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.

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.

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.

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.

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.

An Alternative Option for Gender-Affirming Revision Vaginoplasty: The Tubularized Urachus-Peritoneal Hinge Flap.

INTRODUCTION: Gender-affirming peritoneal vaginoplasty has been described, and previous descriptions are modifications of the Davydov technique. AIM: To describe our alternative technique for gender-affirming peritoneal vaginoplasty (PV) using a single-pedicled, urachus-peritoneal hinge flap, discussing proposed advantages. METHODS: Retrospective review of all consecutive transfeminine patients with neovaginal shortening after prior penile inversion vaginoplasty (PIV) who underwent our PV technique from May 2019 to July 2022.  PV was performed via combined transperineal and laparoscopic (robot-assisted) approaches. After spatulation of the neovaginal remnant, a midline, inferiorly based urachus-peritoneal hinge flap was elevated craniocaudally from the umbilicus to the mid-posterior bladder. The free end of the flap was flipped posteriorly and sutured to posterior edge of the open canal remnant, forming a peritoneal pouch. The lateral edges of the pouch were sutured together for water-tight closure. Patients resumed dilation on POD 6 and douching on POD 10. MAIN OUTCOME MEASURES: Ten transfeminine patients underwent PV, with good outcomes. We measured: Pre-op penile and scrotal skin lengths, intra-op tubularized scrotal skin length, pre and post-op vaginal depth and width (immediate and at last follow-up). RESULTS: Pre-op: mean neovaginal depth was 9.2cm (SD 1.5); width was 12cm. Immediate post-op: mean depth was 15.1 cm (SD 2.2 cm, mean net increase: 5.9 cm). At mean follow-up of 18.3 months, mean depth was 12.5 cm (SD 2.1 cm, mean net increase: 3.3 cm) and width was 12 cm. There were no immediate post-op complications. Eight (80%) of the 10 patients report satisfactory vaginal receptive intercourse. The other 2 have not yet attempted vaginal receptive intercourse. CLINICAL IMPLICATIONS: Advantages of the proposed technique over existing techniques include no tension on peritoneal suture lines and total exclusion of the rectum. STRENGTHS AND LIMITATIONS: Strengths include a short learning curve for urologic surgeons with robotic experience.  The study is limited by small sample size. CONCLUSIONS: Our PV technique is a safe and effective option for salvage peritoneal vaginoplasty after primary PIV. Smith SM, Yuan N, Stelmar J, et al. An Alternative Option for Gender-Affirming Revision Vaginoplasty: The Tubularized Urachus-Peritoneal Hinge Flap. Sex Med 2022;10:100572.

Hypoxia-inducible factor pathway genes predict survival in metastatic clear cell renal cell carcinoma.

PURPOSE: Hypoxia inducible factor (HIF) pathway alterations drive progression of clear cell renal cell carcinoma (ccRCC). We aim to evaluate genes within the canonical and non-canonical HIF pathways as predictors of survival in metastatic ccRCC. MATERIALS AND METHODS: Gene expression was determined from 324 archival pretreatment nephrectomy specimens from CALGB90206, a phase III trial of patients treated with interferon alpha (INF-α) vs. INF-α plus bevacizumab. TaqMan RT-qPCR was performed using RNA from tumors macrodissected based on review by genitourinary pathology. RESULTS: A total of 35 HIF-related genes were assessed by Cox regression analysis. After adjusting for sex and Memorial Sloan Kettering Cancer Center risk score (MSKCC-RS), 11 genes predicted OS: HIF2A (HR 1.059, P = 0.012), EGLN3 (HR 1.089, P = 0.012), VEGFC (HR 0.904, P = 0.039), VEGFD (HR 1.085, P = 0.016), FLT4 (HR 1.093, P = 0.038), CCND1 (HR 1.077, P = 0.026), TGFA (HR 1.127, P = 0.003), EGFR (HR 1.151, P = 0.028), VHL (HR 0.764, P = 0.002), HSP90AA1 (HR 0.845, P = 0.002), and PTEN (HR 1.163, P = 0.050); 7 genes predicted PFS: HIF2A (HR 1.060, P = 0.011), CCND1 (HR 1.082, P = 0.016), TGFA (HR 1.096, P = 0.026), EP300 (HR 1.171, P = 0.031), VHL (HR 0.775, P = 0.007), HSP90AA1 (HR 0.871, P = 0.015), and TP53 (HR 1.119, P = 0.050). Most of these genes validated as significant predictors of survival in the external, TCGA dataset. In multivariate analysis of all externally validated genes, VEGFC (HR 0.906, P = 0.043), TGFA (HR 1.122, P = 0.003), CITED2 (HR 1.113, P = 0.035) and EP300 (HR 1.136, P = 0.049) predicted OS; and HIF2A (HR 1.049, P = 0.036) and EP300 (HR 1.199, P = 0.010) predicted PFS. EGLN3 (HR 1.156, P = 0.045) and BNIP3 (HR 1.254, P = 0.049) significantly interacted with treatment status and predicted PFS in patients treated with IFN-α and IFN-α+bevacizumab, respectively. CONCLUSIONS: We identified specific gene isoforms in both the canonical and non-canonical HIF pathways associated with metastatic RCC survival. EGLN3 and BNIP3 showed significant interaction with treatment arm and may be predictive of treatment response. We have identified genes for future prospective investigation as predictive biomarkers and novel drug targets.

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.

Predictors of disparity between targeted and in-zone systematic cores during transrectal MR/US-fusion prostate biopsy.

BACKGROUND: The combination of targeted and systematic biopsies during MR/US-fusion prostate biopsy improves cancer detection over either modality alone. OBJECTIVE: To identify factors associated with disparity in detection of prostate cancer between systematic and targeted biopsies in magnetic resonance imaging positive zones. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed 171 men receiving initial MR/US fusion biopsy at our institution from 2015 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Disparity was defined as positive targeted but negative systematic biopsy within an magnetic resonance imaging-positive zone (PIRADS 3+), or vice versa. Multivariable logistic regression was used to identify factors associated with disparity in detection of cancer on a per lesion basis. RESULTS AND LIMITATION: Three hundred and fifty-five lesions were targeted. For any cancer and clinically significant prostate cancer (csPCa), 37 (10%) and 24 (7%) lesions were target positive/systematic negative, respectively, while 30 (8%) and 23 (6%) lesions were target negative/systematic positive. In multivariable analysis, anterior location (OR 4.1, 95% CI 1.5-11.4, P = 0.007) was associated with csPCa target positive/systematic negative disparity, while higher prostate volume (OR 1.14, 95% CI 1.0-1.29, P = 0.04) was associated with csPCa target negative/systematic positive disparity. Shorter distance from apex (OR 1.02, 95% CI 1.01-1.04, P = 0.02) was associated with target positive/systematic negative disparity for any cancer. Limitations included relatively limited sample size and lack of prostatectomy specimen as a gold standard. CONCLUSIONS: Anterior or apical lesion location favors better disease capture on targeted biopsies. When doing systematic-only biopsies, surgeons may consider sampling the anterior zone separately.

Cholesterol-Lowering Intervention Decreases mTOR Complex 2 Signaling and Enhances Antitumor Immunity.

PURPOSE: There is a need for strategies to prevent prostate cancer. Cholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease and has been proposed for chemoprevention. Using preclinical models and a window-of-opportunity clinical trial, we describe an adaptive antitumor immunity resulting from cholesterol lowering. EXPERIMENTAL DESIGN: Statins do not reliably lower serum cholesterol in mice. Therefore, oral ezetimibe was administered to mice to lower serum cholesterol to clinically relevant levels and evaluated the final adaptive immune response. T-lymphocytes-specific mTORC2 knockout mice were used to evaluate mTOR signaling and antitumor immunity. Pretreatment and posttreatment prostate tumors and lymphocytes were examined from a window-of-opportunity clinical trial where men with prostate cancer were treated with 2 to 6 weeks of aggressive cholesterol-lowering intervention prior to radical prostatectomy. RESULTS: Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and had enhanced central CD8+ T-cell memory. In mice and in patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. T-lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In patients, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas. CONCLUSIONS: Lowering serum cholesterol decreased signaling through mTORC2 and enhanced antitumor CD8+ T-cell memory. We provide a rationale for large-scale clinical testing of cholesterol lowering strategies for prostate cancer chemoprevention.

Patient- and tumor-level risk factors for MRI-invisible prostate cancer.

BACKGROUND: Multiparametric MRI is highly sensitive for detection of clinically significant prostate cancer, but has a 10-20% false negative rate. It is unknown if there are clinical factors that predict MRI invisibility. We sought to identify predictors of MRI-invisible (MRI(-)) disease. METHODS: Men undergoing MRI/US-fusion targeted + systematic biopsy by two surgeons at our institution from 2015 to 2018 were reviewed. Patient demographics, clinical data, MRI metrics, and biopsy pathology results were obtained by chart review. An MRI(-) tumor was defined as a positive systematic biopsy in a zone without an MRI lesion. Factors associated with presence of MRI(-) tumors were identified using stepwise multivariable logistic regression. RESULTS: Of 194 men included in the analysis, 79 (41%) and 25 (13%) men had GG1+ and GG2+ MRI(-) tumors, respectively. On multivariable analysis, only Black race was associated with presence of GG1+ MRI(-) tumors (OR 2.2, 95% CI 1.02-4.96). Black race (OR 3.5, 95% CI 1.24-9.87) and higher PSA density (OR 2.0, 95% CI 1.34-3.20) were associated with presence of GG2+ MRI(-) tumors. In non-Black and Black men, detection of MRI(-) tumors on systematic biopsy upgraded patients from no disease to GG2+ disease 1% and 11% of the time, respectively, and from GG1 to GG2+ disease 42% and 60% of the time, respectively. CONCLUSIONS: Black race and PSA density were associated with presence of MRI(-) prostate cancer. Further study on racial differences is warranted based on these results. Surgeons should consider pre-biopsy risk factors before deciding to omit systematic prostate biopsy regardless of mpMRI results.

Robot-Assisted Surgery for Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma is a rare malignancy for which surgery provides definitive management. Open radical nephroureterectomy was the gold standard treatment, but laparoscopic and robot-assisted approaches are alternative options. Kidney-sparing approaches are feasible for carefully selected patients with ureteral cancer. This article discusses the evaluation of patients with upper tract urothelial carcinoma and definitive management using robot-assisted surgical approaches. Patients with urothelial carcinoma of the upper tract can be treated with robot-assisted nephroureterectomy, distal ureterectomy, and segmental ureterectomy.

Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis.

CONTEXT: Multiparametric magnetic resonance imaging (mpMRI) detects most, but not all, clinically significant prostate cancer. The genetic basis of prostate cancer visibility and invisibility on mpMRI remains uncertain. OBJECTIVE: To systematically review the literature on differential gene expression between mpMRI-visible and mpMRI-invisible prostate cancer, and to use bioinformatic analysis to identify enriched processes or cellular components in genes validated in more than one study. EVIDENCE ACQUISITION: We performed a systematic literature search of the Medline, EMBASE, PubMed, and Cochrane databases up to January 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The primary endpoint was differential genetic features between mpMRI-visible and mpMRI-invisible tumours. Secondary endpoints were explanatory links between gene function and mpMRI conspicuity, and the prognostic value of differential gene enrichment. EVIDENCE SYNTHESIS: We retrieved 445 articles, of which 32 met the criteria for inclusion. Thematic synthesis from the included studies showed that mpMRI-visible cancer tended towards enrichment of molecular features associated with increased disease aggressivity, including phosphatase and tensin homologue (PTEN) loss and higher genomic classifier scores, such as Oncotype and Decipher. Three of the included studies had accompanying publicly available data suitable for further bioinformatic analysis. An over-representation analysis of these datasets revealed increased expression of genes associated with extracellular matrix components in mpMRI-visible tumours. CONCLUSIONS: Prostate cancer that is visible on mpMRI is generally enriched with molecular features of tumour development and aggressivity, including activation of proliferative signalling, DNA damage, and inflammatory processes. Additionally, there appears to be concordant cellular components and biological processes associated with mpMRI conspicuity, as highlighted by bioinformatic analysis of large genetic datasets. PATIENT SUMMARY: Prostate cancer that is detected by magnetic resonance imaging (MRI) tends to have genetic features that are associated with more aggressive disease. This suggests that MRI can be used to assess the likelihood of aggressive prostate cancer, based on tumour visibility.

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.

Development and Validation of a Genomic Tool to Predict Seminal Vesicle Invasion in Adenocarcinoma of the Prostate.

PURPOSE: Pretreatment estimates of seminal vesicle invasion (SVI) are challenging and significantly influence the management of prostate cancer. We sought to improve current models to predict SVI through the development of an SVI prediction genomic signature. PATIENTS AND METHODS: A total of 15,889 patients who underwent radical prostatectomy (RP) with available baseline clinical, pathology, and transcriptome data were retrieved from the GRID registry (ClinicalTrials.gov identifier: NCT02609269) and other retrospective cohorts. These data were divided into a training (n = 6,766), test (n = 3,363), and two validation (n = 5,062 and 698) cohorts. Multivariable logistic regression was performed to assess the predictive effect of the genomic SVI (gSVI) classifier in the presence of established nomograms (Partin Tables and Memorial Sloan Kettering Cancer Center [MSKCC]). RESULTS: In the training cohort, univariable filtering identified 2,132 genes that were differentially expressed between RP tumors with and without SVI. Model parameters were tuned to maximize the area under the curve (AUC) in the testing cohort, resulting in a logistic generalized linear model with 581 genes. The gSVI model scores range from 0 to 1. In the first validation set, gSVI showed superior discrimination of patients with and without SVI at RP compared with other prognostic signatures trained to predict distant metastasis or clinical recurrence. Of the 698 patients in the second validation set, gSVI combined with the MSKCC nomogram had a superior AUC (0.86) compared with either nomogram individually (0.81). CONCLUSION: The gSVI represents a novel and validated expression signature to predict the presence of SVI before treatment with surgery. This genomic tool adds discriminatory power to existing clinical predictive nomograms and may help with pretreatment counseling and decision making.

Decipher identifies men with otherwise clinically favorable-intermediate risk disease who may not be good candidates for active surveillance.

BACKGROUND: We aimed to validate Decipher to predict adverse pathology (AP) at radical prostatectomy (RP) in men with National Comprehensive Cancer Network (NCCN) favorable-intermediate risk (F-IR) prostate cancer (PCa), and to better select F-IR candidates for active surveillance (AS). METHODS: In all, 647 patients diagnosed with NCCN very low/low risk (VL/LR) or F-IR prostate cancer were identified from a multi-institutional PCa biopsy database; all underwent RP with complete postoperative clinicopathological information and Decipher genomic risk scores. The performance of all risk assessment tools was evaluated using logistic regression model for the endpoint of AP, defined as grade group 3-5, pT3b or higher, or lymph node invasion. RESULTS: The median age was 61 years (interquartile range 56-66) for 220 patients with NCCN F-IR disease, 53% classified as low-risk by Cancer of the Prostate Risk Assessment (CAPRA 0-2) and 47% as intermediate-risk (CAPRA 3-5). Decipher classified 79%, 13% and 8% of men as low-, intermediate- and high-risk with 13%, 10%, and 41% rate of AP, respectively. Decipher was an independent predictor of AP with an odds ratio of 1.34 per 0.1 unit increased (p value = 0.002) and remained significant when adjusting by CAPRA. Notably, F-IR with Decipher low or intermediate score did not associate with significantly higher odds of AP compared to VL/LR. CONCLUSIONS: NCCN risk groups, including F-IR, are highly heterogeneous and should be replaced with multivariable risk-stratification. In particular, incorporating Decipher may be useful for safely expanding the use of AS in this patient population.

Considerations for the Next Clinical Trial Evaluating the Role of Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma.

Trials SWOG 8949 and EORTC 30947 had the same eligibility criteria and established the role of cytoreductive nephrectomy for metastatic renal cell carcinoma. The more recently published CARMENA trial calls into question the need for cytoreductive nephrectomy. A systematic comparison of CARMENA and SWOG 8949 suggests that cytoreductive nephrectomy may be beneficial for patients receiving immunotherapy but not targeted therapy. The approval of immune checkpoint inhibitors for previously untreated metastatic renal cell carcinoma underlines the need for another randomized phase 3 trial of cytoreductive nephrectomy for patients receiving powerful modern immunotherapies.