Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma.

Type 2 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) is a multi-functional enzyme that possesses 3alpha-, 17beta- and 20alpha-HSD, as well as prostaglandin (PG) F synthase activities and catalyzes androgen, estrogen, progestin and PG metabolism. Type 2 3alpha-HSD was cloned from human prostate, is a member of the aldo-keto reductase (AKR) superfamily and was named AKR1C3. In androgen target tissues such as the prostate, AKR1C3 catalyzes the conversion of Delta(4)-androstene-3,17-dione to testosterone, 5alpha-dihydrotestosterone to 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), and 3alpha-diol to androsterone. Thus AKR1C3 may regulate the balance of androgens and hence trans-activation of the androgen receptor in these tissues. Tissue distribution studies indicate that AKR1C3 transcripts are highly expressed in human prostate. To measure AKR1C3 protein expression and its distribution in the prostate, we raised a monoclonal antibody specifically recognizing AKR1C3. This antibody allowed us to distinguish AKR1C3 from other AKR1C family members in human tissues. Immunoblot analysis showed that this monoclonal antibody binds to one species of protein in primary cultures of prostate epithelial cells and in LNCaP prostate cancer cells. Immunohistochemistry with this antibody on human prostate detected strong nuclear immunoreactivity in normal stromal and smooth muscle cells, perineurial cells, urothelial (transitional) cells, and endothelial cells. Normal prostate epithelial cells were only faintly immunoreactive or negative. Positive immunoreactivity was demonstrated in primary prostatic adenocarcinoma in 9 of 11 cases. Variable increases in immunoreactivity for AKR1C3 was also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy and urothelial (transitional) cell metaplasia. We conclude that elevated expression of AKR1C3 is highly associated with prostate carcinoma. Although the biological significance of elevated AKR1C3 in prostatic carcinoma is uncertain, AKR1C3 may be responsible for the trophic effects of androgens and/or PGs on prostatic epithelial cells.

5alpha-Androstane-3alpha,17beta-diol activates pathway that resembles the epidermal growth factor responsive pathways in stimulating human prostate cancer LNCaP cell proliferation.

5alpha-Androstane-3alpha,17beta-diol (3alpha-diol) is considered to have no androgenic effects in androgen target organs unless it is oxidized to 5alpha-dihydrotestosterone (5alpha-DHT). We used microarray and bioinformatics to identify and compare 3alpha-diol and 5alpha-DHT responsive gene in human prostate LNCaP cells. Through a procedure called 'hypervariable determination', a similar set of 30 responsive genes involving signal transduction, transcription regulation, and cell proliferation were selected in 5alpha-DHT-, 3alpha-diol-, and epidermal growth factor (EGF)-treated samples. F-means cluster and networking procedures showed that the responsive pattern of these genes was more closely related between 3alpha-diol and EGF than between 5alpha-DHT and 3alpha-diol treatments. We conclude that 3alpha-diol is capable of stimulating prostate cell proliferation by eliciting EGF-like pathway in conjunction with androgen receptor pathway.

A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis.

PURPOSE: This pilot study was designed to evaluate the feasibility of a multicenter, randomized, clinical trial in interstitial cystitis (IC). Secondary objectives were to evaluate the safety and efficacy of oral pentosan polysulfate sodium (PPS), hydroxyzine, and the combination to consider their use in a larger randomized clinical trial. MATERIALS AND METHODS: A 2 x 2 factorial study design was used to evaluate PPS and hydroxyzine. Participants met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC and reported at least moderate pain and frequency for a minimum of 6 months before study entry. The primary end point was a patient reported global response assessment. Secondary end points included validated symptom indexes and patient reports of pain, urgency and frequency. The target sample size was 136 participants recruited during 10 months. RESULTS: A total of 121 (89% of goal) participants were randomized over 18 months and 79% provided complete followup data. The response rate for hydroxyzine was 31% for those treated and 20% for those not treated (p = 0.26). A nonsignificant trend was seen in the PPS treatment groups (34%) as compared to no PPS (18%, p = 0.064). There were no treatment differences for any of the secondary end points. Adverse events were mostly minor and similar to those in previous reports. CONCLUSIONS: The low global response rates for PPS and hydroxyzine suggest that neither provided benefit for the majority of patients with IC. This trial demonstrated the feasibility of conducting a multicenter randomized clinical trial in IC using uniform procedures and outcomes. However, slow recruitment underscored the difficulties of evaluating commonly available IC drugs.

Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study.

PURPOSE: We ascertained whether combined cisplatin, methotrexate and bleomycin have efficacy for treating locally advanced or metastatic carcinoma of the penis, and evaluate the toxicity resulting from this regimen. MATERIALS AND METHODS: Patients had biopsy proved locally advanced or metastatic epidermoid carcinoma of the penis. Chemotherapy consisted of 75 mg./m.2 cisplatin infused intravenously on day 1, 25 mg./m.2 intravenous bolus of methotrexate on days 1 and 8, and 10 unit per m.2 intravenous bolus of bleomycin on days 1 and 8 with a cycle length of 21 days. Our study was performed as a standard phase II evaluation with 2 stages of accrual. RESULTS: Enrolled in this study were 45 patients, including 40 who were evaluable for a response. There were 5 complete and 8 partial responses for a 32.5% response rate. Five treatment related deaths occurred and 6 of the 36 remaining patients evaluable for toxicity had 1 or more life threatening toxic episodes. CONCLUSIONS: A regimen of cisplatin, methotrexate and bleomycin appears to have promising results. However, toxicity was prodigious, and an emphasis of future research should be to decrease toxicity.

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer.

BACKGROUND: Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. METHODS: We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. RESULTS: Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. CONCLUSIONS: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

Wilms' tumor with renal cell carcinoma overgrowth in a 3-year-old child.

Wilms' tumors that contain features of both renal cell carcinoma and classic Wilms' tumor histology are rare. Even though nine such cases have been previously reported in the literature, we report the first case of a Wilms' tumor with an overwhelmingly renal cell carcinoma histologic pattern.

Influence of hepatic function on serum levels of prostate specific antigen.

PURPOSE: Recent studies have suggested that the primary site of metabolism for prostate specific antigen (PSA) is the liver. We evaluated men undergoing liver transplantation to determine whether chronic hepatic insufficiency affected serum PSA levels and whether improved hepatic function altered serum PSA levels. MATERIALS AND METHODS: Ten men with a mean age of 46 years (range 23 to 67) undergoing liver transplantation were evaluated. Liver function tests, including serum bilirubin, serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase, as well as serum PSA were determined 1 day before and a mean of 12.6 months (range 4 to 18) after transplantation. RESULTS: Serum bilirubin and serum glutamic-oxaloacetic transaminase declined significantly after liver transplantation. There was no difference in mean serum PSA levels before and after liver transplantation. CONCLUSIONS: Our results suggest that severe hepatic dysfunction does not significantly alter the serum concentration of PSA. These data, combined with recent investigations demonstrating an intrahepatic mechanism for PSA elimination, suggest that the liver has a significant reserve to metabolize the relatively small quantities of PSA in the circulation.

Prostate-specific antigen (PSA) and PSA density: racial differences in men without prostate cancer.

BACKGROUND: Many physicians now use serum prostate-specific antigen (PSA) to screen for prostate cancer in asymptomatic men. Whether or not a prostate biopsy should also be performed depends on an accurate definition of what constitutes a normal PSA value. Until recently, studies conducted to establish normal serum PSA values have involved study populations that have included few African-American men. PURPOSE: We sought to compare serum PSA levels and PSA density (i.e., serum PSA level/prostate volume ratio) in African-American and white men without histologic evidence of prostate cancer. METHODS: We reviewed the medical records of 826 consecutive men who underwent one or more prostate biopsies at the Veterans Affairs Medical Center in Shreveport, LA, from January 1993 through December 1995. In this retrospective review, we recorded patient's age, race, serum PSA level, digital rectal examination result, ultrasound-determined prostate volume, indications for biopsy, and biopsy results. Data from a total of 752 consecutive men who were either white or African-American and whose indication for biopsy included a serum PSA of greater than 4.0 ng/mL and/or an abnormal digital rectal examination were analyzed. To examine possible differences in serum PSA level, PSA density, prostate volume, and patient age, the two-sided Student's t test was employed. Multivariate linear regression analysis was used to determine if serum PSA levels were associated with the patient's age, race, or prostate volume in men without prostate cancer. RESULTS: Of the 752 men included in this analysis, 254 had histologic evidence of prostate cancer and 498 did not. Of the 498 men without prostate cancer, 367 (74%) men were white and 131 (26%) were black. There were no racial differences in age or calculated prostate volume. Serum PSA levels and calculated PSA density, however, were significantly (both P < .0001) higher in African-American men that in white men. A multivariate linear regression analysis indicated that race and prostate volume were independent variables associated with serum PSA level. For African-American and white men, serum PSA values of greater than 4 ng/mL were associated with prostate cancer with sensitivities of 89.5% and 81.9%, respectively, and specificities of 38.2% and 52.3%, respectively. CONCLUSION: Among biopsied men without histologic evidence of prostate cancer, African-Americans have a significantly higher PSA level and PSA density than similarly aged white men. IMPLICATIONS: Published criteria for normal PSA level and density have been derived primarily from white men and may not be directly applicable to other populations. Race-specific data are needed to fully optimize PSA as a tumor marker in racial populations that are at high risk for prostate cancer death.

Prostate specific antigen is metabolized in the liver.

PURPOSE: The site of metabolism of prostate specific antigen (PSA) was determined. MATERIALS AND METHODS: In a prospective study, during clinically indicated left and right heart catheterizations for various cardiac diseases in 12 men (mean age 62.5 +/- 8.3 years, standard deviation), selective blood samples were obtained from the infra-renal, infra-hepatic and supra-hepatic inferior vena cava, renal vein, superior vena cava, pulmonary artery and femoral artery. Mean PSA concentration was calculated for all vascular sites. Using a paired Student t test, the mean difference between the afferent and efferent PSA concentrations across the renal, hepatic, pulmonary and pelvic circulation was calculated. RESULTS: The hepatic gradient between the infra-hepatic and suprahepatic inferior vena cava showed the greatest decrease (0.11 +/- 0.16 ng./ml. or 8.3%) in PSA concentration and was statistically significant (p = 0.04). A smaller decrease across the pulmonary circulation was statistically insignificant. No decrease in the PSA concentration was noted across the renal circulation. The PSA concentration increased significantly (0.19 +/- 0.18 ng./ml. or 16.3%, p = 0.003) across the pelvic circulation, confirming the release of PSA from the prostate. CONCLUSIONS: PSA is released from the prostate. The kidneys and lungs do not have a significant role in elimination of PSA, and the liver appears to be the most likely site of its metabolism. Although our sample size is small and the PSA range is narrow, our results strongly support these conclusions.

Analysis of immunological alterations associated with testicular prostheses.

PURPOSE: Recipients of silicone gel filled testicular prostheses were evaluated for the possible immunological abnormalities of human adjuvant disease. MATERIALS AND METHODS: Medical record audits were performed for 48 recipients of a silicone gel filled testicular prosthesis. Seven patients consented to a detailed health profile questionnaire, physical examination and serological testing. RESULTS: Retrospective chart analyses and physical examinations were unremarkable. Serological results and questionnaire responses varied. One patient with signs and symptoms suggestive of human adjuvant disease underwent prosthesis removal but adjacent tissues had no evidence of silicosis. Long-term followup was poor. CONCLUSIONS: Immunological alterations were present in 71.4% of examined recipients but they may have been coincidental. Careful followup of recipients of a silicone gel filled testicular prosthesis is needed.

The impact of 5-alpha-reductase inhibitors on the number of prostatectomies for benign prostatic hyperplasia.

To determine the impact of a 5-alpha-reductase inhibitor on the need for surgical treatment of symptomatic benign prostatic hyperplasia (BPH) in clinical urologic practice, we retrospectively reviewed records of 794 patients treated with pharmacotherapy or surgery (or both). The number of transurethral resections of the prostate (TURPs) performed during the 30 months since introduction of finasteride was compared with the number performed during the 30 months before finasteride became available. The alpha-blockers doxazosin and prazosin were used during both times for the treatment of BPH. Of the 619 patients treated with drugs, 88.5% received finasteride for a mean of 249.6 days. The alpha-blockers, either alone or combined with finasteride, were prescribed for 11.5% of patients for a mean of 179 days. In the 30 months after the introduction of finasteride, 65 patients underwent TURP: 28 of these men had initially received drug therapy. In contrast, 138 TURPs were performed in the 30 months prior to the availability of finasteride. The use of a 5-alpha-reductase inhibitor as primary medical therapy for symptomatic BPH decreased the number of prostatectomies by 52.9% (65 vs 138). This observation warrants corroboration through additional prospective studies.

Cellular PSA in benign and malignant prostate.

To determine the relationship of carcinoma of the prostate and cellular production of prostate-specific antigen, cytosol levels of PSA were measured in benign and malignant fresh prostate tissue harvested from radical prostatectomy specimens. Wedge biopsies were taken from benign (N = 21) and malignant (N = 74) prostate tissue and were immediately fixed in liquid nitrogen, and then homogenized and differentially centrifuged, and the cytosol fractions extracted. The remaining specimen was sent for routine pathologic assessment. The Hybritech methodology was used to measure the cytosol PSA and standard protein analysis was used for cytosol protein (CP) measurement. There was a significantly greater concentration of PSA in malignant tissue (P = 0.046). Also, when benign and malignant tissue were available from a single prostate (N = 17), these differences in cytosol PSA were even greater (P = 0.002). In addition, there was no significant difference when serum PSAs from the malignant tissue were ranked according to Gleason score and placed into three different histologic grades (i.e., Gleason scores 2-4, 5-6, and 7-10).

Techniques for bypassing and stenting ureteral obstructions.

The advent of current endourological equipment and combined cystoscopic fluoroscopy allows the urologist to divert and/or stent the majority of benign and malignant ureteral obstructions in either a retrograde or antegrade fashion. We report on our recent experience in managing 105 obstructed renal units to formulate a troubleshooting endourological algorithm for bypassing and stenting ureteral obstructions. The methods described allow for safe and successful stent diversion in the majority of patients with ureteral obstruction requiring initial or primary endourological management. The algorithm presents alternative techniques for bypassing and stenting ureteral obstructions.

Evaluation of the current incidence of nodal metastasis from prostate cancer.

To determine the influences of transrectal ultrasonography, prostate-specific antigen (PSA), and heightened public awareness of prostate cancer stage at diagnosis, we prospectively evaluated our most recent 173 patients who had a pelvic lymphadenectomy from 1987 to 1991. All patients had clinically localized prostate cancer and underwent bilateral limited pelvic lymph node dissections (N = 173); 19 (10.7%) were found to have nodal metastasis. Pathologic tumor stage and grade information was available for 168 patients who had a simultaneous radical prostatectomy. Clinical T-stage data revealed that only one patient had a T3 lesion. Pathologic T stage showed 7.1% to be T1a (12/168), 4.1% to be T1b (7/168), 13.7% to be T2a (23/168), 34.5% to be T2b (58/168), and 40.5% to be T3 lesions (68/168). Metastatic nodal involvement was not seen in any T1a, T1b, or T2a lesions. A Gleason's score of less than 5 lesions was predictive of no nodal metastasis. The clinical stage was upstaged pathologically in none of the T1a, 16.7% of the clinical T1b, 75% of the T2a, and 73% of the T2b lesions. With regard to serum PSA, 27% of those patients with a level > 20 ng/ml had nodal metastasis (6/22) in this series. Although an elevated PSA was not predictive of tumor nodal metastasis, no patient with a normal PSA had nodal metastasis. Although the distribution of pathologic T stages is similar to that reported in the literature, our low incidence of nodal metastasis may suggest that prostate cancer is being diagnosed earlier.

Anatomic, functional, and pathologic changes from internal ureteral stent placement.

The anatomic, hydrodynamic, functional, and pathologic changes associated with unilateral internal ureteral stenting were evaluated in 20 female canines. Selective glomerular filtration rates (GFR) were measured with technetium 99m diethylenetriamine pentaacetic acid (DTPA) renal scans (N = 14) prior to and several weeks after unilateral internal stent placement. Cystometry and cystography were done at weekly intervals to determine if reflux occurred and to measure the intravesical pressure to produce this reflux (N = 16). Ureteral lumenal capacities of mid 6-cm ureteral segments of stented and unstented ureters were compared. The mid-ureteral lumenal volumes were three times greater in the stented ureters (p < 0.002). There were no significant differences in the selective GFR before and after stenting. Low-pressure vesicoureteral reflux occurred at a mean intravesical pressure of 13.7 cm of water and was present in 84.6 percent (11/13) of the canines whose stents did not migrate or obstruct from encrustation. There were no significant alterations in serum chemistries or blood counts. Fluoroscopic imaging also showed ineffective ureteral peristalsis. This study confirms that internal ureteral stents cause vesicoureteral reflux and significant lumenal dilation without altering renal function.