Acupuncture in the treatment of psychogenic erectile dysfunction: first results of a prospective randomized placebo-controlled study.

In a prospective study, we investigated the potentially curative effect of acupuncture in patients with psychogenic erectile dysfunction (pED). A total of 22 patients with pED were randomized into two groups. They were either treated with acupuncture specific against ED (treatment group) or acupuncture specific against headache (placebo group). Nonresponders of the placebo group were crossed over to the treatment group. Prior to acupuncture, serum sexual hormone levels, IIEF score, nocturnal penile tumescence testing for three nights (Rigiscan) and the erectile response to 50 mg sildenafil were evaluated. Out of 21 patients, 20 completed the study, including 10 patients after crossover. A satisfactory response was achieved in 68.4% of the treatment group and in 9% of the placebo group (P=0.0017). Another 21.05% of the patients had improved erections, that is, sufficient rigidity under simultaneous treatment with 50 gm sildenafil. The results of our pilot study indicate that acupuncture can be an effective treatment option in more than two-thirds of patients with psychogenic erectile dysfunction.

Variations of components of the plasminogen activation system with the cell cycle in benign prostate tissue and prostate cancer.

BACKGROUND: Components of the fibrinolytic system are involved in tumor cell invasion and metastasis. Previous investigations suggested a cell cycle-dependent expression of urokinase-type plasminogen activator (u-PA) in epithelial cells. In order to determine a correlation of cell cycle phases with the fibrinolytic system, we investigated the expression of u-PA, tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1) in normal and tumor-containing prostate extracts and analyzed a possible relationship with flow cytometry-determined proliferative activity of the samples. Cell cycle phases were correlated with fibrinolytic parameters in prostate tissue. METHODS: Samples were obtained from patients undergoing radical prostatectomy for prostate cancer and separated into two portions for DNA analysis and the detection of u-PA, t-PA, and PAI-1. Flow cytometric analysis was performed according to the Vindelov technique. The concentrations of u-PA, t-PA, and PAI-1 were determined from tissue extracts after homogenization by an enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: Correlations of u-PA and t-PA expression with the frequency of G0/G1, S, G2M, S-phase fraction (SPF), and proliferation index (PI) for normal prostate and prostate cancer revealed no significant correlation. The only significant finding was observed in normal tissue revealing a positive correlation between PAI-1 expression and G0/G1 and a negative correlation with S-phase, SPF, and PI. No dependence of PAI-1 expression on different cell phases was found in prostate cancer. Furthermore, no significant correlation of u-PA, t-PA, and PAI-1 with cell cycles in organ-confined ( or = pT3a) tumors was found. No significant correlation in prostate cancer of components of the fibrinolytic system differentiated according to tumor grade or perineural tumor infiltration and cell cycle analysis was found. Only in highly differentiated G1 (Gleason 2-4) cancer, u-PA had a significant positive correlation with G2M-phase. CONCLUSION: Absence of a correlation between levels of components of the fibrinolytic system and cell cycle phases suggests that the reported association between increases of some of these components and aggressive biological behavior of prostate cancer is secondary to non-cell cycle-related mechanisms.

Fluorescence endoscopy with 5-aminolevulinic acid reduces early recurrence rate in superficial bladder cancer.

PURPOSE: Several investigators have demonstrated an approximately 20% higher tumor detection rate by 5-aminolevulinic acid (ALA) fluorescence endoscopy compared to standard white light cystoscopy, and suggested a reduction in tumor recurrences when fluorescence endoscopy was performed as standard procedure during transurethral resection. We test this hypothesis. MATERIALS AND METHODS: In a prospective randomized multicenter study 102 patients underwent transurethral resection of bladder tumor(s) either with white light or ALA fluorescence assisted endoscopy. A second look transurethral resection with ALA fluorescence endoscopy was performed 6 weeks after the initial operation. RESULTS: At second look transurethral resection tumor was detected in 20 of 51 patients (39%) in the white light group and in 8 of 51 (16%) in the ALA fluorescence endoscopy group. This difference was statistically significant (p = 0.005). CONCLUSIONS: ALA fluorescence endoscopy is an innocuous and inexpensive diagnostic procedure that significantly improves bladder tumor detection rates compared to standard white light endoscopy. In our controlled study ALA fluorescence endoscopy reduced the residual tumor detection rate at second look transurethral resection by 59%.

Expression of the VEGF-receptor Flt-1 in benign, premalignant and malignant prostate tissues.

PURPOSE: Vascular endothelial growth factor (VEGF) is one of the most potent regulators of angiogenesis and has been shown to act upon two tyrosine kinase family receptors: c-fms-like tyrosine kinase (Flt-1) and fetal liver kinase. Preliminary reports have emphasized that expression of VEGF receptors is endothelial cell-specific. In this study we verified the localization and distribution of Flt-1 protein and mRNA expression in prostatic adenocarcinoma (CaP) as well as prostate intraepithelial neoplasia (PIN) and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: 30 selected surgical specimens exhibiting areas with CaP, PIN and BPH histology were evaluated for Flt-1 protein expression by immunohistochemistry. Results were compared with tumor differentiation (Gleason-Score), serum-PSA and clinical followup. Flt-1 synthesis by prostatic carcinoma cell lines, freshly isolated BPH epithelial cells (BPH-EC) and stromal cells was investigated using RT-PCR and intron spanning primer. RESULTS: VEGF receptor Flt-1 specific anti-sera revealed significant staining of prostatic endothelial cells, but the reactivity was not restricted to endothelial cells. BPH-epithelial cells of all specimens reacted significantly with anti-Flt-1. In contrast, tumor cells failed to react with anti-Flt-1 in 56% of the specimens. BPH-EC revealed a uniform anti-Flt-1 reactivity, which was less pronounced and weaker in PIN. Loss of anti-Flt-1 reactivity of prostatic tumor cells did not correlate with preoperative PSA serum levels but increased with tumor dedifferentiation. Interestingly, tumor cells of all CaP specimens with a Gleason score of >8 exhibit no anti-Flt-1 immunoreactivity. Accordingly while PC3, DU145 and LNCaP cells were negative when tested using RT-PCR all BPH tissue derived BPH-EC revealed Flt-1 coding mRNA expression. CONCLUSIONS: Widespread distribution of VEGF receptor Flt-1 in BPH, PIN and prostate cancer specimens suggests that VEGF function in prostate is not restricted to endothelial cells and angiogenesis. However, since the receptor is lost in CaP cells and with tumor dedifferentiation, these yet unknown effects of VEGF on epithelial cells are obviously suppressed with malignant transformation.

Expression of c-kit and kit-ligand in benign and malignant prostatic tissues.

The tyrosine kinase receptor c-kit and its ligand [kit ligand (KL) or stem cell factor (SCF)] exert a broad range of biological activities during organogenesis and normal cell development. Recent studies have revealed that altered c-kit levels occur in a variety of malignancies and cancer cell lines. KL has also been shown to stimulate the growth of malignant cells, as well as to promote chemotaxis. We had previously reported expression of KL in stroma cells of normal human prostate. The present study was undertaken in order to analyze the patterns of expression of c-kit and KL in a well characterized set of prostatic tissues, including normal prostate (n=4), benign prostatic hyperplasia (BPH) (n=53) and adenocarcinoma (n=46) samples. The distribution of c-kit and KL proteins was studied by immunohistochemical analyses, while transcript levels were determined by in situ hybridization with specific RNA probes on a subset of the benign and malignant tissues referred above. In addition, reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to determine levels of c-kit and KL expression in cultures of epithelial and stroma cells, as well as in the prostate cancer cell lines LNCaP, DU145 and PC3. c-kit protein in normal prostate was exclusively detected in mast cells by immunohistochemistry and in situ hybridization. However, c-kit transcripts, but not c-kit protein, were detected in low levels and with an heterogeneous pattern in basal epithelial cells of ducts and acini. c-kit in BPH was detected in epithelial cells in 9 of 53 (17%) specimens. c-kit protein expression in malignant epithelial cells was identified in 1 of 46 (2%) tumors. However, c-kit transcripts were detected in low levels by in situ hybridization in most of the tumors analyzed. KL protein and transcripts in normal prostate were detected in high levels in stroma cells. However, epithelial cells were unreactive for anti-KL antibody, but showed low levels of KL transcripts mainly in cells of the basal layer. Basal epithelial cells in hyperplastic glands showed KL expression in 13 of 53 (24%) specimens. KL protein in tumor cells was noted in 18 of 46 (39%) cases. c-kit transcripts were not found in normal prostate and in the 3 cancer cell lines analyzed by RT-PCR, however, it was present in cultured epithelial cells of BPH, and in cultures of stroma cells from both normal and BPH. The majority of cultured cell lines of epithelial and stromal origin displayed considerable levels of KL. In addition all prostate cell lines studied showed significant levels of KL transcripts. In summary, co-expression of c-kit and KL in a subset of BPH cases may suggest an autocrine mode of signaling. Data from this study reveals that altered patterns of c-kit and KL expression are associated with BPH and adenocarcinoma of prostate. It appears that KL induces mast cells proliferation and maturation and enhances their release of protease. This could explain the accumulation of mast cells at tumor sites, a phenomenon that was not observed in normal prostate or BPH samples.

Predictability and significance of multifocal prostate cancer in the radical prostatectomy specimen.

Multifocal prostate cancer has been reported in 50-76% of all cases of radical retropubic prostatectomy (RRP) specimens, but the clinical and prognostic significance of this finding is still unclear. A retrospective analysis of patients who underwent RRP between 1993 and 1997 was performed. Preoperative screening parameters and 4-mm RRP specimen sections were examined. The location, Gleason score, and extracapsular extension of the tumor recorded. Three hundred eight cases were reviewed. Mean follow-up was 4.2 +/- 1 years (range 2-6 years). Two hundred six patients (66.9%) had multifocal prostate cancer and 102 (33.1%) had unifocal prostate cancer. Of those with multifocal disease, 63% had two foci and 37% had three or more foci. There were statistical significant differences between both groups with respect to preoperative prostate-specific antigen (PSA) density of the transition zone (PSA-TZ), free/total (f/t) PSA, as well as percentage of patients with organ confined disease, high-grade tumors, and local recurrence. PSA-TZ (p = .001) and f/t PSA (p = .004) were significantly different between patients with unifocal and multifocal disease (0.9 vs. 2.2 ng/mL/cc and 18% vs. 6.5%, respectively). However, preoperative PSA (11.2 vs. 12.8 ng/mL; p = .09) and PSA density (0.17 vs. 0.19 ng/mL/cc; p = .07) were not able to predict unifocality or multifocality. These data suggest that multifocal prostate cancer is associated with higher grade, stage, and recurrence rate than unifocal prostate cancer. Preoperative PSA-TZ (> 1.5 ng/mL/cc) and f/t PSA (<9%) may predict multifocality in the RRP specimen.

N-acetylneuraminic acids (nana): a potential key in renal calculogenesis.

N-Acetylneuraminic acids (NANA) promote binding of calcium ions to macromolecules and cells, increase the intrinsic viscosity of glycoproteins and facilitate gel formation in water. Since these properties are crucial in urinary calculogenesis, we evaluated NANA levels in urine and serum as well as their expression in kidney tissues. Using a modified thiobarbituric acid assay, the evaluation of free and bound NANA in 24-h urine samples revealed a ratio of 1.87 in 33 non-stone-formers but a reversed ratio of 0.84 in 41 recurrent calcium oxalate stone-formers. Time kinetics revealed a gradual rise in NANA expression until 48 h of culture and a significantly higher release into supernatants of papillary renal epithelial cells (REC) when compared with cortical REC. To examine NANA distribution in kidney tissues, paraffin-embedded biopsies from five normal and six stone-forming kidneys were labeled with the biotinylated NANA-specific lectins Maackia amurensis (MAA) and Sambucus nigra (SNA). Immunohistochemistry revealed intense luminal MAA reactivity of distal tubular REC and collecting ducts in 96.7% and 91.5% of normal and stone-forming kidneys respectively. By contrast, there was a marked difference between normal and stone-forming kidneys for SNA reactivity (17.7% vs 95%) at the same locations. Finally, the glycocalyx of recurrent stone-formers showed altered sialylglycoside linkages [alpha(2,6) instead of alpha(2,3)] that may indicate an altered REC function. Given the calcium-binding potential of NANA, their increased local concentration within the glycocalyx layer in the distal nephron may either initiate stone formation or facilitate attachment of microcrystals to REC.

Validation of a 10-minute dipstick test for serum prostate-specific antigen.

OBJECTIVE: The aim of this study was to determine the clinical usefulness of a recently developed one-step dipstick test for rapid (10 min) and semiquantitative analysis of serum prostate-specific antigen (PSA). The cutoff value of this semiquantitative dipstick test is 4.0 ng/ml. METHODS: PSA levels of 238 serum samples were simultaneously determined by this dipstick test and by a 'classic' monoclonal antibody based PSA enzyme immunoassay. Interassay variations of the dipstick test were determined by repetitive analyses (n = 10) of three serum pools containing 1, 6, and 15 ng PSA/ml. Recovery studies with graded amounts of PSA were performed in normal sera (n = 5) as well as in those with elevated creatinine (n = 5) and bilirubin (n = 5) levels. RESULTS: A total of 139 serum samples had PSA levels, determined by the enzyme immunoassay, < 4.0 ng/ml; 132 (94.9%) of which were negative with the dipstick test, and 7 (5.1%) were false-positive. Samples with a PSA value < 2.0 ng/ml (n = 102) were correctly recognized in 98.1% of the cases by the dipstick test. Serum samples with a PSA value of 4-10 ng/ml were false-negative in 10 of 41 cases (24.4%), the remaining (75.6%) were true positives. Samples containing PSA levels > or = 10 ng/ml (n = 58) were consistently positive. Hence, the overall concordance rate was 92.9%. Analyses of interassay variation of three pools of sera containing 1, 6, and 15 ng PSA/ml revealed a high reproducibility of this test. Elevated levels of bilirubin and creatinine did not interfere with the dipstick test result. CONCLUSIONS: This semiquantitative one-step PSA test is capable of distinguishing serum PSA levels with a cutoff value of 4.0 ng/ml with an overall concordance rate of 92.9%. Advantages of this test are the cheap, simple, and fast test procedure, the avoidance of any instrumentation, and the fact that the results are available within 10 min.

Cytophotometry in the monitoring of bladder cancer under intravesical chemotherapy.

OBJECTIVE: We evaluated the DNA cytophotometry in 446 bladder washing samples from 64 patients under mitomycin C after superficial bladder cancer during an observation period of up to 5 years. The aim of the study was to identify patients at high risk of recurrence despite chemotherapy-induced atypical, hence noninformative cytology. METHODS: The prognostic value of cytology and ploidy during chemotherapy was compared with regard to recurrence rates and the median time to recurrence. RESULTS: Aneuploidy identified 8 of 10 patients recurring within 12 months out of 17 patients with atypia at first presentation after surgery, whereas no recurrence was seen after atypia and diploid histograms (p = 0.005, mean follow-up period 62 months). Aneuploidy was the most accurate indicator of short-time recurrence (p < 0.001 by multivariate analysis). Follow-up data showed a relative risk of recurrence of 12.7 following histogram shifts towards aneuploidy and of 1.6 for positive shifts in cytology. CONCLUSION: Cytophotometry is superior to cytology in predicting the outcome in patients under chemotherapy for superficial transitional cell cancer of the bladder.

Primary metastatic carcinoma of the prostate in younger men: a plea to think over usual therapeutic strategies.

METHOD: The time from first diagnosis of primary multiple metastatic prostate carcinoma until progression and until death in patients less than 60 years old under two different therapeutic regimens was evaluated. RESULTS: In the group with pure androgen deprivation (n = 21), the mean time until progression was 11.3 (6-55) months, the mean survival time being 21.4 (11-75) months. In the group with androgen deprivation plus cytostatic therapy (n = 10), progression was noted after 26.7 (15-77) months with a medium survival time of 26.2 (16-82) months. CONCLUSION: The data argue in favor of changing the usual treatment strategy to combination therapy in "young' patients with primary metastatic prostatic cancer.

The clinical value of urinary cytology: 12 years of experience with 615 patients.

AIMS: To analyse the diagnostic value of cytological examination compared with histological findings in a large series of patients (n = 615) with tumours of the urinary tract epithelium. METHODS: Cytological examinations (n = 785) after bladder washing and exfoliative cytology were retrospectively compared and correlated with histological findings. In addition, 1527 bladder washings were obtained during follow up of patients after transurethral resection of bladder tumours. RESULTS: Cytology in bladder washings (overall diagnostic accuracy 66%) provides considerably more information that exfoliative cytology (overall accuracy 49%). Cytological examinations (n = 1125) in patients with bladder tumours receiving intravesical cytostatic drugs (for example, mitomycin C) yielded suspicious or positive results in 28% of patients, without being confirmed by endoscopy during follow up. CONCLUSION: Our results illustrate two major drawbacks of urinary cytology. First, a high rate of false positive results in patients on intravesical chemotherapy. Second, a high rate of false negative results in highly differentiated carcinomas, stressing the need for additional diagnostic tests such as staining with monoclonal antibodies directed against tumour antigens or assessment of ploidy.

Expression of transforming growth factor-alpha and the epidermal growth factor receptor in human prostate tissues.

Cells respond to certain soluble factors that bind to cell surface receptors possessing intrinsic tyrosine kinase activity. Overexpression of these molecules has been associated with tumor progression. Enhanced prostatic cancer cell growth in vitro has been reported in the presence of certain growth factors. To characterize the patterns of expression of the epidermal growth factor receptor (EGFr) and transforming growth factor-alpha (TGF alpha), we studied tissue from 107 prostate specimens using immunohistochemistry. We observed that epithelial cells of normal (n = 4) and benign prostatic (n = 56) tissues express EGFr but were unreactive for TGF alpha, while stroma cells in these tissues express TGF alpha but not EGFr. However, coexpression of EGFr and TGF alpha was identified in 22 of 46 prostatic adenocarcinomas studied. These results suggest that the major mode of action of EGFr/TGF alpha in normal and benign prostate is that of a paracrine or juxtacrine loop, the ligand being expressed in the stroma cells and the receptor in the epithelial cells. Since a subset of prostatic carcinomas coexpressed the ligand and the receptor in their tumor cells, it is suggested that an independent autocrine signaling mechanism may occur and grant a selective advantage for the growth of prostate cancers.

The impact of ejaculation on serum prostate specific antigen.

In a pilot study including 18 patients between 20 and 39 years old serum prostate specific antigen (PSA) was evaluated before as well as 1 and 7 days after ejaculation. In 13 patients who had more than 0 ng./ml. PSA before ejaculation (mean 1.44 ng./ml.) there were statistically significant decreases in serum PSA down to 0.17 ng./ml. and 0.29 ng./ml., respectively (p = 0.0001). These results suggest a physiological relationship between ejaculation and decreased serum PSA levels. Due to the clinical significance of PSA in the diagnosis and monitoring of prostate cancer, further studies are needed including men of risk age and untreated prostate cancer patients.

Is transrectal ultrasonography needed to rule out prostatic cancer with normal findings at digital rectal examination and normal serum prostate-specific antigen?

In a prospective study, 288 consecutive patients without evidence for prostatic carcinoma at digital rectal examination (DRE) and scheduled for prostatectomy because of benign prostatic hyperplasia (BPH) were examined by transrectal ultrasonography (TRUS) and serum prostate-specific antigen (PSA) measurement prior to surgery. 46 patients were found to have a carcinoma at histological examination of the surgical specimens. 14 carcinomas were detected preoperatively by TRUS and biopsy (10 pT1, 3 pT2, 1 pT3) of 32 patients with suspicious, i.e., hypoechoic, lesions at TRUS. Among the remaining 256 patients with normal findings at TRUS, another 32 carcinomas were found at histological examination of the surgical specimen. Of the 14 carcinomas detected by TRUS, 13 were found within a group of 57 patients with PSA levels > 7 ng/ml corresponding to a cancer detection rate of 22.8% in this group. In 231 patients with PSA < 7 ng/ml, the use of TRUS was successful in detecting only 1 carcinoma (cancer detection rate 0.4%). These results suggest that the use of TRUS is dispensible in 80% of palpably normal patients without affecting the cancer detection rate.

Correlation between gamma seminoprotein in seminal plasma and ejaculate parameters.

Gamma seminoprotein (G-SM) levels in seminal plasma were determinated in 62 ejaculates using an enzymimmunoassay. There was no statistical significant difference in G-SM between men with normozoospermia (n = 14), asthenozoospermia (n = 17), OAT-syndrome (n = 18) and azoospermia (n = 13). Also there was no correlation of G-SM levels in those samples with normal (n = 14) or pathological (n = 35) motility and normal (n = 17) or pathological (n = 32) swelling test. Ejaculates with high viscosity (n = 12) showed similar G-SM levels than those with normal (n = 50) viscosity. According to these results seminal G-SM levels does not appear to provide an useful marker for evaluation of male fertility.

Gamma-seminoprotein--a new tumour marker in prostatic cancer? Results of a pilot study.

Serum levels of gamma-seminoprotein (GSM), prostate specific antigen (PSA) and prostate specific acid phosphatase (PAP) were examined, using enzyme immunoassay, in 250 patients with prostatic disease. The results indicated that the highest specificity was obtained with GSM (94%) and the lowest with PSA (60%). In contrast, the highest sensitivity in newly detected carcinomas (n = 41) was obtained with PSA (71%), whereas that of GSM (51%) was comparable to that of PAP (44%). Of 41 patients with newly detected prostatic cancer, 35 (85%) showed a significant increase in at least 1 of the tumour markers. Five of 6 patients whose markers were within normal limits had incidental carcinomas. During follow-up, PSA was raised in 88%, GSM in 66% and PAP in 55% within 12 months prior to clinical progression. Our results suggest that the determination of GSM may be of value in the serological detection and monitoring of prostatic cancer. These findings must be confirmed by further studies with larger numbers of patients and longer follow-up.

Estramustine phosphate in secondary hormone-resistant carcinoma of the prostate.

In this retrospective study, 71 patients with secondary hormone-refractory prostatic carcinomas were treated with estramustine phosphate (EMP), at three different dosages (280, 560, 840 mg orally). All patients were completely followed up until cancer-induced death. In 12 cases of further progression polychemotherapy was administered. As this was not a randomized study, an analysis of statistical significance was not performed. The higher dosages of EMP caused an extended progression-free interval accompanied by an equally considerable alleviation of carcinoma-induced pain. The overall survival time was not influenced by subsequent polychemotherapy. An elevation of liver function parameters was observed in 5 patients. One of these patients died of toxic liver damage, possibly therapy-related, on the basis of a preexisting cirrhosis. Cardiovascular side effects were not observed. With regard to survival time, the positioning of polychemotherapy as a third-line treatment for prostatic cancer should be examined critically. Before administration of high-dose EMP, it is mandatory to control liver functions carefully.