Chi-Hsiung Wang

417. Intratumoral Delivery of Oncolytic Adenovirus Expressing Decorin Inhibits Growth and Metastases of 4T1 Breast Tumors in Syngeneic Immune Competent BALB/c Mice Model

During the advanced stage of breast cancer, majority of the patients develop distal metastases that eventually lead to mortality. Unfortunately, conventional strategies generally invoke limited therapeutic responses in patients with tumor metastases. Therefore, the development of novel and highly effective therapies for the treatment of distal metastases of breast cancer is an unmet need in medicine. Decorin (DCN) is a small leucine-rich proteoglycan and is often down-regulated in tumor stroma of breast cancer patients. Our previous work demonstrated that systemic delivery of Ad.dcn, an oncolytic adenovirus expressing DCN, significantly inhibited skeletal metastases and the tumor induced bone destruction in MDA-MB-231 bone metastasis model. However, the therapeutic responses of Ad.dcn in immune-competent models have never been examined. In this study, we showed that non-replicated adenovirus Ad(E1-). dcn mediated high level expression of human DCN in 4T1 cells, and inhibited the expression of tyrosine kinase receptor MET, β-catenin and vascular endothelial growth factor A. To examine the anti-tumor responses of Ad.dcn, we established subcutaneous 4T1 tumors in BALB/c mice. Ad.dcn was delivered intratumorallly (2.5×1010VPs) on day 7 post-cell inoculation, and a repeat dose was given on day 10. Our data showed that Ad.dcn inhibited the growth of local tumors as measured by the caliper as well as by the Bioluminescence Imaging (BLI). At the terminal time point (day 25) we also observed a significant reduction in the tumor weight. Analysis of BLI in real time also demonstrated that Ad.dcn significantly reduced the tumor metastases to lung. On day 25 Ad.dcn group had fewer metastases (2/8 mice), compared to buffer treated group (7/8 mice). Similar reductions in lung metastases were observed by H&E staining. Moreover, Ad.dcn treatment reduced the expression of Th2 cytokines (IL-2, IL-4 and IL-10) in the tumors, which will potentially activate the antitumor immune responses. Furthermore, Ad.dcn also reduced the expression of N-cadherin and vimentin in the tumors, indicating Ad.dcn could also potentially reduce tumor metastases by inhibiting epithelial-mesenchymal transition (EMT) of the tumor cells. Taken together, our results suggested that Ad.dcn not only inhibited the growth of local tumor, but also prevented the distal metastases of tumor. Combining these results in the 4T1 tumor model, and previously examined MB-MDA-231 bone metastases model, we propose the following model of Ad.dcn-mediated inhibition of tumor growth and metastases. Ad.dcn is taken up by tumor cells after systemic or intratumoral delivery, and then replicates in tumor cells and kills them. Tumor cells produce and release high level of decorin protein into tumor microenvironment. Decorin then targets multiple tumor and stromal components to activate anti-tumor immune responses, decrease angiogenesis, and inhibit EMT. Therefore, Ad.dcn is a potential therapeutic strategy for the treatment of breast cancer and its distal metastases.Y.Y. and W.X. made equal contribution. L.W. and P.S. are the corresponding Authors.

MP57-01 GERMLINE MUTATIONS IN DNA REPAIR GENES ARE SIGNIFICANTLY ENRICHED IN LETHAL PROSTATE CANCER AND ARE ASSOCIATED WITH DISEASE SURVIVAL

METHODS: We underwent an IRB approved prospective evaluation comparing clinician and patient measurements utilizing the UWPEN application for measurement of penile angulation. Patients presenting to the University of Washington with Peyronie’s disease and clinical indication for duplex ultrasound were consented and given an intracavernosal injection of Alprostadil. A clinician took measurements using a goniometer and tape measure as a gold standard. Follow-up measurements were obtained using the UWPEN application. The clinician left the room while the patient took UWPEN application measurements. We compared measurements between the goniometer, clinician, and patient using an ANOVA test in the statistics package R. As a secondary outcome, we also evaluated survey results from patients regarding their experience with using the application. RESULTS: There was no significant difference in measurements between goniometer, clinician, and patient measurements of the penis while erect; for dorsal measurements (p 1⁄4 0.78), lateral measurements (p 1⁄4 0.20) and girth (p 1⁄4 0.99). We observed some variability in lateral measurements early in our experience. Overall, patients felt positive about using the application and were interested in home use to evaluate their progress with treatment. CONCLUSIONS: Artificial elections to assess the degree and direction of penile angulation in clinic is time-consuming, costly and invasive. The UWPEN application may help make standardized measurements at home. There is a large degree of consistency between clinician and patient measurements. The majority of patients felt comfortable using the application.

MP13-16 FACTORS THAT PREDISPOSE TO LOWER URINARY TRACT SYMPTOMS IN DIABETIC MEN: RESULTS FROM THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES)

INTRODUCTION AND OBJECTIVES: It has been demonstrated that sleep disorders (SDOs) are associated with the prevalence of nocturia in men. While previous literature supports that patients with obstructive sleep apnea (OSA), insomnia, and restless leg syndrome (RLS) are at increased risk of nocturia, the risk of daytime lower urinary tract symptoms (LUTS) in these groups has not been established. We sought to investigate the frequency of LUTS in men with and without different types of SDO. METHODS: We examined the National Health and Nutrition Examination Survey (NHANES) database between 2006-2008. Men age 18-70 years who completed the sleep questionnaires in addition to the prostate and kidney forms were included in the study. LUTS was defined as having one more of the following symptoms: hesitancy, incomplete emptying, or nocturia (>1⁄42). Physician-diagnosed SDOs were self reported by patients. Statistical analyses were used to compare groups of men with and without a SDO. RESULTS: Of the 6185 men who completed all of the survey questions, 437 (7.1%) men reported a SDO. The clinical characteristics of men with and without a SDO are shown in Table 1. Men with SDOs were significantly older and significantly more likely to be Caucasian, have increased BMI and report more medical co-morbidities compared to men without SDOs. There was a significantly higher proportion of men with SDOs who reported nocturia compared to those without SDOs (39% vs 27.7%; p <.0001). Additionally, these men had a significantly higher risk of LUTS (including daytime LUTS) than men without SDOs (34.4% vs 22.8%, p <.0001). Men with OSA (31.7%) were significantly more likely to report >1⁄42 LUTS compared to men with insomnia (18.2%) or RLS (12.5%) (p1⁄4.0002). CONCLUSIONS: Older age, Caucasian race, elevated BMI, and increased comorbidity score appear to be associated with an increased risk of LUTS in men with SDOs. While men with SDOs report increased nocturia, they are also more likely to experience bothersome daytime LUTS. This is particularly relevant for men with OSA compared to other SDOs. Based upon the present data, clinicians should consider assessing LUTS in men with SDOs as intervention could improve both nighttime and daytime urinary symptoms.

MP17-02 TNFα ANTAGONISTS REDUCE INCIDENCE OF BPH IN PATIENTS WITH AUTOIMMUNE INFLAMMATORY CONDITIONS

(red arrowhead in Fig.1D) IL-18 levels were elevated in banked urine specimens of BPH patients. CONCLUSIONS: Co-localized immunoreactivity of NLRP1, and its downstream product IL-18 supports the assembly and activation of inflammasome in BPH specimens positive for infiltration of inflammatory cells. Recapitulation of findings from the animal model demonstrate that inflammasome plays a major role in the prostatic inflammation associated with BPH and therefore inflammasome targeted therapies can be an option for BPH management.

MP14-18 VERY LOW RISK VS. LOW RISK PROSTATE CANCER DESIGNATIONS IN AN ACTIVE SURVEILLANCE COHORT

INTRODUCTION AND OBJECTIVES: NCCN guidelines differentiate between very low risk (VLR) and low risk (LR) prostate cancer based onEpsteinCriteria. Thesecategories havenot beenwell studied in anactive surveillance population. We sought to determine if these risk groups were meaningful in regards to recategorization of overall risk category on confirmation and surveillance biopsies in an active surveillance population. METHODS: Men eligible for active surveillance were designated eitherVLR (stageT1c,PSAdensity 0.15ng/mL/mL,Gleasonscore 6, 2 positive biopsy cores, 50% cancer per core) or LR (stage T1c/T2a, PSA 10 ng/mL, and Gleason score 6). Risk recategorization was defined as Gleason 7, T2b or greater, and PSA > 10 ng/mL on subsequent biopsy or clinical treatment of prostate cancer. Basic demographics including age, race, BMI, PSA and prostate volume were collected. Comparisons between VLR and LRwere conducted using chisquare test, t-test, and Mann-Whitney U test. Logistic regression was used to examine the association between initial risk category and recategorization at confirmation and surveillance biopsies. RESULTS: 122 men were initially categorized as VLR while 62 were LR. Average age of the cohort was 65.4 7.0 years with 85.4% Caucasian. There was no difference in age, BMI or race between risk categories. Median prostate volume was 44.5 (IQR 34.0 61.5) mL vs. 31.0 (IQR 24.8 39.5) mL (p<0.001) in the VLR and LR groups, respectively. Overall, men were followed for a median of 36.6 months ( IQR 29.9-52.5). There were no statistically significant differences in the frequency of risk recategorization among VLR patients with 1 vs. 2 cores positive on initial biopsy. At confirmation biopsy, 15 (12.3%) of VRL and 18 (29.0%) of LR were recategorized (p1⁄40.005). After adjustment for age, PSA, PCA3, and the presence of perineural invasion, LR patients were significantly more likely to be recategorized at confirmation biopsy compared to VLR (OR 1⁄4 3.47, 95 % CI 1⁄4 [1.23 9.83] p1⁄40.019). During follow up surveillance biopsies, 21(17.2%) of VRL and 18 (29.0%) of LR were recategorized. (p1⁄40.064). CONCLUSIONS: Patients initially designated LR have a higher risk for recategorization during both confirmation and surveillance biopsies compared to those with VLR disease. However, it should be noted that approximately 25% of all men initially believed to have VLR will ultimately be found to have more aggressive pathology. This calls into question whether this VLR designation provides a false sense of security for patients and treating physicians.

MP1-20 DISTINGUISHING INDOLENT FROM AGGRESSIVE PROSTATE CANCER IN ACTIVE SURVEILLANCE USING PARTIALWAVE SPECTROSCOPY TO MEASURE NANOCYTOLOGICAL FIELD CARCINOGENESIS

INTRODUCTION AND OBJECTIVES: Field carcinogenesis (FC) is a well-documented phenomenon that occurs in prostate cancer (PC). We have developed a novel biophotonics technology, partial wave spectroscopic (PWS) microscopy, or nanocytology, which quantifies intranuclear organization beyond the limits of conventional light microscopy. Our previous data within 7 other cancers has demonstrated that PWS-detected alterations in histologically normal cells are a highly accurate biomarker of FC, cancer risk, and disease aggressiveness. We hypothesized that PWS could be used to distinguish aggressive disease PC patients undergoing active surveillance (AS). METHODS: PWS nanocytology was performed on core tissue samples obtained on the initial surveillance biopsy from 38 men undergoing AS. PWS was performed on histologically normal prostatic epithelium that was not adjacent to the cancerous tissue. The “disorder length” (Ld) was measured in 40 glandular epithelial cells for each sample. Patients were grouped by clinical outcomes stratified by success or failure of AS for 3 years. RESULTS: The baseline clinical characteristics of men were not significantly different between progressors (n1⁄420) and non-progressors (n1⁄418) and included: mean age 66.5 5.6 years, mean BMI of 28.1 4.0, median PSA of 4.73ng/ml, and mean prostate volume of 42.5 20.7mL. Using PWS, the Ld was found to be significantly increased in the progressors compared to nonprogressors (p1⁄40.002). This was associated with an effect size of 110% with 80% sensitivity and 85% specificity. CONCLUSIONS: PWS nanocytological assessment of FC can predict disease progression in AS. This novel technology has the potential to mitigate overtreatment of PC.

MP74-18 FINDINGS OF ASAP/PIN ARE ASSOCIATED WITH DISEASE PROGRESSION IN ACTIVE SURVEILLANCE

INTRODUCTION AND OBJECTIVES: Occasionally, patients with a detectable serum PSA after prostatectomy exhibit a normal value after repeating the study. Given the patient anxiety associated with serum PSA values, we evaluated whether any clinical characteristics were predictive of a false positive result. METHODS: A prospective database was maintained for all men who underwent radical prostatectomy by a single surgeon (73% robotic, 27% retropubic). Of 602 patients, 562 had at least one post operative PSA determination. Biochemical recurrence was defined as a serum PSA of 0.1 ng/ml or greater. PSA values were drawn every 4 or 6 months depending on the recurrence risk. All PSA values of 0.1 ng/ml or greater were repeated at our reference laboratory using the chemiluminescence method. RESULTS: During follow up, twelve percent of patients (67/ 562) had a serum PSA of 0.1 ng/ml or greater. After repeating all detectable values at our reference laboratory, 11 of these 67 patients had a serum PSA less than 0.1 ng/ml for a false positive rate of 16.4%. The true biochemical recurrence rate was 10% (56/562) after a median follow up of 20.8 months (range 2 to 99). All patients with two consecutive serum PSA values of 0.1 ng/ml or greater continued to exhibit a PSA rise above 0.2. The mean false positive serum PSA level was 0.25 ng/ml (range: 0.1 to 0.5), and 82% of false positive results had been performed at community laboratories (p< 0.001). Patients with a false positive serum PSA were also less likely to have a higher prostatectomy Gleason score (p<0.001) or pathologic T3 disease (p < 0.001), but had no differences in body mass index, age, preoperative serum PSA, prostate size, or surgical margins compared with those with a true positive result. CONCLUSIONS: Approximately 16% of patients with a detectable PSA after radical prostatectomy may have false biochemical failure. Repeating the serum PSA in all patients with a detectable level is paramount before making treatment recommendations, especially if the study was not performed in a reference laboratory and the patient had Gleason score 6, negative margins, and organ confined disease.