Charles B. Brendler

Experience with Gleason’s Histopathologic Grading in Prostatic Cancer

The inaccuracy of clinical staging as a predictor of the biologic potential of prostatic cancer has prompted evaluation of additional methods of assessment. We reviewed 228 patients with prostatic adenocarcinoma who presented during a 4-year period. Of the 228 patients 144 with no detectable bony disease underwent staging pelvic lymphadenectomy with or without preliminary bilateral pedal lymphangiography. Histopathologic specimens of the primary diagnostic prostatic biopsy were classified with Gleasons grading system of tumor differentiation. Of the patients with Gleasons sum of 8, 9 or 10, 93 per cent had regional nodal metastases, regardless of preliminary clinical stage. Furthermore, no patient with Gleasons sum of 2, 3 or 4 had nodal metastatic disease. The incidences of falsely positive and falsely negative lymphangiograms were 29 and 35 per cent, respectively, reflecting the unreliability of pedal lymphangiography to predict nodal involvement accurately in patients with prostatic cancer. The Gleason system of histopathologic grading was reliable and reproducible, and afforded an accurate prediction of the surgical stage of disease.

Staging Pelvic Lymphadenectomy for Carcinoma of the Prostate: Risk Versus Benefit

A total of 125 patients underwent limited staging lymphadenectomy for adenocarcinoma of the prostate. Of these patients 19 per cent with clinical stage B1 disease, 52 per cent with clinical stage B2 disease and 59 per cent with clinical stages C disease had positive nodes. There was 1 death secondary to myocardial infarction and postoperative complications occurred in 7.2 per cent of the 125 patients. Limited staging pelvic node dissection provides information regarding nodal dissection similar to that identified after more extensive dissection and it can be accomplished with little morbidity.

Return of Serum Prostate Specific Antigen to Undetedtable Level Following Removal of Solitary Lymph Node Metastasis

Historically pelvic lymph node metastasis of prostate cancer has been considered a systemic disease that is incurable by regional therapy, including surgery and radiation. We report a case in which an isolated pelvic lymph node recurrence was removed during low anterior resection of the rectum. The patient had previously undergone radical retropubic prostatectomy and bilateral pelvic lymphadenectomy for adenocarcinoma of the prostate. Serum prostate specific antigen (PSA), which had become detectable 1 year after radical retropubic prostatectomy, returned to an undetectable level following low anterior resection of the rectum. PSA remained undetectable for 18 months postoperatively. CASE REPORT A 67-year-old man with a PSA of 12.1 ng./ml. and clinical stage T2b Gleason grade 3 4 7 adenocarcinoma of the prostate underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. The right neurovascular bundle to the penis was excised widely with the prostate because of palpable tumor in the right lobe of the gland. Final pathological evaluation revealed high volume bilateral Gleason grade 3 4 7 adenocarcinoma of the prostate with perineural and perivascular invasion. In the right lobe there was extensive extraprostatic extension of tumor into the periprostatic and periseminal vesicle tissue. However, all surgical margins, both seminal vesicles and the pelvic lymph nodes were negative for tumor. PSA decreased to less than 0.10 ng./ml. postoperatively and remained undetectable for 1 year. At 1-year followup PSA was 0.12 ng./ml. A repeat test showed a PSA of 0.14 ng./ml. Rectal examination demonstrated no evidence of locally recurrent tumor. However, stool hemoculture was positive, and the patient subsequently underwent colonoscopy, which revealed a large polyp 10 cm. from the anus. Low anterior resection of the rectum was performed with a temporary diverting colostomy. Final pathological evaluation showed well differentiated adenocarcinoma of the rectum with all surgical margins negative. However, 1 of 4 pericolic lymph nodes contained a focus of metastatic adenocarcinoma of the prostate. Three months after rectal surgery PSA was again undetectable. PSA remained undetectable for 18 months postoperatively, and 2.5 years following the original radical retropubic prostatectomy and bilateral pelvic lymphadenectomy. DISCUSSION Pelvic lymph node metastasis of prostate cancer is presumed to be a systemic disease that is incurable surgically. This traditional concept has recently been challenged by Studer et al, who reported that extensive pelvic lymph node dissection may be curative in patients with carcinoma of the prostate and bladder as demonstrated at short-term followup. 1, 2 Our case supports this hypothesis in that delayed removal of a single positive perirectal lymph node 1 year following radical prostatectomy and bilateral pelvic lymphadenectomy resulted in PSA returning to an undetectable level, at which it remained for 18 months of followup. Obviously, it would be impractical to attempt to remove the presacral and pericolic lymph nodes in all patients at high risk who undergo radical prostatectomy. However, it may be worthwhile to perform a meticulous dissection of the hypogastric lymph nodes as well as the external iliac and obturator lymph nodes in an attempt to cure the patient with low volume lymph node metastases. Bader et al found that the hypogastric lymph nodes were positive in 62% of patients with positive lymph nodes who had undergone radical prostatectomy, and these nodes were the only site of metastatic nodal disease in 20% of the patients. 3 In patients with positive lymph nodes undergoing radical cystectomy 5-year survival was 29%. Survivors had positive nodes at any site in the pelvis but, again, these were located predominantly along the hypogastric artery. 2 We would agree that longer followup is needed but at least in our patient a second extensive pelvic lymphadenectomy appears to have had therapeutic benefit in removing minimal residual lymphatic disease.

Ad5/48 Hexon Oncolytic Virus Expressing sTGFβRIIFc Produces Reduced Hepatic and Systemic Toxicities and Inhibits Prostate Cancer Bone Metastases

We are interested in developing oncolytic adenoviruses for the treatment of prostate cancer (PCa) bone metastases. A key limitation of Adenovirus 5 (Ad5) is that upon systemic administration, it produces major liver and systemic toxicities. To address this issue, a chimaeric Ad5/48 adenovirus mHAd.sTβRFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sTβRFc expressing soluble transforming growth factor beta receptor II-Fc fusion protein (sTGβRIIFc), were replaced by those of Ad48. mHAd.sTβRFc, like Ad.sTβRFc, was replication competent in the human PCa cells, and produced high levels of sTGβRIIFc expression. Compared to Ad.sTβRFc, the systemic delivery of mHAd.sTβRFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sTβRFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-α, and interleukin-6 levels, while mHAd.sTβRFc produced much reduced responses of these markers. Intravenous delivery of Ad.sTβRFc or mHAd.sTβRFc (5 × 10(10) viral particles/mouse) in nude mice bearing PC-3-luc PCa bone metastases produced inhibition of bone metastases. Moreover, a larger dose of the mHAd.sTβRFc (4 × 10(11) viral particles /mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sTβRFc could be developed for the treatment of PCa bone metastases.

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.

CHEK2 MUTATIONS INCREASE RISK FOR PROSTATE CANCER BUT DO NOT DIFFERENTIATE RISK OF LETHAL FROM INDOLENT DISEASE

INTRODUCTION AND OBJECTIVES: A recent study published in the New England Journal of Medicine found that CHEK2 germline pathogenic mutations are associated with metastatic prostate cancer (PCa) risk. The objective of this study is to assess whether CHEK2 germline mutations differentiate risk of lethal from indolent PCa. METHODS: A retrospective case-case study of 261 patients who died of PCa and 352 patients with localized PCa of European American descent was conducted. Germline DNA from each of the 613 subjects was sequenced for DNA repair genes and cancer-related genes through whole exome sequencing (WES) or targeted sequencing. Mutations were annotated according to the American College of Medical Genetics guidelines. RESULTS: Among the 613 PCa patients in the study, 11 (1.79%) carried CHEK2 germline pathogenic mutations, which was significantly higher than the estimate from the general population (ExAC database: 0.61%, P<0.0001). However, the mutation carrier rate in lethal PCa patients (5/2611⁄41.92%) was not significantly higher than either the localized cases in our study (6/3521⁄41.70%, P1⁄41.00) or in The Cancer Genome Atlas (2/4061⁄40.49%, P1⁄40.12). Among lethal cases, CHEK2 mutation carriers and non-carriers had similar mean age of death (77.0 and 73.0 years, respectively, P1⁄40.72) and mean time to death (10.0 and 8.0 years, respectively, P1⁄40.96). In the survival analysis of the entire study, CHEK2 mutations did not predict PCa-specific survival (Figure, log-rank P1⁄40.86, comparing with non-carriers). In contrast, germline mutations of BRCA1/2 and ATM predicted worse PCa specific survival (all log-rank P<0.05, comparing with CHEK2 carriers and non-carriers). CONCLUSIONS: CHEK2 germline mutations increase risk for PCa, but do not differentiate risk of lethal from indolent disease or PCaspecific survival. Source of Funding: The study is partially supported by the National Key Basic Research Program Grant 973 of China (2012CB518301), the Key Project of the National Natural Science Foundation of China (81130047), PCW Fund, and the Rob Brooks Fund for Personalized Cancer Care at NorthShore University HealthSystem.

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.

Adult UrologyOncology: Prostate/Testis/Penis/UrethraFactors Affecting Quality of Life at Different Intervals After Treatment of Localized Prostate Cancer: Unique Influence of Treatment Decision Making Satisfaction, Personality and Sexual Functioning

PURPOSEnUsing patient reported outcomes measures we identified the most informative set of factors associated with quality of life in a large sample of men treated for localized prostate cancer.nnnMATERIALS AND METHODSnWe examined relationships with quality of life using FACIT (Functional Assessment of Chronic Illness Therapy). We also hypothesized variables in a sample of men diagnosed with localized prostate cancer who represented different time points since treatment, including less than 12xa0months in 70, 1 to 3 years in 344, greater than 3 to 5 years in 291 and greater than 5 years in 97. Correlative measures included subscales of MAX-PC (Memorial Anxiety Scale for Prostate Cancer), short forms of PROMIS® and SOMS (Surgical Outcomes Measurement System), TDM-SATS (Treatment Decision-Making Satisfaction Scale) and subscales of the BFI (Big Five Inventory) of personality.nnnRESULTSnQuality of life was significantly associated with hypothesized variables across different time cohorts. In regression models several factors accounted for most of the variability in quality of life scores depending on time since treatment, including 47%, 22%, 29% and 27% at less than 12 months, 1 to 3 years, greater than 3 to 5 years and greater than 5 years, respectively. Upon examining the unique contribution of these variables, treatment decision making satisfaction was the only variable to have a significant and unique contribution to quality of life across all 4 time cohorts (standardized coefficients 0.33, 0.27, 0.31 and 0.49, respectively, p <0.01). In the cohort with 1 to 3 years since treatment erectile function and neurotic personality style also had unique associations with quality of life (standardized coefficients 0.25 and -0.20, respectively).nnnCONCLUSIONSnWhen considering the short-term and the longer term quality of life of a man after treatment for localized prostate cancer, our findings highlight the importance of treatment decision making satisfaction, erectile function and personality.

MP90-12 INHERITED RISK FOR OTHER TYPES OF CANCER AMONG MEN WITH OR WITHOUT PROSTATE CANCER BASED ON THE GENETIC RISK SCORE

(CWR22Rv1) and AR -ve cell line (DU145). Xenografted PC3 tumors in nude mice also showed NE differentiation when mice were treated with Dovitinib. The exact mechanistic underpinnings of this NE differentiation are unclear, but seem to be supported through MAPK and PI3K signaling pathways. CONCLUSIONS: Our study for the first time demonstrates that Dovitinib can induce neuroendocrine in AR +ve and AR eve PCa cell lines, both in vitro and in vivo. It provides a robust tool to study the NE differentiation process in vitro and identify vulnerabilities for therapeutic intervention. The NE differentiation might be a potential mechanism of resistance development to Dovitinib therapy, and thus could have critical clinical implications.