Expression and function of the leucine zipper protein Par-4 in apoptosis.

The prostate apoptosis response-4 (par-4) gene was identified by differential screening for genes that are upregulated when prostate cancer cells are induced to undergo apoptosis. The par-4 gene is induced by apoptotic signals but not by growth-arresting, necrotic, or growth-stimulatory signals. The deduced amino acid sequence of par-4 predicts a protein with a leucine zipper domain at its carboxy terminus. We have recently shown that the Par-4 protein binds, via its leucine zipper domain, to the zinc finger domain of Wilms' tumor protein WT1 (R. W. Johnstone et al., Mol. Cell. Biol. 16:6945-6956, 1996). In experiments aimed at determining the functional role of par-4 in apoptosis, an antisense par-4 oligomer abrogated par-4 expression and activator-driven apoptosis in rat prostate cancer cell line AT-3, suggesting that par-4 is required for apoptosis in these cells. Consistent with a functional role for par-4 in apoptosis, ectopic overexpression of par-4 in prostate cancer cell line PC-3 and melanoma cell line A375-C6 conferred supersensitivity to apoptotic stimuli. Transfection studies with deletion mutants of Par-4 revealed that full-length Par-4, but not mutants that lacked the leucine zipper domain of Par-4, conferred enhanced sensitivity to apoptotic stimuli. Most importantly, ectopic coexpression of the leucine zipper domain of Par-4 inhibited the ability of Par-4 to enhance apoptosis. Finally, ectopic expression of WT1 attenuated apoptosis, and coexpression of Par-4 but not a leucine zipperless mutant of Par-4 rescued the cells from the antiapoptotic effect of WT1. These findings suggest that the leucine zipper domain is required for the Par-4 protein to function in apoptosis.

Presence of circulating prostate cells in the bone marrow of patients undergoing radical prostatectomy is predictive of disease-free survival.

PURPOSE: To determine whether the presence of circulating prostate cells in the bone marrow is associated with disease-free survival in patients undergoing radical prostatectomy. MATERIALS AND METHODS: We evaluated the bone marrow of 86 patients with clinically localized prostate cancer treated by radical prostatectomy for the presence of circulating prostate cells using reverse-transcriptase polymerase chain reaction (RT-PCR) amplification of prostate-specific antigen (PSA) mRNA. Follow-up duration ranged from 1 to 43 months (mean, 15.4). RESULTS: Two of 47 patients (4%) with negative RT-PCR PSA results and 10 of 39 patients (26%) with positive RT-PCR PSA results have had disease recurrence. Patients whose RT-PCR PSA results were positive had a significantly shorter disease-free survival period than those patients with negative RT-PCR PSA results (P = .004). RT-PCR status correlated significantly with serum PSA level (P = .001) and pathologic stage (P = .003). Based on Cox's proportional hazards models, RT-PCR status was found to be a significant predictor of disease-free survival. However, after controlling for PSA level, RT-PCR status was not significant in predicting disease-free survival. CONCLUSION: RT-PCR PSA of bone marrow may be a useful pretreatment prognostic test for patients undergoing radical prostatectomy. Currently, this test should not be used to determine if patients receive definitive local therapy.

Androgen deprivation and four courses of fixed-schedule suramin treatment in patients with newly diagnosed metastatic prostate cancer: A Southwest Oncology Group Study.

PURPOSE: To assess the feasibility of administering a combination of suramin and hydrocortisone in addition to androgen deprivation in a cooperative group setting; to assess the feasibility of treatment with multiple courses of suramin; and to assess progression-free and overall survival in patients with newly diagnosed metastatic prostate cancer who underwent such treatment. PATIENTS AND METHODS: Patients with newly diagnosed metastatic prostate cancer who had adequate hematologic, hepatic, renal, neurologic, and coagulation parameters were treated by combined androgen deprivation and suramin plus hydrocortisone. Suramin was administered on a 78-day fixed dosing schedule (one cycle), and suramin treatment cycles were repeated every 6 months for a total of four cycles. The statistical design was developed on the basis of the feasibility of administering suramin, as judged by the number of patients who developed neurotoxicity of grade 3 or higher or by treatment interruption of 4 weeks or longer due to any persistent suramin-related toxicity. RESULTS: Of the 62 patients enrolled onto the study between August 1994 and January 1997, 59 were eligible and assessable for toxicity on the first cycle. Thirty-two (54%) of 59 patients received a second cycle, 13 (22%) of 59 patients received a third cycle, and only five patients (8%) received a fourth cycle. During the first cycle, 27 patients were removed from the study: 17 because of toxicity, five because of disease progression, two who had died, and three because of other reasons. There was one therapy-related death. Grade 4 toxicities were noted in 11 and three patients during first and second courses, respectively. Neurotoxicity of grade 3 or higher was observed in nine and seven patients during the first and second cycles, respectively. Fifteen patients had treatment interruptions of 4 weeks or longer. Overall, only 54% (95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity. CONCLUSION: Suramin plus hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.

Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line.

The second most prevalent urological malignancy in middle aged and elderly men is bladder cancer, with 90% of the cases being transitional cell carcinomas. The success of current systemic and intravesical therapeutic agents, such as cisplatin, thiotepa, Adriamycin, mitomycin C, and bacillus Calmette-Guerin, is limited with recurrence rates reduced to 17-44%. In addition, most of these agents require instrumentation of the urinary tract and are delivered at a significant cost and potential morbidity to the patient. Fluroquinolone antibiotics such as ciprofloxacin, which can be administered p.o., may have a profound effect in bladder cancer management. This is primarily based on limited in vitro studies on tumor cells derived from transitional cell carcinoma of the bladder that revealed a dose- and time-dependent inhibition of cell growth by ciprofloxacin at concentrations that are easily attainable in the urine of patients. However, the mechanism(s) by which ciprofloxacin elicits its biological effects on bladder cancer cells is not well documented. Our experimental data confirm previous studies showing the in vitro cell growth inhibition of the transitional cell carcinoma of the bladder cell line HTB9 and further showed the induction of cell cycle arrest at the S/G2-M checkpoints. In addition, we found down-regulation of cyclin B, cyclin E, and dephosphorylation of cdk2 in ciprofloxacin-treated bladder tumor cells. There was also an up-regulation of Bax, which altered the Bax:Bcl-2 ratio, which may be responsible for mitochondrial depolarization reported to be involved prior to the induction of apoptosis. The cyclin-dependent kinase inhibitor p21WAF1 level was found to be decreased within 12 h of ciprofloxacin treatment and disappeared completely when HTB9 cells were treated with 200 microg/ml ciprofloxacin for 24 h. The down-regulation of p21WAF1 closely correlated with poly(ADP-ribose) polymerase cleavage and CPP32 activation. Recent studies revealed that p21WAF1 protects cells from apoptosis by arresting them in G1 and further binds to pro-caspase-3, preventing its activation and thus, inhibiting the apoptotic cascade. Hence, the down-regulation of p21WAF1, together with the alterations in Bax and cdk2 as observed in our studies, may define a novel mechanism by which ciprofloxacin inhibits tumor cell growth and induces apoptotic cell death. The results of our current studies provide strong experimental evidence for the use of ciprofloxacin as a potential preventive and/or therapeutic agent for the management of transitional cell carcinoma of the bladder.

Effect of neoadjuvant androgen deprivation on circulating prostate cells in the bone marrow of men undergoing radical prostatectomy.

Our objective was to determine the effect of neoadjuvant hormonal therapy on the presence of circulating prostate cells in patients undergoing radical prostatectomy for prostate cancer. A total of 60 patients at high risk for extraprostatic disease were analyzed for the presence of circulating prostate cells using reverse transcriptase PCR (RTPCR) amplification of the prostate-specific antigen mRNA. Twenty-nine patients underwent radical prostatectomy for a clinical T2b-c tumor or a stage T1c-T2a tumor and a serum prostate-specific antigen level > or =10ng/ml (radical prostatectomy alone), and 31 similarly staged patients received neoadjuvant hormonal therapy before radical prostatectomy (neoadjuvant). Bone marrow samples were used for RTPCR analysis. Twenty-four percent and 58% of the radical-prostatectomy-alone patients and neoadjuvant patients had organ-confined disease, respectively (P = 0.007). In the radical-prostatectomy-alone group, 77% and 14% of patients with extraprostatic and organ-confined disease were RTPCR positive, respectively (P = 0.03). However, in the neoadjuvant group, 46% and 28% of patients with extraprostatic and organ-confined disease were RTPCR positive, respectively (P = 0.29). For patients that were RTPCR positive, 45 % of the neoadjuvant patients had organ-confined disease compared with 6% in the radical-prostatectomy-alone patients (P = 0.018). These data suggest that a subset of the neoadjuvant patients are converted to organ confined disease without eliminating the prostate cells in the bone marrow. Our data suggest that hormonal therapy before radical prostatectomy decreases the occurrence of extraprostatic disease but, to a lesser degree, the incidence of circulating prostate cells. This may partially explain why hormonal therapy before radical prostatectomy has not improved disease-free survival.

Cellular proliferation and prevalence of micrometastatic cells in the bone marrow of patients with clinically localized prostate cancer.

The presence of prostate cancer cells in the bone marrow (BM) of patients with clinically localized disease is associated with an increased chance of disease recurrence; however, not all patients develop recurrence. We therefore sought to determine the phenotype of individual micrometastatic cells as a potential method to better predict disease outcome. Immunostaining was performed on BM cells from 46 patients whose BM RNA fraction had been identified to contain prostate-specific antigen mRNA. The prevalence of micrometastatic cells among BM mononuclear cells was determined using an anticytokeratin antibody. Mib-1 antibody was used to determine the percentage of micrometastatic cells that were proliferating. Micrometastatic cells were found in 96% of patient samples, with a 30-fold variation in prevalence ranging from 0.1-3.26/10(5) BM cells. Prior androgen ablation was associated with a reduced prevalence of micrometastatic cells (P = 0.010). In 68% of patients, some micrometastatic cells were judged to be proliferating at proportions ranging from 1 of 11 (9%) to 4 of 4 (100%). Higher Gleason score of the primary tumor was associated with a higher proliferative proportion of micrometastatic cells (P = 0.038). We conclude that, in patients with clinically localized disease, there is wide variability in the prevalence of micrometastatic cells and the proportion which are proliferating. Long-term follow-up will determine whether the development of clinically obvious metastatic disease is related to higher prevalence of micrometastatic cells in the marrow or the proportion that are proliferating.

Matrix metalloproteinase-9 expression in bladder washes from bladder cancer patients predicts pathological stage and grade.

The matrix metalloproteinases (MMPs), in particular the gelatinases (MMP-2 and MMP-9) have been associated with tumor cell invasion and metastasis in many human cancers. Here we examined the expression of proMMP-2 (gelatinase A) and proMMP-9 (gelatinase B) proteins in the cellular component of bladder washes obtained from 65 patients. Twenty-six patients had active bladder cancer, 24 had a history of bladder cancer but no evidence of active disease at the time of cystoscopy (recurrence-free), and 15 patients had lesions other than bladder cancer (controls). The results were correlated with the cytological findings of the bladder wash and the histopathological results of the tumor resection when performed. In patients with active transitional cell carcinoma of the bladder, 71 and 38% had expression and overexpression of the latent form of MMP-9 (proMMP-9), respectively. In contrast, neither latent nor active MMP-2 could be detected in any of the samples examined, regardless of tumor status. Overexpression of proMMP-9 correlated with higher grade (P = 0.003) and pathological stage (P = 0.04) of disease in the active bladder cancer group. No significant gelatinase expression was detected in the recurrence-free and control cases. Compared with urine cytology, proMMP-9 expression had an overall higher sensitivity for bladder cancer identification (71 versus 54%, P = 0.11). Detection of proMMP-9 in bladder washes may be a novel approach for the identification of patients with more aggressive forms of bladder cancer.

Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors.

PURPOSE: The prognostic significance of Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder is largely unknown. Accurate determination of Her-2/neu overexpression may have therapeutic importance. EXPERIMENTAL DESIGN: Eighty consecutive cases of muscle-invasive urothelial carcinoma of the bladder treated by radical cystectomy with available follow-up were analyzed. In each case, one representative section was stained with anti-Her-2/neu. Staining was graded as 1 = faint/equivocal, 2 = moderate, and 3 = strong and was considered positive if > or =2. In those cases with a metastasis, the stain was also performed in the metastatic tumor. Results were correlated with survival. RESULTS: Twenty-two (28%) cases were considered Her-2/neu-positive in the primary tumor, and 17 of 32 (53%) were considered Her-2/neu-positive in the lymph node metastasis. Median survival for Her-2/neu-positive primary tumors was 33 months, compared with 50 months for Her-2/neu-negative cases (P = 0.46). Similarly, Her-2/neu overexpression in the lymph node metastasis did not predict survival. Sixty metastatic urothelial carcinomas were further studied by comparing Her-2/neu expression in the primary tumor with that of the lymph node and/or distant metastasis. Forty-five percent of Her-2/neu-negative primary tumors had a Her-2/neu-positive lymph node metastasis, whereas only one case (8%) of Her-2/neu-positive primary tumors was Her-2/neu-negative in the lymph node metastasis (P = 0.009). Similarly, 67% of Her-2/neu-negative primary tumors had a Her-2/neu-positive distant metastasis, whereas no Her-2/neu-positive primary tumor was negative in the metastasis (P = 0.429). CONCLUSIONS: Her-2/neu overexpression in primary or metastatic tumor did not predict survival in this cohort of muscle-invasive tumors. Overexpression in the primary tumors consistently predicts overexpression in a distant or regional metastasis. However, some Her-2/neu-negative primary tumors may show overexpression in their corresponding metastasis. Her-2/neu analysis in a metastasis may be necessary to accurately determine Her-2/neu status in metastatic bladder urothelial carcinoma.

Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.

An inverse association has been observed between dietary intake of lycopene and the risk of prostate cancer. We investigated the effects of lycopene supplementation in patients with prostate cancer. Twenty-six men with newly diagnosed, clinically localized (14 T(1) and 12 T(2)) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) twice daily or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of differentiation and apoptosis were assessed by Western blot analysis on benign and malignant parts of the prostate gland. Prostatectomy specimens were entirely embedded, step-sectioned, and evaluated for pathological stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. Eleven (73%) subjects in the intervention group and two (18%) subjects in the control group had no involvement of surgical margins and/or extra-prostatic tissues with cancer (P = 0.02). Twelve (84%) subjects in the lycopene group and five (45%) subjects in the control group had tumors <4 ml in size (P = 0.22). Diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia was present in 10 (67%) subjects in the intervention group and in 11 (100%) subjects in the control group (P = 0.05). Plasma prostate-specific antigen levels decreased by 18% in the intervention group, whereas they increased by 14% in the control group (P = 0.25). Expression of connexin 43 in cancerous prostate tissue was 0.63 +/- 0.19 absorbance in the lycopene group compared with 0.25 +/- 0.08 in the control group (P = 0.13). Expression of bcl-2 and bax did not differ significantly between the two study groups. IGF-1 levels decreased in both groups (P = 0.0002 and P = 0.0003, respectively). The results suggest that lycopene supplementation may decrease the growth of prostate cancer. However, no firm conclusions can be drawn at this time because of the small sample size.

The impact of race on biochemical disease-free survival in early-stage prostate cancer patients treated with surgery or radiation therapy.

PURPOSE: To assess the impact of race on biochemical freedom from recurrence in patients with early-stage prostate cancer treated either by radical prostatectomy or radiation therapy. METHODS: Between July 1989 and December 1994, 693 patients with early-stage prostate cancer were treated with radiation (302 patients) or by radical prostatectomy (391 patients) at Barbara Ann Karmanos Cancer Institute/Wayne State University. Stage, Gleason score, race, pretreatment PSA, and follow-up PSA values were abstracted. There were 387 Caucasian males (CM) and 306 African-American males (AAM). None of the patients received hormone therapy. Radiation therapy was delivered using photon irradiation (249 patients, median dose 69 Gy) or mixed neutron/photon irradiation (53 patients, median dose 10 NGy + 38 PGy). Median follow-up was 36 months (range 2-70) for CM and 35 months (range 1-70) for AAM. RESULTS: Thirty-seven percent of patients treated surgically were AAM, compared to 53% in the radiation group (p = 0001). AAM had a higher median prostate-specific antigen (PSA) than CM (9.78 ng/ml vs. 8.0 ng/ml, p = 0.01). Thirty-three percent of AAM had a pretreatment PSA greater than 15 ng/ml compared to 20% of CM (p = 0.00001). Disease-free survival (DFS) by race was equivalent at 36 months, 81% for CM and 77% for AAM (p = NS). For patients with PSA < or =15, DFS rates were 87% and 85% for CM and AAM, respectively. DFS rates for patients with PSA >15 were 61% for CM and 64% for AAM (p = NS). Significant prognostic factors on multivariate analysis included pretreatment PSA (p = 0.0001) and Gleason score (p = 0.0001). CONCLUSION: Race does not appear to adversely affect biochemical disease-free survival in males treated for early-stage prostate cancer. African-American males with early-stage prostate cancer should expect similar biochemical disease-free survival rates to those seen in Caucasian males.

Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival.

Although grading is valuable prognostically in pTa and pT1 papillary urothelial carcinoma, it is unclear whether it provides any prognostic information when applied to the invasive component in muscle-invasive carcinoma. The authors analyzed 93 cases of muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy for which follow-up information was available. Each case was graded using the Malmström grading system for urothelial carcinoma, applied to the invasive component. Pathologic stage, lymph node status, and histologic invasion pattern were also recorded and correlated with progression-free survival. Thirty-four cases (37%) were pT2, 40 (43%) were pT3, and 19 (20%) were pT4. Of the 77 patients who had a lymph node dissection at the time of cystectomy, 34 (44%) had metastatic carcinoma to one or more lymph nodes. The median survival for pT2, pT3, and pT4 stages was 85, 24, and 29 months, respectively (p = 0.0001). Lymph node-negative and lymph node-positive patients had a median survival of 63 and 23 months, respectively (p = 0.0001). Fifteen patients (16%) were graded as 2b and 78 patients (84%) were graded as 3. Median survival of patients graded as 2b was 34 months compared with 31 months for patients graded as 3 (p value not significant). Three invasive patterns were recognized: nodular (n = 13, 14%), trabecular (n = 39, 42%), and infiltrative (n = 41, 44%). The presence of any infiltrative pattern in the tumor was associated with a median survival of 29 months, compared with 85 months in tumors without an infiltrative pattern (p = 0.06). Pathologic T stage and lymph node status remain the most powerful predictors of progression in muscle-invasive urothelial carcinoma. In this group of patients histologic grade, as defined by the Malmström system and as applied to the invasive component, provided no additional prognostic information. An infiltrative growth pattern may be associated with a more dismal prognosis.

Sensitivity of immunohistochemistry and polymerase chain reaction in detecting prostate cancer cells in bone marrow.

Occult micrometastases detected by immunohistochemistry have prognostic significance in patients with localized breast cancer. To determine the usefulness of this technique and of polymerase chain reaction in detecting occult prostate cancer, we evaluated the sensitivity and specificity of immunohistochemistry and polymerase chain reaction amplification of mRNA to detect prostate cancer cells in bone marrow samples. We used cells from an established prostate cancer cell line (LNCAP) mixed with lymphocytes at various dilutions from 10(5) cancer cells in 10(6) lymphocytes to 1:10(6). Both techniques had a 100% specificity and identified cancer cells at all dilutions. Polymerase chain reaction was more sensitive than immunohistochemistry at the lowest dilutions (10(-5) and 10(-6), p = 0.033). We have evaluated seven patients with prostate cancer for micrometastases. Both of the patients with known metastatic prostate cancer and one of the five patients with clinically localized tumors had micrometastases. Detection of micrometastases may be useful in the staging of prostate cancer.

Female pseudohermaphroditism due to congenital adrenal hyperplasia complicated by adenocarcinoma of the prostate and clear cell carcinoma of the endometrium.

The presence of prostatic glandular tissue in female pseudohermaphrodites has previously been documented. However, prostatic neoplasia in this clinical setting has not been reported. A karyotypic female with congenital adrenal hyperplasia due to 21-hydroxylase deficiency developed a prostatic adenocarcinoma associated with elevated serum prostatic specific antigen levels and osteoblastic skeletal metastases. This demonstrates that this tissue in pseudohermaphrodites can become malignant. In addition, the patient subsequently developed clear cell carcinoma of the endometrium, possibly related to radiation therapy for the prostatic adenocarcinoma. This demonstrates that female pseudohermaphrodites may be at risk not only for malignancies seen in genotypic females but also prostate cancer.

Renal sarcomas of childhood.

Renal sarcomas in infants and children are extremely uncommon. Previously classified as Wilms tumors with unfavorable histology, these tumors were thought to be variants of Wilms tumors but in general have a worse prognosis. Our recent experience with 4 cases of renal sarcomas indicate that these tumors must be approached individually and treated appropriately. Their histologic picture and their varying response to surgery and chemotherapy suggest that these unusual tumors are not variants of Wilms tumors but instead sarcomas unrelated to the classic Wilms tumors.

Incidence of urethral involvement in female bladder cancer: an anatomic pathologic study.

OBJECTIVES: To evaluate risk factors for urethral involvement in female patients undergoing cystectomy for bladder cancer and to define potential candidates for orthotopic continent urinary diversion. METHODS: From 1990 to 1996, 43 female patients underwent cystectomy for primary bladder malignancy. Bladder mapping studies were performed with special attention to tumor location, multifocality, pathologic stage and grade, presence of carcinoma in situ (CIS), and the relationship of these factors to urethral involvement. RESULTS: Of the 43 patients evaluated, 7 (16.3%) had urethral involvement by tumor. Two patterns of urethral invasion were identified: 5 patients had tumors in the vascular or lymphatic channels of the periurethral tissue, and 2 had tumors in the mucosa or submucosa. Three of the 12 patients with tumors located at the trigone and 4 of the 26 with CIS of the bladder had tumor in the urethra. Three of the 5 patients with vaginal involvement had tumor in the urethra. Only vaginal involvement was significantly associated with urethral involvement (P = 0.02). CONCLUSIONS: Vaginal involvement was the only preoperative factor that was associated with presence of tumor in the urethra. Five patients with urethral involvement had submucosal tumors without concomitant CIS of the urethra. Before the performance of orthotopic urinary diversions, intraoperative full-thickness bladder neck biopsies are needed to accurately evaluate the female urethra.

Orthotopic urinary diversion is a viable option in patients undergoing salvage cystoprostatectomy for recurrent prostate cancer after definitive radiation therapy.

OBJECTIVES: To evaluate whether orthotopic urinary diversion is a viable option for patients undergoing cystoprostatectomy for radio-recurrent prostate cancer (RRPC). METHODS: Between 1990 and 1996, we performed 34 salvage surgeries for RRPC, including 26 radical retropubic prostatectomies and 8 cystoprostatectomies. We determined the operative and postoperative complication rates and pathologic stage for the 8 patients undergoing cystoprostatectomy. RESULTS: Of the 8 patients in whom cystoprostatectomy was performed, 5 underwent ileal conduit diversion and 3 underwent orthotopic neobladder reconstruction. There were no intraoperative complications or perioperative mortalities. In the group with orthotopic neobladder, postoperative complications included pyelonephritis in 1 patient and prolonged ileus in another. In the group with ileal conduit, no short-term complications occurred; 1 patient developed an incisional hernia on long-term follow-up. All patients with neobladder reconstruction are continent during the day. One patient wears one pad at night. The other 2 are continent at night. CONCLUSIONS: Orthotopic urinary diversion is a valid option for selected patients with RRPC who require a cystoprostatectomy. This procedure can be performed with minimal complications, resulting in good continence and good quality of life.

Prostate cancer histologic trends in the metropolitan Detroit area, 1982 to 1996.

OBJECTIVES: One of the concerns regarding the widespread use of serum prostate-specific antigen (PSA) as a screening tool for prostate cancer is the possibility that it may detect latent or clinically insignificant cancers. One indicator of clinical importance is thought to be histologic grade, with clinically unimportant cancers more likely to be well differentiated and clinically important tumors more likely to be moderately or poorly differentiated. METHODS: Data from the metropolitan Detroit population-based Surveillance, Epidemiology, and End Results Program were examined to determine trends in prostate cancer histologic grading before and after the introduction of PSA screening. RESULTS: From 1989 through 1996, the most recent year for which data are available, a dramatic increase in the incidence of prostate cancer occurred in the Detroit area, corresponding to the routine use of PSA as a screening test for prostate cancer. Local stage cancer demonstrated the largest increase in incidence. The incidence of moderately differentiated cancers also rose substantially during the same period; the incidence of poorly differentiated tumors remained about the same, and the incidence of well differentiated tumors decreased. Coincident with the increasing proportion of moderately differentiated cancers was a significant increase in the proportion of prostate biopsies performed (P = 0.001). CONCLUSIONS: These population-based data add important evidence that prostate cancers identified with PSA are more likely to be moderately than well differentiated. Additionally, if the definition of clinical significance depends on histopathologic grade, this finding could further be interpreted as evidence that PSA is more likely to detect clinically significant prostate cancer.

"Stand-up" urologic endoscopy.

OBJECTIVES: To report the advantages of performing diagnostic and therapeutic urologic endoscopic procedures with the urologic surgeon in the standing-up position. METHODS: Our 25-year institutional experience with more than 10,000 cases of transurethral ablation of the prostate and other urologic endoscopic procedures, performed by the urologist in the standing-up position, was examined. A questionnaire of all 55 of our former urology residents was carried out to determine current practice trends. RESULTS: We have noted no drawbacks from performing transurethral surgery in the standing-up position. Ninety-two percent of the respondents believe that the standing-up position was more comfortable for endoscopic surgery than the sitting-down position. CONCLUSIONS: the standing-up technique of transurethral surgery minimizes positional stresses on the urologist's cervical and thoracic spine while optimizing endoscopic visualization and maneuverability. We recommend it in preference to the conventional sitting-down technique.

Familial paraganglioma.

Extra-adrenal pheochromocytomas and paragangliomas are rare tumors of neural crest origin, most commonly found in the retroperitoneum. Because these tumors are so uncommon, relatively little is known about their natural history. Comparisons between adrenal pheochromocytomas and extra-adrenal pheochromocytomas have appeared in the medical literature. Like pheochromocytomas, paragangliomas may occur as functional or nonfunctional tumors. Furthermore, although the hereditary occurrence of pheochromocytomas is well documented, the familial nature of paragangliomas is unclear. We present the first report of a mother and son with nonfunctional paragangliomas occurring in the same anatomic location and describe their care and treatment.

Impact of location and multifocality of positive surgical margins on disease-free survival following radical prostatectomy: a comparison between African-American and white men.

OBJECTIVES: Although the rate of positive surgical margins is higher in African-American men (AAM) than in white men (WM), the impact of this difference on survival is not clear. Furthermore, it is unknown whether there are racial differences in the distribution of the positive surgical margins after radical retropubic prostatectomy (RRP). We investigated the differences between AAM and WM in terms of the site and multifocality of the positive surgical margins and their effect on disease-free survival (DFS) following RRP. METHODS: Between January 1991 and December 1995, 493 patients (288 WM and 205 AAM) were treated with RRP as monotherapy. Positive surgical margins were observed in 179 patients (86 WM and 93 AAM). Patients were divided in two groups: group 1 = WM and group 2 = AAM. The incidence and location of the positive surgical margins and their correlation with DFS were determined and compared. RESULTS: Overall, AAM had a higher rate of positive surgical margins than WM (48% versus 33%, respectively, P = 0.001). There was no significant difference in the frequency of multifocality of the positive margins (P = 0.4). Positive surgical margins were located significantly more often at the base in AAM (P = 0.015); however, the location of the positive surgical margins did not impact on DFS between groups. In those with multifocal positive surgical margins, AAM had a worse DFS compared with WM (P = 0.03). CONCLUSIONS: Race is an independent prognostic factor for DFS in patients with positive surgical margins. There were no differences in DFS between WM and AAM based on the margin location. In WM, prognostic factors for DFS in those with positive surgical margins were preoperative serum prostate-specific antigen, Gleason score, and pathologic stage. Conversely, in AAM none of these parameters were significant predictors of failure.