Serum adiponectin concentrations and tissue expression of adiponectin receptors are reduced in patients with prostate cancer: a case control study.

PURPOSE: Adiponectin, an adipocyte-secreted hormone with insulin-sensitizing effects, has been inversely associated with several hormonally dependent malignancies, including breast, endometrial, and colorectal cancer. Few studies have examined serum adiponectin in relation to prostate cancer, and expression of adiponectin receptors has previously not been assessed in prostate tumors. EXPERIMENTAL DESIGN: We collected plasma samples and covariate data in the context of a case-control study of 300 Greek men, including 75 prostate cancer cases, 75 patients with benign prostatic hyperplasia (BPH), and 150 healthy controls. Prostate tissue samples were taken from 72 cases and 27 noncases and examined for relative expression of adiponectin receptors AdipoR1 and AdipoR2 using immunohistochemistry. RESULTS: Prostate cancer patients had significantly lower plasma adiponectin concentrations as compared with men with BPH and healthy controls (7.4 +/- 5.0 versus 11.5 +/- 6.4 and 12.8 +/- 8.0 ng/mL, respectively). Men in the top two quartiles of adiponectin had a 71% to 73% reduced risk of prostate cancer as compared with men in the lowest quartile after adjusting for age, body mass index, and additional potential confounders. We found no similar relationship between adiponectin and risk of BPH. Results from immunohistochemistry experiments show weaker expression of adiponectin receptors AdipoR1 and AdipoR2 in cancerous versus healthy prostate tissue. CONCLUSIONS: Higher serum adiponectin is associated with a marked reduction in risk of prostate cancer, but not BPH, independently of other risk factors. Malignant prostate tissue samples have reduced expression of adiponectin receptors as compared with benign prostate tissue. These results support a role for adiponectin in the pathogenesis of prostate cancer.

Efficacy of tolterodine in preventing urge incontinence immediately after prostatectomy.

PURPOSE: Urgency and urge incontinence are frequently observed after prostatectomy. Although symptoms ameliorate within a relatively short time, they usually cause significant stress and anxiety to the patient as far as their duration is concerned. Aim of our study was to determine the efficacy of tolterodine in preventing urgency and urge incontinence after catheter removal in patients that underwent prostatectomy for benign prostate hyperplasia. PATIENTS AND METHODS: Twenty-seven patients with moderate/severe lower urinary tract symptoms due to benign prostatic enlargement, scheduled for prostatectomy, were randomised into two groups, Group A (14 pts) received tolterodine 2 mg b.i.d starting the day of surgery, while group B patients received no such treatment. Tolterodine treatment was discontinued 15 days after catheter removal. All patients completed the International Prostatic Symptom Score (IPSS) and the International Continence Society (ICS-BPH) forms the day before surgery, and three times more, one, fifteen and thirty days after catheter removal. RESULTS: Pre-operative total 1PSS and frequency of urgency/urge incontinence as determined by questions 3 and 4 of the ICS-BPH questionnaire were equally distributed between groups. Tolterodine was well tolerated and no adverse effects were reported. Post-operative IPSS and QoL scores did not differ between groups. However, the frequency of urge incontinence both the first day and fifteen days after catheter removal was significantly lower in the tolterodine group (16.6% vs. 69.2%, p=0.004 and 8.3% vs. 38.4%, p=0.039, respectively). CONCLUSION: Tolterodine was well tolerated in all patients and had a beneficial effect regarding the postoperative urge incontinence. Trials of a larger scale could determine which patients would benefit more, especially according to the presence of storage lower urinary tract symptoms prior to surgery.

Characterization of the human urine proteome by preparative electrophoresis in combination with 2-DE.

The protein components of urine are useful indicators of renal function and human health in general. Urine samples are easily attainable making them ideal substrates for biomarker research. Analysis of the urine proteome however, has been hindered by the great variability of the urine specimens, and the presence of various proteins in low abundance or modified forms. To alleviate some of these problems urine samples from five different individuals were pooled, concentrated and the proteome characterized by a combination of preparative electrophoresis and 2-DE, followed by PMF. A total of 778 protein spots corresponding to 141 different gene products were identified. In comparison, 171 spots corresponding to 44 unique proteins were identified in the unfractionated starting material. Among the proteins identified from the preparative electrophoresis were many of low abundance such as proteins involved in signal transduction. Furthermore, the median molecular mass of the identified proteins from the preparative electrophoresis was significantly lower in comparison to the proteins identified from the unfractionated starting material (39 886 Da versus 71 317 Da, respectively). Concluding, application of this methodology provides a coherent analysis of the urine proteome and contributes to the generation of the urine protein map in health and disease.

MLH1 mismatch repair gene product is associated with apoptotic potential of urothelial bladder carcinomas.

BACKGROUND: Mismatch repair genes are possibly involved in the tumorigenesis and/or progression of bladder cancer, as has been reported in colorectal and other cancers. MATERIALS AND METHODS: The protein expression of one of these genes (MLH1) was examined in 121 patients with urothelial carcinoma (UC) of the bladder by an immunohistochemical technique. RESULTS: Reduced expression of MLH1 protein was detected in 56 cases (46%) and was significantly more frequent in pT2 UCs (p=0.039). In superficial disease (Ta-T1 tumors), preserved expression of the MLH1 protein was detected in tumors with high proliferation indices, as evidenced by Ki-67 immunostaining (p=0.046). Interestingly, low MLH1 levels were positively-associated with the possibly low apoptotic potential of the tumor cells, as evidenced by decreased caspase-3 (CPP32) immunoreactivity (p=0.050). CONCLUSION: A significant proportion of UCs revealed low positivity percentages for MLH1 expression, probably reflecting MLH1 gene dysfunction in the respective cases. Preserved MLH1 expression was associated with highly proliferating cells, which are more likely to need DNA repair systems. A reduced expression of MLH1 may exert an adverse influence on the apoptotic potential of cancer cells.

Nuclear hTERT immunohistochemical expression is associated with survival of patients with urothelial bladder cancer.

BACKGROUND: The role of telomere in tumorigenesis is complex. While telomerase activation is suggested to be necessary for tumor growth, it may also help in diminishing genetic instability. The expressions of the telomerase reverse transcriptase/hTERT and the telomerase associated protein-1/hTEP-1 were investigated in relation to clinicopathological parameters and various proliferative and apoptotic biological markers. MATERIALS AND METHODS: The immunohistochemical method ABC/HRP was performed on paraffin sections of 132 patients with urothelial bladder carcinomas to detect the proteins hTERT, hTEP-1, Ki-67, bcl-2, p53 and caspase-3. RESULTS: The hTEP-1 protein was localized in the cytoplasm of cancerous cells (56.6%), while the hTERT protein was detected in the nuclei and the cytoplasm of cancerous cells (57.6% and 45.5%, respectively). hTEP-1 demonstrated an association with lower stage of the disease (p = 0.036), as well as both nuclear and cytoplasmic hTERT (p = 0.018 and p = 0.0001, respectively). Cytoplasmic hTERT showed inverse correlation with the mutant p53 protein (p = 0.047), while both cytoplasmic hTERT and hTEP-1 demonstrated parallel correlation with caspase-3 (p = 0.004 and p = 0.048, respectively). Nuclear hTERT associated with improved overall survival in multivariate analysis (p = 0.007). CONCLUSION: The association of the hTERT protein with low stage urothelial carcinomas and improved patients' survival is in keeping with the idea that the early activation of telomerase may protect against genetic instability and the prevalence of aggressive malignant clones.

Delayed life-threatening haematuria from a renal pseudoaneurysm caused by blunt renal trauma treated with selective embolization.

Pseudo-aneurysms complicating blunt renal traumas, although very rare, represent significant causes of secondary haematuria, potentially life-threatening. Initial surgical repair of the injured kidney does not preclude the presence of an obscure pseudo-aneurysm that could become evident later on. We herein present a patient with a grade III blunt renal trauma initially treated surgically. Thirty days after the trauma, he developed secondary haematuria caused by a renal pseudo-aneurysm located far from the oversewed area. This vascular lesion was successfully treated using selective arterial embolization.

Combination of LHRH analog with somatostatin analog and dexamethasone versus chemotherapy in hormone-refractory prostate cancer: a randomized phase II study.

OBJECTIVES: To evaluate prospectively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer (HRPC) in a randomized Phase II study. HRPC presents a challenging therapeutic problem. Salvage chemotherapy is the usual approach at this stage of the disease. The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC. METHODS: Forty patients with HRPC were randomized to receive one of two treatments. Group 1 underwent chemotherapy (estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days) and group 2 the combination of a somatostatin analog (lanreotide 30 mg intramuscularly every 14 days) and dexamethasone (4 mg tapered to 1 mg), in addition to androgen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog (triptorelin 3.75 mg intramuscularly every 28 days). The clinical and prostate-specific antigen (PSA) response, overall survival, time to progression, and toxicity were compared between the two groups. RESULTS: The data of 20 patients in group 1 and 18 in group 2 were analyzed. The demographic and clinical data were similar in the two groups at study entry. A PSA response (decrease of greater than 50%) was observed in 45% of group 1 and 44% of group 2. The difference was not statistically significant. A partial clinical response was observed in 29% and 30% of groups 1 and 2, respectively. Again, the difference was not statistically significant. Changes in performance status and pain score during treatment were not significantly different in the two groups. Hematologic toxicity was more frequent in group 1 (80% of patients), and mild diabetes was more frequent in group 2 (22% of patients). The overall survival was 18.8 months in group 1 and 18 months in group 2 (not statistically significant). The time to progression was 6 versus 4 months and, in the PSA responder subgroup, it was 8 versus 7.7 months in groups 1 and 2, respectively (neither difference was statistically significant). CONCLUSIONS: The results of our randomized Phase II study indicated that the new combination treatment (luteinizing hormone-releasing hormone analog, somatostatin analog, and dexamethasone) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response, overall survival, and time to progression. A larger prospective Phase III trial is required to confirm our observations.

Pain during transrectal ultrasonography guided prostate biopsy: a randomized prospective trial comparing periprostatic infiltration with lidocaine with the intrarectal instillation of lidocaine-prilocain cream.

Prostate biopsy is usually performed without anesthesia. We evaluated the patient's perception of pain/discomfort experienced during the procedure in terms of the type of anesthesia used: periprostatic infiltration with 2% lidocaine, or intrarectal instillation of lidocaine-prilocain cream. A total of 198 patients were divided into three groups: group 1 (control group, n=40) received sonographic gel intrarectally prior to biopsy, group 2 (n=75) were given intrarectal instillation of lidocaine-prilocain cream, and group 3 (n=80) received periprostatic anesthesia by injecting 10 ml of 2% lidocaine. Pain after each biopsy was assessed using an 11-point linear visual analog pain scale. The mean pain scores were 5.1 in group 1, 4.8 in group 2, and 2.5 in group 3, resulting in a significant difference between group 3 and both groups 1 and 2, but not between groups 1 and 2. The incidence of biopsy-related adverse events did not differ among groups. Transrectal ultrasonographic guided periprostatic anesthesia is superior to intarectal instillation of lidocaine-prilocain cream.

Transitional cell carcinoma of ureteral stump after radical nephrectomy in a patient with a history of bladder carcinoma.

Transitional cell carcinoma (TCC) of ureteral stump after radical nephrectomy is rare. Following nephrectomy patients with a prior history of bladder cancer must have their ureteral stumps evaluated. Furthermore, the presence of hematuria should alert the urologist to a possible TCC in the ureteral stump. We present a patient who developed TCC of the ureteral stump after radical nephrectomy.

Clinical efficacy of distigmine bromide in the treatment of patients with underactive detrusor.

PURPOSE: The aim of this study was to assess the clinical efficacy of distigmine bromide, an anticholinesterase agent, deemed to improve detrusor function thereby restoring normal voiding patterns in patients suffering from detrusor underactivity. MATERIALS AND METHODS: A total of 27 patients (11 men and 16 women) with poor detrusor function were included in the study. The diagnosis was established using pressure-flow studies. All patients received distigmine bromide at a dose of 5 mg three times daily for 4 weeks and re-attended for a follow-up urodynamic investigation. The results of baseline pressure-flow studies were compared to those after completion of treatment. RESULTS: Treatment with distigmine bromide resulted in a statistically significant reduction of residual volume and percent residual volume, obviating the need for intermittent self-catheterisation in 11 patients. In addition, maximum flow rate and detrusor pressure at maximum flow increased, although not significantly. The drug was generally well tolerated by the majority of patients. CONCLUSION: Distigmine bromide shows clinical efficacy in patients with poor detrusor function and may therefore be used alternatively in selected cases.

The immunomodulating effect of interferon-gamma intravesical instillations in preventing bladder cancer recurrence.

PURPOSE: The purpose is to investigate the prophylactic effect of intravesically instillated recombinant IFN-gamma against recurrence of superficial transitional cell carcinoma of the bladder and to evaluate its effect in local immune response, presumably mediating its therapeutic efficacy. EXPERIMENTAL DESIGN: We prospectively randomized in two groups 123 patients with initially diagnosed superficial transitional cell carcinoma and stage Ta, T1, grade 2 tumors, who underwent transurethral tumor resection (TUR). In group A, 60 patients received IFN-gamma (1.5 x 10(7) IU/instillation), whereas 63 patients, consisting of the control group B, received mitomycin C (40 mg/instillation). The annual administration schedule consisted of eight weekly followed by four biweekly and then by eight monthly instillations for both regimens. We also analyzed the immunophenotype of the intratumoral and intramural leukocytes by immunohistochemical and flow-cytometric techniques. To this purpose, tumor samples were obtained at TUR and random biopsies at TUR and during cystoscopy at 6 and 12 months, and bladder washings were collected before TUR and at preselected time points. RESULTS: In group A, 44 of 60 (73.4%) patients, and in group B, 36 of 63 (57.2%) patients, were tumor free during the median follow-up period of 26.5 months (range, 3-49 months). IFN-gamma was well tolerated. Six months after starting treatment, follicular cystitis was detected in patients responding to IFN-gamma. After IFN-gamma instillations, statistically significant increases in T cells, T-helper cells, T-cytotoxic cells, natural killer cells, and total leukocytes, as well as in the number of B cells expressing intercellular adhesion molecule-1 and total leukocytes expressing HLA-DR, were observed by flow cytometry in tissue specimens and bladder washings. CONCLUSIONS: Recombinant IFN-gamma appears to be effective against stage Ta, T1, grade 2 bladder tumors' recurrence. Recruitment and activation of intramural leukocytes seem to be involved in the mechanism of IFN-gamma action.

Tissue inhibitor of metalloproteinase-2 as a multifunctional molecule of which the expression is associated with adverse prognosis of patients with urothelial bladder carcinomas.

PURPOSE: Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase (MMP) activity controlling the breakdown of extracellular matrix components and, thus, play an important role in the process of invasion and metastasis. Moreover, there are several new functions, growth control, apoptosis, and angiogenesis-, in which TIMPs seem to be involved. The aim of this study was to elucidate the role of TIMP-2 in human urothelial cancer assessing TIMP-2 protein expression in 106 urothelial bladder carcinomas and evaluating its importance relative to clinicopathologic parameters (age, gender, histological grade, and stage) and patient survival, as well as to markers associated with cell growth and apoptosis (Ki-67, p53, and bcl-2). EXPERIMENTAL DESIGN: Immunohistochemistry (avidin-biotin complex method-horseradish peroxidase) was performed to detect TIMP-2, Ki-67, p53, and bcl-2 proteins using monoclonal and polyclonal antibodies. Statistical analysis was univariate and multivariate. RESULTS: TIMP-2 immunohistochemical expression was observed in stromal fibroblasts and in cancerous cells in 26.4% and 69.8% of cases, respectively. TIMP-2 stromal but not cancerous cell expression associated significantly with the high histological grade of carcinomas (P < 0.0001) and the advanced stage of the disease (P = 0.001). TIMP-2 either stromal or cancerous cell expression correlated significantly with the expression of Ki-67 proliferation indice (P = 0.02 and P = 0.044, respectively) and the mutant p53 protein (P = 0.043 and P = 0.045, respectively). In univariate survival analysis patients with positive TIMP-2 stromal cell immunohistochemical expression had a significantly worse overall survival in comparison with TIMP-2 stromal cell-negative patients (log rank test: P = 0.0002). However, in multivariate survival analysis the only independent survival factors were the stage of the disease and patient age. CONCLUSIONS: TIMP-2 protein expression in either the stromal or cancerous cells is associated with the proliferation index Ki-67 and the apoptosis-related protein p53. These findings are in keeping with in vitro studies reporting a growth-promoting ability of TIMP-2 and its involvement in apoptosis regulation. On the other hand, TIMP-2 stromal cell expression only was associated with adverse prognosis of urothelial bladder cancer patients.

Immunohistochemical detection of gastrin releasing peptide in patients with prostate cancer.

Gastrin releasing peptide (GRP) is a neuropeptide that has been suggested to play a role in the development of some malignancies. Our aim was: (1) to identify the expression of GRP in cancerous prostate glands, and (2) to correlate its expression to various pathological parameters and to the patient's clinical outcome. Using standard immunohistochemistry, we evaluated GRP expression in both biopsy and radical prostatectomy specimens from 30 patients with prostatic adenocarcinomas. GRP was expressed in 18 radical prostatectomy specimens (60%) and in 15 biopsies (50%). There was an association between positive immunoexpression of GRP, relapse ( P=0.029) and advanced tumor stages (i.e. pT3, pT4) ( P=0.049). In the respective biopsies, GRP immunostatus was similar to that observed in the subsequent radical prostatectomy specimens. GRP immunoexpression may be of some value as a diagnostic and prognostic marker. Patients whose pathology specimens demonstrate GRP immunopositivity should be closely monitored, since they appear to be at higher risk of disease progression and relapse.

Preoperative nested reverse transcription-polymerase chain reaction for prostate specific membrane antigen predicts non-organ confined disease in radical prostatectomy specimens.

The aim of this study was to access the utility of the reverse transcriptase-polymerase chain reaction (RT-PCR) assay for prostatic specific membrane antigen (PSMA) in predicting non-organ confined (NOC) disease in final radical prostatectomy (RP) specimens. Nested RT-PCR for PSMA was performed on the blood of 33 patient candidates for RP, 20 patients with untreated metastatic disease and 20 healthy men. The final pathology report on the 33 RP patients was compared with the RT-PCR results and Partin nomograms. In the RP group, 4/18 patients with confined disease and 9/15 with NOC disease had positive RT-PCR assays. Sensitivity, specificity, positive and negative predictive values for RT-PCR were 60%, 77.7%, 69% and 70%, respectively. The Partin tables for this group of patients showed a sensitivity, specificity, positive and negative predictive values of 75%, 71%, 60% and 83%, respectively. P-values for the Partin tables and the RT-PCR assay were respectively 0.014 and 0.037. RT-PCR of PSMA has an independent predictive value and could help predict NOC disease in clinically localized prostate cancers, but is still less efficient than Partin tables.

Immunohistochemical study of pro-apoptotic factors Bax, Fas and CPP32 in urinary bladder cancer: prognostic implications.

Apoptosis is a process which can retard the progress of malignant tumours. In the present study we investigated the immunohistochemical expression of three pro-apoptotic proteins (Bax, Fas receptor and caspase 3 - CPP32) as well as the apoptotic index (TUNEL Index) in 53 urothelial carcinomas of the urinary bladder. We examined all possible relationships between these factors and clinicopathological variables, as well as the patients' disease free survival. All three markers, and in particular the Fas receptor, were detectable in a remarkable proportion of specimens, however, none of the markers examined was associated with any clinicopathological parameter. In multivariate statistical analysis, Bax emerged as an independent predictor of a favourable prognosis. It is noteworthy that none of the pro-apoptotic markers examined was directly linked with the apoptotic rate of the malignant cells.

In vivo effect of the lipido-sterolic extract of Serenoa repens (Permixon) on mast cell accumulation and glandular epithelium trophism in the rat prostate.

The Serenoa repens lipido-sterolic extract (SRLSE, Permixon, Pierre Fabre Medicament, Castres, France) is used to treat benign prostate hyperplasia. We studied the in vivo effect of SRLSE on mast cell accumulation and the histological characteristics of the rat ventral prostate. Adult Wistar rats received either tocopherol or SRLSE (50 and 100 mg/kg body weight, respectively) every second day for 90 days. Histological features were studied in hematoxylin-eosin stained tissue sections while mean mast cell numbers were determined in Giemsa-stained sections. The central region of the ventral prostate in treated animals showed significant changes with acinar epithelium becoming flat or low cuboidal. In the same region, mean mast cell number per optical field in the control, low-dose and high-dose groups were, respectively, 4.7+/-0.7, 3.4+/-1.0 and 2.4+/-0.6, showing a dose-dependent, statistically significant decrease. Administering SRLSE significantly reduces mast cell accumulation and provokes epithelium atrophy within the central area of the rat ventral prostate. These phenomena may participate in the clinical activity of the drug.

Partial vesiculectomy in an infertile man with seminal vesicle cyst, ipsilateral renal agenesis, and cryptorchidism.

Congenital seminal vesicle cysts associated with renal agenesis are uncommon, but are currently detected more frequently with the use of sectional imaging procedures. Approximately 200 cases have been reported. The unique feature of our case is the combination of this disorder with an ipsilateral undescended testis. Our patient underwent partial vesiculectomy, in which the cyst was removed and the seminal vesicle remnant with its vas deferens was preserved. A review of the infertile cases and the impact of surgical treatment on fertility are discussed. Features that render partial vesiculectomy applicable and the potential effect of this procedure on fertility are highlighted.