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Radionuclide imaging will change the role of computed tomography and magnetic resonance imaging (CT/MRI) for prostate cancer (CaP) staging. Current guidelines recommend abdominopelvic imaging for new cases of CaP categorized as unfavorable intermediate risk (UIR) or higher. We assessed the performance characteristics of CT/MRI based on the National Comprehensive Cancer Network (NCCN) guidelines and developed a model that predicts cN1 disease using conventional imaging.We selected patients in the National Cancer Database diagnosed with CaP from 2010 to 2016 with available age, prostate specific antigen, clinical locoregional staging, biopsy Gleason grading, and core information. Multivariate logistic regression (MLR) was used on a undersampled training dataset using cN1 as the outcome. Performance characteristics were compared to those of the three most recent versions of the NCCN guidelines.A total of 443,640 men were included, and 2.5% had cN1 disease. Using CT/MRI only, the current NCCN guidelines have a sensitivity of 99%, and the number needed to image (NNI) is 24. At the same sensitivity, the cN1 risk was 1.6% using the MLR. The NNI for UIR alone is 341. Using the MLR model and a threshold of 10%, the PPV is 10.3% and 64% of CTs/MRIs could be saved at a cost of missing 6% of cN1 patients (or 0.15% of all patients).The NCCN guidelines are sensitive for detecting cN1 with CT/MRI, however, the number needed to image is 24. Obtaining CT/MRI for nodal staging when patients have a cN1 risk of 10% would reduce total imaging while still remaining sensitive. As novel PET tracers becomes increasingly used for initial CaP staging, well calibrated prediction models trained on the outcome of interest should be developed as decision aids for obtaining imaging.

PDF file 374K, Supplementary Figure 1. Validation of PTEN immunohistochemistry

Purpose: To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia.Experimental Design: Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR.Results: Comparative analyses identified 954 transcript alterations associated with cancer (q < 0.01%), including 149 differentially expressed genes with no known functional roles. Gene expression changes associated with ischemia and surgical removal of the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched in categories related to cellular metabolism, energy use, signal transduction, and molecular transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy.Conclusions: Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.

Supplementary Tables S1-S3 from Molecular Alterations in Prostate Carcinomas that Associate with In vivo Exposure to Chemotherapy: Identification of a Cytoprotective Mechanism Involving Growth Differentiation Factor 15

Purpose: To identify molecular alterations associating with in vivo exposure of prostate carcinoma to chemotherapy and assess functional roles modulating tumor response and resistance.Experimental Design: Patients with high-risk localized prostate cancer (tumor-node-metastasis ≥ T2b or prostate-specific antigen ≥ 15 ng/mL or Gleason glade ≥ 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. Gene expression changes associated with chemotherapy were determined by a random variance t test. Several were verified by quantitative reverse transcription PCR. In vitro analyses determining the influence of growth differentiation factor 15 (GDF15) on chemotherapy resistance were done.Results: Gene expression changes after chemotherapy were measured in 31 patients who completed four cycles of neoadjuvant chemotherapy. After excluding genes shown previously to be influenced by the radical prostatectomy procedure, we identified 51 genes with significant transcript level alterations following chemotherapy. This group included several cytokines, including GDF15, chemokine (C-X-C motif) ligand 10, and interleukin receptor 1β. Overexpression of GDF15 or exposure of prostate cancer cell lines to exogenous recombinant GDF15 conferred resistance to docetaxel and mitoxantrone.Conclusions: Consistent molecular alterations were identified in prostate cancer cells exposed to docetaxel and mitoxantrone chemotherapy. These alterations include transcripts encoding cytokines known to be regulated through the nuclear factor-κB pathway. Chemotherapy-induced cytokines and growth factors, such as GDF15, contribute to tumor cell therapy resistance and may serve as targets to improve responses.

PDF file 41K, Appendix: Detailed Sequencing information for the solid tumor Sequenom panel

Supplementary Data from Prostate Cancer–Associated Gene Expression Alterations Determined from Needle Biopsies

PDF file 56K, Supplementary figure legend

Purpose: The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy. We examined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer.Experimental Design: Forty-eight samples of formalin-fixed paraffin-embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy–based sequencing. In addition, PTEN loss and erythroblast transformation-specific–related gene (ERC) translocations were examined using immunohistochemistry (IHC) in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations.Results: Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan–Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse-free survival, 19 versus 106 months (P = 0.01).Conclusions: This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. Although point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high-risk prostate cancer treated with chemotherapy followed by surgery. Clin Cancer Res; 20(5); 1306–12. ©2013 AACR.

Supplementary Figures 1-4 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figure Legends 1-4 from Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

Supplementary Figure Legends 1-12 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figure 3 from Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

Supplementary Figure 2 from Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

Supplementary Figures 7-9 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figure 12 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figure 1 from Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

Supplementary Figures 5-6 from ID1 Enhances Docetaxel Cytotoxicity in Prostate Cancer Cells through Inhibition of p21

Supplementary Figure 4 from Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

Background The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. Objective To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). Design, setting, and participants Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. Outcome measurements and statistical analysis The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer–specific, and metastasis-free survival, and time to androgen deprivation therapy. Results and limitations A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2–103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p = 0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58–1.11; p = 0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32–0.92; p = 0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43–0.99; p = 0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. Conclusions Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage ≥ pT3b (ClinicalTrials.gov number NCT00132301). Patient summary In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

Age-related factors including oxidative stress play an important role in prostate carcinogenesis. We hypothesize that germline single-nucleotide polymorphisms (SNPs) in oxidative stress pathway are associated with prostate cancer (PCa) risk. In this study, we aim to examine which of these SNPs is associated with PCa. Participants included in this analyses came from the “Genetic Susceptibility, Environment and Prostate Cancer Risk Study” conducted at the Veterans Affairs Portland Health Care System. After applying exclusion criteria, 231 PCa cases and 382 prostate biopsy-negative controls who had genotyping data on twenty-two single-nucleotide polymorphisms (SNPs) in six genes (MAPK14, NRF2, CAT, GPX1, GSTP1, SOD2, and XDH) associated with oxidative stress pathway were included in the analyses. The genotyping of SNPs was conducted by the Illumina BeadXpress VeraCode platform. We investigated these SNPs in relation to overall and aggressive PCa risk using logistic regression models controlling for relevant covariates. One SNP in the MAPK14 (rs851023) was significantly associated with incident PCa risk. Compared to men carrying two copies of allele A, the presence of one or two copies of the G allele was associated with decreased risk of PCa [OR (95% CI) 0.19 (0.06–0.51)]. There was no statistically significant association between other SNPs in the NRF2, CAT, GPX1, GSTP1, SOD2, and XDH genes and PCa risk. The MAPK14 gene SNP rs851023 was associated with PCa and aggressive PCa risk after multiple comparison adjustment. Further studies in other populations or functional studies are needed to validate the finding.

Upper tract urothelial carcinoma with clinically positive regional lymph nodes is an aggressive disease state with a high propensity for metastasis and death. The current literature is limited regarding national practice patterns and outcomes in this patient population.We identified 1,658 patients in the NCDB (National Cancer Database) who had cN+M0 upper tract urothelial carcinoma. Patients were stratified into treatment groups. We compared baseline patient and tumor characteristics between the groups, and completed survival analysis using a multivariate Cox regression model.There were 1,658 patients in the final study population. Preoperative chemotherapy was the least performed treatment. That group comprised 6.8% of the overall population and was associated with the highest median overall survival of 36 months compared to 21 months for adjuvant chemotherapy, 14 for chemotherapy only, 10 for surgery without perioperative chemotherapy and 5 for no treatment. On multivariate analysis preoperative chemotherapy was associated with improved median overall survival compared to that in the adjuvant chemotherapy group (HR 0.58, 95% CI 0.38-0.87). There was no statistically significant difference in survival between the chemotherapy only and the surgery only groups. Of patients in the preoperative chemotherapy group 34.6% achieved pN0 status compared to 10.3% of those who underwent surgery as initial therapy.Preoperative chemotherapy was the least performed treatment strategy in the management of cN+M0 upper tract urothelial carcinoma but it was associated with the highest median overall survival. There was no difference in survival between the chemotherapy only and the surgery only groups. Overall these results suggest that initial chemotherapy is appropriate in this population when feasible.

PURPOSE Radiotherapy (RT) plus long-term androgen suppression (AS) are a standard treatment option for patients with high-risk localized prostate cancer. We hypothesized that docetaxel chemotherapy (CT) could improve overall survival (OS) and clinical outcomes among patients with high-risk prostate cancer. PATIENTS AND METHODS The multicenter randomized NRG Oncology RTOG 0521 study enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned to receive standard long-term AS plus RT with or without adjuvant CT. RESULTS A total of 612 patients were enrolled; 563 were evaluable. Median prostate-specific antigen was 15.1 ng/mL; 53% had a Gleason score 9 to 10 cancer; 27% had cT3 to cT4 disease. Median follow-up was 5.7 years. Treatment was well tolerated in both arms. Four-year OS rate was 89% (95% CI, 84% to 92%) for AS + RT and 93% (95% CI, 90% to 96%) for AS + RT + CT (hazard ratio [HR], 0.69; 90% CI, 0.49 to 0.97; one-sided P = .034). There were 59 deaths in the AS + RT arm and 43 in the AS + RT + CT arm, with fewer deaths resulting from prostate cancer in the AS + RT + CT arm versus AS + RT (23 v 16 deaths, respectively). Six-year rate of distant metastasis was 14% for AS + RT and 9.1% for AS + RT + CT, (HR, 0.60; 95% CI, 0.37 to 0.99; two-sided P = .044). Six-year disease-free survival rate was 55% for AS + RT and 65% for AS + RT + CT (HR, 0.77; 95% CI, 0.59 to 1.00; two-sided P = .053). CONCLUSION For patients with high-risk nonmetastatic prostate cancer, CT with docetaxel improved OS from 89% to 93% at 4 years, with improved disease-free survival and reduction in the rate of distant metastasis. The trial suggests that docetaxel CT may be an option to be discussed with selected men with high-risk prostate cancer.

Neoadjuvant chemotherapy is an important adjunct to cystectomy for managing muscle invasive bladder cancer. Using the National Cancer Database we investigated factors that predict failure to undergo surgery following multi-agent chemotherapy for nonmetastatic muscle invasive bladder cancer.We performed a cohort study in patients diagnosed with cT2-4aN0M0 urothelial cell carcinoma of the bladder between 2004 and 2013 who underwent multi-agent chemotherapy. We excluded those with surgery prior to chemotherapy, clinical T4b disease and those who received radiotherapy. Socioeconomic and clinical predictors, including time from diagnosis to treatment, were analyzed using logistic regression for the receipt of surgery after chemotherapy. Cox proportional hazards modeling was applied to perform time dependent analysis.Of the 4,640 patients who met our study inclusion and exclusion criteria 4,244 (91%) proceeded to surgery. Negative predictors of surgery included African American or Hispanic race (OR 0.58, p = 0.007 and 0.48, p = 0.002, respectively), increasing age (OR 0.44, p0.001) and greater time between diagnosis and chemotherapy initiation (fourth quartile greater than 59 days, OR 0.51, p0.001). African American race (HR 0.79, p0.001), Medicare (HR 0.86, p 0.001) and other government insurance (HR 0.73, p0.001) were associated with delayed chemotherapy.Increasing age, African American or Hispanic race and longer time to chemotherapy predicted failure to undergo surgery. Furthermore, African American race was associated with delayed chemotherapy. Chemotherapy was also delayed in patients on Medicare or other government insurance. Longer time to neoadjuvant chemotherapy is a modifiable risk factor that should be closely observed in multimodal cancer treatment.

Objective To evaluate the length of contact between dominant tumor foci and the prostatic capsule as a sign of extracapsular extension at endorectal multiparametric MR imaging. Materials and methods We retrospectively identified 101 patients over a three-year interval who underwent endorectal multiparametric prostate MR imaging prior to radical prostatectomy for prostate cancer. Two readers identified the presence of dominant tumor focus (largest lesion with PI-RADS version 2 score of 4 or 5), and measured the length of tumor capsular contact and likelihood of extracapsular extension by standard criteria (1–5 Likert scale). Results were analyzed using histopathological review as reference standard. Results Extracapsular extension was found at histopathological review in 27 patients. Reader 1 (2) identified dominant tumor in 79 (73) patients, with mean tumor capsular contact length of 18.2 (14.0) mm. The area under the receiver operating characteristic curve for identification of extracapsular extension by tumor capsular contact length was 0.76 for reader 1 and 0.77 for reader 2, with optimal discrimination at values of 18 mm and 21 mm, respectively. In the subset of patients without obvious extracapsular extension by standard criteria (Likert scores 1–3), corresponding values were 0.74 and 0.66 with optimal thresholds of 24 and 21 mm. Conclusion Length of contact between the dominant tumor focus and the capsule is a moderately useful sign of extracapsular extension at endorectal multiparametric prostate MR imaging, including the subset of patients without obvious extracapsular extension by standard criteria, with optimal discrimination at threshold values of 18 to 24 mm.

BackgroundSkeletal metastases often occur in men with castration-resistant prostate cancer (CRPC) where bone biomarkers are prognostic for overall survival (OS). In those with highly elevated markers, there is preferential benefit from bone-targeted therapy. In the phase IIIS0421 docetaxel +/- atrasentan trial, clinical covariates and bone biomarkers were analyzed to identify CRPC subsets with differential outcomes.Subjects and methodsMarkers of bone resorption [N-telopeptide-NTx; pyridinoline-PYD] and formation [C-terminal collagen propeptide-CICP; bone alkaline phosphatase-BAP] were measured in pre-treatment sera. Bone biomarkers and clinical covariates were included in a Cox model for OS; bone markers were added in a stepwise selection process. Receiver operating characteristic (ROC) curves were constructed for risk factor models +/- bone markers. Significant variables were allowed to compete in a classification and regression tree (CART) analysis. Hazard ratios(HR) were calculated by comparing OS in each of the terminal nodes to a reference group in a Cox model.Results750 patients were included. Each bone marker significantly contributed to the risk factor-adjusted OS Cox model, with higher levels associated with worse OS. BAP (HR = 1.15, p = 0.008), CICP (HR = 1.27, p

This review summarizes the current evidence on the potential role of phytol, a microbial metabolite of chlorophyl A, and its metabolites, phytanic and pristanic acids, in carcinogenesis. Primary food sources in Western diets are the nut skin for phytol and lipids in dairy, beef and fish for its metabolites. Phytol and its metabolites gained interest as dietary compounds for cancer prevention because, as natural ligands of peroxisome proliferator-activated receptor-α and -γ and retinoid X receptor, phytol and its metabolites have provided some evidence in cell culture studies and limited evidence in animal models of anti-carcinogenic, anti-inflammatory and anti-metabolic-syndrome properties at physiological concentrations. However, there may be a narrow range of efficacy, because phytol and its metabolites at supra-physiological concentrations can cause in vitro cytotoxicity in non-cancer cells and can cause morbidity and mortality in animal models. In human studies, evidence for a role of phytol and its metabolites in cancer prevention is currently limited and inconclusive. In short, phytol and its metabolites are potential dietary compounds for cancer prevention, assuming the challenges in preventing cytotoxicity in non-cancer cells and animal models and understanding phytol metabolism can be mitigated.

An ongoing controversy exists regarding the effect of dairy products on prostate cancer risk in observational studies. We prospectively investigated the associations between dairy product consumption and prostate cancer risk among men in the United States. After calculating pre-diagnostic intake of individual or subgroups of dairy products using a validated food frequency questionnaire, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for pathologically-verified cases of incident prostate cancer among men, overall, or stratified by severity. Among 49,472 men, 4134 were diagnosed with prostate cancer during an average follow-up period of 11.2 years. The median total dairy intake was 101 g/1000 kcal. Consumption of total, individual, or subgroups of dairy products was not statistically significantly associated with prostate cancer risk overall (HR = 1.05, 95% CI = 0.96&ndash, 1.15 comparing the highest with lowest quartile) or stratified by severity, except for regular-fat dairy product intake with late-stage prostate cancer risk (HR = 1.37, 95% CI = 1.04&ndash, 1.82 comparing the highest with lowest quartile) and 2%-fat milk intake with advanced prostate cancer risk (HR = 1.14, 95% CI = 1.02&ndash, 1.28 comparing the higher than median intake with no intake group). Our findings do not support the previously reported harmful impact of dairy consumption on overall prostate cancer risk among men in the United States.

OBJECTIVES: We prospectively investigated the association between dairy product intake and prostate cancer risk among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) cohort. METHODS: Pre-diagnostic dairy product intake was assessed using a validated food frequency questionnaire. Incident prostate cancer was ascertained by study visits, local cancer registries, or self-reports and only pathologically-verified cases were included in the analysis. In addition to overall prostate cancer, we classified cases by severity (early vs late stage, or low vs high Gleason scores). Using multivariate Cox regression models, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations of prostate cancer risk with dairy product intake, as total (all dairy products), by fat content (low- or high-fat), or by fermentation methods (fermented or non-fermented). RESULTS: Among 49,472 men, 4134 were diagnosed with prostate cancer during an average follow-up period of 11.2 years. The median total dairy product intake was 101 g/1000 Kcal. Total dairy product consumption was not statistically significantly associated with risk of any prostate cancer or stratified by disease severity. The HR (95% CI) comparing the highest with the lowest quartiles of total dairy product intake was 1.05 (0.96–1.15) for overall prostate cancer risk and ranged from 1.00 (0.88–1.14), for risk of prostate cancer with high-Gleason score, to 1.24 (0.93–1.66), for risk of late-stage prostate cancer. The only statistically significant finding in our stratified analyses was a positive association between high-fat dairy product intake and late-stage prostate cancer risk (HR = 1.37, 95% CI = 1.04–1.82, P-trend = 0.02). However, associations with high-fat dairy intake did not differ by stage (P = 0.15), suggesting a chance finding for the positive association with late-stage prostate cancer. CONCLUSIONS: These preliminary findings do not support the previously-reported harmful impact of dairy product consumption on prostate cancer risk among US men. The observed association of high-fat dairy intake with late-stage prostate cancer needs to be confirmed in other studies. FUNDING SOURCES: This study was funded by the Oregon Health & Science University/Oregon State University Cancer Prevention and Control Initiative.

Previous studies suggest compounds such as sulforaphane (SFN) derived from cruciferous vegetables may prevent prostate cancer development and progression. This study evaluated the effect of broccoli sprout extract (BSE) supplementation on blood histone deacetylase (HDAC) activity, prostate RNA gene expression, and tissue biomarkers (histone H3 lysine 18 acetylation (H3K18ac), HDAC3, HDAC6, Ki67, and p21). A total of 98 men scheduled for prostate biopsy were allocated into either BSE (200 µmol daily) or a placebo in our double-blind, randomized controlled trial. We used nonparametric tests to evaluate the differences of blood HDAC activity and prostate tissue immunohistochemistry biomarkers between treatment groups. Further, we performed RNA-Seq analysis on the prostate biopsies and identified 40 differentially expressed genes correlated with BSE treatment, including downregulation of two genes previously implicated in prostate cancer development, AMACR and ARLNC1. Although urine and plasma SFN isothiocyanates and individual SFN metabolites were statistically higher in the treatment group, our results did not show a significant difference in HDAC activity or prostate tissue biomarkers. This study indicates BSE supplementation correlates with changes in gene expression but not with several other prostate cancer biomarkers. More research is required to fully understand the chemopreventive effects of BSE supplementation on prostate cancer.

INTRODUCTION AND OBJECTIVES:Management of small renal masses (SRMs) has changed over the past two decades with the diffusion of minimally invasive techniques and establishment of thermal ablation a...

The aims of this study were to report the clinical outcomes in a cohort of men with high-risk prostate cancer treated with neoadjuvant docetaxel and mitoxantrone 10 years after treatment, identify pretreatment clinical parameters that may be predictors of recurrence, and describe tumor-infiltrating leukocytes present in radical prostatectomy specimens. We conducted a phase I/II study of neoadjuvant docetaxel and mitoxantrone before radical prostatectomy in high-risk localized prostate cancer to determine the feasibility of this combination and predictors of prostate cancer recurrence after cytotoxic chemotherapy. After 10 years of follow-up, 34 (63%) of 54 participants experience a recurrence. In univariate analysis, prostate-specific antigen (PSA) density (P=0.01), pathological stage (P=0.03), lymph node status (P

Dynamic-Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used widely for clinical applications. Pharmacokinetic modeling of DCE-MRI data that extracts quantitative contrast reagent/tissue-specific model parameters is the most investigated method. One of the primary challenges in pharmacokinetic analysis of DCE-MRI data is accurate and reliable measurement of the arterial input function (AIF), which is the driving force behind all pharmacokinetics. Because of effects such as inflow and partial volume averaging, AIF measured from individual arteries sometimes require amplitude scaling for better representation of the blood contrast reagent (CR) concentration time-courses. Empirical approaches like blinded AIF estimation or reference tissue AIF derivation can be useful and practical, especially when there is no clearly visible blood vessel within the imaging field-of-view (FOV). Similarly, these approaches generally also require magnitude scaling of the derived AIF time-courses. Since the AIF varies among individuals even with the same CR injection protocol and the perfect scaling factor for reconstructing the ground truth AIF often remains unknown, variations in estimated pharmacokinetic parameters due to varying AIF scaling factors are of special interest. In this work, using simulated and real prostate cancer DCE-MRI data, we examined parameter variations associated with AIF scaling. Our results show that, for both the fast-exchange-limit (FXL) Tofts model and the water exchange sensitized fast-exchange-regime (FXR) model, the commonly fitted CR transfer constant (K(trans)) and the extravascular, extracellular volume fraction (ve) scale nearly proportionally with the AIF, whereas the FXR-specific unidirectional cellular water efflux rate constant, kio, and the CR intravasation rate constant, kep, are both AIF scaling insensitive. This indicates that, for DCE-MRI of prostate cancer and possibly other cancers, kio and kep may be more suitable imaging biomarkers for cross-platform, multicenter applications. Data from our limited study cohort show that kio correlates with Gleason scores, suggesting that it may be a useful biomarker for prostate cancer disease progression monitoring.

Veterans Administration Portland Health Care System, Oregon Health & Science University, Portland, OR, USA Department of Urology, Oregon Health & Science University, Portland, OR, USA Radiation Medicine, Oregon Health & Science University, Portland, OR, USA *Author for correspondence: Garzotto@ohsu.edu

333 Background: High-risk, localized prostate cancer has a poor prognosis. We hypothesized that adj docetaxel (D) and prednisone and long-term (24 mos) androgen suppression (AS) and radiation therapy (RT) would improve overall survival (OS) and tested this in NRG/RTOG 0521. Results with med follow-up of 5.7 yrs were reported (JCO 37:1159, 2019), showing a benefit of D (HR=0.69, 90% CI: 0.49-0.97, 1-sided p=0.034). Med follow-up is now 10.4 yrs and we report updated results for OS and metastasis (DM). Methods: NRG/RTOG 0521 opened 12/05 and closed 8/09 with targeted accrual of 600 and designed to detect a HR of 0.49, based on improvement in 4-yr OS from 86 to 93%. With 0.05 1-sided type I error and 90% power >78 deaths were required. Pts were stratified by predefined risk groups. Group 1: Gl 9-10, any T; Group 2: Gl 8, PSA

To determine practice patterns for the extent of lymphadenectomy at radical prostatectomy and associations with detection of pN1 prostate cancer, as well as the impact of lymphadenectomy extent on underdetection of pN1 disease and overall survival.Prostatectomy cases in the NCDB from 2004 to 2013 were included. Lymphadenectomy extent was defined by the number of nodes examined. Logistic regression was used to identify risk factors for the top quartile of lymph node count and pN1 disease. This model was created to estimate the expected prevalence of pN1, and generated observed over expected ratios. A Cox regression model was used to evaluate the effect of lymph node count on overall survival.Lymphadenectomy was performed in 209,789 (60%) of 358,522 surgeries, with pN1 in 6,428 (3.08%). Increasing quartiles for lymph node count was associated with pN1 (3-5 nodes OR 2.11; 6-8 nodes OR 3.12; ≥9 nodes OR 5.91, all P0.001). The logistic regression model suggested that 59% of pN1 cases are missed due to low lymph node count. Increased lymph node count was associated with increasing pN1 detection (O/E: 1-2 nodes = 0.18; 3-5 nodes = 0.37; 6-8 nodes = 0.56; ≥9 nodes = 1.01). Cox proportional hazards modeling demonstrated that the top quartile for lymph node count had improved overall survival (HR 0.93, CI 0.87-0.99, P= 0.03).Increasing lymphadenectomy extent was associated with pN1 disease on multivariate analysis, and logistic regression modeling suggested a substantial proportion of pN1 were missed due to low lymphadenectomy extent across all risk groups.

Active surveillance (AS) has been widely implemented within Veterans Affairs' medical centers (VAMCs) as a standard of care for low-risk prostate cancer (PCa). Patient characteristics such as age, race, and Agent Orange (AO) exposure may influence advisability of AS in veterans. The 17-gene assay may improve risk stratification and management selection.To compare management strategies for PCa at 6 VAMCs before and after introduction of the Oncotype DX Genomic Prostate Score (GPS) assay.We reviewed records of patients diagnosed with PCa between 2013 and 2014 to identify management patterns in an untested cohort. From 2015 to 2016, these patients received GPS testing in a prospective study. Charts from 6 months post biopsy were reviewed for both cohorts to compare management received in the untested and tested cohorts.Men who just received their diagnosis and have National Comprehensive Cancer Network (NCCN) very low-, low-, and select cases of intermediate-risk PCa.Patient characteristics were generally similar in the untested and tested cohorts. AS utilization was 12% higher in the tested cohort compared with the untested cohort. In men younger than 60 years, utilization of AS in tested men was 33% higher than in untested men. AS in tested men was higher across all NCCN risk groups and races, particular in low-risk men (72% vs 90% for untested vs tested, respectively). Tested veterans exposed to AO received less AS than untested veterans. Tested nonexposed veterans received 19% more AS than untested veterans. Median GPS results did not significantly differ as a factor of race or AO exposure.Men who receive GPS testing are more likely to utilize AS within the year post diagnosis, regardless of age, race, and NCCN risk group. Median GPS was similar across racial groups and AO exposure groups, suggesting similar biology across these groups. The GPS assay may be a useful tool to refine risk assessment of PCa and increase rates of AS among clinically and biologically low-risk patients, which is in line with guideline-based care.

Background Phase 2 trials evaluating new agents for metastatic castration-resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel. Patients and Methods Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors. Results Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different ( P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5-8.8), 13.4 (11.4-15.6), and 16.3 (10.0-19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42-4.29) compared to patients with an uPR ( P = .002). Conclusion The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate-specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials.