects model and hierarchic summary ROC mode Meta-regression was performed to test for covariate effects of MRI and artificial erection in Q3 and Q4, respectively. EVIDENCE SYNTHESIS. Eight studies and 481 patients were included. The sensitivity and specificity of MRI for Q1 were 86% (95% CI, 73-94%) and 89% (95% CI, 77-95%), respectively. AUC for MRI (0.94; 95% CI, 0.92-0.96) did not differ from clinical staging (0.87; 95% CI, 0.84-0.90; p = .83). For Q3, MRI had sensitivity and specificity of 80% (95% CI, 70-87%) and 96% (95% CI, 85-99%), respectively. For Q4, sensitivity and specificity for MRI with versus without artificial erection were 85% (95% CI, 71-92%) and 93% (95% CI, 77-98%) versus 86% (95% CI, 68-95%) and 84% (95% CI, 70-93%), respectively (p = .50). CONCLUSION. MRI staging of penile cancer may be considered for ≤ T1 versus ≥ T2 disease but did not appear more accurate than clinical staging. High specificity of MRI for diagnosis of ≥ T3 disease suggests that MRI may be useful when organ-sparing approaches are planned. MRI with and without artificial erection showed similar accuracy in local staging. CLINICAL IMPACT. MRI, with or without artificial erection, may be valuable in routine preoperative evaluation of local staging of penile cancer, particularly when organ-sparing options are considered.

A Microcolumn DC Graphene Sensor for Rapid, Sensitive, and Universal Chemical Vapor Detection.

Nearly all existing direct current (DC) chemical vapor sensing methodologies are based on charge transfer between sensor and adsorbed molecules. However, the high binding energy at the charge-trapped sites, which is critical for high sensitivity, significantly slows sensors' responses and makes the detection of nonpolar molecules difficult. Herein, by exploiting the incomplete screening effect of graphene, we demonstrate a DC graphene electronic sensor for rapid (subsecond) and sensitive (ppb) detection of a broad range of vapor analytes, including polar, nonpolar, organic, and inorganic molecules. Molecular adsorption induced capacitance change in the graphene transistor is revealed to be the main sensing mechanism. A novel sensor design, which integrates a centimeter-scale graphene transistor and a microfabricated flow column, is pioneered to enhance the fringing capacitive gating effect. Our work provides an avenue for a broad spectrum real-time gas sensing technology and serves as an ideal testbed for probing molecular physisorption on graphene.

Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.

BACKGROUND: Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. INTERPRETATION: Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. FUNDING: Merck Sharp & Dohme.

Benefit of a more extended pelvic lymph node dissection among patients undergoing radical prostatectomy for localized prostate cancer: A causal mediation analysis.

BACKGROUND: The therapeutic role of extended (ePLND) versus nonextended pelvic lymph node dissection (nePLND) to remove occult micrometastases in men undergoing radical prostatectomy for localized prostate cancer (PC) is conflicting. Therefore, our aim was to quantify the direct effect of ePLND versus nePLND (removal of occult micrometastases), which is not mediated through the detection of nodal disease and potential adjuvant therapy (indirect effect). METHODS: Retrospective, bi-center cohort study of consecutive patients undergoing radical prostatectomy and PLND for PC (January 2006 and December 2016). Patients were followed until April 2018 for the occurrence of either biochemical recurrence or secondary therapy (composite outcome). ePLND was compared to nePLND by unweighted and weighted survival analysis (total effect) as well as by causal mediation analysis (direct and indirect effect). RESULTS: Positive nodal disease was detected in 71 (7%) out of 1008 patients undergoing radical prostatectomy and PLND for PC (ePLND: 368 [36.5%]; nePLND: 640 [63.5%]). Survival analysis demonstrated results in favor of ePLND (unweighted hazard ratio: 0.77 [95% confidence interval: 0.59-1.01], p = .056; weighted hazard ratio: 0.75 [0.56-0.99], p = .044). The causal mediation analysis confirmed the total effect of 0.77 (0.71-0.82). After disentangling this total effect into an indirect effect (via detection of nodal disease and potential adjuvant therapy) and a direct effect (via removal of occult micrometastases), we identified an even more protective direct effect of 0.69 (0.63-0.75). CONCLUSIONS: Our results not only indicate the utility of ePLND but also that its impact is not restricted to a staging benefit and probably involves a therapeutic benefit mediated through the removal of occult micrometastases.

Does prophylactic ureteric stenting at the time of colorectal surgery reduce the risk of ureteric injury? A systematic review and meta-analysis.

AIM: Cystoscopic placement of ureteric stents during colorectal surgery (CRS) may aid in the intraoperative identification of the ureters and thus prevent ureteric injury, but may also be associated with prolonged operating time, increased cost and adverse events. No formal recommendations exist regarding the use of ureteric stents prior to CRS. Our aim was to determine the effect of prophylactic ureteric stent insertion on the risk of ureteric injury among adult patients undergoing CRS. METHOD: A systematic search using the Ovid platform was completed. The primary outcome was risk of ureteric injury. Secondary outcomes included the risk of acute kidney injury (AKI), urinary tract infection (UTI), sepsis, length of stay (LOS) and mortality. The Paule-Mandel pooling and a random effects model was used to produce odds ratios (ORs) with 95% confidence intervals (CIs) for binary outcomes. Standardized mean differences (MD) were reported for continuous variables. Analyses were completed using R3.5. RESULTS: Nine retrospective cohort studies evaluating 98 507 patients were included. The incidence of ureteric injury was 0.6%. Overall, 5.1% of patients underwent ureteric stenting. There was no change in the odds of ureteric injury among stented patients compared with controls (OR 1.30, 95% CI 0.39-4.29, I2  = 25%). Operating time was significantly longer (MD 49.3 min, 95% CI 35.3-63.4, I2  = 96%) in the intervention group. There was no difference in rates of AKI, UTI, sepsis, LOS or mortality between groups. CONCLUSION: Given the retrospective nature of the identified studies, the benefit of prophylactic ureteric stenting remains uncertain. Prophylactic ureteric stenting was not associated with increased patient morbidity but did significantly increase operating time.

A Prospective Randomized Controlled Trial of Irrigation "Bag Squeeze" to Manage Pain for Patients Undergoing Flexible Cystoscopy.

PURPOSE: We determined if the "bag squeeze" technique decreases pain during flexible cystoscopy in men. MATERIALS AND METHODS: This single center, prospective, double-blind, randomized controlled trial recruited 200 consenting participants who were ambulatory, outpatient males who had undergone prior cystoscopy and were not expected to require any secondary procedures. Men with prior urethral stricture or bladder neck contracture were excluded from study. Once eligibility was assessed and consent obtained, participants were randomized to undergo cystoscopy with the bag squeeze (group A) or the sham bag squeeze procedure (group B). Following cystoscopy, participants completed a pain questionnaire (visual analogue scale). Differences in mean pain score between groups were evaluated using Students' t-test with a 2-sided alpha of 0.05. RESULTS: A total of 200 patients were randomized and underwent flexible cystoscopy. Ten participants were ineligible because they required secondary procedures. Among the 190 eligible patients 97 were randomized to bag squeeze (group A) and 93 to sham bag squeeze (group B) with mean pain scores of 1.91 and 3.39, respectively (p <0.005). CONCLUSIONS: This study demonstrated a clinically meaningful decrease in pain for men undergoing flexible cystoscopy when the irrigation bag squeeze technique was used vs placebo bag squeeze. Accordingly, this useful, simple and free method to improve patient comfort during flexible cystoscopy should be adopted by clinicians.

Modifiable lifestyle behaviours impact the health-related quality of life of bladder cancer survivors.

OBJECTIVE: To examine health behaviours in bladder cancer survivors including physical activity (PA), body mass index, diet quality, smoking and alcohol consumption, and to explore their relationship with health-related quality of life (HRQoL). SUBJECTS/PATIENTS AND METHODS: Cross-sectional questionnaire packages were distributed to bladder cancer survivors (muscle-invasive bladder cancer [MIBC] and non-muscle-invasive bladder cancer [NMIBC]) aged >18 years, and proficient in English. Lifestyle behaviours were measured using established measures/questions, and reported using descriptive statistics. HRQoL was assessed using the validated Bladder Utility Symptom Scale, and its association with lifestyle behaviours was evaluated using analysis of covariance (ancova) and multivariate regression analyses. RESULTS: A total of 586 participants completed the questionnaire (52% response rate). The mean (SD) age was 67.3 (10.2) years, and 68% were male. PA guidelines were met by 20% (n = 117) and 22.7% (n = 133) met dietary guidelines. In all, 60.9% (n = 357) were overweight/obese, and the vast majority met alcohol recommendations (n = 521, 92.5%) and were current non-smokers (n = 535, 91.0%). Health behaviours did not differ between MIBC and NMIBC, and cancer treatment stages. Sufficient PA, healthy diet, and non-smoking were significantly associated with HRQoL, and the number of health behaviours participants engaged in was positively associated with HRQoL (P < 0.001). CONCLUSION: Bladder cancer survivors are not meeting guidelines for important lifestyle behaviours that may improve their overall HRQoL. Future research should investigate the impact of behavioural and educational interventions for health behaviours on HRQoL in this population.

Photoselective vaporization of the prostate: study outcomes as a function of risk of bias, conflicts of interest, and industrial sponsorship.

PURPOSE: To investigate the outcomes of comparative studies on photoselective vaporization of the prostate (PVP) as a function of risk of bias (RoB), conflicts of interest (COI), and industrial sponsorship (IS). METHODS: We performed a systematic literature search for comparative studies on PVP [randomized controlled trials (RCTs) and non-randomized comparative studies (NRCSs)]. Study selection as well as comprehensive assessment of RoB, COIs, and IS were performed in duplicate. The identified studies were further rated by two independent board-certified urologists as either PVP-favourable or PVP-unfavourable. Descriptive statistics were performed among all identified studies and among the subgroups of studies rated as favourable and unfavourable, respectively. RESULTS: Sixty-five studies qualified for inclusion (25 RTCs and 40 NRCSs) of which 56 (86%) were rated favourable and 9 (14%) unfavourable. A majority of all studies mentioned the absence/presence of potential COIs (78%). In contrast, a sponsorship statement was only found in 29% of the investigations. Studies rated favourable demonstrated a higher percentage of COIs (39% versus 22%). IS was exclusively found among favourable studies. Furthermore, a serious or critical RoB was more often found in favourably rated NRCSs. CONCLUSIONS: COIs and IS seem to be associated with favourable study outcomes in comparative studies on PVP. The transparency of the whole research process from study conception to the dissemination of the results has to be further improved to prevent a harmful effect of COIs and IS on the internal validity of studies.

Trimodality Therapy for Muscle-Invasive Bladder Cancer: Recent Advances and Unanswered Questions.

PURPOSE OF REVIEW: Bladder-sparing trimodality therapy (TMT) has become an accepted alternative to cystectomy for selected muscle invasive bladder cancer (MIBC) patients unfit for cystectomy or opting for bladder preservation. This review will summarize recent advances in TMT for MIBC. RECENT FINDINGS: A growing body of literature has emerged which supports the use of TMT. However, its delivery is yet to be standardized. The role of chemotherapy and predictive biomarkers remain to be elucidated. Novel bladder-sparing approaches, drug combinations including immunotherapy and targeted therapies are under investigation in clinical trials, with the goal of ultimately enhancing survival and quality of life outcomes. Recent advances in TMT have made bladder preservation possible for MIBC patients seeking an alternative local therapy to cystectomy. With careful patient selection, TMT offers comparable survival outcomes to cystectomy, and improved quality of life as patients are able to successfully retain their bladder.