Elevated periprostatic venous testosterone correlates with prostate cancer progression after radical prostatectomy.

BACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T exposure is similarly thought to be determined from peripheral T exposure. Despite the fact that androgens drive prostate cancer, peripheral T has had no role in the clinical evaluation or treatment of men with localized prostate cancer.METHODSTo assess the role of local androgen delivery in prostate cancer, we obtained blood from the (periprostatic) prostatic dorsal venous complex in 266 men undergoing radical prostatectomy from July 2014 to August 2021 and compared dorsal T (DT) levels with those in circulating peripheral blood (PT) and prostatic tissue. Comprehensive targeted steroid analysis and unbiased metabolomics analyses were performed. The association between the DT/PT ratio and progression-free survival after prostatectomy was assessed.RESULTSSurprisingly, in some men, DT levels were enriched several-fold compared with PT levels. For example, 20% of men had local T concentrations that were at least 2-fold higher than peripheral T concentrations. Isocaproic acid, a byproduct of androgen biosynthesis, and 17-OH-progesterone, a marker of intratesticular T, were also enriched in the dorsal vein of these men, consistent with testicular shunting. Men with enriched DT had higher rates of prostate cancer recurrence. DT/PT concentration ratios predicted worse outcomes even when accounting for known clinical predictors.CONCLUSIONSThese data suggest that a large proportion of men have a previously unappreciated exposure to an undiluted and highly concentrated T supply. Elevated periprostatic T exposure was associated with worse clinical outcomes after radical prostatectomy.FUNDINGNational Cancer Institute (NCI), NIH grants R01CA172382, R01CA236780, R01CA261995, R01CA249279, and R50CA251961; US Army Medical Research and Development Command grants W81XWH2010137 and W81XWH-22-1-0082.

Assessing cancer risk in the anterior part of the prostate using micro-ultrasound: validation of a novel distinct protocol.

PURPOSE: To develop and validate a micro-ultrasound risk score that predicts the likelihood of significant prostate cancer in the anterior zone. METHODS: Patients were enrolled from three expert institutions familiar with micro-ultrasound. The study was conducted in two phases. First, the PRI-MUS anterior score was developed by assessing selected prostate videos from patients who subsequently underwent radical prostatectomy. Second, seven urology readers with varying levels of experience in micro-ultrasound examination evaluated prostate loops according to the PRI-MUS anterior score. Each reader watched the videos and recorded the likelihood of the presence of significant cancer in the anterior part of the prostate in a three-point scale. The coherence among the readers was calculated using the Fleiss kappa and the Cronbach alpha. RESULTS: A total of 102 selected prostate scans were used to develop the risk assessment for anterior zone cancer in the prostate. The score comprised three categories: likely, equivocal, and unlikely. The median (IQR) sensitivity, specificity, positive predictive value, and negative predictive value for the seven readers were 72% (68-84), 68% (64-84), 75% (72-81), and 73% (71-80), respectively. The mean SD ROC AUC was 0.75 ± 2%, while the Fleiss kappa and the Cronbach alpha were 0.179 and 0.56, respectively. CONCLUSION: Micro-ultrasound can detect cancerous lesions in the anterior part of the prostate. When combined with the PRI-MUS protocol to assess the peripheral part, it enables an assessment of the entire prostate gland. Pending external validation, the PRI-MUS anterior score developed in this study might be implemented in clinical practice.

Detection of Clinically Significant Index Prostate Cancer Using Micro-ultrasound: Correlation With Radical Prostatectomy.

OBJECTIVE: To determine the detection of clinically significant prostate cancer (csPCa) index lesion using high resolution transrectal micro-ultrasound (MicroUS) applying PRI-MUS (Prostate Risk Identification using Micro Ultrasound) score v1.0. METHODS: Men who underwent radical prostatectomy following biopsy and MicroUS assessment were included. MicroUS dynamic cine loops of these patients were retrospectively reviewed by an experienced radiologist. The radiologist was aware that patients had undergone radical prostatectomy but was blinded to pathological data. Suspicious sites were assigned a PRI-MUS score. Radical prostatectomy specimens were examined with the quarter mount technique. Detection rate of csPCa index lesion [Grade Group (GG) ≥2] by MicroUS was assessed at a patient level. RESULTS: Twenty-five participants were included in the analysis. The median age was 65.5 years (range 56-74). Median PSA was 6.45 ng/dL (range 2-31.72). Two of 25 patients did not have csPCa (GG1 disease) on radical prostatectomy. MicroUS visualized 20/23 (87%) of the csPCa index lesions [median length 9 mm (range 1.5- 28.5)]. All identified lesions were categorized PRIMUS score 4 or 5. The 3 missed index lesions were in the transition zone [median length 10.5 mm (range 4.5-22.5)]. MicroUS missed 11 non index csPCa in 9 participants [median length 1.5 mm (range 1.5-10.5)]. Of these, 8 were GG2, 2 GG3 and 1 GG5. MicroUS identified the csPCa index lesion in all 9 of these men. CONCLUSION: MicroUS showed the high sensitivity (87%) in detecting index lesions in the prostate gland and identified 100% of index lesions in the peripheral zone.

First American Cancer Patient to Receive Dicycloplatin (DCP) Chemotherapy Achieves Remission After Seven Weeks of DCP Capsules - A Case Report.

BACKGROUND: The majority of bladder cancer patients experience recurrence. Cisplatin is the standard chemotherapy for muscle-invasive bladder cancer though adverse effects are often severe. CASE REPORT: Intravenous (IV) dicycloplatin (DCP) sustained remission in an American bladder cancer patient for five years. A recurrent mass was observed in July 2021. The patient received DCP capsules for seven weeks with no significant side-effects. Complete blood count with differential and a basic metabolic panel showed no adverse effects of DCP capsules on the bone marrow, liver or renal parameters. Cystoscopy after oral DCP found no evident bladder tumors; cytology was negative for high-grade urothelial carcinoma. CONCLUSION: In this patient, DCP-capsules appeared to be as effective as DCP-IV for achieving bladder cancer remission. Both forms of DCP chemotherapy are convenient, active against several cancer types, with decreased adverse effects compared to cisplatin. Both have been available for treating cancer patients in China. A USA clinical trial of DCP in bladder and other cancers appears warranted.

Survival outcomes following radical cystectomy in patients with prior pelvic radiation for prostate cancer: A matched cohort analysis.

OBJECTIVES: To determine the impact of prior pelvic radiation therapy (XRT) on outcomes following radical cystectomy (RC) for bladder cancer. MATERIALS AND METHODS: We performed a retrospective review comparing patients with bladder cancer requiring RC and prior history of XRT for prostate cancer to those undergoing RC without XRT history at our institution from 2011-2018. Propensity score matching was performed with the following variables: age, chronic kidney disease, nutritional deficiency, neoadjuvant chemotherapy use, Charlson comorbidity index, surgical approach, urinary diversion type, and pathologic T-stage. Perioperative, pathologic and oncologic outcomes were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Categorical variables were assessed utilizing the Pearson Chi Square Test, and continuous variables with the Wilcoxon rank-sum test. The Kaplan-Meier method with stratified-log rank was used to compare survival outcomes. Multivariable Cox proportional hazards models were utilized to identify predictors of overall and recurrence free survival. RESULTS: 227 patients were included, of which 47 had radiotherapy for prostate cancer. 47% of patients in the radiation cohort received external beam radiation therapy, 47% received brachytherapy and 7% received both. There were no differences in recurrence-free survival (P = 0.82) or overall survival (P = 0.25). Statistically significant differences in perioperative or postoperative outcomes such as 90-day complication, readmission, mortality rates, or ureteroenteric anastomotic stricture rates were not found. Rates of node-positive disease, median lymph node yield, positive surgical margin rates, lymphovascular invasion, or variant histology were not significantly different between cohorts. CONCLUSIONS: After matching for T-stage and other clinical variables, history of pelvic XRT for prostate cancer in patients who later required RC for bladder cancer, was not associated with an increased rate of perioperative complications or an independent predictor of RFS or OS.

Intravesical sequential gemcitabine and docetaxel versus bacillus calmette-guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG.

INTRODUCTION: Repeat BCG induction remains an option for select non-muscle invasive bladder cancer (NMIBC) patients who fail initial therapy. Alternative salvage intravesical regimens such as Gemcitabine and Docetaxel (Gem/Doce) have been investigated. We aimed to compare the efficacy BCG plus interferon a-2b (BCG/IFN) and Gem/Doce in patients with recurrent NMIBC after a single prior BCG course. METHODS: The National Phase II BCG/IFN trial database and multi-institutional Gem/Doce database were queried for patients with recurrent NMIBC after one prior BCG induction course, excluding those with BCG unresponsive disease. Stabilized inverse probability treatment weighted survival curves were estimated using the Kaplan-Meier method and compared. Propensity scores were derived from a logistic regression model. The primary outcome was recurrence free survival (RFS); secondary outcomes were high-grade (HG) RFS and risk factors for treatment failure. RESULTS: We identified 197 BCG/IFN and 93 Gem/Doce patients who met study criteria. Patients receiving Gem/Doce were older and more likely to have HG disease, CIS, and persistent disease following induction BCG (all P < 0.01). After propensity score-based weighting, the adjusted 1- and 2-year RFS was 61% and 53% after BCG/IFN versus 68% and 46% after Gem/Doce (P = 0.95). Adjusted 1- and 2-year HG-RFS was 60% and 51% after BCG/IFN versus 63% and 42% after Gem/Doce (P = 0.68). Multivariable Cox regression revealed that Gem/Doce treatment was not associated with an increased risk of failure (HR = 0.97, P = 0.89) as compared to BCG/IFN. CONCLUSION: Patients with recurrent NMIBC after a single induction BCG failure and not deemed BCG unresponsive had similar oncologic outcomes with Gem/Doce and BCG/IFN in a post-hoc analysis. Additional prospective studies are needed.

Validating the association of adverse pathology with distant metastasis and prostate cancer mortality 20-years after radical prostatectomy.

PURPOSE: To assess the association of adverse pathology (AP), defined as high-grade (≥ Gleason Grade Group 3) and/or non-organ confined disease, with long-term oncologic outcomes after radical prostatectomy (RP). MATERIALS AND METHODS: Using a stratified cohort sampling design, we evaluated the association of AP with the risk of distant metastasis (DM) and prostate cancer-specific mortality (PCSM) up to 20 years after RP in 428 patients treated between 1987 to 2004. Cox regression of cause-specific hazards was used to estimate the absolute risk of both endpoints, with death from other causes treated as a competing risk. Additionally, subgroup analysis in patients with low and/or intermediate-risk disease, who are potentially eligible for active surveillance (AS), was performed. RESULTS: Within the cohort sample, 53% of men exhibited AP at time of RP, with median follow up of 15.5 years (IQR 14.6-16.6 years) thereafter. Adverse pathology was highly associated with DM and PCSM in the overall cohort (HR 12.30, 95% confidence interval [CI] 5.30-28.55, and HR 10.03, 95% CI 3.42-29.47, respectively, both P < 0.001). Adverse pathology was also highly associated with DM and PCSM in the low/intermediate-risk subgroup (HR 10.48, 95% CI 4.18-26.28, and 8.60, 95% CI 2.40-30.48, respectively, both P < 0.001). CONCLUSIONS: Adverse pathology at the time of RP is highly associated with future development of DM and PCSM. Accurate prediction of AP may thus be useful for individualizing risk-based surveillance and treatment strategies.

GPS Assay Association With Long-Term Cancer Outcomes: Twenty-Year Risk of Distant Metastasis and Prostate Cancer-Specific Mortality.

PURPOSE: To assess the association between the Oncotype DX Genomic Prostate Score (GPS) result and long-term oncological outcomes following radical prostatectomy (RP). METHODS: We evaluated the association of the GPS result assayed from the index lesion from RP tissue with the risk of distant metastases (DM) and prostate cancer-specific mortality (PCSM) over the 20 years following RP in a stratified cohort sample of 428 patients from 2,641 treated between 1987 and 2004. Cox regression of cause-specific hazards was used to estimate the absolute risk of both end points, with death from other causes treated as a competing risk. A correction for regression to the mean (RM) was applied since the GPS test was developed using this cohort. Exploratory analysis using presurgical parameters and the GPS test as prognostic variables was performed to assess the additional value of the GPS test on 20-year risk of DM and PCSM. Model discrimination was measured using the area under the receiver operating characteristic curve. RESULTS: The GPS test appears to be independently associated with both 20-year risk of DM and PCSM with a low false discovery rate. Per 20-unit increase in GPS, multivariable analysis with RM correction estimated hazard ratios of 2.24 (95% CI, 1.49 to 3.53) and 2.30 (95% CI, 1.45 to 4.36) for DM and PCSM, respectively. Accuracy of models including clinical risk factors alone appeared to improve when including the GPS test in assessing risk of both end points. CONCLUSION: The results suggest that the GPS test provides information on the risk for the meaningful long-term outcomes of DM and PCSM.

Comparison of Oncologic Outcomes Following Open and Robotic-assisted Radical Cystectomy with both Extracorporeal and Intracorporeal Urinary Diversion.

OBJECTIVES: To compare oncologic endpoints between open radical cystectomy (ORC) and robotic-assisted radical cystectomy with extracorporeal urinary diversion (eRARC) or intracorporeal urinary diversion (iRARC). MATERIALS AND METHODS: Retrospective review of all patients undergoing curative-intent radical cystectomy with urinary diversion for urothelial bladder cancer at a single-institution from 2010-2018. Primary outcomes included recurrence location and rates, recurrence-free (RFS) and overall survival (OS). Survival estimates were obtained using the Kaplan-Meier method and compared using log-rank analysis. Cox proportional-hazards model was used to identify predictors of survival. RESULTS: 265, 366 and 285 patients underwent ORC, eRARC, and iRARC, respectively (n = 916). Median follow-up was 52, 40 and 37 months for ORC, eRARC and iRARC, respectively (P < 0.001). Ileal conduit was more commonly performed in iRARC (85%, P < 0.001). Neobladder rates did not vary. Neoadjuvant (p=0.4) or adjuvant therapy use (P = 0.36), pT-stage (P = 0.28) or pN-stage (P = 0.1) did not differ. Positive soft tissue margin rates were higher in ORC (7.2%-ORC, 3.6%-eRARC, 3.2%-iRARC, P = 0.041). Differences in recurrence rates or location were not observed. Surgical approach was not associated with any survival endpoint on proportional-hazards or Kaplan-Meier analysis. Hazard ratios and 95% CI for RFS were 1 (0.72-14) and 0.93 (0.66-1.3) for eRARC and iRARC, respectively, when compared to ORC as the referent. CONCLUSION: These findings from a large, single-institution in conjunction with randomized-controlled trial data suggest that RARC does not compromise perioperative or long-term oncologic outcomes when compared to ORC.

The Clinical and Pathologic Relevance of a Prostate MRI Diagnosis of "Prostatitis".

OBJECTIVE: To investigate the relationship between magnetic resonance imaging evidence of prostatitis with clinical symptomatology. Non-malignant abnormalities in peripheral zone are common in prostate multiparametric prostate magnetic resonance imaging (mpMRI). These findings are sometimes reported as "prostatitis" or "inflammation" and lead to patient anxiety and urologic referral. METHODS: Retrospective review of patients undergoing prostate mpMRI (2016-2017) was performed. Two cohort groups based on the presence of "prostatitis" or "inflammation" in the radiology report were identified. Clinical characteristics included age, prostate specific antigen, biopsy/intervention history, true lower urinary tract symptoms (LUTS), pain, use of urologic medications, prostate volume, and PIRADS score. Pathologic finding of inflammation was recorded. Groups were compared using chi-square for dichotomous variables and t-tests for continuous variables. RESULTS: One hundred and four patients were identified with "prostatitis/inflammation" and 273 without. Report of LUTS was high in both groups (58% and 62% for prostatitis and no prostatitis respectively, P= .49), though report of moderate/severe LUTS (physician description or IPSS of 8-19 and 20+) was more common in the no prostatitis group (7% vs 18%, P= .008). Use of urologic medication was similar between the 2 groups (31% and 37% for prostatitis and no prostatitis respectively, P = .23). Biopsy finding of inflammation was more common in the prostatitis group (57% vs 43% P = .027). Reports of pelvic pain, dysuria, or urinary findings of inflammation were uncommon in both groups. CONCLUSION: While mpMRI findings of prostatitis may indicate NIH Category IV prostatitis, there is no evidence of correlation with categories I, II or III prostatitis nor with symptomatic LUTS, and patients should be reassured that further investigation is not warranted.

Comparison of Major Complications at 30 and 90 Days Following Radical Cystectomy.

OBJECTIVES: To better understand the time-course in which major complications occur after radical cystectomy and to describe associations with complications at 30 and 90 days. METHODS: A database of radical cystectomy cases was queried for preoperative, perioperative, and postoperative data. Follow-up extended to 90 days postsurgery and included major complications (Clavien III-V). Early (30-day) and late (90-day) complication rates were compared via McNemar's test, and patient characteristics were compared across complication time groups by one-way ANOVA or Fisher's exact tests. Multinomial logistic regression was used to explore associations between patient characteristics and complication timing. RESULTS: Of 969 patients undergoing radical cystectomy, 210/969 (21.7%) experienced a complication within 90 days. The rate of major complication significantly differed at 30 and 90 days (14.4% [conflict of interest (CI): 12.4%-16.9%] vs 21.7% [CI: 19.2%-24.4%] respectively, P ≤.0001). Chronic obstructive pulmonary disease (COPD) (P = .03), Charlson Comorbidity Index (P = .02), and Indiana pouch diversion (P = .002) were significant predictors of early complication. Diabetes was the strongest predictor for late complication (OR: 2.42; P = 0.01). Diabetes was also a significant predictor for late genitourinary complications (OR 3.39; P = .01), and smoking history was a significant predictor for late infectious complications (OR 3.61; P = .01). CONCLUSION: We identified a significant number of complications occurring after 30 days postcystectomy, including the majority of deaths and genitourinary complications. These findings suggest that assessment of complications exclusively at 30 days would fail to capture a large proportion of major complications and deaths. Understanding the time-course of complications postcystectomy will serve to better inform design of future outcome studies.

Comparison of renal function after open radical cystectomy, extracorporeal robot assisted radical cystectomy, and intracorporeal robot assisted radical cystectomy.

PURPOSE: Renal function outcomes following robot-assisted radical cystectomy (RARC) have not been well established. We sought to compare long-term renal function outcomes between open radical cystectomy, RARC with extracorporeal urinary diversion and intracorporeal urinary diversion at a high volume institution. MATERIALS AND METHODS: We retrospectively reviewed our institutional bladder cancer database for patients who underwent RC from 2010 to 2019 with pre-operative estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73m2. Changes in renal function were assessed through locally weighted scatter plot smoothing and comparison of median eGFR between surgical groups. Chronic Kidney Disease Stage 3B was defined as eGFR < 45 ml/min/1.73m2. Renal function decline was defined as a ≥10 ml/min/1.73m2 drop in eGFR. Kaplan Meier method with log-rank was used to compare CKD 3B-free survival and renal function decline. Cox Proportional Hazards model was used to identify predictors of CKD 3B. RESULTS: Six hundred and forty four patients were included with median follow-up of 32 months (IQR 12-56). Preoperative characteristics were similar among the groups with no differences in median pre-operative eGFR (ORC: 74.6, extracorporeal urinary diversion: 74.3, intracorporeal urinary diversion: 71.6 ml/min/1.73m2, P=0.15). Median postoperative eGFR on follow up was not different between groups (P=0.56). 33% of patients developed CKD 3B. There were no differences in CKD 3B-free survival by surgical approach (P = 0.23) or urinary diversion (P = 0.09). 64% of patients experienced renal function decline with a median time of 2.4 years (P 0.23). Predictors of CKD were pathologic T3 disease or greater (HR: 1.77, P = 0.01), ureteroenteric anastomotic stricture (HR: 2.80, P < 0.001), preoperative CKD Stage 2 (HR: 1.81, P =0.02), and preoperative CKD Stage 3A (HR: 5.56, P < 0.001). CONCLUSION: Renal function decline is common after RC. Tumor stage, pre-operative eGFR, and ureteral stricture development, not surgical approach, influence renal function decline.

Germline HSD3B1 Genetics and Prostate Cancer Outcomes.

Dihydrotestosterone synthesis in prostate cancer from adrenal DHEA/DHEA-sulfate requires enzymatic conversion in tumor tissues. 3ß-hydroxysteroid dehydrogenase-1 is an absolutely necessary enzyme for such dihydrotestosterone synthesis and is encoded by the gene HSD3B1 which comes in 2 functional inherited forms described in 2013. The adrenal-permissive HSD3B1(1245C) allele allows for rapid dihydrotestosterone synthesis. The adrenal-restrictive HSD3B1(1245A) allele limits androgen synthesis. Studies from multiple cohorts show that adrenal-permissive allele inheritance confers worse outcomes and shorter survival after castration in low-volume prostate cancer and poor outcomes after abiraterone or enzalutamide treatment for castration-resistant prostate cancer. Here, we review the clinical data and implications.

Initial Results from the M-STONE Group: A Multi-Center Collaboration to Study Treatment Outcomes in Nephrolithiasis Evaluation.

Introduction: Despite proven effectiveness of medications in preventing stone recurrence, compliance with pharmacotherapy (PT) is often poor because of cost, side effects, and impact on lifestyle. We sought to compare the risk of stone recurrence between patients managed with conservative therapy (CT) vs PT controlling for aggressiveness of stone disease. Materials and Methods: The Multi-center collaboration to Study Treatment Outcomes in Nephrolithiasis Evaluation (MSTONE) database contains patient data and outcomes from July 2001 to April 2015 across four centers. The database was queried for patients whose stone disease was managed with CT alone (fluid and dietary recommendations) vs PT. Patients were risk stratified according to number of previous passed stones. Within each risk group, we compared CT vs PT with respect to 2-year stone event rate and stone event-free survival (SEFS) using the Kaplan-Meier method. Results: A total of 245 patients, with a median follow-up of 29 months (interquartile range = 16-44), were identified, including 93 on CT and 152 on PT. The overall 2-year stone event rate was 38% for all patients. Stone events at 2 years occurred less frequently in the PT group compared with the CT group (31% vs 44%, p = 0.043), with the difference most pronounced in the high-risk group (71% vs 32% for CT and PT, respectively, p = 0.058). The 30-month SEFS was significantly higher for PT (58%) than CT (46%) overall. When stratified by risk group, 30-month SEFS was statistically significantly higher for PT than CT in the intermediate risk group (65% vs 45% for PT and CT, respectively). Conclusion: Controlling for aggressiveness of stone disease, PT was more effective than CT in reducing and delaying stone-related events. However, CT appeared to be as effective as PT in low-risk patients. PT is best reserved for recurrent stone formers, regardless of metabolic background.

Uretero-Enteric Anastomotic Stricture Following Radical Cystectomy: A Comparison of Open, Robotic Extracorporeal, and Robotic Intracorporeal Approaches.

OBJECTIVES: To compare the incidence of benign uretero-enteric anastomotic strictures between open cystectomy, robotic cystectomy with extracorporeal urinary diversion, and robotic cystectomy with intracorporeal urinary diversion. The effect of surgeon learning curve on stricture incidence following intracorporeal diversion was investigated as a secondary outcome. PATIENTS AND METHODS: Patients who underwent radical cystectomy at an academic hospital between 2011 and 2018 were retrospectively reviewed. The primary outcome, incidence of anastomotic stricture over time, was assessed by a multivariable Cox proportional hazards regression. A Cox regression model adjusting for sequential case number in a surgeon's experience was used to assess intracorporeal learning curve. RESULTS: Nine hundred sixty-eight patients were included: 279 open, 382 robotic extracorporeal, and 307 robotic intracorporeal. Benign stricture incidence was 11.3% overall: 26 (9.3%) after open, 43 (11.3%) after robotic extracorporeal, and 40 (13.0%) after robotic intracorporeal. An intracorporeal approach was associated with anastomotic stricture on multivariable analysis (HR 1.66; P = .05). After 75 intracorporeal cases, stricture incidence declined from 17.5% to 4.9%. Higher sequential case volume was independently associated with reduced stricture incidence (Hazard Ratio per 10 cases: 0.90; P = .02). CONCLUSION: An intracorporeal approach to urinary reconstruction following robotic radical cystectomy was associated with an increased risk of benign uretero-enteric anastomotic stricture. In surgeons' early experience with intracorporeal diversion the difference in stricture incidence was more pronounced compared to alternative approaches; however, increased intracorporeal case volume was associated with a decline in stricture incidence leading to a modest difference between the 3 surgical approaches overall.

Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma.

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1ß, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

Single-dose replicating RNA vaccine induces neutralizing antibodies against SARS-CoV-2 in nonhuman primates

The ongoing COVID-19 pandemic, caused by infection with SARS-CoV-2, is having a dramatic and deleterious impact on health services and the global economy. Grim public health statistics highlight the need for vaccines that can rapidly confer protection after a single dose and be manufactured using components suitable for scale-up and efficient distribution. In response, we have rapidly developed repRNA-CoV2S, a stable and highly immunogenic vaccine candidate comprised of an RNA replicon formulated with a novel Lipid InOrganic Nanoparticle (LION) designed to enhance vaccine stability, delivery and immunogenicity. We show that intramuscular injection of LION/repRNA-CoV2S elicits robust anti-SARS-CoV-2 spike protein IgG antibody isotypes indicative of a Type 1 T helper response as well as potent T cell responses in mice. Importantly, a single-dose administration in nonhuman primates elicited antibody responses that potently neutralized SARS-CoV-2. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection from SARS-CoV-2 infection.

Neurogenic bladder monitoring using the cystomanometer and cystoelastometer.

INTRODUCTION: Patients with neurogenic bladder (NGB) require periodic urodynamics (UDS) to evaluate bladder function, which in turn helps guide management. At times, bladder decompensation or hydronephrosis may develop in patients between urodynamic testing intervals. Increased surveillance has improved outcomes in other chronic conditions (e.g., diabetes). Two novel devices, the cystomanometer (CM) and cystoelastometer (CEM), have been developed at the authors' institution to allow for home bladder pressure monitoring. The handheld CM can be attached to the end of any catheter and records the opening bladder pressure along with a time stamp. In addition, the CEM actively evacuates urine via a pump and records the urine volume evacuated. For safety, the pump slows and stops as it detects increasing resistance. Data are stored and transmitted wirelessly from both devices to a smartphone. A novel phone application stores, displays, and transmits data to a secure hospital server. OBJECTIVE: This aim of this study was to validate the function of the CM and CEM and their accuracy relative to UDS. STUDY DESIGN: Institutional review board approval was obtained. All patients with NGB managed with intermittent catheterization undergoing routine UDS were eligible for study inclusion. At the completion of UDS, the instillation port of the 6-French dual-lumen UDS catheter was connected to the CM or CEM. Bladder parameters were simultaneously recorded using the device and UDS during bladder emptying. Correlative statistics were calculated. RESULTS: A total of 36 patients (30 children/6 adults; age range from 1.2 to 38 years [median: 7.5 years]) underwent CM testing. Strong pressure correlation with UDS was identified (R2 = 0.89). A total of 42 patients (30 children/12 adults; age range of 2.9-85.2 years [median: 12.2 years]) underwent CEM testing. Again, strong pressure correlation was found (R2 = 0.77). Cystoelastometer volume measurements were highly correlated with measured volumes (Fig. 4, R2 = 0.98). DISCUSSION: Both the CM and CEM functioned well and transmitted the data wirelessly to a smartphone. The data from these devices were strongly correlated with simultaneous data from the UDS. A limitation is that these devices were used by healthcare providers, and therefore, use by patients or their parents/caregivers at home has not been demonstrated. CONCLUSION: The CM and CEM devices provide accurate bladder pressure and volume measurements. The potential for improved patient monitoring and care is promising. Reliability testing and the effects of such monitoring on patient outcomes remain to be determined.

Obesity diminishes response to PD-1-based immunotherapies in renal cancer.

BACKGROUND: Obesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes. METHODS: We investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, 'BMI' ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString. RESULTS: With obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1ß in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors. CONCLUSIONS: We find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1ß levels, highlighting the need for continued study of this critical issue.