Anti-PD-1 immunotherapy with androgen deprivation therapy induces robust immune infiltration in metastatic castration-sensitive prostate cancer.

When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.

A Transcriptome-Based Precision Oncology Platform for Patient-Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies.

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. SIGNIFICANCE: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

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.

A Phase I Trial of Intravesical Cabazitaxel, Gemcitabine and Cisplatin for the Treatment of Nonmuscle Invasive bacillus Calmette-Guérin Unresponsive or Recurrent/Relapsing Urothelial Carcinoma of the Bladder.

PURPOSE: For patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer, multi-agent intravesical trials have been limited. In this study we investigate the safety of intravesical cabazitaxel, gemcitabine and cisplatin in the salvage setting. MATERIALS AND METHODS: This was a dose escalation, drug escalation trial for patients with bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer who declined or were ineligible for radical cystectomy. All patients underwent a 6-week induction regimen of sequentially administered cabazitaxel, gemcitabine and cisplatin. Complete response was defined as no cancer on post-induction transurethral bladder tumor resection and negative urine cytology, while partial response allowed for positive cytology. Responders continued with maintenance cabazitaxel and gemcitabine monthly for the first year and bimonthly for the second year. RESULTS: A total of 18 patients were enrolled. Mean age was 71 years, median followup was 27.8 months (range 16.3 to 46.9) and mean number of previous rounds of intravesical therapies before trial enrollment was 3.7. Nine patients (50%) had received intravesical chemotherapy after bacillus Calmette-Guérin and 7 (39%) were previously treated in a phase I clinical trial setting. At enrollment 6 (33%) subjects had T1 disease and 13 (72%) had carcinoma in situ. There were no dose limiting toxicities. Initial partial and complete response rates were 94% and 89%, respectively. At 1 year recurrence-free survival was 0.83 (range 0.57 to 0.94) and at 2 years estimated recurrence-free survival was 0.64 (0.32 to 0.84). CONCLUSIONS: In this high risk and highly pretreated cohort of bacillus Calmette-Guérin unresponsive or recurrent/relapsing nonmuscle invasive bladder cancer cases combination intravesical cabazitaxel, gemcitabine and cisplatin was a well tolerated and potentially effective regimen.

The Prevalence of Bladder Cancer During Cystoscopy for Asymptomatic Microscopic Hematuria.

OBJECTIVE: To investigate the rate of bladder cancer in patients undergoing cystoscopic evaluation for asymptomatic microscopic hematuria (AMH) in order to identify groups at sufficiently low-risk for bladder cancer in whom invasive testing may be avoided. METHODS: We performed a retrospective review of patients who underwent cystoscopic evaluation for AMH between 2010 and 2018. Age, gender, smoking status, history of pelvic radiation, and number of red blood cells per high-power field on urine microscopy were recorded. We used logistic regression to explore the association between specific risk factors and a diagnosis of bladder cancer on cystoscopy. RESULTS: Among the 2118 patients who underwent cystoscopy for AMH, 25 patients (1.2%) were diagnosed with a bladder cancer, all of which were nonmuscle invasive urothelial carcinoma. There were no bladder cancers detected in patients under the age of 50. Older age and positive smoking history were significantly associated with bladder cancer. CONCLUSION: Bladder cancer was an uncommon finding on cystoscopy among patients being evaluated for AMH, especially in younger patients. We confirmed several known risk factors for bladder cancer, including older age and smoking history. Further studies are required to evaluate the utility of cystoscopy for identifying latent bladder cancers in low-risk patients.

Conservative Management Following Complete Clinical Response to Neoadjuvant Chemotherapy of Muscle Invasive Bladder Cancer: Contemporary Outcomes of a Multi-Institutional Cohort Study.

PURPOSE: We report the outcomes in patients with muscle invasive bladder cancer from 2 institutions who experienced a clinically complete response to neoadjuvant platinum based chemotherapy and elected active surveillance. It was unknown whether conservative treatment could be safely implemented in these patients. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with muscle invasive bladder cancer at our institutions who elected surveillance following a clinically complete response to transurethral resection of bladder tumors and neoadjuvant chemotherapy from 2001 to 2017. A clinically complete response was defined as absent tumor on post-chemotherapy transurethral resection of bladder tumor, negative cytology and normal cross-sectional imaging. RESULTS: In the 148 patients followed a median of 55 months (range 5 to 145) the 5-year disease specific, overall, cystectomy-free and recurrence-free survival rates were 90%, 86%, 76% and 64%, respectively. Of the patients 71 (48%) experienced recurrence in the bladder, including 16 (11%) with muscle invasive disease and 55 (37%) with noninvasive disease. Salvage radical cystectomy prevented cancer specific death in 9 of 12 patients (75%) who underwent cystectomy after muscle invasive relapse and in 13 of 14 (93%) after noninvasive relapse. CONCLUSIONS: We observed high rates of overall and disease specific survival with bladder preservation in patients who achieved a clinically complete response to neoadjuvant chemotherapy. These outcomes support the safety of active surveillance in carefully selected, closely monitored patients with muscle invasive bladder cancer. Future studies should aim to improve patient selection by identifying biomarkers predicting invasive relapse and developing novel imaging methods of early detection.

Outcomes Following Clinical Complete Response to Neoadjuvant Chemotherapy for Muscle-invasive Urothelial Carcinoma of the Bladder in Patients Refusing Radical Cystectomy.

OBJECTIVE: To investigate survival outcomes of patients with muscle-invasive bladder cancer (MIBC) that demonstrate complete clinical response (cT0) to neoadjuvant chemotherapy (NAC) and then reject subsequent radical cystectomy (RC). METHODS: A retrospective chart review identified patients with MIBC who were cT0 after platinum-based NAC. cT0 was defined as negative cytology, cystoscopy with transurethral resection of bladder tumor, and imaging. cT0 patients refusing for RC were followed up with cytology, cystoscopy with biopsy, and cross-sectional imaging. RESULTS: Forty-eight patients were identified with MIBC that were cT0 after NAC. Seven patients underwent immediate RC, whereas 41 elected bladder preservation with close surveillance. Of those remaining 41 patients, mean age was 68 ± 11 years with median follow-up of 35 months. NAC regimens were 46% methotrexate/vinblastine/doxorubicin/cisplatin, 39% gemcitabine/cisplatin, and 15% other platinum-based therapies. Five-year cancer-specific survival was 87%, disease-free survival was 58%, and cystectomy-free survival was 79%. A total of 19 patients (46%) relapsed with 5.4-month median recurrence time. CONCLUSION: Bladder preservation may be a reasonable option in a highly select subset of patients with MIBC who are complete clinical responders after NAC. For those patients that were cT0 after NAC and refused or were ineligible for RC, 5-year disease-free survival was nearly 60% and cancer-specific survival was nearly 90%. Future studies should focus on identifying clinical and molecular factors associated with a durable pathologic complete response after NAC.

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.

Outcomes and Prognostic Factors of Primary Urethral Cancer.

OBJECTIVE: To identify prognostic and treatment factors for primary urethral cancer using a nationwide database. MATERIALS AND METHODS: The National Cancer Database was queried for all cases of primary urethral cancer from 2004 to 2013. Patients with other cancer diagnoses, metastasis, or diagnosis on autopsy were excluded. Proportional hazards regression was used to identify independent predictors of overall survival in patients with primary urethral cancer. Because we hypothesized that predictors may covary by sex, we also performed regression analysis stratified by sex. RESULTS: We identified 1268 men and 869 women with primary urethral cancer. Women tended to have more advanced tumors and adenocarcinoma histology. Median survival for the entire cohort was 49 months (43-55), with 5- and 10-year survival rates of 46% and 31%, respectively. On multivariate analysis, age, race, stage, grade, and Charlson comorbidity index were independent predictors of overall survival. Histology was not a predictor of overall survival in the combined model; however, adenocarcinoma in women increased hazards of death, whereas it decreased hazards of death in men when compared with squamous cell carcinoma. CONCLUSION: Men and women with primary urethral cancer had significant differences in histology, grade, and nodal status. In addition to several expected disease-related factors, black race was associated with increased mortality for patients with primary urethral cancer.

Perioperative blood transfusion in radical cystectomy: Analysis of the National Surgical Quality Improvement Program database.

OBJECTIVES: To determine whether perioperative blood transfusion is associated with worse 30-day postoperative outcomes in radical cystectomy patients. METHODS: Utilizing the National Surgical Quality Improvement Program database, we identified 2934 patients diagnosed with bladder cancer (International Classification of Diseases Ninth Revision codes 188-188.9) who underwent radical cystectomy (Current Procedure Terminology codes 51570, 51575, 51580, 51585, 51590, 51595, 51596) between 2005 and 2013. Patients were stratified by transfusion status and assessed based on four composite postoperative outcomes: morbidity, surgical site infection, mortality and readmission. Multivariate regression models were used to determine significant independent predictors of the composite outcomes. RESULTS: Overall, 40.1% of patients received a transfusion, and there were significant differences in baseline variables such as age, sex, body mass index, smoking history and comorbidities. Transfusion was associated with increased morbidity, surgical site infection, readmission, operative time and length of stay on unadjusted analyses. On multivariate regression, transfusion was associated with increased morbidity (OR 1.361, 95% CI 1.131-1.638) and surgical site infection (OR 1.371, 95% CI 1.070-1.757). CONCLUSIONS: Perioperative blood transfusion is associated with increased risk of postoperative infection and morbidity. Previous work in this area has focused on negative long-term oncological outcomes, but this is the first study to examine short-term postoperative outcomes. Future research should focus on the immunosuppressive mechanism of perioperative blood transfusion and on restrictive transfusion guidelines for oncology patients.

Robotic radical prostatectomy in patients with high-risk disease: a review of short-term outcomes from a high-volume center.

PURPOSE: Patients with high-risk prostate cancer have historically been treated with multimodal therapy and considered poor candidates for minimally invasive surgery. We reviewed our experiences with robot-assisted radical prostatectomy (RARP) in patients with high-risk clinical features. MATERIALS AND METHODS: Clinical database review identified high-risk patients undergoing RARP by two high-volume robotic surgeons. D'Amico's criteria for high-risk prostate cancer were utilized: prostate-specific antigen ≥ 20 ng/mL, clinical stage ≥ T2c, or preoperative Gleason grade ≥ 8. About 148 patients were identified in the study group. Mean age at surgery was 60.9 years, and mean body mass index was 27.9. Mean estimated blood loss was 150 cc and the transfusion rate was 2.7%. Median hospital stay was 1 day and the rate of major complications (Clavien grade ≥ 3) was 3.4%. RESULTS: Bilateral nerve preservation was feasible in 28.4%, and the rate of positive surgical margins was 20.9%. Final pathology demonstrated extra-capsular disease in 54.1% of patients and 12.3% had lymph node involvement. At 2 years of follow-up, 21.3% of patients had experienced biochemical recurrence or had persistent disease after treatment. Continence was 91.2% (1 pad or less) and total impotence (inability to masturbate) was 48.3%. CONCLUSIONS: RARP does not compromise oncologic or functional outcomes in patients with high-risk prostate cancer. Although long-term study is necessary to validate oncologic and functional outcomes, our data suggest that the presence of high-risk disease is not a contraindication to a minimally invasive approach for radical prostatectomy at experienced centers.

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.