Neoadjuvant androgen deprivation therapy with or without Fc-enhanced non-fucosylated anti-CTLA-4 (BMS-986218) in high risk localized prostate cancer: a randomized phase 1 trial.

Men with high-risk localized prostate cancer exhibit high rates of post-surgical recurrence. In these patients, androgen deprivation therapy (ADT) is immunomodulatory, however increased infiltration of regulatory T cells (Tregs) may limit the antitumor immune effects of ADT. We designed a neoadjuvant clinical trial to test whether BMS-986218 - a next-generation non-fucosylated anti-CTLA-4 antibody engineered for enhanced antibody-dependent cellular cytotoxicity or phagocytosis (ADCC/P) - depletes intratumoral Tregs and augments the response to ADT. In this single-center, two-arm, open-label study, 24 men with high-risk localized prostate cancer were randomized to receive a single dose of ADT with or without two pre-operative doses of BMS-986218 (anti-CTLA4-NF) prior to radical prostatectomy. Treatment was well tolerated and feasible in the neoadjuvant setting. A secondary clinical outcome was the rate of disease recurrence, which was lower than predicted in both arms. Mechanistically, anti-CTLA4-NF reduced ADT-induced Treg accumulation through engagement of CD16a/FCGR3A on tumor macrophages, and depth of Treg depletion was quantitatively associated with clinical outcome. Increased intratumoral dendritic cell (DC) frequencies also associated with lack of recurrence, and pre-clinical data suggest ADCC/P-competent anti-CTLA-4 antibodies elicit activation and expansion of tumor DCs. Patients receiving anti-CTLA4-NF also exhibited phenotypic signatures of enhanced antitumor T cell priming. In total, this study provides the first-in-human evidence of Treg depletion by glycoengineered antibodies targeting CTLA-4 in humans and their potential in combination with ADT in prostate cancer patients with high-risk of recurrence.

A population-based analysis of risk factors and outcomes of prostatic abscess.

BACKGROUND: Prostate abscess is a severe complication of acute bacterial prostatitis. To date, a population-based analysis of risk factors and outcomes of prostatic abscess has not been performed. METHODS: Using the National Inpatient Sample from 2010 to 2015, we identified rates of prostatic abscess among non-elective hospitalizations for acute prostatitis. Significant Elixhauser comorbidities and risk factors were analyzed using survey-weighted logistic regression. Additional survey-weighted regression models were constructed to analyze sepsis, in-hospital mortality, length of hospital stay (LOS), and total hospital charges. RESULTS: A weighted total of 126,103 hospitalizations for acute prostatitis was identified, with 6,775 (5.4%) hospitalizations with prostatic abscess. Numerous risk factors for prostatic abscess were identified, with a history of prostate biopsy (adjusted OR: 5.7; p < 0.001), complicated diabetes mellitus (adjusted OR: 3.23, p < 0.001), and urethral stricture (adjusted OR: 3.15; p < 0.001) having the greatest magnitude of developing abscess. Moreover, those diagnosed with prostatic abscess had increased odds of sepsis (adjusted OR: 1.71, p < 0.001), in-hospital mortality (adjusted OR: 2.73, p < 0.001), LOS (adjusted Incidence Rate Ratio: 1.86, p < 0.001), and total hospital charges (adjusted Ratio: 2.06, p < 0.001). CONCLUSIONS: Numerous risk factors were associated with the development of prostatic abscess, with those diagnosed experiencing greater odds of sepsis, in-hospital mortality, longer LOS, and greater hospital charges. Ultimately, better understanding of risk factors associated with this condition will enable clinicians to identify patients at high risk, thereby expediting and tailoring management.

Collecting duct carcinoma of the kidney: Disease characteristics and treatment outcomes from the National Cancer Database.

OBJECTIVE: To use a large population-level database to assess survival outcomes for collecting duct renal cell carcinoma (CDRCC). MATERIALS AND METHODS: The National Cancer Database was queried for all cases of CDRCC and clear cell renal cell carcinoma (CCRCC) from 2004 to 2013. After removing patients with other cancer diagnoses, the analytic cohort was composed of 201,686 CCRCC and 577 CDRCC cases. Kaplan-Meier and cox proportional hazards analysis were employed to model survival. RESULTS: Compared to CCRCC, patients with CDRCC presented with higher grade and stage, node positive, and metastatic disease (70.7% vs. 30.0% with metastasis; P<0.001). Overall median survival for CDRCC was 13.2 months (95% CI: 11.0-15.5) compared to the 122.5 months (95% CI: 121.0-123.9) for CCRCC. On multivariate analysis of the CDRCC cohort, increasing T stage, high-grade disease, and metastasis were predictors of mortality. Of 184 patients with metastatic CDRCC, 113 underwent cytoreductive nephrectomy (CNx) whereas the rest were treated with chemo/radiation or observed. Survival outcomes were improved in patients who received both CNx with chemo/radiation compared to CNx alone (hazard ratio = 0.51, 95% CI: 0.32-0.79) or chemo/radiation alone (hazard ratio = 0.57, 95% CI: 0.37-0.89) on multivariate analysis. CONCLUSION: CDRCC is an aggressive subtype of renal cell carcinoma. Median survival is 13 months after diagnosis, drastically lower than for CCRCC. More than 70% of patients have metastatic disease at diagnosis. Chemo/radiation in addition to CNx is associated with a survival benefit over single mode therapy.

Synchronous cryoablation of multiple renal lesions: short-term follow-up of patient outcomes.

OBJECTIVES: To report on various perioperative and short-term clinical outcomes of 7 patients who underwent cryoablation of multiple renal lesions during the same operative setting. Cryotherapy is the most well studied minimally invasive ablative technique for the treatment of renal tumors. METHODS: A retrospective analysis of our institutional renal cryotherapy database yielded a total of 7 patients who underwent synchronous cryoablation of > 1 renal lesion between August 2005 and May 2007. RESULTS: Mean patient age was 63.9 years, and median follow-up was 23.3 months (range 7-28 months). Five patients had ablation of 2 renal lesions, 1 had 3 lesions, and 1 had 4 lesions. The mean greatest diameter of any single lesion was 2.0 cm (range 0.7-7.5 cm). Mean preoperative serum creatinine was 1.5 mg/dL (range 0.7-3.6 mg/dL), which increased to a mean of 1.7 mg/dL (range 0.7-3.6) at last follow-up. Mean estimated blood loss was 138 mL (range 38-300 mL). There were 2 complications--ureteral stenting because of postoperative renal colic, and blood transfusion for decreased hematocrit. Of the 17 lesions, 7 were found to be conventional renal cell carcinoma, 4 papillary, 2 myelolipoma, and 1 oncocytoma (unavailable for 3 lesions). Mean length of hospital stay was 2.3 days (range 1-6 days). At last follow-up, computed tomography scanning demonstrated no recurrences in any patient. CONCLUSIONS: Cryoablation of multiple renal lesions at one setting may be successfully performed with few complications, with minimal short-term loss of renal function as estimated by serum creatinine, and with short-term evidence of tumor destruction.