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Purpose: We determined whether the pattern of low detectable prostate specific antigen during the first 3 years of followup after radical prostatectomy would predict subsequent biochemical recurrence., Materials and Methods: An institutional database was queried to identify 1,136 patients who underwent open retropubic or robot-assisted radical prostatectomy between January 5, 1993 and December 29, 2008. After applying exclusion criteria we used serum prostate specific antigen and the prostate specific antigen pattern during the first 3 years of followup to divide 566 men into 3 groups, including 1) undetectable prostate specific antigen (0.03 ng/ml or less), 2) low detectable-stable prostate specific antigen (greater than 0.03 and less than 0.2 ng/ml, no 2 subsequent increases and/or prostate specific antigen velocity less than 0.05 ng per year) and 3) low detectable-unstable prostate specific antigen (greater than 0.03 and less than 0.2 ng/ml, 2 subsequent increases according to NCCN criteria and/or prostate specific antigen velocity 0.05 ng per year or greater). The primary end point was biochemical recurrence, defined as prostate specific antigen 0.2 ng/ml or greater, or receipt of radiation therapy beyond 3 years of followup., Results: Seven-year biochemical recurrence-free survival was 95%, 94% and 37% in the undetectable, low detectable-stable and low detectable-unstable groups, respectively (log rank test p <0.0001). On multivariate analysis the prostate specific antigen pattern during 3 years postoperatively (undetectable vs low detectable-unstable HR 15.9 and vs low detectable-stable HR 1.6), pathological T stage (pT2 vs greater than pT2 HR 1.8), pathological Gleason score (less than 7 vs 7 HR 2.3 and less than 7 vs 8-10 HR 3.3) and surgical margins (negative vs positive HR 1.8) significantly predicted biochemical recurrence., Conclusions: The combination of prostate specific antigen velocity and NCCN criteria for biochemical recurrence separated well men with low detectable prostate specific antigen after radical prostatectomy into those who required treatment and those who could be safely watched., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Epidemiological studies indicate that calcium channel blocker (CCB) use is inversely related to prostate cancer (PCa) incidence. The association between CCB use and PCa aggressiveness at the time of radical prostatectomy (RP) and outcome after RP was examined., Methods: Medication use, PCa aggressiveness and post-RP outcome were retrieved from a prospectively populated database that contains clinical and outcome for RP patients at Roswell Park Cancer Institute (RPCI) from 1993 to 2010. The database was queried for anti-hypertensive medication use at diagnosis for patients with ≥1 year follow-up. Recurrence was defined using NCCN guidelines. Chi-Square tests assessed the relationship between CCB use and PCa aggressiveness. Cox regression models compared the distribution of progression-free survival (PFS) and overall survival (OS) with adjustment for covariates. Results for association between CCB usage and PCa aggressiveness were validated using data from the population-based North Carolina-Louisiana Prostate Cancer Project (PCaP)., Results: 48%, 37%, and 15% of RPCI's RP patients (n = 875) had low, intermediate, and high aggressive PCa, respectively. 104 (11%) had a history of CCB use. Patients taking CCBs were more likely to be older, have a higher BMI and use additional anti-hypertensive medications. Diagnostic PSA levels, PCa aggressiveness, and margin status were similar for CCB users and non-users. PFS and OS did not differ between the two groups. Tumor aggressiveness was associated with PFS. CCB use in the PCaP study population was not associated with PCa aggressiveness., Conclusions: CCB use is not associated with PCa aggressiveness at diagnosis, PFS or OS., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. In phase 1 trials, prostate-specific antigen (PSA) declines were seen in patients with advanced prostate cancer. We conducted a single-arm phase 2 study evaluating KX2-391 in men with chemotherapy-naïve bone-metastatic castration-resistant prostate cancer (CRPC)., Methods: We treated 31 patients with oral KX2-391 (40 mg twice-daily) until disease progression or unacceptable toxicity. The primary endpoint was 24-week progression-free survival (PFS); a 50 % success rate was pre-defined as clinically significant. Secondary endpoints included PSA progression-free survival (PPFS) and PSA response rates. Exploratory outcomes included pharmacokinetic studies, circulating tumor cell (CTC) enumeration, and analysis of markers of bone resorption [urinary N-telopeptide (uNTx); C-telopeptide (CTx)] and formation [bone alkaline phosphatase (BAP); osteocalcin]., Results: The trial closed early after accrual of 31 patients, due to a pre-specified futility rule. PFS at 24 weeks was 8 %, and median PFS was 18.6 weeks. The PSA response rate (≥ 30 % decline) was 10 %, and median PPFS was 5.0 weeks. Additionally, 18 % of men with unfavorable (≥ 5) CTCs at baseline converted to favorable (<5) CTCs with treatment. The proportion of men with declines in bone turnover markers was 32 % for uNTx, 21 % for CTx, 10 % for BAP, and 25 % for osteocalcin. In pharmacokinetic studies, median C max was 61 (range 16-129) ng/mL, and median AUC was 156 (35-348) ng h/mL. Common toxicities included hepatic derangements, myelosuppression, fatigue, nausea, and constipation., Conclusion: KX2-391 dosed at 40 mg twice-daily lacks antitumor activity in men with CRPC, but has modest effects on bone turnover markers. Because a C max of ≥142 ng/mL is required for tubulin polymerization inhibition (defined from preclinical studies), higher once-daily dosing will be used in future trials.

The development of vaccines against specific types of cancers will offer new modalities for therapeutic intervention. Here, we describe the synthesis of a novel vaccine construction prepared from spherical gold nanoparticles of 3-5 nm core diameters. The particles were coated with both the tumor-associated glycopeptides antigens containing the cell-surface mucin MUC4 with Thomsen Friedenreich (TF) antigen attached at different sites and a 28-residue peptide from the complement derived protein C3d to act as a B-cell activating "molecular adjuvant". The synthesis entailed solid-phase glycopeptide synthesis, design of appropriate linkers, and attachment chemistry of the various molecules to the particles. Attachment to the gold surface was mediated by a novel thiol-containing 33 atom linker which was further modified to be included as a third "spacer" component in the synthesis of several three-component vaccine platforms. Groups of mice were vaccinated either with one of the nanoplatform constructs or with control particles without antigen coating. Evaluation of sera from the immunized animals in enzyme immunoassays (EIA) against each glycopeptide antigen showed a small but statistically significant immune response with production of both IgM and IgG isotypes. Vaccines with one carbohydrate antigen (B, C, and E) gave more robust responses than the one with two contiguous disaccharides (D), and vaccine E with a TF antigen attached to threonine at the 10th position of the peptide was selected for IgG over IgM suggesting isotype switching. The data suggested that this platform may be a viable delivery system for tumor-associated glycopeptide antigens.

Background: Reduced expression of prostate-derived Ets transcription factor (PDEF) leads to morphologic change as well as increased migration and invasiveness of prostate cancer cells. However, the clinical relevance of PDEF expression and its relationship to anti-apoptotic protein survivin is yet to be determined., Methods: Tissue microarrays of 73 prostate carcinomas and their adjacent benign prostate tissue, as well as 50 benign prostates were evaluated for PDEF expression by immunohistochemistry. Results were confirmed in available tumor tissues using Western blot and RT-PCR. Expression of survivin in prostate carcinoma and benign tissues were determined using Western blot. Results and correlation with clinical data were statistically analyzed., Results: Patients' specimens with low Gleason scores (GS < 5) expressed higher levels of PDEF protein and lower levels of survivin protein when compared with moderate-to-high GS tumors (GS > 6). Patients with PDEF-positive tumor survived significantly longer (P < 0.0001) than patients with PDEF-negative tumor, and the 8-year survival rate was 94% and 40%, respectively. PDEF expression was detected at the highest levels in benign tissues and was down-regulated or lost in 30 recently diagnosed prostate carcinomas. Re-expression of PDEF in prostate cancer cells inhibited survivin expression. Treatment of prostate cancer cells with methylseleninic acid resulted in restoration of PDEF expression, down-regulation of survivin, and inhibition of tumor cell growth when compared with untreated controls (P < 0.05)., Conclusions: These studies demonstrated an inverse correlation between PDEF and survivin expression, and that up-regulation of PDEF was associated with a favorable prognosis in patients with clinically localized prostate cancer., (Copyright © 2011 Wiley-Liss, Inc.)

Background: The balance between apoptotic and proliferative processes determines the enlargement of a tumor. Accurate measurement of apoptotic and proliferative rates from diagnostic prostate biopsies would allow calculation of tumor growth rates in a population-based prostate cancer (CaP) study. Automated image analysis may be used if proliferation and apoptotic biomarkers provide clearly resolved immunostained images., Methods: Clinical CaP aggressiveness was assigned as low, intermediate or high using clinical criteria for 46 research subjects with newly diagnosed CaP. Diagnostic biopsy sections from the research subjects were dual-labeled for proliferation biomarker, Ki-67 and apoptotic biomarker, apoptotic chromatin condensation inducer in the nucleus (ACINUS). Apoptotic biomarkers, caspase-3 and terminal deoxyribonucleotidyltransferase mediated dUTP-biotin nick end labeling (TUNEL) were labeled separately. Images from immunostained sections were analyzed using automated image analysis and tumor growth rates computed. Association between clinical CaP aggressiveness and tumor growth rates was explored., Results: Sixteen subjects had high, 17 had intermediate, and 13 had low clinical CaP aggressiveness. Positive immunostaining was localized to the nucleus for Ki-67, ACINUS, and TUNEL. A statistically significant linear trend across clinical CaP aggressiveness categories was found when tumor growth rates were calculated using ACINUS (P = 0.046). Logistic regression and ROC plots generated showed ACINUS (AUC = 0.677, P = 0.048) and caspase-3 (AUC = 0.694, P = 0.038) to be better predictors than TUNEL (AUC = 0.669, P = 0.110)., Conclusions: ACINUS met the criteria for automated image analysis and for calculation of apoptotic rate. Tumor growth rates determined using automated image analysis should be evaluated for clinical prediction of CaP aggressiveness, treatment response, recurrence, and mortality.

Purpose: We determined the response rate to and safety of a dual 5alpha-reductase inhibitor, dutasteride, in men with castration recurrent prostate cancer., Materials and Methods: A total of 28 men with asymptomatic castration recurrent prostate cancer were treated with 3.5 mg dutasteride daily (luteinizing hormone-releasing hormone treatment continued), and evaluated monthly for response and toxicity. Eligibility included appropriate duration antiandrogen withdrawal, baseline prostate specific antigen 2.0 ng/ml or greater and a new lesion on bone scan, increase in measurable disease using Response Evaluation Criteria in Solid Tumors criteria, or 2 or more consecutive prostate specific antigen measurements increased over baseline. Outcomes were progression, stable disease, partial response (prostate specific antigen less than 50% of enrollment for 4 or more weeks) or complete response., Results: There were 25 evaluable men with a mean age of 70 years (range 57 to 88), a mean prostate specific antigen of 61.9 ng/ml (range 5.0 to 488.9) and mean Gleason score 8 (range 6 to 10), 15 of whom had bone metastases. Eight men had 10 grade 3 or higher adverse events using National Cancer Institute Common Terminology Criteria, all of which were judged to be unrelated to treatment. Of the 25 men 14 had disease progression by 2 months, 9 had stable (2.5, 3, 3, 4, 4, 5, 5, 8.5, 9 months) disease, 2 had a partial response and none had a complete response. Overall median time to progression was 1.87 months (range 1 to 10, 95% CI 1.15-3.91)., Conclusions: Dutasteride rarely produces biochemical responses in men with castration recurrent prostate cancer. However, further study is warranted given its favorable safety profile.