Early effects of castration on the vascular system of the rat ventral prostate gland.

Recent studies have found that blood flow to the rat ventral prostate gland is drastically reduced at an early time after castration. These observations caused us to reevaluate the effects of castration on the various cell populations of the ventral prostate, especially those in the prostatic vascular system. Sections of ventral prostate glands obtained at different times after castration were analyzed using the TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick END labeling) staining method to quantify apoptosis in different cell types. The results of this analysis showed a significant increase in TUNEL staining of prostate endothelial and (nonendothelial) stromal cells as early as 12 h postcastration that continued to 24 h after castration. In contrast, TUNEL labeling of prostate epithelial cells was not significantly increased compared with control values until 72 h after castration. The use of dual immunohistochemical staining procedures (anti-CD31 for endothelial cells or antismooth muscle actin for smooth muscle cells combined with TUNEL labeling) allowed us to confirm that the TUNEL-positive vascular cells at these early times after castration were endothelial in nature, whereas smooth muscle cells surrounding the prostate glands or portions of the afferent vascular endothelium were rarely TUNEL labeled. Electron microscopic evaluation of ventral prostate tissues at 48 h after castration provided further morphological evidence for the occurrence of apoptosis in prostate endothelial cells. Finally, the Lendrum-Fraser histochemical procedure used to identify fibrin leakage in tissues with vascular damage was applied to sections of the ventral prostate gland. This stain revealed diffuse fibrin accumulation in periglandular areas outside the capillaries and blood vessels in prostates from 24-h castrated rats, but not in prostates of sham-operated rats. Our results confirm an early effect of castration on the vascular system of the rat ventral prostate identified by increased apoptosis of endothelial cells and vascular leakiness. As these changes temporally precede the loss of epithelial cells, we propose that they may be causal rather than incidental to regression of the rat ventral prostate after castration.

Exisulind, a selective apoptotic antineoplastic drug.

Exisulind (Aptosyn, Cell Pathways, Inc.) is the first of a new class of targeted, pro-apoptotic drugs that show promise in the treatment of cancer. These agents induce apoptosis (i.e., programmed cell death) in a broad range of pre-cancerous and cancerous tissues without affecting normal cells. The antineoplastic effect of exisulind appears to be the result of activation of protein kinase G (PKG) which leads to multiple downstream effects culminating in apoptosis. Exisulind has demonstrated antineoplastic activity in solid tumour and haematological cancer cell lines and is an inhibitor of tumour growth in rodent models of colon, prostate, bladder, mammary and lung cancer. Preclinical data evaluating selective apoptotic antineoplastic drugs (SAANDs) in combination with various chemotherapy drugs indicates additive or synergistic antineoplastic effects. In clinical studies, exisulind prevented colorectal polyp formation in patients with familial adenomatous polyposis (FAP) over 24 months. In a randomised, placebo-controlled study of prostate cancer patients, exisulind inhibited the rise of prostate-specific antigen (PSA) in men with PSA progression after radical prostatectomy. Exisulind has been well-tolerated by most patients in clinical trials. In conclusion, preclinical evidence and early clinical results suggest that exisulind and other drugs in this class may have wide applications in treating cancer both as monotherapy and in combination with chemotherapy and other targeted agents.

MacLeod revisited: sperm count distributions in 374 fertile men from 1971 to 1994.

OBJECTIVES: There has been an enormous amount of interest as to whether sperm counts are declining over time. We sought to compare a contemporary group of fertile men to those from the MacLeod study of 1951 to ascertain whether sperm counts in fertile men have changed over time. METHODS: We obtained sperm count data from 374 fertile men who banked sperm in Minnesota prior to vasectomy from 1971 to 1994 and compared them to sperm count distributions from the 1000 fertile men of MacLeod's study. Semen analyses were performed as per World Health Organization guidelines using identical techniques in both the present and MacLeod studies. RESULTS: The contemporary group had a mean sperm count of 102 +/- 81 x 10(6)/mL (median 85 x 10(6)/mL) compared to 107 +/- 74 x 10(6)/mL (median 90 x 10(6)/mL) for MacLeod's data. There are no significant differences in mean or median sperm counts or sperm count distributions between the groups. CONCLUSIONS: We find remarkable similarities in sperm count distributions in cohorts of fertile men from 1951 and 1971 to 1994. Sperm counts in fertile men have not changed appreciably in the 40 years since MacLeod's report.

Worldwide variations in sperm counts.

OBJECTIVES: Based on the premise that various human disease processes manifest differently depending on geography, we set out to determine whether sperm counts vary from different nations and different regions within the United States. METHODS: We reviewed the literature of all significant population-based studies that evaluated sperm counts from fertile or presumably fertile men from 1930 to the present. RESULTS: We found that sperm counts did, in fact, vary greatly. Throughout the United States, average sperm counts ranged from a low of 48 million/cc in lowa to a high of 134 million/cc in New York, with multiple values in-between from Texas, Minnesota, Washington State, and California. Internationally, average sperm counts ranged from a low of 52.9 million/cc in Thailand to a high of 102.9 million/cc in France. CONCLUSIONS: We conclude that sperm counts are subject to a wide range of variation among geographic locations.

Leiomyoma of bladder: report of case and review of literature.

We recently treated a patient with leiomyoma of the bladder and reviewed the 37 most recent cases in the English language literature. Mean patient age was forty-four years. Women made up 76 percent of the patients. Patients presented most commonly with obstructive urinary symptoms (49%), irritative symptoms (38%), hematuria (11%), or flank pain (13%); 19 percent were asymptomatic. Almost all patients had cystoscopy (87%) and intravenous urograms (IVU) (81%), but fewer had masses on bimanual examination (57%), ultrasound (49%), or computed tomography (CT) scan (35%). Most patients were treated with open resection (62%), while 30 percent were treated with transurethral resection (TUR). Almost all patients were cured with a single procedure (89%). Leiomyoma of the bladder is rare and readily cured with excision.

Incidence of external spermatic veins in patients undergoing inguinal varicocelectomy.

OBJECTIVES: To determine the incidence of external spermatic veins at inguinal varicocelectomy. METHODS: A prospective study was performed by making intraoperative observations on 78 varicocelectomies (47 patients) performed by a single surgeon. All patients were referred for evaluation of male infertility and had a palpable varicocele present when examined while performing a Valsalva maneuver in the upright position. Varicocelectomies were performed via the inguinal approach using x 2.5 loupe magnification. Presence of external spermatic veins was defined as visualization (with x 2.5 loupe magnification) of veins on the floor of the inguinal canal traveling posterolateral to the spermatic cord that then subsequently exited the spermatic cord before passing through the internal inguinal ring. Age, anesthetic technique, and need for incision of the external inguinal ring were also recorded for each patient. RESULTS: One third of patients had undergone left-sided varicocelectomies, while two thirds had undergone bilateral procedures. External spermatic veins were identified in 15% of left-sided varicoceles and 19% of right-sided ones. Of 31 patients undergoing bilateral varicocelectomies, 19% had at least 1 external spermatic vein. Of these patients, only 2 (7%) had a unilateral right external spermatic vein, none had a unilateral left external spermatic vein, and 4 (13%) had bilateral external spermatic veins. Overall, of all patients studied, 16% had at least 1 external spermatic vein. Follow-up at 1 year showed no evidence of clinical recurrence in any patient. CONCLUSIONS: These results emphasize the importance of distal gonadal venous anatomy in the surgeon's choice of the proper approach to varicocele repair, since external spermatic veins are only accessible via an inguinal approach.

Association of radionuclide bone scan and serum alkaline phosphatase in patients with metastatic renal cell carcinoma.

OBJECTIVES: We assessed the frequency of bone metastases, their association with serum alkaline phosphatase (AP), and prognostic capabilities of AP in patients with renal cell carcinoma (RCC), using bone scan as the reference standard for diagnosis. METHODS: We conducted a retrospective review of patients with metastatic RCC treated with either autologous ex vivo activated T-lymphocytes and cimetidine (ALT) or cimetidine alone. RESULTS: Twenty-eight of 90 patients (31%) had evidence of bone metastases by bone scan. With 100 mg/ dL as the upper limit of normal, 11 of 28 (39%) patients with bone metastases had normal AP levels. Of these 11 patients, 8 had bone pain. Of the 3 asymptomatic patients with bone metastasis and normal AP levels, only 1 had bone as the only site of metastasis and would have been incorrectly staged without the scan. Patients with bone metastases had a significantly shorter median survival than those without bone metastases (13.8 versus 25.3 months; P < 0.05). Among patients without bone metastases who had elevated AP levels, those treated with ALT had significantly longer median survivals than those treated with cimetidine alone (27.6 versus 14.5 months; P < 0.05). Overall, patients treated with ALT had a significantly longer median survival than the ones treated only with cimetidine (21 versus 8.5 months; P < 0.05). Overall, the median survival for patients with elevated AP levels (10 months) was not significantly different from that of those with normal AP levels (13 months). CONCLUSIONS: In a high-risk group of patients with metastatic RCC, 31% had bone metastases. Elevated AP levels, the presence of bone pain, or the presence of other metastases correctly predicted bone metastasis in all but 1 patient. A bone scan may safely be omitted in patients with RCC, normal AP levels, and no bone pain. However, AP elevation itself had little prognostic capability in these patients.

Reconstruction of urinary and gastrointestinal tracts in total pelvic exenteration: experience at Columbia-Presbyterian Medical Center.

OBJECTIVES: To examine the effectiveness of and complications from total pelvic exenteration (TPE) with maintenance of urethral and anal sphincter function for locally invasive tumors of the pelvis. METHODS: A retrospective review of 4 patients who have undergone TPE with urethral and anal sphincter preservation at Columbia-Presbyterian Medical Center in the last 2 years was performed with attention to perioperative morbidity and mortality, disease-free status, and need for further operative procedures. RESULTS: Two patients had colorectal adenocarcinoma, 1 had squamous cell carcinoma of the cervix, and 1 had prostate sarcoma. All had urinary tract reconstruction with orthotopic neobladder creation, and 3 of 4 had primary low rectal anastomoses for gastrointestinal reconstruction. One patient underwent creation of a J rectal pouch. One of 4 patients had received radiation therapy for the disease prior to surgery. There was no operative or perioperative mortality. Two of 4 patients required reoperation, 1 in the immediate postoperative period for repair of a left ureteral stricture, and the other 13 months postoperatively for repair of a rectal-neobladder fistula. With a mean follow-up of 25 months (range, 21 to 43 months), 3 of 4 patients are alive and free of disease. All living patients are continent of urine and 2 of 3 are continent of stool. CONCLUSIONS: Our experience confirms that TPE can be effective in controlling a variety of locally advanced pelvic tumors and can be performed in conjunction with simultaneous genitourinary and gastrointestinal reconstruction with minimal morbidity.

Relationship between antisperm antibodies and testicular histologic changes in humans after vasectomy.

OBJECTIVE: To determine whether or not there is an association between testicular histologic changes and antisperm antibodies in vasectomized men. METHODS: Morphometry was performed on testicular biopsy specimens obtained from 19 vasectomized men and 21 fertile control subjects. Antisperm antibody status was determined on the serum of each patient and control subject using the indirect immunobead assay. RESULTS: Significant increases in seminiferous tubule wall thickness (p < 0.001), focal interstitial fibrosis (p < 0.001), and percent composition of interstitium (p < 0.01) were observed in vasectomized men as compared with control subjects. Serum antisperm activity was present in 74 percent of the vasectomized men but none in the control subjects (p < 0.001). There was no association between testicular histologic changes and immune status. CONCLUSIONS: Vasectomized men exhibit significant testicular histologic changes and increased autoimmune activity as compared with fertile control subjects. These histologic changes are not directly associated with antisperm antibody status, suggesting that some other pathophysiologic process must be responsible.

Effect of demographic factors, urinary peak flow rates, and Boyarsky symptom scores on patient treatment choice in benign prostatic hyperplasia.

OBJECTIVES: To determine the effect of patient's age, race, Boyarsky score, and urinary flow rate on type of treatment selected for benign prostatic hyperplasia (BPH) and to evaluate maintenance of treatment at 1-year follow-up. METHODS: Subjects in this prospective study, conducted in a referral center prostate clinic, were 174 consecutive patients, aged 67.6 +/- 10.8 years (mean +/- SD), with previously untreated BPH. Patients underwent structured interviews and uroflowmetry, then completed the Boyarsky Symptom Index. Blinded to these data, one physician described four treatment categories in a nonjudgmental fashion, always using the same order: watchful waiting; finasteride and alpha-blocker; thermal therapy, balloon dilation, and a prostate stent; and transurethral prostate resection. Treatment choice was entirely that of the patient. Independent variables were patient's age, race, symptom score, and uroflow; the dependent variable was treatment choice. At 1 year, the same physician interviewed patients to evaluate maintenance of therapy. RESULTS: Only symptom score and flow rate were predictive of treatment choice, high scores and low flow being associated with more aggressive treatment choices (P = 0.001). Most patients, regardless of symptom severity, chose interventions less aggressive than surgery and more aggressive than watchful waiting. At 1 year, 85% of patients continued to be maintained on their original treatment. CONCLUSIONS: Men with mild or moderate BPH prefer interventions of moderate aggressiveness; race and age make little or no difference. If maintenance of treatment indicates patient satisfaction, most patients appear to remain satisfied with therapy they select.

Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis.

OBJECTIVES: Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. METHODS: Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 10(7) LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. RESULTS: Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P<0.0001) but no change in the number of BrdU positive cells. CONCLUSIONS: This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

Geographic variations in sperm counts: a potential cause of bias in studies of semen quality.

OBJECTIVE: To determine whether geographic variations in sperm counts might bias conclusions drawn from studies of semen quality. DESIGN: Reanalysis of published data from a meta-analysis of 61 studies from 1938 to 1990 that concluded a worldwide decline in semen quality over the last 50 years. MAIN OUTCOME MEASURES: Influence of geographic location on sperm counts. RESULTS: Of 61 studies in the meta-analysis, only 20 included > or = 100 men. These 20 studies collectively comprised 91% of the total men studied. We focused our reanalysis on these 20 studies. Of the studies before 1970, all were from the United States and 80% were from New York. These studies represented locations with the highest sperm counts. In contrast, after 1970, 80% of the studies were from locations not represented earlier, including five studies from third world countries, where sperm counts were low. CONCLUSIONS: Sperm counts vary dramatically among different geographic locations.

Semen analyses in 1,283 men from the United States over a 25-year period: no decline in quality.

OBJECTIVE: To determine whether semen quality has changed in the United States over the last 25 years. DESIGN: Retrospective review. SETTING: Three U.S. sperm banks, Cryogenic Laboratories, Inc. (Roseville, Minnesota), Idant Laboratories (New York, New York), and California Cryobank, Inc. (Los Angeles, California). INTERVENTION: None. MAIN OUTCOME MEASURES: Age at sample collection, sperm concentration, volume, motility, and days of abstinence before sample collection were determined for each man. Linear and multiple regression analyses were used to assess changes in these characteristics over time. RESULTS: Controlling for the effects of age and duration of abstinence, there was a slight but significant increase in mean sperm concentration but no change in either motility or semen volume over the 25-year period. Both sperm motility and semen volume decreased with increasing age at sample collection. Both sperm concentration and semen volume increased as a function of duration of abstinence. There were significant differences in mean (+/- SEM) sperm concentrations (10(6) sperm/mL) and motilities between the different sperm banks with California lowest (72.7 +/- 3.1, 51.4% +/- 1.1%, respectively), Minnesota higher (100.8 +/- 2.9, 56.0%, respectively), and New York highest (131.5 +/- 3.5, 58.2% +/- 0.5%, respectively). CONCLUSIONS: Our data show no decline in sperm counts over a 25-year period in 1,283 men who banked sperm before vasectomy at three distinct geographical sites in the United States.

External beam radiation therapy does not offer long-term control of prostate cancer.

In the absence of large, contemporary, randomized series comparing external beam radiation and radical prostatectomy, definitive conclusions regarding relative efficacy are difficult to establish. This article examines series in which an objective, comparable end point was used and prostate-specific antigen (PSA) response was assessed. With follow-up of less than 5 years, PSA-based recurrence rates are similar for external beam radiation and radical surgery; however, the 10- and 15-year control rates are significantly lower in the population of patients treated with external beam radiation. The authors conclude that external beam radiation therapy as a single modality does not equal radical prostatectomy in comparably staged and followed patients.

Development of a hammerhead ribozyme against BCL-2. II. Ribozyme treatment sensitizes hormone-resistant prostate cancer cells to apoptotic agents.

BACKGROUND: Several lines of evidence strongly implicate a crucial role for the apoptosis suppressing bcl-2 oncogene in the genesis of hormone-refractory human prostate cancer. By efficiently destroying the intracellular bcl-2 mRNA, one might be able to make the prostate cancer cell responsive again to conventional apoptotic stimuli such as androgen withdrawal. To achieve this end, we have devised a catalytic antisense RNA strategy (Ribozyme) for bcl-2 and evaluated its gene therapeutic potential. METHODS AND RESULTS: Bcl-2 overexpressing LNCaP prostatic carcinoma cells (LNCaP/bcl-2) were transfected with the anti-bcl-2 ribozyme RNA using a polyamine-based transfection reagent and the reduction in the intracellular bcl-2 mRNA levels was followed by a ribonuclease protection assay. Using a cell viability assay, prior ribozyme transfection and subsequent application of apoptotic stimuli such as serum starvation or phorbol ester treatment caused a 30% increase in cell death by apoptosis than with these apoptotic stimuli alone. CONCLUSIONS: The results obtained strongly support the ability of a potential anti-bcl-2 ribozyme therapy to synergize with other agents in inducing apoptosis of hormone-resistant human prostate cancer cells.

Detection and treatment of prostate cancer: perspective of the urologist.

We examine changes in the detection and treatment of prostate cancer from the perspective of the urologist. There has been an extraordinary increase in the incidence of prostate cancer (60% from 1990 to 1993). We calculated, based on data from the literature and assumptions about changes in urological practice, that 52% of newly diagnosed cases would be treated by radical prostatectomy in 1993. Extrapolating from the work of Catalona, we derived the number of office consultations, prostate biopsies and orchiectomies associated with the diagnosis and treatment of these tumors. Applying Health Care Financing Administration reimbursements to our figures, we calculated that each urologist would realize $45,370 for prostate cancer care in the Medicare population in 1993. If all patients 50 to 70 years old were screened by American Cancer Society and American Urological Association recommended algorithms, this projection would be $107,919. Despite this enormous economic impact of prostate cancer on the urologist, uncertainties remain concerning the appropriateness of screening and treatment for this disease. Only increased funding for basic research in prostate cancer will resolve these uncertainties.

Seminal vesicle urinary reflux as a complication of transurethral resection of ejaculatory ducts.

Transurethral resection of ejaculatory ducts has become an effective surgical treatment for male infertility caused by ejaculatory duct obstruction. We report on a patient treated successfully by transurethral resection of the ejaculatory ducts for a large midline cyst who postoperatively complained of terminal urinary dribbling lasting several minutes. On video urodynamic study reflux into and delayed drainage from the right seminal vesicle were found.

Urodynamics and the etiology of post-prostatectomy urinary incontinence: the initial Columbia experience.

Post-prostatectomy incontinence is a disabling disorder. Urodynamic studies in 56 patients with post-prostatectomy incontinence were reviewed to determine its etiology. Of the patients 31 had undergone transurethral prostatectomy and 25 radical retropubic prostatectomy. After careful history and neurourological examination, uroflowmetry, post-void residual determination and synchronous multichannel video pressure/flow studies were done. The most common etiology for incontinence was detrusor instability alone, which was present in 34 patients (61%), including 24 (77%) after transurethral resection of the prostate and 10 (40%) after radical retropubic prostatectomy. Stress incontinence alone was present in only 3 patients (5%), including 1 (3%) after transurethral resection of the prostate and 2 (8%) after radical retropubic prostatectomy. Detrusor instability with stress incontinence was present in 19 patients (34%), including 6 (19%) after transurethral resection of the prostate and 13 (52%) after radical retropubic prostatectomy. Of these 19 patients 4 (21%) had poorly compliant bladders. This study demonstrates that stress incontinence alone is a relatively rare cause of post-prostatectomy incontinence, with detrusor instability present in more than 90% of the patients. Accurate diagnosis of post-prostatectomy incontinence etiology could ensure proper treatment for this disorder.