Effects of cavernous nerve reconstruction on expression of nitric oxide synthase isoforms in rats.

OBJECTIVE: To evaluate the expression of nitric oxide synthase (NOS) isoforms after various reconstruction techniques in rats, to improve the understanding of neuronal repair mechanisms after radical prostatectomy, as Schwann cell-seeded guidance tubes have been shown to promote cavernous nerve regeneration, and glial cell-line-derived neurotrophic factor (GDNF)-overexpressing Schwann cells enhance nerve regenerative capacity. MATERIALS AND METHODS: Segments (5 mm) of the cavernous nerve were excised bilaterally, followed by immediate bilateral microsurgical reconstruction. In four rats per group, the eight nerves were reconstructed by autologous nerve grafting (A), interposition of Schwann cell-seeded silicon tubes (B), or silicon tubes seeded with GDNF-hypersecreting Schwann cells (C). Further rats were either sham-operated (D) or had nerve excision without repair (E). Erectile function was evaluated after 6 weeks by re-laparotomy, electrical nerve stimulation and morphological evaluation of reconstructed nerves. NOS isoform mRNA expression was analysed by reverse transcription-polymerase chain reaction in tissue specimens taken from the corpora cavernosa. RESULTS: GDNF-transduced Schwann cell grafts restored erectile function better than untransduced Schwann cell and autologous nerve grafts (88% vs 75% vs 38%; not significant). Tissue specimens in group C had the highest expression of neuronal NOS mRNA in relation to the neuronal marker PGP9.5 among all treatment groups (not significant). Compared to nerve grafts (A) and negative controls (E) nNOS/PGP9.5 expression was significantly higher (P < 0.05). Both inducible NOS and endothelial NOS expression did not differ significantly among the various groups. Morphological evaluation showed significantly larger cross-sectional areas and a higher percentage of neural tissue than in untransduced Schwann cell grafts (P < 0.05). CONCLUSIONS: Restoration of erectile function is paralleled by an increase of neuronal NOS expression in rats. Further experiments will determine the physiological role of neuronal NOS in erectile nerve repair processes.

Alfuzosin 10 mg once daily for treating benign prostatic hyperplasia: a 3-year experience in real-life practice.

OBJECTIVES: To assess the 3-year efficacy and safety of the selective alpha(1)-blocker alfuzosin at 10 mg once daily in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in 'real-life practice'. The influence of treatment response on the risk of acute urinary retention (AUR) and BPH-related surgery was also analysed. PATIENTS AND METHODS: In all, 689 European men (mean age 67.6 years) were enrolled by general practitioners in a 3-year open-label study with alfuzosin at 10 mg once daily. They were asked to complete the International Prostate Symptom Score (IPSS), its eighth question (bother score), and the Danish Prostatic Symptom Score for sexual function (DAN-PSSsex). Efficacy was analysed at the endpoint in the intent-to-treat population. The impact of baseline variables (age, PSA level, IPSS and bother severity) and dynamic variables (IPSS worsening of >or=4 points and bother at the last available assessment under treatment) on the risk of AUR and BPH-related surgery was evaluated. RESULTS: With alfuzosin, IPSS improved by 6.4 points (-33.4%) from baseline (P < 0.001), reaching >or=3 points and >6 points in 71.3% and 47.2% of men, respectively. There were also significant (P < 0.001) improvements from baseline in nocturia (-0.8, -25.5%), bother score (-1.7, -40.7%) and DAN-PSSsex weighted scores with treatment. Symptom relief was rapid and maintained over 3 years. Overall, 78 men (12.4%) had an IPSS worsening of >or=4 points, 16 (2.6%) had AUR, and 36 (5.7%) required BPH-related surgery. Symptom deterioration during treatment and high baseline PSA values were the best predictors of AUR and BPH-related surgery. Alfuzosin was well tolerated, dizziness being the most frequent adverse event (4.5%) possibly related to vasodilatation. Ejaculatory disorders were uncommon (0.4%). Changes in blood pressure remained marginal, including in men aged >or=65 years and those receiving antihypertensive agents. CONCLUSION: Alfuzosin administered for 3 years at 10 mg once daily in real-life practice is effective and well tolerated. High PSA values and symptom worsening under treatment appear the best predictors of AUR and BPH-related surgery in the long term. Treatment with alfuzosin might thus help to identify patients at risk of LUTS/BPH progression in order to optimize their management.

Inhibition of the multidrug-resistant phenotype by targeting YB-1 with a conditionally oncolytic adenovirus: implications for combinatorial treatment regimen with chemotherapeutic agents.

Bearing in mind the limited success of available treatment modalities for the therapy of multidrug-resistant tumor cells, alternative and complementary strategies need to be developed. It is known that the transcriptional activation of genes, such as MDR1 and MRP1, which play a major role in the development of a multidrug-resistant phenotype in tumor cells, involves the Y-box protein YB-1. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In addition, it has been reported previously that YB-1 is an important factor in adenoviral replication because it activates transcription from the adenoviral E2-late promoter. Here, we report that an oncolytic adenovirus, named Xvir03, expressing the viral proteins E1B55k and E4orf6, leads to nuclear translocation of YB-1 and in consequence to viral replication and cell lysis in vitro and in vivo. Moreover, we show that Xvir03 down-regulates the expression of MDR1 and MRP1, indicating that recruiting YB-1 to the adenoviral E2-late promoter for viral replication is responsible for this effect. Thus, nuclear translocation of YB-1 by Xvir03 leads to resensitization of tumor cells to cytotoxic drugs. These data reveal a link between chemotherapy and virotherapy based on the cellular transcription factor YB-1 and provide the basis for formulating a model for a novel combined therapy regimen named Mutually Synergistic Therapy.

Value of 11C-choline PET and contrast-enhanced CT for staging of bladder cancer: correlation with histopathologic findings.

UNLABELLED: Lymph node involvement is a major prognostic factor in bladder cancer, but the accuracy of conventional imaging modalities for the prediction of regional and distant metastatic diseases is limited. This study was performed to compare the diagnostic accuracies of contrast-enhanced CT and PET with (11)C-choline for the staging of urothelial bladder cancer. METHODS: Twenty-seven patients (median age, 69.1 y) who had urothelial bladder cancer and who were referred for radical cystectomy and pelvic lymph node dissection (PLND) on the basis of a histologic evaluation after transurethral resection of bladder cancer (TURB) were studied. PET scanning, using 2 multiring whole-body tomographs, was performed 5 min after intravenous injection of approximately 370-500 MBq of (11)C-choline. In addition, conventional bone scintigraphy and contrast-enhanced CT were performed. After imaging, cystectomy and PLND were performed in all patients. Pathologic (11)C-choline uptake that could not be explained by intestinal activity was noted as a positive result. Node positivity was determined by size on CT: nodes measuring more than 1 cm in the long axis were described as being positive for tumor. Histopathologic findings were used as a reference. RESULTS: The presence of residual bladder cancer (pTa-pT4) was correctly detected in 21 of 25 histologically tumor-positive patients (84%) by CT and in 24 of 25 patients (96%) by (11)C-choline PET. Lymph node involvement was correctly detected in 4 of 8 patients (50%) by CT and in 5 of 8 patients (62%) by (11)C-choline PET. The median size of the 3 nodes with false-negative PET results was 9 mm (range, 6-21 mm), and the median size of the metastatic lesions within the lymph nodes was 3 mm (range, 1-15 mm). CT resulted in 6 (22%) false-positive lymph nodes, whereas none was demonstrated by (11)C-choline PET; these data indicated a significantly higher accuracy of PET than of CT (P < 0.01). Both modalities missed a small peritoneal metastasis verified by histologic evaluation. No positive results were obtained from bone scintigraphy. CONCLUSION: These preliminary data suggest that (11)C-choline PET is comparable to CT for detecting residual bladder cancer after TURB but appears to be superior to CT for the evaluation of potential additional lymph node metastases. (11)C-choline PET should be further evaluated for staging in patients who have bladder cancer and who are scheduled for radical cystectomy.

Immunohistochemical assessment of a testicular tumor in a 63-year-old patient: proposal for an integrated clinicopathologic approach.

A 63-year-old man was admitted to our hospital for complaints of a painless knot in his right testicle. The patient underwent orchiectomy for suspicion of malignancy. Pathologic examination detected a firm, circumscribed mass that consisted histologically of noncohesive, large, undifferentiated tumor cells diffusely infiltrating the testicular interstice. Because of the patient's advanced age and the structure of the neoplastic cells, the differential diagnosis favored a lymphoma over a malignant germ cell tumor but also included a dedifferentiated metastatic neoplasm. Immunohistochemistry was tailored accordingly and was completed using three successive panels of antibodies. Immunostaining with the first panel of antibodies directed against leukocyte epitopes (CD45, CD20, and CD3) remained negative and made a lymphoma unlikely. The subsequent panel (cytokeratin AE1/3, cytokeratin 18, and HMB-45) helped to rule out a malignant melanoma and aided to settle the diagnosis of a metastatic carcinoma. The reaction pattern of the last panel of antibodies pointed to a pulmonary origin of the putative primary tumor (PSA-negative, TTF-1-positive, and CK20-negative). The diagnosis of a metastasized poorly differentiated adenocarcinoma of the lung was confirmed by autopsy 5 months later. This case represents the extremely rare occurrence of a testicular metastasis as a primary manifestation of an occult neoplasm and shows the usefulness of an integrated site-specific clinicomorphologic approach that should precede and guide the choice of diagnostic immunoreagents.

Therapeutic vaccination with an interleukin-2-interferon-gamma-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial.

Immunotherapy with whole cell cancer vaccines has been tested in various tumor types. This study investigated the safety profile and antitumor activity of an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant human interleukin-2 and human interferon-gamma. Thirty HLA-A*0201-matched patients with progressive, castration-resistant prostate cancer received four intradermal injections on days 1, 15, 29, and 92, and then every 90 days, as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, and 27 patients received 15 million cells per injection. The primary study criteria were safety and the difference in prostate-specific antigen doubling time (PSA-DT), determined in the pretreatment phase (before the start of vaccination) and in the trial treatment phase (during vaccination). No dose-limiting or autoimmune toxicity was seen. During vaccination there was a significant prolongation of the PSA-DT compared with the prevaccination period (prolongation from 63 to 114 days; p < 0.01; intention to treat). In addition, results showed a period of PSA stabilization of at least 12 weeks, together with stable bone scans in 12 of 30 patients, and 3 patients sustained a >50% decrease in PSA versus baseline. The median overall survival time from first vaccination was 32 months (mean value, 34 months). Immune monitoring revealed T cell stimulation in the majority of patients. This vaccine strategy was found to be safe and well tolerated and was accompanied by prolongation of PSA-DT. The results of this trial warrant clinical development of this vaccine.

GDNF-transduced Schwann cell grafts enhance regeneration of erectile nerves.

BACKGROUND: Schwann cell-seeded guidance tubes have been shown to promote cavernous nerve regeneration, and the local delivery of neurotrophic factors may additionally enhance nerve regenerative capacity. The present study evaluates whether the transplantation of GDNF-overexpressing Schwann cells may enhance regeneration of bilaterally transected erectile nerves in rats. METHODS: Silicon tubes seeded with either GDNF-overexpressing or GFP-expressing Schwann cells were implanted into the gaps between transected cavernous nerve endings. Six (10 study nerves) or 12 wk (20 study nerves) postoperatively, erectile function was evaluated by relaparotomy, electrical nerve stimulation, and intracavernous pressure recording, followed by ultrastructural evaluation of reconstructed nerves employing bright-field and electron microscopy. Additional animals were either sham-operated (positive control; 20 study nerves) or received bilateral nerve transection without nerve reconstruction (negative control; 20 study nerves). RESULTS: The combination of GDNF delivery and Schwann cell application promoted an intact erectile response in 90% (9 of 10) of grafted nerves after 6 wk and in 95% (19 of 20) after 12 wk, versus 50% (5 of 10) and 80% (16 of 20) of GFP-expressing Schwann cell grafts (p=0.02). The functional recovery was paralleled by enhanced axonal regeneration in GDNF-overexpressing Schwann cell grafts, as indicated by larger cross-sectional areas and a significantly higher percentage of neural tissue compared with GFP-transduced controls. CONCLUSIONS: These findings demonstrate that the time required to elicit functional recovery of erectile nerves can be reduced by local delivery of GDNF. In terms of clinical application, this enhanced nerve repair might be critical for timely reinnervation of the corpus cavernosum as a prerequisite for functional recovery in men.

The role of inflammation and infection in the pathogenesis of prostate carcinoma.

Prostatitis and prostate carcinoma are both frequent entities of prostatic diseases. Epidemiological studies show significant associations between infection and inflammation and prostatic carcinoma. However, because of various confounding factors the results of these studies are inconclusive. Further findings are therefore needed to confirm the hypothesis that prostatic infection and inflammation might be a cause of prostatic carcinoma. We reviewed selected reports on the role of inflammation and infection in the pathogenesis of prostate carcinoma. Extensive genetic analyses show that several gene products, e.g. 2'-5'-oligoadenylate (2-5 A)-dependent Rnase, macrophage scavenger receptor 1 and Toll-like receptor-4, influence the susceptibility of prostate cells to infectious agents. Proliferative inflammatory atrophy (PIA) could be a connection between prostatitis and prostatic carcinoma. In the transition from PIA to prostatic intraepithelial neoplasia, the function of cellular detoxification is gradually lost by silencing of glutathione-S transferase, a detoxifying enzyme. This cellular feature leads to an increased susceptibility of the prostatic epithelial cells to genomic damage by inflammatory oxidants or nutritional carcinogens. Consecutive somatic genome damage might then arise which modulates the further pathogenesis of prostate carcinoma. Summarising these epidemiological, genetic and cell biological aspects, infectious prostatitis might have a causative role in the complex and multifactorial process of prostate carcinogenesis.

The value of a second transurethral resection for T1 bladder cancer.

OBJECTIVE: To evaluate a series of repeat transurethral resections (TURs) of tumour in patients with T1 bladder cancer, usually used to ensure a complete resection and to exclude the possibility muscle-invasive disease. PATIENTS AND METHODS: In all, 136 consecutive patients had a second TUR because of a histopathological diagnosis of T1 transitional cell carcinoma (TCC) after their initial TUR. Of the 136 patients, 101 were first presentations and 35 had recurrent tumours. The second TUR was done 4-6 weeks later. The evaluation included the presence of previously undetected residual tumour, changes to histopathological staging/grading, and tumour location. RESULTS: In all, 71 patients (52%) had residual disease according to findings from specimens obtained during the second TUR. The staging was: no tumour, 65 (48%); Ta, 11 (8%); T1, 32 (24%); Tis, 15 (11%); and > or = T2, 13 (10%). Histopathological changes that worsened the prognosis (>T1 and or concomitant Tis) were found in 21% of patients. Residual malignant tissue was found in the same location as the first TUR in 86% of the patients, and at different locations in 14%. Overall, 28 patients (21% of the original 136) had a radical cystectomy as a consequence of the second TUR findings. CONCLUSIONS: A routine second TUR should be advised in patients with T1 TCC of the bladder, to achieve a more complete tumour resection and to identify patients who should have a prompt cystectomy.

Influence of blood transfusions during radical retropubic prostatectomy on disease outcome.

OBJECTIVES: Blood transfusion in patients with malignant neoplasms may alter the disease outcome because of a theoretical immunomodulatory effect. This effect may reduce prostate-specific antigen (PSA)-free and disease-specific survival in patients with prostate cancer after radical prostatectomy. However, the results in published studies have been contradictory, and this effect has not yet been determined. METHODS: We evaluated 1412 patients after radical prostatectomy from 1984 to 2003 in a retrospective analysis, with a special focus on the rate and type of blood transfusions, specifically heterologous versus autologous blood. Univariate analysis and Cox regression analysis were performed to evaluate the impact of blood transfusions on disease outcome. RESULTS: The overall transfusion rate was 56.7%. The rate dropped from 88.9% in 1988 to 9.1% in 2002. PSA recurrence (greater than 0.5 ng/mL) was noted in 11.0% in patients without and in 26.0% with blood transfusions, which was not statistically significant on Kaplan-Meier analysis. Again, no difference was noted when patients were stratified according to the type (autologous versus heterologous) or the amount (2 U or less versus more than 2 U) of blood transfusion. Evaluating overall survival, again no differences were found. The established Cox regression model also proved that blood transfusions had no impact on disease outcome. CONCLUSIONS: Our retrospective analysis did not detect any effect of blood transfusions in patients with prostate cancer after radical prostatectomy. If a negative adverse effect occurs, this effect must be minimal. However, the infectious risk and the costs of blood transfusions should be reason enough to reduce blood loss and the transfusion rate further in patients with prostate cancer.

Long-term efficacy and safety of alfuzosin 10 mg once daily: a 2-year experience in 'real-life' practice.

OBJECTIVE: To assess the 2-year efficacy and safety of alfuzosin 10 mg once daily, a selective alpha(1)-adrenoceptor antagonist, in men complaining of lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia (BPH), in 'real life' practice. PATIENTS AND METHODS: In all, 839 European men with LUTS (mean age 67.3 years) were enrolled by general practitioners in a 2-year open-label study with alfuzosin 10 mg once daily. They were asked to complete the International Prostate Symptom Score (IPSS), its appended eighth question (bother score), and the five domains (sexual drive, erection, ejaculation, problem assessment, and overall satisfaction) of the Brief Male Sexual Function Inventory (BSFI). The results were analysed at the endpoint in the intent-to-treat population. RESULTS: At the endpoint the total IPSS improved by 7 points (-38.5%) from baseline (P < 0.001) with 76.9% and 49.7% of men having an improvement of > or = 3 points and >6 points, respectively. There were also significant improvements in nocturia (-0.9, -30%; P < 0.001) and bother score (-1.8, -43%; P < 0.001) from baseline. Most patients (56%) perceived symptom relief within the first 2 weeks of treatment. All BSFI domains significantly improved from baseline (P < 0.05; <0.001 for overall satisfaction) and these improvements were more marked in men with severe LUTS at baseline. Alfuzosin 10 mg was well tolerated; the most common adverse event related to vasodilatation was dizziness/postural dizziness (3.1%). Ejaculatory disorders were uncommon (0.3%). Changes in blood pressure remained marginal, including in elderly men and those receiving antihypertensive agents. CONCLUSIONS: Alfuzosin 10 mg administered for 2 years in real practice is effective in improving LUTS and quality of life, and is well tolerated from a cardiovascular perspective, including in elderly men and those receiving antihypertensive co-medication. Ejaculatory disorders are uncommon. Alfuzosin may even slightly improve various domains of sexual function, such as sexual drive, erection, ejaculation and satisfaction with sexual life.

Prostate cancer volume -- can it be predicted preoperatively?

INTRODUCTION: The prostate cancer volume (PCvol) is described as a significant predictor for tumor progression after radical prostatectomy, but its determination has not become a routine procedure yet due to high demands on technical standards, labor intensity, and costs. The objective of this study is to predict the PCvol by using common preoperative variables. MATERIAL AND METHODS: Between 1996 and 2001, 365 whole-mounted prostatectomy specimens, processed according to the Stanford protocol, were used for computerized reconstruction of the total PCvol. Widely accepted preoperative variables such as prostate-specific antigen (PSA), digital rectal examination findings, and Gleason score and grading (WHO) of the biopsy cores were correlated and analyzed for a relation to the PCvol by Spearman rho method and Mann-Whitney U test. Integrating these parameters in a multiple linear regression model, independent variables predicting the PCvol were determined, multiplied by their risk factors, and used for calculation of the estimated PCvol. In order to evaluate the precision of our results, we correlated measured and estimated tumor volumes. A nomogram was constructed, in order to visualize our results. RESULTS: Multiple linear regression analysis revealed categorized PSA, grading (WHO), and Gleason score to be independent predictors for the PCvol. The estimated PCvol ranged from 0.5 to 9.8 cm(3) and the measured PCvol from 0.02 to 53 cm(3). An identical mean value of 4.1 cm(3) was observed. The Spearman rho method showed a highly significant correlation (coefficient = 0.5) between estimated and measured PCvol (p < 0.001). CONCLUSIONS: The PCvol is regarded as a significant predictive parameter of tumor progression after radical prostatectomy, but due to its time-consuming determination, it has not become a routine procedure yet. Currently used preoperative parameters such as PSA and grading (WHO) and Gleason score of the biopsy cores do predict the total tumor volume. These results were reconfirmed by correlation analysis. Consequently, by use of our nomogram, the labor-intensive measurement of the PCvol becomes unnecessary.

Optimization of prostatic biopsy: a prospective randomized trial comparing the sextant biopsy with a 10-core biopsy. Impact of prostatic region of sampling.

OBJECTIVE: New prostatic biopsy protocols suggest to increase the core numbers to enhance detection. Additional cores are usually sampled from the lateral part of the p-zone. We direct the sextant biopsy to the most lateral part of the p-zone, therefore we investigated if there is a gain by adding 4 median biopsy cores. MATERIAL AND METHODS: The prospective randomized trial (n = 200) compared our modified sextant biopsy to a 10-core strategy with 2 additional median cores on both sides. Directed biopsies to suspicious areas were allowed in both groups. Morbidity was assessed by a self-administered questionnaire. RESULTS: PC detection was 32% for 6 cores and 40% for 10 cores. Four patients were detected only by median biopsies. Using the binomial distribution table the gain of 4% is statistically significant. There was no statistical difference in morbidity, but a trend towards a higher rate of side effects in the 10-core group. CONCLUSIONS: The gain in prostate cancer detection rate by additional median biopsies is low, but statistically significant. There is no difference in morbidity and patient acceptance is high, therefore we favor the 10-core biopsy in our patients.

Alfuzosin 10 mg once daily improves sexual function in men with lower urinary tract symptoms and concomitant sexual dysfunction.

OBJECTIVE: To assess the effect on sexual function of alfuzosin 10 mg once daily, a uroselective alpha(1)-blocker, in men with lower urinary tract symptoms (LUTS) suggestive of bladder outlet obstruction. PATIENTS AND METHODS: In all, 3076 men (mean age 65.9 years) were treated for 1 year with alfuzosin 10 mg in 'real life' practice. They were asked to complete the International Prostatic Symptom Score (IPSS), its appended eighth question (bother score) and the Danish Prostatic Symptom Score questionnaire for sexual dysfunction (DAN-PSSsex). The results were analysed at the endpoint in the intent-to-treat population. RESULTS: At baseline, 2434 (79.1%) men were sexually active and answered correctly at least one item of the DAN-PSSsex. Sexual dysfunction was highly prevalent (reduced stiffness of erection, 65.3%; reduced volume of ejaculate, 63.2%; pain/discomfort on ejaculation, 20.2%), and was strongly related to the severity of LUTS and impairment of quality of life. At the endpoint, alfuzosin significantly improved the total IPSS (-6.1, - 32%) and bother score (-1.4, - 33.2%, both P < 0.001) over baseline. In those men with sexual dysfunction there were significant improvements in weighted scores related to reduced rigidity of erection (-0.5), reduced amount of ejaculate (-0.4) and pain/discomfort on ejaculation (-1.2, all P < 0.001) over baseline. The perceived improvements were more marked in men with severe LUTS or a severe bother score at baseline. CONCLUSIONS: Sexual dysfunction is highly prevalent in men with LUTS and related to the baseline IPSS and bother score. Alfuzosin 10 mg once daily for 1 year is effective in improving LUTS and quality of life, and is well tolerated. It may even improve sexual function in those men with concomitant erectile and/or ejaculatory dysfunction.

Symptom deterioration during treatment and history of AUR are the strongest predictors for AUR and BPH-related surgery in men with LUTS treated with alfuzosin 10 mg once daily.

OBJECTIVES: To assess the predictors of acute urinary retention (AUR) and/or surgery related to benign prostatic hyperplasia (BPH) in 3514 men complaining of lower urinary tract symptoms and treated for 6 months with the selective alpha1-blocker alfuzosin at 10 mg once daily. METHODS: The impact of baseline (age, prior AUR, prostate-specific antigen tertiles, lower urinary tract symptoms severity, and bother score) and dynamic (International Prostate Symptom Score [IPSS] worsening of 4 points or greater and bother greater than 3 during treatment) variables on the risk of AUR/BPH-related surgery was assessed using Kaplan-Meier curves and log-rank tests. Associated hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. RESULTS: Of the 3514 men analyzed, 140 (4%) experienced a first episode of conservatively managed AUR before inclusion. Of those 140 men, 5 (3.6%) had AUR relapse during alfuzosin treatment and 6 (4.3%) underwent BPH-related surgery. Of those 3374 men without prior AUR, 19 (0.6%) experienced AUR during treatment and 41 (1.2%) underwent BPH-related surgery. During treatment, the most important predictors of AUR were prior AUR (HR 6.35, 95% CI 2.31 to 17.40; P < 0.01), IPSS worsening of 4 or greater (HR 3.34, 95% CI 1.11 to 9.99; P = 0.03), and bother score greater than 3 (HR 3.32, 95% CI 1.29 to 8.53; P < 0.01) at endpoint. Other variables (age, PSA, baseline IPSS, and bother) had much less predictive value. Similar results were observed regarding the risk of AUR and/or BPH-related surgery. CONCLUSIONS: The results of this 6-month real life practice study suggest that prior AUR and symptom deterioration during treatment with alfuzosin 10 mg once-daily (IPSS worsening of 4 or more points, bother score greater than 3) were the strongest predictors of AUR and AUR/BPH-related surgery in men with lower urinary tract symptoms.

In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines.

BACKGROUND: The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145. METHODS: The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram. RESULTS: Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells. CONCLUSIONS: The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.

Transcutaneous IL-2 uptake mediated by Transfersomes depends on concentration and fractionated application.

INTRODUCTION: Transfersomes (TF) are new, ultradeformable carriers with characteristics that enable them to penetrate the skin spontaneously. TFs are able to transport noninvasively both low- and high-molecular-weight molecules into the body. MATERIALS AND METHODS: TFs contain phosphatidylcholine and sodium cholate. Recombinant human interleukin-2 (Proleukin, Chiron) was added to the TFs and incubated for 24 h at 4 degrees C. The immunotransfersomes (ITF) were isolated from free interleukin-2 (IL-2) by filtration (Centrisart, Sartorius). Twenty-five thousand, 50,000 and 150,000 IU pure IL-2 and ITFs, which had been incubated with the same concentrations of IL-2, were applied subcutaneously (s.c.) (n = 8) and epicutaneously (e.c.) (n = 8) to mice. The IL-2 serum concentrations in the mice were then measured by ELISA after 2, 4, 6, 8, 10 and 24 h. Fractionation of the transdermal IL-2 application was also examined as a means of improving uptake. RESULTS: In concentrations of 25,000 and 50,000 IU IL-2, the subcutaneous application of ITFs resulted in a longer lasting IL-2 serum concentration than did the subcutaneous application of pure IL-2. While at 25,000 IU, the epicutaneous application of ITFs resulted in serum concentrations comparable to those resulting from s.c. application, at 50,000 and 150,000 IU, only 50% and 22.6% of the maximum serum concentration resulting from the s.c. application of pure IL-2 was obtained. Fractionating the transdermal IL-2 application improved uptake. CONCLUSION: We were able to show that biologically active IL-2 can be bonded to TFs up to 75%. It is possible to transport IL-2 through the skin using TFs. Both the concentration-dependent saturation of the TFs with IL-2 and fractionation of the application resulted in differing degrees of transcutaneous IL-2 uptake.

Cadherin-6: a new prognostic marker for renal cell carcinoma.

PURPOSE: Cadherin-6, a new cell adhesion molecule of the cadherin family, is expressed in normal kidney and renal cell carcinoma. First results demonstrated that the expression of cadherin-6 in renal cell carcinoma may have prognostic value. We prospectively evaluated the importance of cadherin-6 in renal tumors in a large cohort of patients. MATERIALS AND METHODS: A total of 216 patients with renal cell carcinoma who underwent tumor nephrectomy were evaluated for cadherin-6 expression by immunohistochemistry and immunoblotting. The expression pattern was correlated with known prognostic factors of renal cell carcinoma. Statistical analysis was performed by the Mann-Whitney U and Pearson chi-square tests. Multivariate analysis was performed by the proportional hazard Cox model. RESULTS: Cadherin-6 expression in renal cell cancer correlated with known prognostic factors, such as pT stage (p = 0.03), pN stage (p = 0.001), histological growth pattern (p = 0.001), M stage (p = 0.06) and renal venous involvement (p = 0.019). There was no correlation with tumor grading (p = 0.74) or tumor size (p = 0.84). We developed a relative risk factor for renal cell cancer for our patients using the multivariate proportional hazard Cox model, which showed a statistically significant correlation with cadherin-6 expression (p = 0.028). CONCLUSIONS: Cadherin-6, a new cell adhesion molecule of the cadherin family, is specifically expressed in the proximal tubule of normal kidneys and in renal cell cancer. In our prospective analysis the pattern of cadherin-6 expression correlated with known prognostic factors of renal cell cancer on univariate and multivariate analysis. Our data suggest that cadherin-6 is a new prognostic factor for renal cancer.

Influence of transrectal ultrasound probe on prostate cancer detection in transrectal ultrasound-guided sextant biopsy of prostate.

OBJECTIVES: To determine whether end-fire probes increase the prostate cancer (PCa) detection rate. Enhancing the PCa detection rate is the main goal of biopsy protocols. Prostate biopsy is limited by side-fire probes to a longitudinal axis, but end-fire probes allow biopsy cores to also be taken in the transverse section. METHODS: A total of 2625 patients underwent systematic sextant biopsy in three institutions using the same protocol. Three different ultrasound probes were used-the Kretz Combisone and Bruel & Kjaer side-fire probes and the ATL HDI end-fire probe. We retrospectively evaluated the influence of the probe on the PCa detection rate. RESULTS: The Kretz probe was used in 384 men, the Bruel & Kjaer probe in 598 men, and the ATL probe in 1643 men. Overall, 35.2% had PCa detected. Analyzing all patients, no statistically significant difference (P = 0.73) was found for the probes, but the subgroup with a prostate-specific antigen level of 4 to 10 ng/mL demonstrated a statistically significant improvement in the detection rate using the end-fire probe (31.3% versus 24.5% and 21.5% for the side-fire probes, P = 0.01). Patients with nonpalpable PCa also demonstrated a statistically significant increase in detection with the end-fire probe (P = 0.004). Multivariate analysis confirmed that the ultrasound probe is an independent parameter to enhance the PCa detection rate. CONCLUSIONS: Our results showed that end-fire probes provide a statistically significant improvement in the PCa detection rate compared with side-fire probes in patients with a prostate-specific antigen level of 4 to 10 ng/mL and nonpalpable disease. The reason could be the facilitated sampling in the most lateral part of the peripheral zone. Our results suggest that the widespread use of end-fire probes for prostate biopsy could enhance the PCa detection rate.

Morbidity of prostatic biopsy for different biopsy strategies: is there a relation to core number and sampling region?

OBJECTIVES: The standard sextant prostatic biopsy is a safe procedure associated with low morbidity. Newer biopsy protocols suggest an increase in core numbers or sampling in distinct areas. In this respect we investigated the morbidity of different biopsy regimens. METHODS: Morbidity was assessed using self-administered questionnaires 1 week and 1 month after biopsy in a prospective randomized trial of 405 men with three different biopsy protocols. We compared a sextant biopsy regimen to a 10-core biopsy strategy, as well as patients with a re-biopsy including t-zone sampling. We investigated pain during and after biopsy, gross hematuria, rectal bleeding, hematospermia, fever and chills. RESULTS: There is a trend towards a more painful biopsy and higher rate of side effects if the number of core samples is increased, this difference did not reach statistical significance. There was no increase in severity of side effects. Regarding the rate and severity of side effects of biopsy strategies to different areas of the prostate we could not find a difference. About 95% of patients would accept a repeat biopsy based on their experience on first biopsy. CONCLUSIONS: Morbidity of transrectal prostatic biopsy is low and increasing the number of cores correlates with a minor and statistically not significant increase in the rate of side effects. Transrectal sextant prostatic biopsy and extensive biopsy protocols are generally well tolerated and widely accepted from patients.