Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Perioperative complications and oncological outcomes of open versus robotic-assisted radical cystectomy: a propensity score-matched study.

PURPOSE: To conduct a comparative effectiveness analysis between robot-assisted radical cystectomy (RARC) and open approach (ORC). MATERIALS AND METHODS: A retrospective cohort study was conducted involving all patients undergoing radical cystectomy and urinary diversion for invasive bladder cancer at our institution from 2010 to 2018. Of a total 296 patients, we matched ORC and RARC cases based on age, BMI, Charlson comorbidity index, pathological TN staging of the tumor, prior radiotherapy, and type of diversion. The perioperative complications and oncological outcomes were compared. RESULTS: Eighty-nine patients were matched in the ORC and RARC groups. The median operative time was longer in RARC group (430 min) than that of ORC group (372 min) (p = 0.03); however, the median estimated blood loss (EBL) was significantly lower in RARC group (500 ml) than that of ORC (700 ml) (p < 0.0001). The median length of hospital stay (LOS) was significantly reduced in the RARC group (7 days) compared to the ORC group (8 days) (p = 0.02). There were no significant differences between both groups in 30- and 90-day postoperative complications (p = 0.3 and p = 0.2, respectively). A total of 68 deaths (38.2%) were observed, of which 36 (40.4%) were in ORC group while 32 (36%) were in RARC group (p = 0.5). The results were comparable in both groups regarding 5-year survival rate and cancer-specific survival (p = 0.3 and p = 0.1, respectively). CONCLUSION: RARC showed better perioperative outcomes in the form of less EBL and shortened LOS compared to ORC group. However, both RARC and ORC provide similar postoperative oncologic control, in terms of similar positive surgical margins, cancer-specific rates, and 5-year survival rates.

Urinary Analysis of FGFR3 and TERT Gene Mutations Enhances Performance of Cxbladder Tests and Improves Patient Risk Stratification.

PURPOSE: Cxbladder tests are urinary biomarker tests for detection of urothelial carcinoma. We developed enhanced Cxbladder tests that incorporate DNA analysis of 6 single nucleotide polymorphisms for the FGFR3 and TERT genes, in addition to the current 5 mRNA biomarkers and clinical risk factors. MATERIALS AND METHODS: Two multicenter, prospective studies were undertaken in: (1) U.S. patients with gross hematuria aged ≥18 years and (2) Singaporean patients with gross hematuria or microhematuria aged >21 years. All patients provided a midstream urine sample and underwent cystoscopy. Samples were retrospectively analyzed using enhanced Cxbladder-Triage (risk stratifies patients), enhanced Cxbladder-Detect (risk stratifies patients and detects positive patients), and the combination enhanced Cxbladder-Triage × Cxbladder-Detect. RESULTS: In the pooled cohort (N=804; gross hematuria: n=484, microhematuria: n=320), enhanced Cxbladder-Detect had a sensitivity of 97% (95% CI 89%-100%), specificity of 90% (95% CI 88%-92%), and negative predictive value of 99.7% (95% CI 99%-100%) for detection of urothelial carcinoma. Overall, 83% of patients were enhanced Cxbladder-Detect-negative (ie, needed no further work-up). Of 133 enhanced Cxbladder-Detect-positive patients, 59 had a confirmed tumor, of which 19 were low-grade noninvasive papillary carcinoma or papillary urothelial neoplasm of low malignant potential. In total, 40 tumors were high-grade Ta, T1-T4, Tis, including concomitant carcinoma in situ. Of the 74 patients with normal cystoscopy, 41 were positive by single nucleotide polymorphism analysis. Enhanced Cxbladder-Triage and enhanced Cxbladder-Detect had significantly better specificity than the first-generation Cxbladder tests (P < .001). CONCLUSIONS: This study in ethnically diverse patients with hematuria showed the analytical validity of the enhanced Cxbladder tests.

Early Detection of Prostate Cancer: AUA/SUO Guideline Part II: Considerations for a Prostate Biopsy.

PURPOSE: The summary presented herein covers recommendations on the early detection of prostate cancer and provides a framework to facilitate clinical decision-making in the implementation of prostate cancer screening, biopsy, and follow-up. This is Part II of a two-part series focusing on initial and repeat biopsies, and biopsy technique. Please refer to Part I for discussion of initial prostate cancer screening recommendations. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. The systematic review was based on searches in Ovid MEDLINE and Embase and Cochrane Database of Systematic Reviews (January 1, 2000-November 21, 2022). Searches were supplemented by reviewing reference lists of relevant articles. RESULTS: The Early Detection of Prostate Cancer Panel developed evidence- and consensus-based guideline statements to provide guidance in prostate cancer screening, initial and repeat biopsies, and biopsy technique. CONCLUSIONS: The evaluation of prostate cancer risk should be focused on the detection of clinically significant prostate cancer (Grade Group 2 or higher [GG2+]). The use of laboratory biomarkers, prostate MRI, and biopsy techniques described herein may improve detection and safety when a prostate biopsy is deemed necessary following prostate cancer screening.

Early Detection of Prostate Cancer: AUA/SUO Guideline Part I: Prostate Cancer Screening.

PURPOSE: The summary presented herein covers recommendations on the early detection of prostate cancer and provides a framework to facilitate clinical decision-making in the implementation of prostate cancer screening, biopsy, and follow-up. This is Part I of a two-part series that focuses on prostate cancer screening. Please refer to Part II for discussion of initial and repeat biopsies as well as biopsy technique. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. The systematic review was based on searches in Ovid MEDLINE and Embase and Cochrane Database of Systematic Reviews (January 1, 2000-November 21, 2022). Searches were supplemented by reviewing reference lists of relevant articles. RESULTS: The Early Detection of Prostate Cancer Panel developed evidence- and consensus-based guideline statements to provide guidance in prostate cancer screening, initial and repeat biopsy, and biopsy technique. CONCLUSIONS: Prostate-specific antigen (PSA)-based prostate cancer screening in combination with shared decision-making (SDM) is recommended. Current data regarding risk from population-based cohorts provide a basis for longer screening intervals and tailored screening, and the use of available online risk calculators is encouraged.

Unrecognized sexual dysfunction in gay and bisexual men after prostate cancer treatment: the antecedents and impact of anodyspareunia.

BACKGROUND: Anodyspareunia may be an adverse outcome of prostate cancer (PCa) treatment for gay, bisexual, and other men who have sex with men (GBM). AIM: The aims of this study were to (1) describe the clinical symptoms of painful receptive anal intercourse (RAI) in GBM following PCa treatment, (2) estimate the prevalence of anodyspareunia, and (3) identify clinical and psychosocial correlates. METHODS: This was a secondary analysis of baseline and 24-month follow-up data from the Restore-2 randomized clinical trial of 401 GBM treated for PCa. The analytic sample included only those participants who attempted RAI during or since their PCa treatment (N = 195). OUTCOMES: Anodyspareunia was operationalized as moderate to severe pain during RAI for ≥6 months that resulted in mild to severe distress. Additional quality-of-life outcomes included the Expanded Prostate Cancer Index Composite (bowel function and bother subscales), the Brief Symptom Inventory-18, and the Functional Assessment of Cancer Therapy-Prostate. RESULTS: Overall 82 (42.1%) participants reported pain during RAI since completing PCa treatment. Of these, 45.1% experienced painful RAI sometimes or frequently, and 63.0% indicated that the pain was persistent. The pain at its worst was moderate to very severe for 79.0%. The experience of pain was at least mildly distressing for 63.5%. Painful RAI worsened for a third (33.4%) of participants after completing PCa treatment. Of the 82 GBM, 15.4% were classified as meeting criteria for anodyspareunia. Antecedents of anodyspareunia included a lifelong history of painful RAI and bowel dysfunction following PCa treatment. Those reporting symptoms of anodyspareunia were more likely to avoid RAI due to pain (adjusted odds ratio, 4.37), which was negatively associated with sexual satisfaction (mean difference, -2.77) and self-esteem (mean difference, -3.33). The model explained 37.2% of the variance in overall quality of life. CLINICAL IMPLICATIONS: Culturally responsive PCa care should include the assessment of anodyspareunia among GBM and explore treatment options. STRENGTHS AND LIMITATIONS: This is the largest study to date focused on anodyspareunia among GBM treated for PCa. Anodyspareunia was assessed with multiple items characterizing the intensity, duration, and distress related to painful RAI. The external validity of the findings is limited by the nonprobability sample. Furthermore, the cause-and-effect relationships between the reported associations cannot be established by the research design. CONCLUSIONS: Anodyspareunia should be considered a sexual dysfunction in GBM and investigated as an adverse outcome of PCa treatment.

Strategic Planning and Essential Steps for Establishing a Uterine Transplant and Rehabilitation Program: From Idea to Reality.

UTx is performed to address absolute uterine infertility in the presence of uterine agenesis, a nonfunctional uterus, or after a prior hysterectomy. After the initial success of UTx resulting in a livebirth (2014) in Sweden, there are over 70 reported UTx surgeries resulting in more than 40 livebirths worldwide. Currently, UTx has been performed in over 10 countries. As UTx is transitioning from an "experimental procedure" to a clinical option, an increasing number of centers may contemplate a UTx program. This article discusses essential steps for establishment of a successful UTx program. These principles may be implemented in cis- and transgender UTx candidates.

Race reporting and disparities regarding clinical trials in bladder cancer: a systematic review.

PURPOSE: To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees. METHODS: A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder cancer patients enrolled in clinical trials. The review was conducted in accordance with the PRISMA statement. RESULTS: We identified 544 clinical trials meeting our initial search criteria, with only 24 (4.4%) studies reporting racial demographic data. Enrollees were largely Caucasian (81-98%), with a strikingly small proportion of enrolled patients consisting of African-Americans (2-8%) and Hispanics (2-5%). Only one of the studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups and performed analyses stratified by race. CONCLUSION: Race is poorly studied in bladder cancer clinical trials. Trial cohorts may not reflect multicultural populations. The potential association between race and efficacy, safety or tolerability of the tested interventions is unknown. Given the up to twofold increase in bladder cancer-specific death among African-Americans, further research is needed to address the impact of race in clinical trials, while encompassing socioeconomic factors and disease risk factor exposures.

Diagnosing Prostate Cancer: The Role of Intravesical Prostatic Gland Protrusion on Accuracy of Prostate Biopsies.

PURPOSE: We evaluated the association between intravesical prostate protrusion (IPP) and the detection rate of clinically significant prostate cancer (csPCa) on magnetic resonance imaging (MRI)-transrectal ultrasound (TRUS) fusion targeted biopsy (TB). MATERIALS AND METHODS: A total of 538 consecutive men who underwent MRI-TRUS fusion TB and concomitant systematic biopsy were evaluated. IPP on MRI was independently measured by 4 blinded reviewers. The primary outcome was per-lesion detection of csPCa on TB. We assessed the association between IPP and csPCa detection on TB, controlling for age, prostate specific antigen, Prostate Imaging Reporting and Data System® (PI-RADS®) score, prostate volume, targeted cores sampled and previous biopsy experience. RESULTS: A total of 847 PI-RADS 3 or greater lesions were targeted across 570 biopsies. Intra- and interrater reliability for measuring IPP was strong. A total of 81 (14.2%), 127 (22.3%), 237 (41.6%) and 125 (21.9%) men had 0, small, medium and large IPP, respectively. A total of 230, 392 and 196 lesions were PI-RADS 3, 4 and 5, respectively. Of the lesions 198 (34.7%) had csPCa on TB. The overall relationship between IPP size and csPCa found on TB was not significant; however, large IPP is associated with a significantly lower rate of csPCa detection than 0 IPP (p=0.007). Every mm increase in IPP is associated with a 5.6% decrease in the odds of csPCa detection on TB (p=0.004) and a 66.5% decrease in odds of detection in large IPP compared to 0 IPP (p=0.003). CONCLUSIONS: As the size of the IPP and volume increase, there is a decrease in the detection rate of csPCa on MRI-guided TB. These findings may be driven by poor MRI-TRUS co-registration and prostate asymmetry.

Utility of Blue Light Cystoscopy for Post-bacillus Calmette-Guérin Bladder Cancer Recurrence Detection: Implications for Clinical Trial Recruitment and Study Comparisons.

PURPOSE: The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guérin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with non-muscle invasive bladder cancer (NMIBC) undergoing BCG. MATERIALS AND METHODS: Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence. RESULTS: Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15). CONCLUSIONS: BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.

Role of blue-light cystoscopy in detecting invasive bladder tumours: data from a multi-institutional registry.

OBJECTIVES: To evaluate the role of blue-light cystoscopy (BLC) in detecting invasive tumours that were not visible on white-light cystoscopy (WLC). PATIENTS AND METHODS: Using the multi-institutional Cysview registry database, patients who had at least one white-light negative (WL-)/blue-light positive (BL+) lesion with invasive pathology (≥T1) as highest stage tumour were identified. All WL-/BL+ lesions and all invasive tumours in the database were used as denominators. Relevant baseline and outcome data were collected. RESULTS: Of the 3514 lesions (1257 unique patients), 818 (23.2%) lesions were WL-/BL+, of those, 55 (7%) lesions were invasive (48 T1, seven T2; 47 unique patients) including 28/55 (51%) de novo invasive lesions (26 unique patients). In all, 21/47 (45%) patients had WL-/BL+ concommitant carcinoma in situ and/or another T1 lesions. Of 22 patients with a WL-/BL+ lesion who underwent radical cystectomy (RC), high-risk pathological features leading to RC was only visible on BLC in 18 (82%) patients. At time of RC, 11/22 (50%) patients had pathological upstaging including four (18%) with node-positive disease. CONCLUSIONS: A considerable proportion of invasive lesions are only detectable by BLC and the rate of pathological upstaging is significant. Our present findings suggest an additional benefit of BLC in the detection of invasive bladder tumours that has implications for treatment approach.

Creation and Psychometric Validation of the Sexual Minorities and Prostate Cancer Scale (SMACS) in Sexual Minority Patients-The Restore-2 Study.

BACKGROUND: Existing measures of sexual functioning in prostate cancer survivors focus primarily on erectile function and do not adequately measure the experiences of sexual minority men. AIM: To develop and psychometrically evaluate a new scale to measure sexual functioning among sexual minority men with prostate cancer. METHODS: Sexual minority prostate cancer patients (n = 401) completed an online battery of urinary and sexual functioning tests in 2019, including a new 37-item instrument about their sexual functioning post-treatment for prostate cancer. OUTCOMES: We used confirmatory factor analysis to determine the construct validity of a new scale including five subscales: a four-factor model for all participants (n = 401) evaluated Sexual Satisfaction, Sexual Confidence, Frequency of Sexual Problems, and Urinary Incontinence in Sex. A single-factor model completed only by participants who had attempted or desired receptive anal sex (n = 255) was evaluated in the fifth subscale: Problematic Receptive Anal Sex. To evaluate criterion validity, we calculated the intercorrelations between each Sexual Minorities and Prostate Cancer Scale (SMACS) subscale and four related scales: the Expanded Prostate Cancer Index Composite-50 (EPIC), the Functional Assessment of Cancer Therapy-Prostate, the Brief Symptom Inventory-18, and the International Consultation on incontinence questionnaire. Cronbach's alphas were calculated to measure internal consistency (ie, reliability). RESULTS: Cronbach's alpha values ranged from 0.64 to 0.89. Loadings (0.479-0.926) and model fit indices were strong (Root Mean Square Error of Approximation: 0.085, Standardized root mean squared residual: 0.063, comparative fit index: 0.927, Tucker-Lewis Index: 0.907). For criterion validity, Sexual Satisfaction, Sexual Confidence, and Frequency of Sexual Problems were moderately correlated with EPIC function and bother scores (r = 0.50-0.72) and Urinary incontinence in sex correlated moderately with EPIC Urinary Function and International Consultation on incontinence questionnaire scores (0.45-0.56). CLINICAL IMPLICATIONS: The SMACS can be used by clinicians and researchers to comprehensively measure sexual functioning in sexual minority men, in conjunction with existing scales. STRENGTHS AND LIMITATIONS: This new scale is validated in a large, geographically diverse cohort of sexual minority cancer survivors and fills an important gap in existing measures of sexual functioning. Limitations include a lack of a validation sample. CONCLUSION: The SMACS is a valid and reliable new scale that measures sexual minority men's experience of urinary incontinence in sex, problematic receptive anal sex, and sexual distress. Polter EJ, Kohli N, Rosser BRS, et al. Creation and Psychometric Validation of the Sexual Minorities and Prostate Cancer Scale (SMACS) in Sexual Minority Patients-The Restore-2 Study. J Sex Med 2022;19:529-540.

Recruiting an underserved, difficult to reach population into a cancer trial: Strategies from the Restore-2 Rehabilitation Trial for gay and bisexual prostate cancer patients.

BACKGROUND/AIMS: Sexual minorities are small and under-researched populations that are at disproportionate risk for cancer and poor cancer outcomes. Described as a "hidden population," the principal research challenge has been to develop effective methods to identify and recruit such cancer patients into cancer studies. Online recruitment strategies, as well as targeted clinic recruitment using patient-entered sexual orientation and gender identity data from electronic medical records have potential to transform recruitment, but studies testing the effects of how to recruit using these have not been published. METHODS: In 2019, we conducted a naturalistic, three-arm, stratified prospective study to compare three recruitment strategies: (a) clinic based recruitment of prostate cancer patients from gay health and urology clinics; (b) directly from the gay community; and (c) online recruitment (through cancer support, sex/dating, and social sites). For each strategy, we estimated time, workload, and direct costs involved. To study how recruitment strategy may affect sampling, we tested for retention rates, demographic and outcome differences across sites. Using these methods, we successfully recruited 401 gay and bisexual prostate cancer patients into a randomized, controlled, 24-month trial testing an online sexual and urinary rehabilitation curriculum tailored for this population. RESULTS: There were seven key results. First, it is possible to recruit substantial numbers of sexual minority men into prostate cancer studies provided online recruitment methods are used. Second, we observed big differences in dropout during study onboarding by recruitment source. Third, within online recruitment, the online sex/dating application (app) was the most successful and efficient, followed by the cancer support site, and then the social networking site. Fourth, while clinics were the cheapest source of recruitment, they were time intensive and low in yield. Fifth, the cancer support site and sex/dating app recruits differed by several characteristics, with the former being more rehabilitation-focused while the latter were younger and more sexually active. Sixth, we found almost no differences in outcomes across the three online recruitment sites. Seventh, because retention in online studies has been a concern, we confirm very low attrition at 3- and 6 months into the trial. CONCLUSION: For sexual minority cancer research, more research on how to use sexual orientation and gender identity electronic medical record data for clinic-based recruitment is needed. For other small or hard-to-reach populations, researchers should compare and publish online versus offline recruitment strategies.

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.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

A phase II randomized placebo-controlled trial of pomegranate fruit extract in men with localized prostate cancer undergoing active surveillance.

INTRODUCTION OR OBJECTIVE: Men with favorable-risk prostate cancer (PCa) on active surveillance may benefit from intervention strategies to slow or prevent disease progression and the need for definitive treatment. Pomegranate and its extracts have shown antiproliferative and proapoptotic effects in cell lines and animal models, but its effect on human prostate cancer as a target tissue remain unclear. Objectives of this trial include pomegranate's ability to alter serum and prostate tissue biomarkers and the ability of an active surveillance cohort to adhere to a chemoprevention trial for 1 year. METHODS: Men with organ-confined, favorable-risk PCa on AS were randomly assigned to receive pomegranate fruit extract (PFE) 1000 mg (n = 15) or placebo (n = 15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the 1-year intervention. Plasma and urinary biomarkers were analyzed utilizing immunoassays and HPLC. Tissue proteins were assessed by immunohistochemistry (IHC) and measured by automated quantitation. RESULTS: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the 1-year intervention. No differences in plasma insulin-like growth factor-1 (IGF-1) levels, prostate-specific antigen doubling time, or biopsy kinetics were observed. Metabolites including urolithin A and urolithin A-gluc were detected more frequently in the PFE arm in both urine and plasma (p < .001 and p = .006, respectively). IHC analyses revealed reductions from baseline in 8-OHdG (a DNA damage marker) (p = .01) and androgen receptor expression (p = .04) in prostate tumor associated with PFE treatment. CONCLUSION: PFE administration for 12-month was well-tolerated and the protocol followed in an active surveillance population. Analyses suggest that PFE contains bioactive compounds capable of altering biomarkers involving oxidative stress and androgen signaling in prostate tumor and normal-appearing adjacent tissue. No alterations in the IGF axis were noted. This finding of study adherence and target activity provides a rationale for the further investigation of PFE in the active surveillance population.

The Diagnostic Performance of Cxbladder Resolve, Alone and in Combination with Other Cxbladder Tests, in the Identification and Priority Evaluation of Patients at Risk for Urothelial Carcinoma.

PURPOSE: Cxbladder (Cxb) tests combine genomic biomarkers in urine with phenotypic and clinical data to classify hematuria patients into those at low/high probability of urothelial carcinoma (UC). Cxbladder Resolve (CxbR) is designed for use after Cxb Triage (CxbT) and Detect (CxbD), where CxbT-positive tests reflex to CxbD and CxbD-positive to CxbR to identify patients at high probability of high-impact tumors (HIT; high grade Ta, Tis or T1-T3). This study validated the diagnostic performance of CxbR in identifying HIT, and validated the algorithm of Cxb tests to segregate high-impact from low-impact tumors. MATERIALS AND METHODS: CxbR was developed in 863 hematuria patients in 3 studies in United States, Australia and New Zealand. CxbR, separately and combined with other Cxb tests, was validated in a prospective, observational U.S. study in 548 hematuria patients. All UC diagnoses were confirmed by histopathology. RESULTS: In the development data set, CxbR sensitivity was 92.4% (95% CI 83.3-96.7) and specificity 93.8% (95% CI 86.8-97.2) for identifying HIT within the high priority category. During external validation, sequential Cxb tests correctly ruled out 87.6% of patients from further workup (negative predictive value 99.4%); 100% of HIT were correctly identified (specificity 96.3%), and 3 low-grade tumors were missed. In both studies, all patients with HIT were correctly assigned to prioritized evaluation. CONCLUSIONS: CxbR has high sensitivity and specificity, correctly identifying all HIT. Sequential Cxb tests accurately segregate patients with a low vs high probability of HIT, focusing resources on those patients, with a diagnostic yield 4.8-fold higher than American Urological Association guideline stratification.

Impact of Preoperative Immunonutrition on Perioperative Outcomes following Cystectomy.

PURPOSE: Radical cystectomy (RC) for the management of muscle-invasive bladder cancer remains a morbid procedure with high rates of perioperative complications. The role of preoperative immunonutritional supplementation (pre-INS) in improving post-RC outcomes is promising and needs further validation. MATERIALS AND METHODS: We performed a retrospective review of 204 patients who underwent RC for bladder cancer at a single institution, comparing patients who received oral L-arginine-based pre-INS, and those who did not. Preoperative features, postoperative complications, and readmission data were collected. Outcomes of interest included development of high-grade (Clavien-Dindo III-V) complications, readmission within 30 days, ileus, total parenteral nutrition (TPN) requirement, postoperative infection, and length of stay (LOS). Categorical and continuous outcomes were assessed using Fisher's exact test and Welch T-test, respectively. Multivariable logistic regression (MLoR) analysis was used to identify predictive factors for our outcomes. RESULTS: Patients who received pre-INS had significantly lower odds of requiring postoperative TPN (17.3% vs 35.6%; Fisher p=0.015, OR=0.38) and developing postoperative infection (25% vs 45%; Fisher p=0.003; OR=0.41) but no significant difference in the rates of other outcomes. On MLoR, when adjusting for age, gender, body mass index, Charlson comorbidity index, undergoing neoadjuvant chemotherapy and operative features, pre-INS was a significant predictor of postoperative infection (Fisher p=0.02; OR=0.35) but not for high-grade complications, readmission, ileus, needing TPN or LOS. CONCLUSIONS: Preoperative immunonutrition with an L-arginine-based supplement is associated with significant reduction in postoperative infection, one of the most common complications of RC.

Making a case "against" focal therapy for intermediate-risk prostate cancer.

INTRODUCTION: Focal therapy (FT) for localized prostate cancer (PCa) is a promising treatment strategy. Although, according to guidelines, it should be regarded as an experimental option, its introduction into clinical practice has occurred at an accelerated speed. It is, thus, crucial for Urologists to understand FT limitations and potential drawbacks that may derive from its use. METHODS: We performed a literature search of peer-reviewed English language articles using Pubmed and the words "focal therapy" AND "prostate cancer" to identify relevant articles. Web search was complemented by manual search. RESULTS: From a biological perspective, in contrast with the index lesion theory, which still needs to be better supported, PCa is a multifocal and multiclonal entity. Also, the effects of FT on PCa microenvironment are unclear. From a clinical perspective, patient selection is still not precisely defined. Even when all variables potentially decreasing mpMRI and biopsy accuracy are optimized, up to one out of two men may be incorrectly selected for FT, leaving a significant proportion of clinically significant PCa (csPCa) untreated. Underestimation of PCa volume and variant histologies are other additional mpMRI potential limitations. No RCTs have been performed against the standard of care to support FT. There is absence of long-term results and FT series reaching medium-term follow-up have non-optimal oncological control with significant re-treatment needs. When PCa recurs/persists after FT, little is known about the appropriate management strategies and their outcomes. Finally, the optimal follow-up scheme post-FT remains unclear. CONCLUSIONS: Several arguments are present against the use of FT for localized PCa. Studies are needed to overcome current limitations and support FT before it can be included as part of the standard management of prostate cancer.

Enhanced recovery after surgery (ERAS) following radical cystectomy: is it worth implementing for all patients?

PURPOSE: To report the overall effect of ERAS protocol implementation in patients undergoing radical cystectomy and its impact on the length of hospital stay (LOS) and surgical outcomes considering their comorbid conditions. METHODS: Retrospective cohort study including 296 patients (146 non-ERAS patients vs. 150 ERAS patients) undergoing radical cystectomy and urinary diversion from 2010 to 2018. Age-adjusted Charlson Comorbidity Index (ACCI) score eight was set as cut off value between low-risk and high-risk patients. The primary outcome was LOS. Secondary outcomes were time to bowel movements, tolerance of regular diet, the incidence of postoperative ileus, postoperative complications, and 30- and 90-day readmission rates. RESULTS: A higher comorbidity burden was identified in the ERAS group compared to non-ERAS patients (p = 0.04). Median (IQR) LOS for non-ERAS was group 8(4) and 8(5) for ERAS group (p = 0.07). ERAS group demonstrated shorter time to resume bowel movements as well as time to tolerance of regular diet (p = 0.007, p = 0.023, respectively). Low-risk patients managed by the ERAS protocol demonstrated a significantly shortened gastrointestinal (GIT) recovery time (p = 0.001) as well as a reduction of LOS (p = 0.04). No significant reduction of LOS was identified for patients with higher comorbidity when placed on the ERAS protocol (p = 0.65). There were no significant differences in postoperative complications or readmission rates between groups. CONCLUSION: ERAS protocol implementation following radical cystectomy showed significant improvements in GIT recovery, nevertheless, it did not result in a decrease in LOS or readmission rates. Low-risk patients appeared to derive more benefit from ERAS protocol implementation than high-risk patients.