Effectiveness, pharmacokinetics, and safety of a new sustained-release leuprolide acetate 3.75-mg depot formulation for testosterone suppression in patients with prostate cancer: a Phase III, open-label, international multicenter study.

BACKGROUND: A microencapsulated, sustained-release formulation of leuprolide acetate 3.75 mg has been developed. OBJECTIVE: This study investigated the effectiveness, pharmacokinetics, and safety profile of a 1-month leuprolide acetate 3.75-mg depot formulation for suppressing testosterone concentrations in patients with prostate cancer. METHODS: This was a Phase III, open-label, international multicenter clinical trial. Patients with prostate cancer who, in the judgment of the investigators, could benefit from androgen deprivation therapy received 6 monthly intramuscular injections of leuprolide acetate 3.75-mg depot. Plasma testosterone concentrations were determined at specific times throughout the study. The primary end point was the proportion of successful patients over the total number of evaluable patients (ie, patients with evaluable testosterone concentrations at all monthly assessments and no missing values due to treatment-related adverse events). Treatment success was defined as testosterone suppression below the clinical castration level (ie,

Wilms tumor in a 37-year-old.

UNLABELLED: Wilms tumor is rare in adults. Though the approach to diagnosis and treatment of adult Wilms tumor (AWT) is closely modeled on recommendations for childhood Wilms tumor, views differ on how aggressive the treatment should be. We report a case of a 37-year-old with Stage III favorable histology AWT. A radical nephrectomy was performed and the patient was due for chemotherapy. Recent advances, controversies and current recommendations in the treatment of AWT are discussed. KEYWORDS: Adult; Wilms tumor; Kidney.

IL15 can reverse the unresponsiveness of Wilms' tumor antigen-specific CTL in patients with prostate cancer.

PURPOSE: The Wilms' tumor antigen 1 (WT1) is overexpressed in several leukemias and solid tumors, but there is currently limited information regarding its role in prostate cancer. This study aimed to investigate WT1 expression in prostate cancer, and to determine the number and function of WT1-specific T cells in the peripheral blood of patients. EXPERIMENTAL DESIGN: Immunohistochemistry was used to assess WT1 expression in cancer tissues. Human leukocyte antigen A2 (HLA-A2) tetramers served to detect WT1-specific T cells, and peptide-specific stimulation was used to assess T-cell function in vitro. RESULTS: Immunohistochemistry of tissue arrays comprising 36 cancer and 8 normal prostate samples revealed nuclear WT1 staining in 39% of cancer samples, but not in normal prostate tissues. Tetramer analysis revealed a low frequency of WT1-specific T cells in 20 of 38 HLA-A2-positive patients. In vitro stimulation with WT1 peptide plus interleukin 2(IL2) and interleukin 7 (IL7) did not lead to an accumulation of WT1-specific T cells in any of the patient samples, although all patients were able to generate T-cell responses against Melan-A/MART1 control peptide. Stimulation with WT1 peptide in the presence of interleukin 15 (IL15), a cytokine that was shown to reverse tolerance of murine tumor-specific T cells, was able to restore the expansion and IFNgamma production of WT1-specific T cells in a subgroup of prostate cancer patients. CONCLUSION: The observation that IL15 can restore the function of WT1-specific T cells that were unresponsive to IL2 has implications for vaccination and immunotherapeutic strategies that aim to enhance WT1-specific T cell immunity in patients.

Greenlight prostatectomy: a challenge to the gold standard? A review of KTP photoselective vaporization of the prostate.

The use of lasers to carry out resection of the prostate gland is an ever-evolving field which has seen several different modalities of laser light used with varying success. This review looks at what makes the traditional transurethral resection of prostate the gold standard and provides the evidence on the evolution of the laser prostatectomy in trying to usurp it as the favored procedure for symptomatic benign prostatic hyperplasia. In particular, we show how the latest laser technology in the form of the Greenlight laser is challenging not only other lasers such as the holmium laser, but may form a strong contender to replace the transurethral resection of prostate.

Urachal tumour: clinical and radiological features of a poorly understood carcinoma.

Urachal tumours are rare vesical neoplasms. We report a case of urachal adenocarcinoma in a 31-year-old patient.

Molecular load of pathologically occult metastases in pelvic lymph nodes is an independent prognostic marker of biochemical failure after localized prostate cancer treatment.

PURPOSE: Thirty percent of patients treated with curative intent for localized prostate cancer (PC) experience biochemical recurrence (BCR) with rising serum prostate-specific antigen (sPSA), and of these, approximately 50% succumb to progressive disease. More discriminatory staging procedures are needed to identify occult micrometastases that spawn BCR. PATIENTS AND METHODS: PSA mRNA copies in pathologically normal pelvic lymph nodes (N0-PLN) from 341 localized PC patients were quantified by real-time reverse-transcriptase polymerase chain reaction. Based on comparisons with normal lymph nodes and PLN with metastases and on normalization to 5 x 10(6) glyceraldehyde-3'-phosphate dehydrogenase mRNA copies, normalized PSA copies (PSA-N) and a threshold of PSA-N 100 or more were selected for continuous and categorical multivariate analyses of biochemical failure-free survival (BFFS) compared with established risk factors. RESULTS: At median follow-up of 4 years, the BFFS of patients with PSA-N 100 or more versus PSA-N less than 100 was 55% and 77% (P = .0002), respectively. The effect was greatest for sPSA greater than 20 ng/mL, 25% versus 60% (P = .014), Gleason score 8 or higher, 21% versus 66% (P = .0002), stage T3c, 18% versus 64% (P = .001), and high-risk group (50% v 72%; P = .05). By continuous analysis PSA-N was an independent prognostic marker for BCR (P = .049) with a hazard ratio of 1.25 (95% CI, 1.001 to 1.57). By categorical analysis, PSA-N 100 or more was an independent variable (P = .021) with a relative risk of 1.98 (95% CI, 1.11 to 3.55) for BCR compared with PSA-N less than 100. CONCLUSION: PSA-N 100 or more is a new, independent molecular staging criterion for localized PC that identifies high-risk group patients with clinically relevant occult micrometastases in N0-PLN, who may benefit from additional therapy to prevent BCR.

Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration.

OBJECTIVE: To evaluate the pharmacokinetics, tolerability and effect on endocrinology of bicalutamide given as once-daily monotherapy at doses of >150 mg to patients with locally advanced (M0) or metastatic (M1) prostate cancer, with efficacy as a secondary endpoint. PATIENTS AND METHODS: Patients were initially enrolled to receive bicalutamide 300 mg in a non-randomized phase, after which further patients were randomized to higher bicalutamide doses (in 150 mg increments) or castration. Overall, 248 patients received bicalutamide at 300 mg (21), 450 mg (95) or 600 mg (42), or castration (90). RESULTS: Systemic exposure to bicalutamide stabilised at a dose of approximately 300 mg, as determined by pharmacokinetic analysis. The tolerability of high doses of bicalutamide was similar to that of the 150 mg dose, with no increase in the incidence of adverse events. Patients receiving bicalutamide had early increases in the mean levels of oestradiol, testosterone and luteinizing hormone, which were maintained throughout the study. Levels of these hormones rapidly decreased in the castration group and remained low. From baseline (first day of treatment) to 12 weeks there was an equivalent reduction in prostate-specific antigen (PSA) levels across all four groups. At a median follow-up of 5 years, there was no significant survival difference between patients who received bicalutamide and those who received castration, either in M0 or M1 disease. CONCLUSION: The low median PSA level (180 ng/mL) of patients with M1 disease might account for the lack of survival difference between the treatment groups. Further studies are needed to assess whether high-dose bicalutamide monotherapy can provide equivalent efficacy to castration in patients with M1 prostate cancer.

The use of polymer (Hem-o-lok) clips for management of the renal hilum during laparoscopic nephrectomy.

OBJECTIVE: Control of the renal pedicle is the most challenging step during laparoscopic nephrectomy. The standard method is to clip the artery and control the vein with an endovascular gastrointestinal anastomosis stapler. However, this device is expensive and has been reported to malfunction, leading to major complications even death. We describe an easy, quick, and cost-effective alternative technique. METHODS: From June 2002 to July 2005, two surgeons used this simplified technique to control the renal vein during laparoscopic nephrectomy. After pedicle dissection and control of the artery with a clip, the vein was grasped and gently pulled with a laparoscopic Babcock to reduce its diameter. Two Hem-o-lok clips (Weck Closure Systems, Research Triangle Park, NC) were easily placed on the renal vein, which was then transacted safely. RESULTS: We used this technique successfully for 130 consecutive laparoscopic nephrectomies (10 simple, 47 radical, 7 nephroureterectomies, and 66 live donor nephrectomies). No perioperative complications occurred with this technique in this series. There was no increase in the warm ischemia time when used during laparoscopic live donor nephrectomy. CONCLUSIONS: The Hem-o-lok technique is easy, safe, and rapid and offers cost savings when compared to the endovascular gastrointestinal anastomosis stapler. We recommend its use during laparoscopic nephrectomy and live donor nephrectomy.

The incidence and treatment of lymphoceles after radical retropubic prostatectomy.

OBJECTIVE: To determine the incidence and treatment of lymphoceles after retropubic radical prostatectomy (RP). PATIENTS AND METHODS: Up to January 2004, 260 patients who had a retropubic RP in one institution by one surgeon were assessed retrospectively, using the patients' notes or the computerized results system to determine whether a lymphocele was suspected and then confirmed by imaging studies (computed tomography or ultrasonography). RESULTS: Nine patients developed symptomatic lymphoceles; eight of these were detected by imaging. Four lymphoceles required intervention while the remainder regressed spontaneously. No complications were reported in the group that was treated. CONCLUSION: The rate of symptomatic lymphocele formation was low after RP, with an overall incidence of 3.5%. Ultrasonography was effective in detecting lymphoceles and ultrasonographically guided percutaneous drainage an effective treatment.

Pharmacodynamic equivalence of a decapeptyl 3-month SR formulation with the 28-day SR formulation in patients with advanced prostate cancer.

AIMS: The objective of the study was to assess the pharmacodynamic equivalence of LHRH analogue triptorelin 3-month and 28-day SR formulations. METHODS: Patients with documented locally advanced or metastatic prostate cancer were randomized to receive one injection of the 3-month formulation (n = 63) or three injections at 28-day intervals of the 28-day formulation (n = 68). Group-chemical castration rates defined as the percentage of patients reaching a testosterone plasma level

The total percentage of biopsy cores with cancer improves the prediction of pathological stage after radical prostatectomy.

OBJECTIVE: To examine whether the simple variable 'percentage of cancer-positive biopsy cores' is a significant predictor of true pathological stage after radical prostatectomy and can be used to improve pathological stage prediction by simple means. PATIENTS AND METHODS: In all, 375 patients had a radical prostatectomy for localized prostate cancer in two UK centres; 260 had complete preoperative staging information. Logistic regression was used and predicted probability graphs constructed to assess predictors of pathological stage. RESULTS: In this study, only PSA (P = 0.004) and percentage cancer-positive biopsy cores (P < 0.001) were significant predictors of pathological stage. The final model was an acceptable classifier for pathological stage (area under the receiver operating characteristic curve 0.76, specificity 85%, sensitivity 47%). A patient with a PSA of 10 ng/mL and one of six cores positive for cancer would have a predicted probability of extraprostatic disease of 20%, whereas the same patient with all six biopsy cores positive would have a predicted probability of extraprostatic disease of 80%. CONCLUSIONS: The percentage of cancer-positive biopsy cores significantly predicts the disease stage after radical prostatectomy. This variable is easy to obtain by the clinician and avoids the need to estimate the percentage of biopsy tissue infiltrated by cancer. This readily available information can easily be computed and may help to counsel patients about realistic expectations of organ-confined disease in relation to surgery as a treatment option.

In vitro deregulation of markers characteristic of human prostate epithelial cells.

We have screened primary cultures of human prostate for the expression of markers reported to be characteristic of specific cell lineages in vivo, in order to ascertain whether human prostate cells in vitro maintain and reflect their in vivo differentiated phenotypes and to evaluate the homogeneity of the populations of cells that can be derived from this tissue. Using single and dual stain immunofluorescent microscopy to analyse very early organoid and subsequently derived monolayer stage cultures, we have observed that expression of markers characteristic of human prostate epithelial cells in vivo is deregulated within 48h, indicating that dissociation of human prostate tissue and cultivation of prostate epithelial cells in culture can result in promiscuous expression of cell type specific markers of prostate epithelial cells. These observations have important implications for studies of cell lineage and differentiation of prostate cells in vitro.

Contractile actions of imidazoline alpha-adrenoceptor agonists and effects of noncompetitive alpha1-adrenoceptor antagonists in human vas deferens.

The contractile actions of imidazoline alpha-adrenoceptor agonists were investigated in human vas deferens longitudinal and circular muscle. The effects of phenoxybenzamine were studied in comparison to dibenamine and SZL-49 (4-amino-6,7-dimethoxy-2-quinazolinyl-4-(2-bicyclo[2,2,2]octa-2,5-dienylcarbonyl-2-piperazine), an alkylating prazosin analogue that discriminates between alpha(1H)- and alpha(1L)-adrenoceptor subtypes. The imidazoline alpha-adrenoceptor agonist, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide hydrobromide), was a potent agonist (pD(2); longitudinal muscle 6.9, circular muscle 6.4) and cirazoline a partial agonist (pD(2); longitudinal muscle 6.1, circular muscle 5.1). Oxymetazoline was less effective, indanidine and clonidine were ineffective. SZL-49 produced a differential inhibition of contractions evoked by A-61603 in circular (alpha(1H)) compared to longitudinal (alpha(1L)) muscle and phenoxybenzamine had the opposite effect. Dibenamine inhibited the contractions comparably in both muscle types and analyses of its partial alkylation of receptors yielded identical estimates of equilibrium dissociation constant (pK(d)) for A-61603 in longitudinal (5.82) and circular (5.84) muscle. Receptor occupancy-response relationships revealed that whilst the muscle types are not different in receptor reserves for A-61603, contraction to the potent imidazoline is more efficiently coupled in longitudinal than in circular muscle. This underlies the markedly different responsiveness of the muscle types to cirazoline or oxymetazoline (alpha-adrenoceptor agonists with lower efficacies relative to A-61603). The differential inhibitory actions of phenoxybenzamine and SZL-49 are discussed.

Asian trends in prostate cancer hormone therapy.

The first Conference on Asian Trends in Prostate Cancer Hormone Therapy was held in September 2001 to serve as a forum for Asian urologists to compare data on prostate cancer and discuss issues regarding the use of hormone therapy. The conference revealed that due to various cultural and philosophical factors, differences exist in prostate cancer management among the Asian countries. In addition, a lack of databases on hormone therapy was exposed in some countries. It was noted that many decisions in the treatment of prostate cancer are influenced by the strategies adopted in Western countries, and that attempts to formulate uniform guidelines for the Asian region have hitherto been unsuccessful. The main findings of the conference are reported in this review.