Phase 1 clinical trial evaluating safety, bioavailability, and gut microbiome with a combination of curcumin and ursolic acid in lipid enhanced capsules.

As screening strategies employ better biomarkers and genetics to identify individuals at an increased risk of prostate cancer, there are currently no chemotherapeutic prevention strategies. With any chemoprevention strategy, the population will be younger and healthier; therefore, they will be less tolerant of side effects. This study translated findings from screening a natural product library and pre-clinical evaluation of curcumin (CURC) in combination with ursolic acid (UA) in prostate cancer models. After manufacturing capsules for each compound, 18 subjects were enrolled. The study used a 3 × 3 phase 1 clinical trial to evaluate CURC (1200 mg/day) and UA (300 mg/day) alone and in combination over a 2-week period with endpoints of safety, bioavailability, and microbiome alterations. After enrolling six subjects in each arm, we found no grade 3 or 4 events and only minor changes in the safety laboratory values. In the pooled analysis of groups, we noted a statistically significant difference between median serum levels of UA when administered alone vs administered in the combination (2.7 ng/mL vs 43.8 ng/mL, p = 0.03). Individuals receiving the combination also had a favorable impact on gut microbiome status and a reduction in "microbiome score" predictive of prostate cancer risk.

Open versus minimally invasive nephroureterectomy in octogenarians: An analysis of surgical approach trends, outcomes, and survival analysis with propensity matching.

INTRODUCTION: Upper tract urothelial carcinoma (UTUC) is a rare disease accounting only for 5%-10% of urothelial carcinoma (UC). For localized high-risk disease, radical nephroureterectomy (RNU) is the standard of care. While minimally invasive (MIS) RNU has not been shown to decisively improve overall survival (OS) compared to open surgery, MIS RNU has been associated with reduced hospital length of stay (LOS), blood transfusion requirements and improved recovery, which are important considerations when treating older patients. The purpose of this study is to examine trends in surgical approach selection and outcomes of open vs. MIS RNU in patients aged ≥80 years. METHODS: Using the National Cancer Database (NCDB), patients aged ≥80 years who underwent open or MIS (either robotic or laparoscopic) RNU were identified from 2010 to 2019. Demographic, patient-related, and disease-specific factors associated with either open or MIS RNU were assessed using multivariate logistic regression models. Survival analysis was conducted using Kaplan-Meier plots and Cox-proportional hazard regression. Inverse probability of treatment weighting (IPTW) was utilized to adjust for confounding variables. Survival analysis was also conducted on the IPTW adjusted cohort using Kaplan-Meier plots and Cox-proportional hazard regression. RESULTS: 5,687 patients were identified, with 1,431 (25.2%) and 4,256 (74.8%) patients undergoing open and MIS RNU respectively. The proportion of RNU performed robotically has increased from 12.5% in 2010 to 50.4% in 2019. MIS was associated with a shorter hospital LOS (4.7 days versus 5.9 days, SMD 23.7%). Multivariate analysis revealed that MIS was associated with a significant reduction in 90-day mortality (OR: 0.571; 95%CI: 0.34-0.96, P = 0.033) and improved median OS (53.8 months [95%CI: 50.9-56.9] vs 42.35 months [95%CI: 38.6-46.8], P < 0.001) compared to open surgery. IPTW-adjusted survival analysis revealed improved median OS with MIS when compared to open surgery, with a survival benefit of 46.1 months (95%CI: 40.2-52.4 months) versus 37.7 months (95%CI: 32.6-46.5 months, P = 0.0034) respectively. IPTW-adjusted cox proportional hazard analysis demonstrated that MIS was significantly associated with reduced mortality (HR 0.76, 95%CI: 0.66-0.87, P < 0.001). CONCLUSION: In octogenarians undergoing RNU, MIS is associated with improved median OS and 90-day mortality.

Impact of rural residence on the presentation, management and survival of patients with non-metastatic muscle-invasive bladder carcinoma.

PURPOSE: To assess the impact of rural and remote residence on the receipt of guidelines-recommended treatment, quality of treatment and overall survival (OS) in patients with non-metastatic muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: Patients with MIBC were identified using National Cancer Database. Patients were classified into three residential areas. Logistic regression models were used to assess associations between geographic residence and receipt of radical cystectomy (RC) or chemoradiation therapy (CRT). Models were fitted to assess quality benchmarks of RC and CRT. RESULTS: We identified 71,395 patients. Of those 58,874 (82.5%) were living in Metro areas, 8,534 (11.9%) in urban-rural adjacent (URA), and 3,987 (5.6%) in urban-rural remote to metro area (URR). URR residence was significantly associated with poor OS compared to URA and Metro residence (HR 0.87, 95% CI 0.81-0.94 and HR 0.90, 95% CI 0.87-0.93, p<0.001). There was no difference in the likelihood of receiving RC and CRT among different residential areas. Among patients who underwent RC; individuals living in URR were less likely to receive neoadjuvant chemotherapy and adequate lymph node dissection, and had a higher probability of positive surgical margin than those living in metro areas. For those who received CRT; individuals living in Metro areas were more likely to receive concomitant systemic therapy compared to URR. CONCLUSIONS: Rural residence is associated with lower OS for MIBC patients and less likelihood of meeting quality benchmarks for RC and CRT. This data should be used to guide further health policy and allocation of resources for rural population.

Robot-assisted retroperitoneal lymph node dissection: a systematic review of perioperative outcomes.

OBJECTIVE: To assess the safety and feasibility of robot-assisted retroperitoneal lymph node dissection (R-RPLND) and to compare the perioperative outcomes of R-RPLND with open RPLND (O-RPLND), as RPLND forms an integral part of the management of testis cancer and R-RPLND is a minimally invasive treatment option for this disease. MATERIALS AND METHODS: The PubMed® , Scopus® , Cochrane Central Register of Controlled Trials, and Web of Science™ databases were searched for studies reporting perioperative outcomes of primary and post-chemotherapy R-RPLND and studies comparing R-RPLND with O-RPLND. RESULTS: The search yielded 42 articles describing R-RPLND, including five comparative studies. The systematic review included 4222 patients (single-arm studies, n = 459; comparative studies, n = 3763). Of 459 patients in the single-arm studies, 271 underwent primary R-RPLND and 188 underwent post-chemotherapy R-RPLND. For primary R-RPLND, the operative time ranged from 175 to 540 min and the major complication rate was 4.1%. For post-chemotherapy R-RPLND, the operative time ranged from 134 to 550 min and the major complication rate was 8.5%. The conversion rate to open surgery was 2.2% in primary R-RPLND and 9.0% in post-chemotherapy R-RPLND. In comparison with O-RPLND, R-RPLND was associated with a lower transfusion rate (14.5% vs 0.9%, P < 0.001) and a lower complication rate (18.5% vs 7.8%, P = 0.002). CONCLUSION: Robot-assisted RPLND has acceptable perioperative outcomes in both the primary and post-chemotherapy settings but a notable rate of conversion to open surgery in the post-chemotherapy setting. Compared with O-RPLND, R-RPLND is associated with a lower transfusion rate and fewer overall complications. Given the potential impact of selection bias, the optimal patient selection criteria for R-RPLND remain to be elucidated.

Patency outcomes of primary inferior vena cava repair in radical nephrectomy and tumor thrombectomy.

OBJECTIVE: The reconstruction of inferior vena cava (IVC) during radical nephrectomy and venous tumor thrombectomy (RN-VTT) is mostly performed with primary repair or with a patch/graft. We sought to systematically evaluate the outcomes of IVC patency over short- to intermediate-term follow-up for patients undergoing primary repair of IVC and to assess the association with survival. METHODS: A retrospective review of patients undergoing RN-VTT between January 2013 and August 2018 was conducted. Patients were followed until death, last available follow-up, or March 2022. The patency outcomes and IVC diameters were studied using follow-up cross-sectional imaging. The χ2 test, Student t test, and Kaplan-Meier survival analysis were used. RESULTS: Seventy-seven patients were included. The mean age was 59.2 ± 12.2 years and 45.4% had Mayo classification level III thrombus or higher. At a median follow-up of 36.5 months (13.3-60.7 months), the 3-year overall survival (OS) was 64%. Sixty patients underwent primary repair of the IVC and 48 of these patients were assessed for IVC patency. Ten patients (20.8%) developed caval occlusion, either from recurrent tumor (8.3%), new-onset bland thrombus (8.3%), or stenosis (4.2). The IVC patency seemed to be a significant predictor of OS (hazard ratio, 2.85; P = .021). Although the IVC diameters decreased significantly at the 3-month postoperative scan at the infrarenal (P = .019), renal (P < .001), and suprarenal (P < .001) levels, they did not decrease further on long-term follow-up imaging. CONCLUSIONS: IVC reconstruction with primary repair results in an overall patency rate of 80.2% with only a 4.0% rate of stenosis. Recurrence of tumor thrombus (8.3%) or bland thrombus (8.3%) are the predominant reasons for IVC occlusion after RN-VTT, and this outcome is associated with poor OS.

Revisiting current National Comprehensive Cancer Network (NCCN) high-risk prostate cancer stratification: a National Cancer Database analysis.

BACKGROUND: High-risk prostate cancer includes heterogenous populations with variable outcomes. This study aimed to compare the prognostic ability of individual high-risk factors, as defined by National Comprehensive Cancer Network (NCCN) risk stratification, in prostate cancer patients undergoing radical prostatectomy. METHODS: We queried the National Cancer Database from 2004 to 2018 for patients with non-metastatic high-risk prostate cancer who underwent radical prostatectomy and stratified them as Group H1: Prostate specific antigen (PSA) > 20 ng/ml alone, Group H2: cT3a stage alone and Group H3: Gleason Grade (GG) group 4/5 as per NCCN guidelines. The histopathological characteristics and rate of adjuvant therapy were compared between different groups. Inverse probability weighting (IPW)-adjusted Kaplan-Meier curves were utilized to compare overall survival (OS) in group H1 and H2 with H3. RESULTS: Overall, 61,491 high-risk prostate cancer patients were identified, and they were classified into Group H1 (n = 14,139), Group H2 (n = 2855) and Group H3 (n = 44,497). Compared to group H1 or H2, pathological GG group > 3 (p < 0.001), pathological stage pT3b or higher (p < 0.001), lymph nodal positive disease (pN1) (p < 0.001) and rate of adjuvant therapy (p < 0.001) were significantly in Group H3. IPW-adjusted Kaplan-Meier curves showed significantly better 5-year OS in group H1 compared to group H3 [95.1% vs 93.3%, p < 0.001] and group H2 compared to group H3 [94.4% vs 92.9%, p < 0.001]. CONCLUSION: PSA > 20 ng/ml or cT3a stage in isolation have better oncologic and survival outcomes compared to GG > 3 disease and sub-stratification of 'High-risk' category might lead to better patient prognostication.

Impact of Finasteride on Survival in Bladder Cancer: A Retrospective Multi-institutional Database Analysis.

INTRODUCTION: Androgen suppression therapy has been associated with a lower incidence of bladder cancer (BCa) or improved overall/cancer-specific survival. Results are ofent conflicting; therefore, we aim to assess the impact of use of finasteride on overall survival (OS) for BCa using multi-institutional database. METHODS: The South Texas Veterans Healthcare System from 5 medical centers was queried for patients with BCa with or without use of finasteride after diagnosis of BCa. The primary outcome was the impact of finasteride use after diagnosis on the OS in BCa and in the high-risk Non-muscle invasive BCa (NMIBC) cohort. RESULTS: A total of 1890 patients were included, amongst which 619 (32.8%) men were classified as finasteride users and 1271 (67.2%) men as controls. At a median (IQR) follow up of 53.8 (27.4, 90.9) months, death due to any cause was noted in 272 (43.9%) finasteride-treated, and 672 (49.3%) control groups (P = .028). The patients in the finasteride group had significantly better OS in overall cohort (112.1 months vs. 84.8 months, P < .001) as well as in the NMIBC cohort (129.3months vs. 103.2 months, P = .0046). The use of finasteride was independently associated with improved OS in both, overall cohort (HR 0.74, 95% CI 0.63-0.86; P < .001) and in the NMIBC cohort (HR = 0.71, 95% CI 0.55-0.93; P = .011). CONCLUSION: Finasteride use is associated with the improved overall survival in patients with BCa, specifically in patients with NMIBC. We, further, propose a randomized clinical trial to investigate the use of finasteride in BCa patients.

Open vs. robot-assisted radical cystectomy with extracorporeal or intracorporeal urinary diversion for bladder cancer A pairwise meta-analysis of outcomes and a network meta-analysis of complications.

INTRODUCTION: There are no meta-analyses of randomized controlled trials (RCTs) comparing open radical cystectomy (OR C) with robot-assisted radical cystectomy (RARC), inclusive of both intracorporeal (iRARC) and extracorporeal (hybrid RARC, hRARC) urinary reconstruction. METHODS: MEDL INE, Embase, Scopus, the International Clinical Trials Registry Platform and ClinicalTrials.gov registries were searched in May 2022. Outcomes of interest included recurrence- or progression-free survival (RFS/PFS), margin status and lymph node yield, mean estimated blood loss (EBL) and operating room time (ORT ), hospital length of stay (LOS ), 90-day complications and readmissions, and quality of life (QoL). Pairwise meta-analyses and network meta-analyses were performed using random-effects models and Bayesian hierarchical random-effects models, respectively. RESULTS: We found no significant differences between RARC and OR C for oncological and most perioperative outcomes: RFS/PFS (hazard ratio [HR ] 0.91, 95% confidence interval [CI] 0.67-1.23); positive surgical margins (odds ratio [OR ] 1.05, 95% CI 0.60-1.85); lymph node yield (mean difference [MD ] -0.63, 95% CI -2.63-1.37); LOS (MD -0.22, 95% CI -1.10-0.65); overall complications (OR 0.81, 95% CI 0.61-1.07); major complications (OR 0.94, 95% CI 0.69-1.30); readmissions (OR 0.90, 95% CI 0.60-1.35); and QoL (standardized MD -0.02, 95% CI -0.17-0.14). We found significantly lower EBL for RARC compared to OR C (MD -312.61, 95% CI -447 to -178.22) at the expense of significantly prolonged ORT (MD 82.34 minutes, 95% CI 44.82-119.86). Network meta-analysis did not find significant differences in complications between hRARC and iRARC. CONCLUSIONS: This meta-analysis confirms the equivalence of RARC and OR C with respect to oncological outcomes.

A comparative analysis of radical cystectomy with perioperative chemotherapy, chemoradiation therapy, or systemic therapy in patients with clinically advanced node-positive bladder cancer (cN2/N3).

Introduction: The management of non-metastatic clinically advanced lymph nodal (cN2/N3) bladder cancer (Stage IIIB) could involve radical cystectomy, chemoradiation, or systemic therapy alone. However, a definitive comparison between these approaches is lacking. This study aims to compare the outcomes of patients undergoing radical cystectomy with pelvic lymph node dissection (RC-PLND), chemoradiation therapy (CRT) or systemic therapy (including immunotherapy) (ST) only in patients with stage IIIB bladder cancer. Materials and methods: A retrospective analysis of the National Cancer Database for patients with stage IIIB urothelial bladder cancer was done from 2004-2019. Patients were classified as Group A: Those who received RC-PLND with perioperative chemotherapy, Group B: Those who received CRT, and Group C: Those who received only ST alone. The primary outcome was overall survival (OS). Inverse probability weighting (IPW)-adjusted Kaplan Meier curves were utilized to compare overall survival (OS) and cox multivariate regression analysis was used to identify predictors for OS. Results: Overall, 2,575 patients were identified. They were classified into Group A (n=1,278), Group B (n=317) and Group C (n=980). Compared to Group B, patients in Group A were younger (SMD=19.6%), had lower comorbidities (SMD=18.2%), had higher income (SMD=31.5%), had private insurance (SMD= 26.7%), were treated at academic centres (SMD=29.3%) and had higher percentage of N2 disease (SMD=31.1%). Using IPW-adjusted survival analysis, compared to Group C, the median OS was significantly higher in Group A (20.7 vs 14.2 months, p<0.001) and Group B (19.7 vs 14.2 months, p<0.001) but similar between Group A and Group B (20.9 vs 19.7 months, p=0.74). Both surgery (HR=0.72 (0.65-0.80), p<0.001) and CRT (0.70 (0.59-0.82), p<0.001) appeared to be independent predictors for OS on cox-regression analysis. The major limitations include bias due to retrospective analysis and non-assessment of cancer-specific survival. Conclusion: In stage IIIB bladder cancer with advanced lymph nodal disease, both RC and CRT offer equivalent survival benefits and are superior to systemic therapy alone.

Diffusion of robot-assisted radical cystectomy: Nationwide trends, predictors, and association with continent urinary diversion.

Objectives: To assess the utilisation trends of robot-assisted radical cystectomy (RARC), rates of performing continent urinary diversions (CUDs), and impact of diffusion of RARC on CUD rates. Methods: We investigated the National Cancer Database for patients with muscle-invasive bladder cancer (MIBC) who underwent RC between 2004 and 2015. Patients were stratified by surgical technique into open (ORC) and RARC groups, and by type of urinary diversion into continent (CUD) and ileal conduit (ICUD) groups. Linear regression models were fitted to evaluate time trends for surgery and conversion techniques. Multivariate logistic regression models were utilised to identify independent predictors of RARC and CUD. Results: A total of 14466 patients underwent RC for MIBC, of which 4914 (34%) underwent RARC. There was a significant increase in adoption of RARC from 22% in 2010 to 40% in 2015 (R2 = 0.96, P < 0.001), this was not associated with a change in the rates of CUD over the same period (P = 0.22). Across all years, ICUD was the primary type of urinary diversion, CUD was only offered in 12% in 2010 compared to 9.9% in 2015 (R2 = 0.33, P = 0.22). Multivariate analysis identified male gender (odds ratio [OR] 1.18, P = 0.03), academic centres (OR 1.74, P = 0.001), and lower T stage (T4 vs T2; OR 0.78, P = 0.03) as independent predictors of CUD, while surgical technique was not associated with odds of receiving CUD (P = 0.8). Conclusions: There is significant nationwide increasing trend of adoption of RARC. This diffusion was not associated with a decline in CUD, which remains significantly underutilised in both ORC and RARC groups. Abbreviations CUD: continent urinary diversion; ICD-O: International Classification of Diseases for Oncology; ICUD: ileal conduit urinary diversion; (N)MIBC: (non-)muscle-invasive bladder cancer; NAC, neoadjuvant chemotherapy; NCDB: National Cancer Database; OR: odds ratio;(O)(RA)RC: (open) (robot-assisted) radical cystectomy.