A Decade of Robotic-Assisted Radical Nephrectomy with Inferior Vena Cava Thrombectomy: A Systematic Review and Meta-Analysis of Perioperative Outcomes.

PURPOSE: Open radical nephrectomy with inferior vena cava thrombectomy (O-CT) is standard management for renal cell carcinoma with inferior vena cava thrombus. First reported a decade ago, robotic-assisted radical nephrectomy with inferior vena cava thrombectomy (R-CT) is a minimally invasive option for this disease. We aimed to perform a systematic review to assess the safety and feasibility of R-CT in terms of perioperative outcomes and compare the outcomes between R-CT and O-CT. MATERIALS AND METHODS: The PubMed®, Scopus®, Cochrane Central Register of Controlled Trials and Web of ScienceTM databases were searched using the free-text and MeSH terms "renal cell carcinoma," "inferior vena cava," "thrombosis" or "thrombus," "robot" and "thrombectomy." Studies reporting perioperative outcomes of R-CT and studies comparing R-CT with O-CT were included. The review was done in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: The search retrieved 28 articles describing R-CT, including 7 comparative studies. This systematic review included 1,375 patients, out of which 329 patients were in single-arm studies and 1,046 patients were in comparative studies. Of the 329 patients who underwent R-CT, 14.7% were level I, 60.9% level II, 20.4% level III and 2.5% level IV thrombus. Operative time ranged from 150 to 530 minutes; blood transfusion was administered in 38.2% (126). The overall complication rate was 30.3% (99). R-CT, in comparison to O-CT, was associated with a lower blood transfusion rate (18.4% vs 64.3%, p=0.002) and a lower complication rate (14.5% vs 36.7%, p=0.005). Major complication and 30-day mortality rates were similar in both groups. CONCLUSIONS: R-CT has acceptable perioperative outcomes in carefully selected patients. Compared with O-CT, R-CT is associated with a lower blood transfusion rate and fewer overall complications. In experienced hands with carefully selected patients, R-CT is feasible and safe, with acceptable outcomes; however, selection bias limits definitive inference of these results, and optimal patient selection criteria remain to be described.

Syngeneic murine model for prostate cancer using RM1 cells transfected with gp100.

BACKGROUND: Prostate cancer (PC) is the most commonly diagnosed solid tumor in men. A major challenge in PC immunotherapy is the lack of an animal model that resembles human adenocarcinoma and allows for manipulation or monitoring of the immune response. Mouse models are needed for preclinical testing of new immunotherapies, whether used alone or in combination with established drugs, and to develop companion biomarkers that can be validated in clinical trials. METHODS: To develop a syngeneic prostate adenocarcinoma model with a well-defined tumor antigen, murine RM1 PC cells were transfected with the endogenous mouse melanoma protein, gp100 (RM1-gp100). Gp100 was attractive because it is a self-protein and it instantly allowed us to use the large trove of immune research tools developed for melanoma research. A dendritic cell (DC) vaccine was used as model immunotherapy to demonstrate that adoptive immunotherapy against gp100 decreases the growth of RM1-gp100 but not RM1. RESULTS: Expressing gp100 did not change the growth of RM1 cell in vitro or in vivo. The DCs pulsed with RM1-gp100 could be used to stimulate Pmel-1 lymphocyte proliferation and activation. Pmel-1 lymphocytes could be adoptively transferred into C57Bl/6 mice that were treated with DCs pulsed with RM1-gp100. The resulting Pmel-1 lymphocytes were monitored to assess the primary cellular immune response and memory response. CONCLUSION: We describe a murine model for prostate adenocarcinoma with a well-characterized antigen that can be used in an immunologically intact mice to monitor the temporal CD8+ lymphocyte-mediated antitumor immunity.

Downregulation of CENPF Remodels Prostate Cancer Cells and Alters Cellular Metabolism.

Metabolic alterations in prostate cancer (PC) are associated with progression and aggressiveness. However, the underlying mechanisms behind PC metabolic functions are unknown. The authors' group recently reported on the important role of centromere protein F (CENPF), a protein associated with the centromere-kinetochore complex and chromosomal segregation during mitosis, in PC MRI visibility. This study focuses on discerning the role of CENPF in metabolic perturbation in human PC3 cells. A series of bioinformatics analyses shows that CENPF is one gene that is strongly associated with aggressive PC and that its expression is positively correlated with metastasis. By identifying and reconstructing the CENPF network, additional associations with lipid regulation are found. Further untargeted metabolomics analysis using gas chromatography-time-of-flight-mass spectrometry reveals that silencing of CENPF alters the global metabolic profiles of PC cells and inhibits cell proliferation, which suggests that CENPF may be a critical regulator of PC metabolism. These findings provide useful scientific insights that can be applied in future studies investigating potential targets for PC treatment.

Development of a Nationally Representative Coordinated Registry Network for Prostate Ablation Technologies.

PURPOSE: The accumulation of data through a prospective, multicenter coordinated registry network is a practical way to gather real world evidence on the performance of novel prostate ablation technologies. Urological oncologists, targeted biopsy experts, industry representatives and representatives of the FDA (Food and Drug Administration) convened to discuss the role, feasibility and important data elements of a coordinated registry network to assess new and existing prostate ablation technologies. MATERIALS AND METHODS: A multiround Delphi consensus approach was performed which included the opinion of 15 expert urologists, representatives of the FDA and leadership from high intensity focused ultrasound device manufacturers. Stakeholders provided input in 3 consecutive rounds with conference calls following each round to obtain consensus on remaining items. Participants agreed that these elements initially developed for high intensity focused ultrasound are compatible with other prostate ablation technologies. Coordinated registry network elements were reviewed and supplemented with data elements from the FDA common study metrics. RESULTS: The working group reached consensus on capturing specific patient demographics, treatment details, oncologic outcomes, functional outcomes and complications. Validated health related quality of life questionnaires were selected to capture patient reported outcomes, including the IIEF-5 (International Index of Erectile Function-5), the I-PSS (International Prostate Symptom Score), the EPIC-26 (Expanded Prostate Cancer Index Composite-26) and the MSHQ-EjD (Male Sexual Health Questionnaire for Ejaculatory Dysfunction). Group consensus was to obtain followup multiparametric magnetic resonance imaging and prostate biopsy approximately 12 months after ablation with additional imaging or biopsy performed as clinically indicated. CONCLUSIONS: A national prostate ablation coordinated registry network brings forth vital practice pattern and outcomes data for this emerging treatment paradigm in the United States. Our multiple stakeholder consensus identifies critical elements to evaluate new and existing energy modalities and devices.

Decipher test impacts decision making among patients considering adjuvant and salvage treatment after radical prostatectomy: Interim results from the Multicenter Prospective PRO-IMPACT study.

BACKGROUND: Patients with prostate cancer and their providers face uncertainty as they consider adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) after undergoing radical prostatectomy. The authors prospectively evaluated the impact of the Decipher test, which predicts metastasis risk after radical prostatectomy, on decision making for ART and SRT. METHODS: A total of 150 patients who were considering ART and 115 who were considering SRT were enrolled. Providers submitted a management recommendation before processing the Decipher test and again at the time of receipt of the test results. Patients completed validated surveys on prostate cancer (PCa)-specific decisional effectiveness and PCa-related anxiety. RESULTS: Before the Decipher test, observation was recommended for 89% of patients considering ART and 58% of patients considering SRT. After Decipher testing, 18% (95% confidence interval [95% CI], 12%-25%) of treatment recommendations changed in the ART arm, including 31% among high-risk patients; and 32% (95% CI, 24%-42%) of management recommendations changed in the salvage arm, including 56% among high-risk patients. Decisional Conflict Scale (DCS) scores were better after viewing Decipher test results (ART arm: median DCS before Decipher, 25 and after Decipher, 19 [P<.001]; SRT arm: median DCS before Decipher, 27 and after Decipher, 23 [P<.001]). PCa-specific anxiety changed after Decipher testing; fear of PCa disease recurrence in the ART arm (P = .02) and PCa-specific anxiety in the SRT arm (P = .05) decreased significantly among low-risk patients. Decipher results reported per 5% increase in 5-year metastasis probability were associated with the decision to pursue ART (odds ratio, 1.48; 95% CI, 1.19-1.85) and SRT (odds ratio, 1.41; 95% CI, 1.09-1.81) in multivariable logistic regression analysis. CONCLUSIONS: Knowledge of Decipher test results was associated with treatment decision making and improved decisional effectiveness among men with PCa who were considering ART and SRT. Cancer 2017;123:2850-59. © 2017 American Cancer Society.

Adjuvant treatment for renal cell carcinoma: do we finally have a major breakthrough?

Clinical parameters can be used to identify patients at greatest risk for recurrence following nephrectomy for clinically localized renal cell carcinoma (RCC). Molecular tools are being developed to improve risk stratification. An increasing list of available treatments for metastatic RCC continues to provide hope that an effective adjuvant therapy will be identified for patients with high-risk, clinically localized disease. In a phase 3 adjuvant therapy trial (S-TRAC), sunitinib increased median disease-free survival in patients with clear cell RCC who were at very high risk. This is the first positive phase 3 adjuvant therapy trial using a targeted therapy. However, a much larger phase 3 trial comparing sunitinib, sorafenib, and placebo (ASSURE) was negative. Careful review of recent adjuvant therapy trials reveals insights about who may benefit from adjuvant therapy and provides lessons for future trial design.

Cancer control of partial nephrectomy for high-risk localized renal cell carcinoma: population-based and single-institutional analysis.

PURPOSE: Cancer control of partial nephrectomy for high-risk localized renal cell carcinoma is unclear. To assess whether PN provides adequate cancer control in high-risk disease (HRD), survival outcomes were compared in both a population-based cohort and an institutional cohort. METHODS: Surveillance, Epidemiology, and End Results database and a prospectively maintained institutional database were queried for patients with RCC who underwent PN or RN for a localized tumor ≤7 cm and were found to have high-grade and/or high-stage disease (HRD). Cancer-specific (CSS) or recurrence-free survival (RFS) and overall survival (OS) were primary outcomes measured and were compared between those who underwent PN and RN using multivariable Cox proportional hazards and propensity analysis. RESULTS: The population cohort consisted of 12,757 (24.9 %) patients with HRD, 85.2 and 14.8 % of which underwent RN and PN, respectively. RN was not associated with CSS (HR 1.23, p = 0.08) but was independently associated with poor OS (HR 1.16, p = 0.031). Propensity analysis showed that RN resulted in a 20 % increased risk of death from all causes (p = 0.008). In the institutional cohort, of 317 patients, 35.9 % had HRD, 56 and 52 of which underwent RN and PN, respectively. Adjusting for age-adjusted Charlson index, RN was a predictor of poor OS (OR 6.20, p = 0.041). Propensity analysis showed that RFS and OS were not related to nephrectomy type (RN HR 0.65, p = 0.627 and RN HR 1.70, p = 0.484). CONCLUSIONS: In patients with pathologic high-risk RCC, partial excision is associated with similar cancer control as compared to radical excision.

Impact of post prostate biopsy hemorrhage on multiparametric magnetic resonance imaging.

INTRODUCTION: Hemorrhage induced by prostate biopsy can interfere with the interpretation of prostate magnetic resonance imaging (MRI). MATERIALS AND METHODS: We reviewed 101 patients who had prostate multiparametric MRI (MP-MRI) and radical prostatectomy. RESULTS: On MRI obtained within 4 weeks following the biopsy, hemorrhage was seen in 26/36 (72.2%) patients. Patients having a MRI between 4-6 weeks of the biopsy had hemorrhage in 8/14 (57.1%) cases. After 6 weeks, hemorrhage was less common but still present in 24/46 (52%) patients. There were five patients who had prostate MRI prior to biopsy and served as a control group. There was no significant correlation between the length of time beyond 6 weeks and the likelihood of having prostate hemorrhage on MRI. The overall sensitivity and specificity of MRI for predicting extracapsular extension (ECE) were 78.6% and 89%, respectively. However, if the analysis was limited to patients with MRI within 6 weeks from the time of biopsy, the sensitivity and specificity were similar: 80% and 90%, respectively. For patients with MRI obtained after 6 weeks, the sensitivity and specificity were 76.9% and 87.9%. CONCLUSIONS: Prostate hemorrhage is seen in the majority of cases within 6 weeks of biopsy and can be seen in nearly half the patients even beyond 6 weeks. However, hemorrhage within 6 weeks of a biopsy does not interfere with assessment for ECE.

Whole-Transcriptome profiling of formalin-fixed, paraffin-embedded renal cell carcinoma by RNA-seq.

BACKGROUND: Formalin-fixed paraffin-embedded (FFPE) tissue samples are routinely archived in the course of patient care and can be linked to clinical outcomes with long-term follow-up. However, FFPE tissues have degraded RNA which poses challenges for analyzing gene expression. Next-generation sequencing (NGS) is rapidly becoming accepted as an effective tool for measuring gene expressions for research and clinical use. However, the feasibility of NGS has not been firmly established when using FFPE tissue. RESULTS: We optimized strategies for whole transcriptome sequencing (RNA-seq) using FFPE tissue. Ribosomal RNA (rRNA) was successfully depleted by competitive hybridization using the Ribo-zero™ Kit (Epicentre Biotechnologies), and rRNA sequence content was less than one percent for each library. Gene expression measured by FFPE RNA-seq was compared to two different standards: RNA-seq from fresh frozen (FF) tissue and quantitative PCR (qPCR). Both FF and FFPE tumors were sequenced on an Illumina Genome Analyzer IIX with an average of 10 million reads. The distribution of FPKMs (fragments per kilobase of exon per million fragments mapped) and number of detected genes were similar between FFPE and FF. RNA-seq expressions from FF and FFPE samples from the same renal cell carcinoma (RCC) correlated highly (r = 0.919 for tumor 1 and r = 0.954 for tumor 2). On hierarchical cluster analysis, samples clustered by patient identity rather than method of preservation. TaqMan qPCR of 424 RCC-related genes correlated highly with FFPE RNA-seq expressions (r = 0.775 for FFPE tumor 1, r = 0.803 for FFPE tumor 2). Expression fold changes were considered, to assess biologic relevance of gene expressions. Expression fold changes between FFPE tumors (tumor 1/tumor 2) correlated well when comparing qPCR and RNA-seq (r = 0.890). Expression fold changes between tumors from different risk groups (our high risk RCC/The Cancer Genome Atlas, TCGA, low risk RCC) also correlated well when comparing RNA-seq from FF and FFPE tumors (r = 0.887). CONCLUSIONS: FFPE RNA-seq provides reliable genes expression data, comparable to that obtained from fresh frozen tissue. It represents a useful tool for discovery and validation of biomarkers.

Disparities With Systemic Therapies for Black Men Having Advanced Prostate Cancer: Where Do We Stand?

PURPOSE: Prostate cancer represents the most common cancer diagnosis in Black men and is the second leading cause of cancer death in this population. Multilevel disparities have been well-documented in Black men with prostate cancer and play a role in poorer survival outcomes when compared with White men with prostate cancer. In this review, we highlight the changing trend in disparities for systemic therapy outcomes in Black men diagnosed with metastatic prostate cancer. METHODS: We reviewed data from real-world registries and prospective clinical trials with a particular focus on equal access settings to compare outcomes to systemic therapies between Black and White men with metastatic prostate cancer. RESULTS: In metastatic prostate cancer, there is growing evidence to suggest that Black men may have similar, if not better, outcomes to systemic therapies than White men with advanced disease, as corroborated by prospective studies and clinical trials where health care delivery and follow-up are more likely to be standardized. CONCLUSION: This review illustrates the importance of nonbiological drivers of racial disparities in Black men with advanced prostate cancer. Mitigating barriers to health care access and delivery as well as including participation in clinical trials will be pivotal to ongoing efforts to address disparities in systemic therapy outcomes for Black men with metastatic prostate cancer.

High-resolution Diffusion-weighted Imaging to Detect Changes in Tumor Size and ADC, and Predict Adverse Biopsy Histology during Prostate Cancer Active Surveillance.

PURPOSE: Majority of men with low-risk prostate cancer can be managed with active surveillance (AS). This study evaluates a high-resolution diffusion-weighted imaging (HR-DWI) technique to predict adverse biopsy histology (AH), defined as Gleason score ≥7 on any biopsy or ≥3 increase in number of positive biopsy cores on systematic biopsies. We test the hypothesis that high-grade disease and progressing disease undergo subtle changes during even short intervals that can be detected by HR-DWI. EXPERIMENTAL DESIGN: In a prospective clinical trial, serial multiparametric MRIs, incorporating HR-DWI and standard DWI (S-DWI) were performed approximately 12 months apart prior to prostate biopsy (n = 59). HR-DWI, which uses reduced field-of-view and motion compensation techniques, was compared with S-DWI. RESULTS: HR-DWI had a 3-fold improvement in spacial resolution compared with S-DWI as confirmed using imaging phantoms. For detecting AH, multiparametric MRI using HR-DWI had a sensitivity of 75% and specificity of 83.9%, and MRI using S-DWI had a sensitivity of 71.4% and specificity of 54.8%. The AUC for HR-DWI was significantly higher (0.794 vs. 0.631, P = 0.014). Secondary analyses of univariable predictors of AH showed tumor size increase [OR 16.8; 95% confidence interval (CI): 4.06-69.48; P < 0.001] and apparent diffusion coefficient (ADC) decrease (OR 5.06; 95% CI: 1.39-18.38; P = 0.014) on HR-DWI were significant predictors of AH. CONCLUSION: HR-DWI outperforms S-DWI in predicting AH. Patient with AH have tumors that change in size and ADC that could be detected using HR-DWI. Future studies with longer follow-up should assess HR-DWI for predicting disease progression during AS. SIGNIFICANCE: We report on a prospective clinical trial using a MRI that has three times the resolution of standard MRI. During AS for prostate cancer, two high-resolution MRIs performed approximately a year apart can detect tumor changes that predict the presence of aggressive cancers that should be considered for curative therapy such as prostatectomy or radiation.

Optical imaging of kidney cancer with novel near infrared heptamethine carbocyanine fluorescent dyes.

PURPOSE: We assessed the application of near infrared heptamethine carbocyanine dyes, including IR-783 and the synthetic analogue MHI-148, as optical imaging agents for the rapid detection of human kidney cancer. MATERIALS AND METHODS: The uptake, retention and subcellular localization of these organic dyes were investigated in cultured kidney cancer cells. Tumor specificity of dye uptake and retention was evaluated by whole body imaging of mice bearing human kidney cancer xenografts or freshly harvested clinical kidney cancer specimens. In addition, dye accumulation at the tissue and cellular levels was confirmed by ex vivo studies with results confirmed by fluorescence imaging of frozen tissue sections. Peripheral blood spiked with kidney cancer cells was stained to simulate the detection of circulating tumor cells. RESULTS: Preferential uptake and retention of carbocyanine near infrared dyes was observed in cultured human kidney cancer cells, human kidney cancer cell spiked whole blood, human kidney cancer xenografts and freshly harvested human kidney cancer tissues compared to normal kidney epithelial cells and normal host organs. CONCLUSIONS: We describe a new class of near infrared heptamethine carbocyanine dyes that show potential for detecting kidney cancer cells in circulating blood and kidney cancer cells in clinical specimens. Near infrared carbocyanine dyes can be further developed as dual modality agents for deep tissue imaging of localized and disseminated kidney cancer in patients.

The potential role for neoadjuvant therapy in renal cell carcinoma.

Surgical resection remains the standard of care for clini- cally localized renal cell carcinoma (RCC). Nearly 1 in 4 patients will have a recurrence after surgery performed with curative intent, and stand to benefit from additional therapy. Currently, no proven adjuvant or neoadjuvant therapies are available. A number of phase 3 adjuvant therapy trials are ongoing that are evaluating small-molecule drugs approved for metastatic RCC. The outcomes of these trials may provide insights for designing future phase 3 neoadjuvant therapy trials. Several phase 2 neoadjuvant trials for RCC have recently been completed or are ongoing. These trials have established the safety and response rates associated with several agents, and will pave the way for future phase 3 trials of neoadjuvant therapy for RCC. Neoadjuvant therapies may be useful for decreasing the risk of recurrence after surgery, maximiz- ing nephron sparing, and evaluating molecular effects of targeted therapies in human tumors.

Stimulation of antitumor immunity by FoxP3-targeting PROTAC.

CD4 + regulatory T cells (Tregs) play a central role in regulating and suppressing anti-tumor immune responses. FoxP3 is a transcription factor and master regulator of the Treg lineage. We developed and characterized a proteolysis targeting chimeric (PROTAC) drug that targets FoxP3 (PF). PF was created by linking the FoxP3 binding peptide P60 to pomalidomide, a ligand for E3 ligase. Ternary complex formation between PF, FoxP3, and cereblon (component of an E3 ligase) was confirmed using surface plasmon resonance assay (cooperativity factor of 2.27). PF decreased mouse and human FoxP3 expression in vitro in a proteasome-dependent manner. In mice, PF decreased FoxP3 in both the spleen and peripheral lymphocytes. PF-treated lymphocytes (human or mice) were better at stimulating CD8 + lymphocyte proliferation and activation. PF treatment decreased RENCA tumor growth in mice. PF enhanced antitumor immunity associated with αPD1 or mTOR inhibitor (mTORi). Lymphocytes from mice treated with PF and mTORi showed reduced metastatic tumor growth in untreated mice, providing further evidence for an adaptive immune response as the mechanism of action. We showed that PF binds FoxP3 and decreases FoxP3 expression in Tregs, reducing Treg function and generating antitumor immunity.

PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer by increasing immune infiltration.

Antitumor immunity requires lymphocytes to localize to the tumor. Prostate cancers (PCs) are immunologically cold and tend to lack T-cell infiltration. Most advanced PCs are insensitive to PD1 blockade therapies. Using syngeneic RM1 prostate tumors, p21-activated kinase-4 (PAK4) knockdown (KD) and pharmacological inhibition was assessed in C57BL/6J mice treated with PD1 antibodies (αPD1). RNASeq was used to characterize the immune response in the tumor. Immunohistochemistry, flow cytometry, and in vivo blocking studies confirmed the role of cell surface proteins in the generation of immune responses. In The Cancer Genome Atlas, PAK4 expression was inversely correlated with immune cell infiltration. PAK4 expression was controlled by the androgen receptor and its pioneering factor, FOXA1. PAK4 KD increased CD8+ T-cell infiltration and expression of IFNγ response genes. PAK4 KD also upregulated angiogenesis and endothelial cell adhesion molecules in the tumor microenvironment, contributing to CD8+ lymphocyte recruitment. Pharmacological inhibition of PAK4 made PC more responsive to immunotherapy with αPD1. A decrease in PAK4 activity increases immune activation and vascularity, which increases CD8+ lymphocyte infiltration into the tumor. Therefore, targeting PAK4 may improve the response of human PC to immunotherapy.

A Phase 2, Double-blind, Randomized Controlled Trial of PROSTVAC in Prostate Cancer Patients on Active Surveillance.

BACKGROUND: There is an unmet clinical need for interventions to prevent disease progression in patients with localized prostate cancer on active surveillance (AS). OBJECTIVE: To determine the immunologic response to the PROSTVAC vaccine and the clinical indicators of disease progression in patients with localized prostate cancer on AS. DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized controlled trial in 154 men with low- or intermediate-risk prostate cancer on AS. INTERVENTION: Participants were randomized (2:1) to receive seven doses of subcutaneous PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy containing a prostate-specific antigen (PSA) transgene and three T-cell co-stimulatory molecules, or an empty fowlpox vector (EV) over 140 d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the change from baseline in CD4 and CD8 T-cell infiltration in biopsy tumor tissue. Key secondary outcomes were safety and changes in prostate biopsy tumor pathology, peripheral antigen-specific T cells, and serum PSA. Continuous variables were compared using nonparametric tests. Categorical variables were compared using Fisher's exact test. RESULTS AND LIMITATIONS: The PROSTVAC/EV vaccination was well tolerated. All except one participant completed the vaccination series. Changes in CD4 or CD8 density in biopsy tumor tissue did not differ between the PROSTVAC and EV arms. The proportions of patients with Gleason upgrading to grade group 3 after treatment was similar between the arms. There were no differences in postvaccination peripheral T-cell responses or the PSA change from baseline to 6-mo post-treatment follow-up between the groups. CONCLUSIONS: In this first-of-kind trial of immunotherapy in patients on AS for prostate cancer, PROSTVAC did not elicit more favorable prostate tissue or peripheral T-cell responses than the EV. There was no difference between the arms in clinicopathologic effects. Despite the null findings, this is the first study reporting the feasibility and acceptability of an immunotherapy intervention in the AS setting. PATIENT SUMMARY: We looked at responses after an experimental prostate cancer vaccine in patients with prostate cancer on active surveillance (AS). Participants who received the vaccine did not show more favorable outcomes than those receiving the control. Despite these findings, this is the first report showing the feasibility and acceptability of immunotherapy for prostate cancer in patients on AS.

Pattern recognition scavenger receptor CD204 attenuates Toll-like receptor 4-induced NF-kappaB activation by directly inhibiting ubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6.

The collaboration and cross-talk between different classes of innate pattern recognition receptors are crucial for a well coordinated inflammatory response and host defense. Here we report a previously unrecognized role of scavenger receptor A (SRA; also known as CD204) as a signaling regulator in the context of Toll-like receptor 4 (TLR4) activation. We show that SRA/CD204 deficiency leads to greater sensitivity to LPS-induced endotoxic shock. SRA/CD204 down-regulates inflammatory gene expression in dendritic cells by suppressing TLR4-induced activation of the transcription factor NF-κB. For the first time, we demonstrate that SRA/CD204 executes its regulatory functions by directly interacting with the TRAF-C domain of TNF receptor-associated factor 6 (TRAF6), resulting in inhibition of TRAF6 dimerization and ubiquitination. The attenuation of NF-κB activity by SRA/CD204 is independent of its ligand-binding domain, indicating that the signaling-regulatory feature of SRA/CD204 can be uncoupled from its conventional endocytic functions. Collectively, we have identified the molecular linkage between SRA/CD204 and the TLR4 signaling pathways, and our results reveal a novel mechanism by which a non-TLR pattern recognition receptor restricts TLR4 activation and consequent inflammatory response.