Trospium chloride has no effect on memory testing and is assay undetectable in the central nervous system of older patients with overactive bladder.

BACKGROUND: Muscarinic receptors in the brain play an important role in cognitive function, especially memory, and there is growing awareness that specific antimuscarinic drugs for overactive bladder (OAB) may have adverse central nervous system (CNS) effects. Selection of an antimuscarinic OAB drug with reduced potential for CNS effects could be especially beneficial in the elderly people, in whom even the modest cognitive impairment may negatively affect independence. PURPOSE: The purpose of the study is to determine if trospium chloride is assay detectable in the CNS of older adults with OAB and to assess whether deterioration of memory occurs in these individuals. METHODS: Twelve cognitively intact older adults (>or=65-75 years old) with OAB were given extended-release trospium chloride 60 mg once daily over a 10-day period to achieve plasma steady-state levels. Standardised memory testing (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised) was performed predose and postdose. Cerebrospinal spinal fluid (CSF) and plasma samples were drawn on day 10 and assayed for trospium chloride. Predose (day 0) and postdose (day 10) results on the memory tests were compared using a reliable change index to assess a meaningful change in learning or memory. RESULTS: Trospium chloride levels in all the CSF samples (n = 72) of all participants were assay undetectable (<40 pg/ml) on day 10 at steady-state peak plasma concentration concurrent with measureable peak plasma values (C(max) = 925 pg/ml). Repeat memory testing revealed no significant net drug effect on learning or recall. CONCLUSIONS: This is the first study to investigate for the presence of an OAB antimuscarinic in the human brain, performed by assaying for concentrations of trospium chloride and correlating with simultaneous clinical cognitive safety measures. The results of both pharmacological and neuropsychological testing support the hypothesis of a lack of detectable CNS penetration for the quaternary amine trospium chloride.

Skeletal fracture associated with androgen suppression induced osteoporosis: the clinical incidence and risk factors for patients with prostate cancer.

PURPOSE: Limited information exists regarding the long-term risk of skeletal fracture in men on androgen suppression for prostate cancer. In addition, the clinical risk factors predisposing them to skeletal fracture are incompletely defined. We define the long-term risk and clinical risk factors for skeletal fracture in patients with prostate cancer on chronic androgen suppression. MATERIALS AND METHODS: A total of 181 consecutive patients with prostate cancer on androgen suppression therapy were evaluated. The primary end point was skeletal fracture. Comprehensive demographic information was gathered, and univariate and multivariate analyses were performed to identify associations with skeletal fracture. RESULTS: The proportion of patients who had survived fracture-free at 5 and 10 years on androgen suppression therapy was 96% and 80%, respectively. The black race (p = 0.009) and increased body mass index (p = 0.024) were identified as protective against androgen suppression associated skeletal fractures. A significant correlation was identified between the duration of androgen suppression and risk of skeletal fracture (p = 0.003). CONCLUSIONS: Patients with prostate cancer treated with androgen suppression are at risk for skeletal fracture, and risk increases with the duration of therapy. Slender white men are at greatest risk. Conversely, black men and those with body mass indexes greater than normal (greater than 25 kg/m(2)) are at minimal risk despite a prolonged duration (10 years) of androgen suppression.

Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm.

PURPOSE: We report the failure to achieve a castrate level of testosterone associated with 3-month depot luteinizing hormone releasing hormone (LH-RH) agonist therapy, which to our knowledge is a previously unrecognized outcome. MATERIALS AND METHODS: We prospectively enrolled in our study 38 men with prostate cancer on 3-month depot LH-RH agonist therapy. We monitored total serum testosterone and prostate specific antigen every 28 days beginning 90 days after the last depot LH-RH agonist injection. Data were analyzed with castrate testosterone defined as less than 50 and 20 ng./dl. or less. RESULTS: Using the 50 and 20 ng./dl. definitions of castrate testosterone 2 (5%) and 5 (13%) of the 38 men, respectively, failed to achieve castrate testosterone. A patient with a nadir testosterone of 70 ng./dl. subsequently underwent orchiectomy and testosterone decreased to 10 ng./dl. thereafter. CONCLUSIONS: A small but potentially important subgroup of men on depot LH-RH agonist therapy fail to achieve a castrate level of testosterone. Our findings support monitoring testicular response when LH-RH agonist therapy is initiated.

A population pharmacokinetic analysis of the penetration of the prostate by levofloxacin.

Prostatitis has remained a pathological entity that is difficult to treat. Part of the difficulty revolves about the putative offending pathogens. For acute prostatitis, members of the Enterobacteriaceae, particularly Escherichia coli, play a central role, while intracellular pathogens such as Chlamydia are more frequently seen in chronic prostatitis. Consequently, a drug needs to be able to penetrate to this specialized site in both the acute and chronic infection forms of the disease and also have potent activity against the most common causative pathogens, both intracellular and extracellular. Levofloxacin has such an activity profile. We wished to document its ability to penetrate to the site of infection. Patients undergoing prostatectomies were administered 500 mg of levofloxacin orally every 24 h for 2 days prior to surgery, and then on the day of surgery, 500 mg was administered as an hour-long, constant-rate intravenous (i.v.) infusion. A set of blood samples was obtained as guided by stochastic optimal design theory. Prostate biopsy times were determined by randomizing subjects into one of four groups, based on the interval after the i.v. dose. All plasma and prostate drug concentrations were comodeled by a population modeling program, BigNPEM, implemented on the Cray T3E Supercomputer housed at the Supercomputer Center at the University of California at San Diego. Penetration was determined as the ratio of the area under the concentration-time curve (AUC) of levofloxacin in the prostate to the plasma levofloxacin AUC. When calculated from the mean population parameters, this penetration ratio was 2.96. We also performed a 1,000-subject Monte Carlo simulation from the mean parameter vector and covariance matrix. The mean penetration ratio here was 4.14 with a 95% confidence interval of 0.20 to 19.6. Over 70% of the population had a penetration ratio in excess of 1.0. Levofloxacin adequately penetrates a noninflamed prostate and should be evaluated for the therapy of prostatitis.

Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making.

OBJECTIVES: Based on methods introduced in the late 1960s and no longer used, serum testosterone level in men after surgical castration was reported to be 50 ng/dL or less. Radioimmunoassay and, subsequently, chemiluminescent methods have supplanted the early analytic methods because of their improved accuracy and ease of testing. The purpose of this study was to define the castrate testosterone level in the era of chemiluminescent testing. METHODS: After bilateral orchiectomy, serum testosterone (total) levels were measured prospectively in 35 prostate cancer patients. RESULTS: The median testosterone value in this patient cohort was 15 ng/dL (0.5 nmol/L; 95% confidence interval 12 to 17 ng/dL). CONCLUSIONS: In a contemporary series, castrate testosterone should be defined as less than 20 ng/dL (0.7 nmol/L). The important biologic and economic implications are discussed.

Serum testosterone-based luteinizing hormone-releasing hormone agonist redosing schedule for chronic androgen ablation: a phase I assessment.

OBJECTIVES: To assess the potential for using the serum testosterone level as the guide for redosing depot luteinizing hormone-releasing hormone (LHRH) agonist and to characterize the duration of castrate level testosterone after the last 22.5-mg leuprolide injection repeatedly administered for the control of prostate cancer. METHODS: Informed consent was obtained from 32 men with prostate cancer (Stage T3N+/- M+/- or greater) treated with 3-month (22.5-mg) leuprolide acetate injection. Serum testosterone and prostate-specific antigen levels were obtained every 28 days beginning on the 90th day after the last 22.5-mg leuprolide injection. The duration of action was the calculated interval, in months, between the last injection and the first noncastrate serum testosterone (greater than 0.2 ng/mL) value. RESULTS: The median duration of castrate level testosterone was 6.0 months (SE +/- 0.15; upper and lower quartile 5.3 and 7.0, respectively). Prostate cancer biochemical (prostate-specific antigen) activity at enrollment and when the castrate testosterone threshold of 0.2 ng/mL was exceeded remained stable, with no significant change observed during this interval (P = 0.52). A significant association was observed between an increasing duration of castration after LHRH agonist injection and advancing patient age (P = 0.03) and increasing duration of hormonal therapy (P = 0.05). CONCLUSIONS: These results suggest that using the serum testosterone level to guide in redosing of long-acting LHRH agonist may provide a novel, effective, and economical method to administer hormonal ablative therapy in patients with prostate cancer. These observations have important implications for product dosing and the design and interpretation of neoadjuvant and intermittent androgen ablative trials.

Clinical and molecular followup after radical retropubic prostatectomy.

PURPOSE: We previously reported evidence of hematogenous dissemination of prostate cells during radical retropubic prostatectomy, and we now provide clinical and molecular reverse transcriptase-polymerase chain reaction (RT-PCR) followup of that patient cohort. MATERIALS AND METHODS: A total of 101 men with clinically localized prostate cancer were prospectively enrolled in the study. The prostate specific antigen (PSA) RT-PCR assay was performed on peripheral venous blood samples preoperatively in 101, during surgery in 29, during and up to 12 weeks after surgery in 50 and at least 1 year postoperatively in 65 patients. Correlation with clinical (PSA) indicators of recurrence was performed. RESULTS: Of the 101 patients 9 demonstrated biochemical evidence of prostate cancer progression (median followup 22 months). Of the 50 men with perioperative molecular results the RT-PCR positive rate increased from 22% preoperatively in 11 to 48% in 24 (p = 0.02) and then decreased to 10% in 4 of 40 men at 1 year postoperatively (p = 0.07). Molecular followup at a minimum of 1 year after radical retropubic prostatectomy was obtained in 65 men, of whom the RT-PCR positive rate decreased from 23% preoperatively in 14 to 9.2% in 6 (p = 0.05). No significant correlation was observed between a persistently positive RT-PCR result and biochemical failure. CONCLUSIONS: Although a significant proportion of men have molecular evidence of hematogenous prostate cell dissemination intraoperatively, longitudinal molecular and clinical followup demonstrates reconversion to a negative status as the predominant trend. At relatively short followup no significant correlation was identified between the RT-PCR result and the PSA progression-free survival.

Angiosarcoma of the bladder: a review.

OBJECTIVES: To present a new case of angiosarcoma of the bladder, review 9 other previously reported cases, and discuss the unique features of our case with regard to presentation, treatment, and clinical course of patients with this exceedingly rare tumor. The utility of multimodality therapy is emphasized. METHODS: We report the latest case of angiosarcoma of the bladder. We also reviewed the world literature (MEDLINE) and discovered 9 previously reported cases of angiosarcoma of the bladder. Presentation, treatment, and clinical course were analyzed. RESULTS: Of the 10 cases, 2 were considered to have arisen from a preexisting bladder hemangioma. Two patients had a history of prior gynecologic malignancies treated with external beam radiotherapy, with subsequent sarcoma formation within the past treatment field. Two other patients presented with skin lesions that predated the discovery of bladder lesions. Only 4 patients presented with primary bladder lesions and no preexisting disease or previous carcinogenic exposure (except for tobacco use). Hematuria was a universal presentation, and treatment was widely variant. Of the 10 patients, 8 died during a period of follow-up of 23 months. Five patients died of tumor-related causes. Mean survival of these 5 was 10.6 months. The 2 most recent patients (including ours) were alive and tumor free at 8 and 32 months, respectively. Both of these patients underwent multimodality oncologic approaches as part of their treatment regimen. CONCLUSIONS: Angiosarcoma of the bladder is exceedingly rare and usually fatal. Prognosis is poorer than that of angiosarcomas in more traditional sites. Regional lymph nodes are typically spared, but local recurrence with eventual distant metastasis is the rule. Optimal therapy has not been determined, but it most likely should involve a multimodal approach combining radical surgery with chemotherapy and radiotherapy.

Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study consideration.

PURPOSE: A time course to serum testosterone normalization after administration of a single 3-month luteinizing hormone-releasing hormone (LH-RH) agonist in the neoadjuvant setting was developed. MATERIALS AND METHODS: A total of 13 men with clinically localized prostate cancer were prospectively assessed for baseline libido, erectile function and mid morning serum testosterone. A single 3-month formulation LH-RH agonist was administered in the neoadjuvant setting before definitive treatment with radical perineal prostatectomy in 7 men or external beam radiotherapy in 6. Baseline and serial testosterone levels were measured 3, 4, 6, 7, 9, 12, 15 and 18 months after injection. Symptoms related to acute testosterone depletion, namely hot flashes and sweats, were recorded on the same schedule. RESULTS: After a single 3-month LH-RH agonist injection median duration of castrate level testosterone (0.2 ng./ml. or less) was 6 months. Median duration of hypogonadal symptoms (hot flashes and sweats) was 13.6 months and resolution paralleled the gradual return of serum testosterone to baseline values. CONCLUSIONS: The 3-month formulation of LH-RH agonist administered in the neoadjuvant setting provides castrate level testosterone for a longer duration than the product labeling suggests. If confirmed, these preliminary observations have important implications for dosing schedule and neoadjuvant study consideration.

Loss of expression of transforming growth factor-beta receptors is associated with poor prognosis in prostate cancer patients.

Transforming growth factor beta (TGF-beta) is a potent inhibitor of proliferation in most cells and exerts its effects through an interaction with membrane receptors type I (TGF-betaRI) and type II (TGF-betaRII). Recently, we have demonstrated a correlation between the loss of expression of TGF-betaRI and TGF-betaRII and increasing Gleason score in archival human prostate cancer tissues. To evaluate the potential prognostic value of this observation, the present study investigated the expression of TGF-beta receptors in association with disease progression after the initial diagnosis in 52 archival human prostate cancer tissues. The expression of both TGF-betaRI and TGF-betaRII was correlated with the Gleason score, clinical tumor stage, 4-year survival rate, and serological recurrence rate after radical prostatectomy. Results revealed that there was a significant association between the Gleason score and the loss of expression of TGF-betaRI (P < 0.025) and TGF-betaRII (P < 0.01). However, only the loss of TGF-betaRI expression showed a statistically significant association with the clinical tumor stage (P < 0.05), 4-year survival rate (P < 0.05), and serological recurrence rate after radical prostatectomy (P < 0.025). Therefore, these data indicate that the loss of TGF-betaRI expression as measured by immunohistochemical staining may be a potential prognostic marker in prostate cancer patients.

Idiopathic thromboembolism as the presenting sign of occult prostate cancer.

OBJECTIVES: Idiopathic thromboembolism has been associated with occult neoplasia; however, very limited information exists regarding a man's risk of occult prostate cancer after an idiopathic thromboembolic event. METHODS: We performed a case-control study of 209 consecutive men diagnosed with prostate cancer over a 3-year period, with 350 men diagnosed with benign prostatic hyperplasia (BPH) serving as control subjects. RESULTS: Men with idiopathic thromboembolism had a fivefold increased risk of prostate cancer compared with the BPH control group (risk ratio = 5.0, P = 0.002). The prostate-specific antigen (PSA) progression-free survival was not adversely affected after an idiopathic thromboembolic event. CONCLUSIONS: Our data suggest that men with idiopathic thromboembolism are at an increased risk for being diagnosed with prostate cancer. In men with idiopathic thromboembolism, attempts to diagnose prostate cancer, including digital rectal examination and serum PSA, warrant consideration.

Prostate specific antigen reverse transcriptase-polymerase chain reaction assay in preoperative staging of prostate cancer.

PURPOSE: Extracapsular extension of prostate cancer occurs in a significant number of men believed to have clinically localized disease. We report the ability of the reverse transcriptase-polymerase chain reaction (RT-PCR) assay to predict preoperatively the pathological stage of cases of clinically localized prostate cancer. MATERIALS AND METHODS: Since October 1994, 82 consecutive men with clinically localized prostate cancer had a venous blood RT-PCR assessment before radical retropubic prostatectomy. The extracted ribonucleic acid was reverse transcribed, amplified and the amplicon identity confirmed by prostate specific antigen (PSA) directed probe hybridization. An additional 31 patients were enrolled to provide appropriate positive (T + Nx/1M2) and negative (human female and benign prostatic hyperplasia) controls. Histological examination of the entire prostatectomy specimen was performed. RESULTS: Positive RT-PCR assay results correlated significantly with skeletal metastases and elevated levels of serum PSA but they did not significantly improve our ability to identify prospectively patients with extracapsular extension over traditional predictors (serum PSA, Gleason score). CONCLUSIONS: The role of molecular techniques in prostate cancer evaluation and prognosis continues to emerge. However, in our study we demonstrate no significant advantage in preoperative staging of prostate cancer using RT-PCR assay with PSA primers.

Long-term results of radical retropubic prostatectomy in men with high grade carcinoma of the prostate.

PURPOSE: We sought to determine the efficacy of radical retropubic prostatectomy in men with high grade adenocarcinoma of the prostate in a population that had not been screened for prostate specific antigen (PSA). MATERIALS AND METHODS: An inception cohort of 116 men surgically treated for prostate cancer between 1980 and 1991 was created in April 1992 and prospectively followed thereafter. Median followup was 7 years (range 2.2 to 14.6). RESULTS: The major cause of death in this group of men was prostate cancer, not competing causes. Ten-year disease specific survival was 96% for organ confined (stage pT2c or less) and 78% for unconfined (stage pT3a or greater) disease. Five and 10-year PSA progression-free survival by pathological stage was 83 and 53% for organ confined disease, and 34 and 22% for unconfined disease with negative pelvic lymph node dissection (p = 0.001). Five and 10-year metastasis-free survival was 96% for organ confined disease, and 81 and 62% for unconfined disease (p = 0.011). Men with pelvic lymph node metastasis had 70 and 30% 5 and 10-year metastasis-free survival, and 75 and 55% disease specific survival, respectively. PSA progression-free survival was 33% at 5 years. A significantly decreased risk of PSA progression was observed in men with unconfined carcinoma who received adjuvant external beam radiotherapy. CONCLUSIONS: In men with high grade prostate cancer the major cause of death was prostate cancer, not competing causes. Pathologically confined carcinoma had a significantly decreased rate of metastatic progression. These observations support the bias that early detection in these men at high risk for cause specific death may favorably impact survival.

Pax-2: a developmental gene constitutively expressed in the mouse epididymis and ductus deferens.

PURPOSE: To characterize expression of the transcriptional activator, Pax-2, in the mouse lower genitourinary tract. MATERIALS AND METHODS: Expression of Pax-2 was studied by Northern analysis, ribonuclease protection and immunohistochemistry. RESULTS: Immunostaining revealed localized expression in the epithelium of the ductus deferens and epididymis at all time points from birth to adulthood. Expression in these structures in adult mice was confirmed by Northern analysis and ribonuclease protection assays. CONCLUSION: Pax-2 is a transcriptional regulator expressed in the epithelium of the ductus deferens and epididymis and may be a regulator of epithelial genes involved in sperm maturation and support.

Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancer tissues.

Transforming growth factor beta1 (TGF-beta1) is a potential regulator of prostate cancer cell growth that signals through a heteromeric complex composed of type I and type II receptors. In the present study, an attempt was made to establish a correlation between expression of TGF-beta receptors and tumor grade in archival human prostate cancer tissues. To this end, immunohistochemical studies for TGF-beta receptors were carried out on 32 cases of human prostate cancer and 8 samples of benign human prostate. In both benign and malignant human prostate tissues, immunoreactivity for both type I and type II receptors was detected predominantly in epithelial cells. In addition, there was an inverse correlation between the loss of expression of TGF-beta1 type I and type II receptors and the tumor grade. Of the 32 prostate cancer cases screened, staining was completely absent in four samples for type II receptor (P < 0.05) and eight samples for type I receptor (P < 0.025). In contrast, all eight samples of benign prostate tissues investigated in this study showed strong staining for both type I and type II receptors. These results, taken together, indicate that human prostate cancer cells frequently have loss of expression of TGF-beta type I and/or type II receptors. Furthermore, these observations provide a potential mechanism for prostate cancer cells to escape the growth-inhibitory effect of TGF-beta.

Molecular detection of prostate epithelial cells from the surgical field and peripheral circulation during radical prostatectomy.

PURPOSE: Prostate cancer progression despite organ confined pathological assessment has been reported in a variable number of men after radical retropubic prostatectomy. To study this phenomenon, we used the prostate specific antigen (PSA) reverse transcriptase-polymerase chain reaction assay. MATERIALS AND METHODS: We prospectively assayed the peripheral venous blood before, during and after surgical manipulation as well as the intraoperative field blood for PSA reverse transcriptase-polymerase chain reaction-positive cells in 22 men undergoing radical retropubic prostatectomy. RESULTS: PSA reverse transcriptase-polymerase chain reaction-positive cells were identified in 20 of the 22 operative field samples (91%) and 4 of 16 (25%) had evidence of intraoperative hematogenous dissemination (p = 0.046). No significant association was identified among Gleason score, pathological stage and the PSA reverse transcriptase-polymerase chain reaction result. CONCLUSIONS: Our results suggest that tumor cell spillage and less frequently hematogenous dissemination may be associated with operative manipulation of the prostate during radical retropubic prostatectomy and may potentially represent mechanisms of failure after radical retropubic prostatectomy.

Expression of the homeotic gene Hox-d13 in the developing and adult mouse prostate.

PURPOSE: To examine expression of the homeotic gene Hox-d13 in the developing mouse prostate. MATERIALS AND METHODS: Expression was assayed by Northern analysis, reverse-transcriptase polymerase chain reaction and in situ hybridization. RESULTS: Expression is present in the urogenital sinus in late gestation and is localized postnatally in the urethral epithelium and prostatic ducts. Expression continues throughout development and persists in the adult prostate. CONCLUSION: A restricted domain of Hox-d13 expression in the developing urogenital tract is consistent with the role of the Hox genes in specifying regional identity during development. Expression in the prostate postnatally suggests additional roles in prostate ductal morphogenesis and/or cell differentiation.