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|ELEVATED SERUM SECRETONEURIN LEVELS IN PATIENTS WITH THERAPY-RESISTANT PROSTATE CANCER.|
Rudolf Ischia, Alfred Hobisch, Richard Bauer, Ulrike Weiss, Rudolf Gasser, Wolfgang Horninger, Georg Bartsch, jun., Dietmar Fuchs, Georg Bartsch, Hans Winkler, Helmut Klocker, Reiner Fischer-Colbrie, Zoran Culigæ Innsbruck, Austria
Introduction and Objectives Secretoneurin (SN) is a neuropeptide generated by processing of the large dense-core vesicle constituent secretogranin II. This study was undertaken to assess clinical significance of SN serum levels in benign and malignant prostate disease.
Methods: SN and chromogranin A levels were measured by radioimmunoassay in sera from patients with benign (n = 28) and malignant prostate disease (n = 48) and healthy controls (n = 16). 18 samples were obtained from patients with pT2 prostate cancer, 10 samples from patients with pT3 tumor, and 20 specimens were from patients with therapy-resistant prostate cancer (D3). Molecular properties of SN-immunoreactivity were analyzed by gel filtration chromatography followed by radioimmunoassay.
Results High SN levels were measured in patients with D3 prostate cancer (58.9 ±8 fmol/ml). SN levels in other patient groups were as follows: pT3 prostate cancer 31.3 ±5.7 fmol/ml, pT2 prostate cancer 24.7 ±3.2 fmol/ml, prostatitis 17.7 ±1.5 fmol/ml, and benign prostate hyperplasia 19.3 ±1.7 fmol/ml. In the age-matched healthy control group SN levels were 23 ±2.1 fmol/ml. Differences between SN levels in patients with advanced prostate cancer and any other group were statistically significant. Chromogranin A levels were also higher in patients with therapy-resistant prostate cancer (73 ±19 U/l) than in any other patient collective. There was a statistically significant correlation between SN and chromogranin A in the group of patients who failed endocrine therapy (r=0.543, p<0.05). Gel-filtration chromatography analysis of patients sera revealed one peak of SN-immunoreactivity at the position where intact SN elutes thus showing that the processed peptide is circulating in the blood.
ConclusionsOur data show that SN levels are elevated in patients who do not respond to endocrine therapy for prostate cancer.
Supported by: Austrian Science Foundation
OXIDATIVE STRESS AND SEMEN SCORE - NEW MEASURES OF SEMEN QUALITY IN PATIENTS UNDERGOING INFERTILITY TREATMENT.
Rakesh K. Sharma, Fabio F. Pasqualotto, David R. Nelson, Anthony J. Thomas, Jr., Ashok AgarwalæCleveland, OH
Introduction and Objectives We developed a new measure of oxidative stress called ROS-TAC score and also reduced 9 sperm characteristics into 2 semen scores. The purpose of this study was to determine if the ROS-TAC and semen scores can be used to quantify the semen quality in patients with various diagnoses of infertility.
Methods: Semen characteristics, reactive oxygen species (ROS) levels, non-enzymatic total antioxidant capacity (TAC) and a composite ROS-TAC score were examined using samples from 238 infertile patients with various clinical diagnoses and 19 normal, healthy donors. ROS-TAC score was determined from levels of ROS and TAC. Principal component analysis was applied to these parameters after log transformation to reduce the effects of varying scales and distribution.
Results Of the 238 patients, the distribution of clinical diagnoses included: varicocele (n = 77), prostatitis and infection (n = 46), vasectomy reversal (n = 43), varicocele and infection (n = 11), idiopathic infertility (n = 36), and others (n = 25). The first principal component (a weighted sum of all semen characteristics accounted for 64.7% of the overall variability) was named "SQ" (semen quality). The second component (a weighted sum of 8 characteristics subtracted from concentration) was considered a measure of relative quantity and was thus named "RQ". The distributions of SQ and RQ among the controls were standardized to a mean of 100 ±10. All groups had SQ values significantly different from control (P <0.03). RQ values were comparable between the controls and all clinical diagnosis, indicating that their concentrations were at levels expected based on the other characteristics. Increased oxidative stress was significantly correlated with both decreasing semen quality (SQ, P <0.001) and relative quantity (RQ, P <0.04) in all clinical diagnoses.
ConclusionsSemen characteristics can be reduced to 2 scores which account for over 80% of the variability expressed by all semen characteristics individually. As these scores are significantly related to oxidative stress, they can be used to evaluate the semen quality and to predict pregnancy outcome.
Supported by: Grant from Cleveland Clinic Foundation
PHASE I CLINICAL TRIAL OF NEOADJUVANT ADENOVIRUS-MEDIATED HSV-TK GENE THERAPY PLUS GANCICLOVIR PRIOR TO RADICAL PROSTATECTOMY
Waleed Hassen, Michael A. Sanford, Pamela Unger, Michael J. Droller, Savio L. C. Woo, Simon J. HallæNew York, NY
Introduction and Objectives In preclinical studies adenovirus mediated Herpes Simplex virus thymidine kinase (Ad. HSV-tk) gene transduction plus ganciclovir (GCV) therapy suppresses growth of prostate cancer. A phase I clinical trial was undertaken to explore Ad. HSV-tk + GCV as neo-adjuvant therapy in patients with clinical stage T1c or T2b/c prostate cancer prior to radical prostatectomy
Methods: Vector was injected via 3 separate transrectal ultrasound (TRUS) guided needle tracts, attempting to localize cancer by the presence of palpable lesions, TRUS findings and/or prior biopsy information. Post-vector injection patients received GCV (5mg/kg/BID) for 1 week, undergoing radical prostatectomy 7-10 days later. Patients are injected once for a single cycle of GCV in 3 patient cohorts at escalating doses, increasing by 1 log increments to a maximum dose of 1x1012 iu.
Results This ongoing trial has completed cohorts at 1x1010 and 1x1011 iu . Grade 2 fevers beginning on the night of the injection were encountered in 4 patients, lasting for 24-48 hours. Two patients had grade 1 WBC toxicity, which resolved after lowering the dose of GCV to 2.5mg/kg for 4 doses. No other treatment related toxicities were noted. One patient developed a DVT prior to prostatectomy, resulting in a delay of surgery until 38 days post- injection. Surgery has not been compromised by the placement of needles nor the resultant inflammatory process. Pathological examination of the prostate noted an inflammatory response similar to that seen in animal studies in 5/6 patients. Inflammation sometimes extended across several centimeters of tissue, while in other instances remained limited. Furthermore, this infiltrate could be seen within both benign and malignant areas of the prostate. PSA was noted to rise in 2/3 patients in the 1x1011 iu cohort compared to none at the lower dose, implying a dose dependant prostatitis. No significant decrease in PSA was noted within the 14-17 days between virus injection and surgery in 5 patients. The remaining patient at 1x1010 iu, who had the delay of surgery, had a PSA drop from 11 to 5.4.
ConclusionsThus far Ad.HSV-tk+GCV has minimal toxicity and appears to have activity in prostate cancer.
Supported by: NY Academy of Medicine, NIH, and Roche Laboratories
INTRARECTAL LIDOCAINE GEL DURING TRANSRECTAL PROSTATE BIOPSY: A RANDOMIZED CONTROLLED PROSPECTIVE STUDY
Thomas Chun, Sajit Bux, Anthony Labadia, Katrina Anastasia, Elayne Miller, John A. Petros, Muta M. IssaæAtlanta, GA
Introduction and Objectives A significant proportion of patients experience discomfort during transrectal prostate biopsy (TPB) yet to date, limited information exists regarding the amount of discomfort or whether local anesthesia can assist in making this procedure more comfortable. The objective of this prospective study is to evaluate the role of intrarectal lidocaine gel as local anesthesia during transrectal prostate biopsy.
Methods: Fifty consecutive patients with abnormal digital prostate exam and/or elevated serum PSA undergoing TBP were enrolled in this study. Patients with history of previous TPB, chronic prostatitis, prostatodynia, anal and rectal conditions, neurological conditions, allergy to lidocaine or on concomitant analgesics/narcotics were excluded. Patients were randomized into two groups; group-A (n=25) underwent intrarectal instillation of 10cc of 2% viscous lidocaine gel approximately 10 minutes prior to the procedure and group-B (n=25) served as control. No supplemental sedation, narcotic, or analgesia was used. Pain control during the procedure was assessed using a 10-point visual linear analogue pain scale.
Results Patients' median age was 63 years in group-A and 66 in group-B (p=0.13). The median PSA was 6.4ng/mL (1.0-263.0) in group-A and 7.2ng/mL (1.3-51.8) in group-B (p=0.33). Group-A patients experienced less pain during the procedure than group-B patients. The median pain score was 2 (1-5) in group-A and 5 (1-7) in group-B (p=0.0001) with 2% and 52% of patients scoring 5 on the pain scale in group-A and group-B, respectively, (p=0.0001). No adverse events were encountered in either group.
ConclusionsIntrarectal 2% lidocaine gel (10cc) is simple, safe, convenient, effective and highly satisfactory method of local anesthesia during transrectal prostate biopsy.
INTERSTITIAL CYSTITIS OR prostatitis? PENTOSAN POLYSULFATE THERAPY FOR MALE CHRONIC PELVIC PAIN SYNDROME
Brenda Johnston, Joe Downey, J. Curtis Nickel, the Canadian PPS/CPPS Research GroupæKingston, ON, Canada
Introduction and Objectives Chronic pelvic pain syndrome (CPPS) in males may not be a specific prostate problem. CPPS in males has similar clinical and perhaps etiological characteristics as interstitial cystitis (IC). The mechanism of action of pentosan polysulfate (PPS), an oral medication indicated for the treatment of IC, is believed to be supplementation of the glycosoaminoglycans of the bladder surface but there is no data to suggest that PPS reaches or is excreted by the prostate. We undertook an open label multi-center phase II pilot study to examine the potential efficacy of PPS in the treatment of CPPS in males, employing outcome tools validated for chronic pelvic pain syndrome in males.
Methods: Patients with a diagnosis consistent with NIH CPPS Category IIIA (inflammatory) were treated with PPS, 100 mg tid, for 6 months. Evaluation at baseline, 3 months and 6 months consisted of symptom severity index (SSI), symptom frequency questionnaire (SFQ), a prostatitis pain index (NIH-CPSI), quality of life assessment (QoL) and subjective global assessment (SGA).
Results 32 Patients (mean age 45.5+/-11 yrs; duration of symptoms 9.2+/-12 yrs) were enrolled in 5 centers. 6 patients withdrew from study. Drug related side effects included hair loss (6%), headache (3%), mild jaundice (3%), mild nausea (3%) and skin flushing (3%).
Outcome Baseline 3 months 6 months Significance
SSI 53.1+/-19.4 40.1+/-28.5 37.5+/-29.5 p = 0.056
SFQ 27.8+/-9.1 20.0+/-11.9 18.7+/-13.7 p < 0.05
NIH-CPSI 14.5+/-3.4 10.3+/-6.0 9.4+/-7.3 p < 0.05
QoL 5.2+/-0.6 4.0+/-1.8 3.9+/-1.8 p < 0.05SGA at 6 months confirmed mild improvement in 30%, moderate in 15% and marked improvement in 15%. 40% of patients had >50% improvement in SFQ; 45% had >50% improvement in SSI, NIH-CPSI and QoL.
ConclusionsPPS is well tolerated and appears to have efficacy in reducing severity and frequency of general symptoms, reducing specific pain symptoms and improving quality of life in many male patients with CPPS. The safey and efficacy of PPS should be compared to placebo in a well designed randomized controlled trial.
Supported by: ALZA Canada, NIH/NIDDK
BACTERIAL CULTURES IN URINE, PROSTATIC FLUID AND SEMEN OF MEN WITH CHRONIC PELVIC PAIN SYNDROME: ROLE OF CULTURE FOR 2 VS 5 DAYS
Daniel A. Shoskes, Carissa Mazurick, Richard Landis, Michael Ruggieri, Robert B. Nadler, Keith Jarvi, Lee Nyberg, NIH Chronic prostatitis Collaborative Research NetworkæTorrance, CA; Philadelphia, PA; Chicago, IL; Toronto, ON, Canada; Washington, DC
INTRODUCTION AND OBJECTIVE: The role of bacterial pathogens in chronic pelvic pain syndrome (CPPS) is controversial. Nevertheless, some patients do respond well to antibiotic therapy despite negative cultures. Prostatic fluid (EPS) may require longer culture duration to detect bacterial growth than the 2 days commonly used for urine. We wished to compare 2 and 5 days of culture for bacterial detection in EPS and urine.
Methods: Between Oct 1998 and Sept 1999 202 patients were enrolled in the National Chronic prostatitis Cohort (CPC) Study who met NIH criteria for CPPS. Specimens from the standard 4 glass test (VB1, VB2, EPS, and VB3) plus semen were cultured and examined for bacterial growth at 2 and 5 days (not all patients had EPS or VB3). Specimens negative at 2 days but positive at 5 days (2-/5+) were analyzed by source, bacterial species and associated inflammation.
Results A high proportion of specimens had bacterial growth (ranging from 62% in VB2 to 80% in EPS) however the majority were for low counts of Gram positive bacteria. Of positive specimens, the proportion that were 2-/5+ was VB1 14.6%, VB2 6.9%, EPS 23.3%, VB3 9.3% and semen 20%. For 2-/5+ samples, Streptococci and Corynebacteria were found in each specimen source, however Staphylococci and E. Coli were only found in EPS, VB3 and semen. Importantly, 3 of 7 EPS specimens positive for E. Coli were 2-/5+ and 2 of these localized to EPS (absent in VB1). Overall, of the 24 EPS 2-/5+ cultures, 63% localized to the prostate. In 21 semen 2-/5+ cultures, 62% localized to the semen. Positive 2-/5+ cultures were associated with higher EPS WBC counts for all bacterial types except E. Coli.
ConclusionsBy culturing EPS or semen for 5 days rather than 2 days, an additional 7.5% will be found positive for bacteria that localize to the prostate. Gram positive bacteria found this way are associated with increased inflammation in EPS.
Supported by: NIH
MECHANISMS OF FAS-MEDIATED APOPTOSIS SIGNALING PATHWAYS IN prostatitis
Jordan D. Dimitrakov, Georges Rawadi, Wolfgang WeidneræGiessen, Germany; Paris, France
Introduction and Objectives Fas ligand (CD95L) inhibits T cell function in immune-privileged organs, yet in most tissues CD95L expression induces potent inflammatory responses dependent on the presence of various cytokines, especially tumor necrosis factor-alpha (TNF-a). We investigated the mechanisms that initiate induction of Fas-mediated apoptosis in the prostate of patients with chronic prostatitis/pelvic pain syndrome (CPPS Group IIIA).
Methods: Cultured prostate epithelial cells (PEC) from 30 biopsy samples of CPPS patients, which WEre insensitive to Fas-mediated apoptosis in spite of Fas antigen expression, were used in these experiments. Cell proliferation and cytotoxicity studies were performed using MTS and lactate dehydrogenase release assays. Surface expression of Fas antigen was analyzed by flow cytometry. The expression and function of apoptosis-signaling molecules, such as caspase-8 and caspase-3, were examined by immunoblot analysis. An RNase protection assay and Western blotting analysis were used to quantify fas antigen mRNA and protein expression.
Results Fas ligation with anti-Fas monoclonal antibody (mAb) resulted in cytotoxic activity against cultured PEC that had been pretreated with TNF-alpha
for 5 days. In contrast, anti-Fas mAb did not show a cytotoxic effect against untreated cultured PEC. A gradual up-regulation of caspase 8 and caspase 3, was observed in TNF-alpha-treated cultured PEC. In addition, Fas ligation to TNF-alpha-treated cultured PEC induced activation of caspase 8 and caspase 3, with subsequent cleavage of poly(ADP-ribose)polymerase (PARP), a substrate of activated caspase 3. More importantly, Z-IETD-FMK, a caspase-8 inhibitor, andAc-DEVD-CHO, a caspase-3 inhibitor, almost completely inhibited Fas-mediated apoptosis of TNF-alpha-treated cultured PEC.
ConclusionsOur results clearly demonstrate that TNF-alpha stimulates sensitizes the cells for Fas-mediated apoptosis, at least in part by up-regulation and activation of caspase-8 and caspase-3.
Supported by: Government
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