Abstract: OBJECTIVES: To describe two predictive models that predict for prostate cancer on biopsy derived from a large screening population. There are no published predictive models that predict prostate cancer in a screened population. METHODS: The patients from the Tyrol screening study of known age, total prostate-specific antigen (PSA) level, digital rectal examination (DRE) findings, prostate volume, and percentage of free PSA, and who underwent an initial prostate biopsy from January 1992 to June 2004 were included (n = 2271). Multivariate logistic regression models were used to develop the biopsy positivity predictive models: nomogram 1, age, DRE, and total PSA; and nomogram 2, age, DRE, total PSA, and percentage of free PSA. The predictive accuracy of the models was assessed in terms of discrimination and calibration. External validation of the nomograms was performed using a urologically referred population of patients who underwent prostate biopsy (n = 599). RESULTS: Both nomograms were well-calibrated internally and externally and discriminated well between patients with positive and negative biopsy findings for both the European and U.S. cohorts (model 2 better than model 1). CONCLUSIONS: Our nomogram with age, total PSA, and DRE had good predictive ability to differentiate between screened patients with cancer on the initial prostate biopsy and those without. Adding the percentage of free PSA improves this predictive power further. These models might aid in clinical decision making regarding the need for biopsy in both European and U.S. populations.
Abstract: OBJECTIVES: The objective of this study was to update an in-depth analysis of the time trend for prostate cancer (PCA) mortality in the population of Tyrol by 5Â years, namely to 2008. In Tyrol, prostate-specific antigen (PSA) tests were introduced in 1988/89; more than three-quarters of all men in the age group 45-74 had at least one PSA test in the past decade. METHODS: We applied the same model as in a previous publication, i.e., an age-period-cohort model using Poisson regression, to the mortality data covering more than three decades from 1970 to 2008. RESULTS: For Tyrol from 2004 to 2008 in the age group 60+ period terms show a significant reduction in prostate cancer mortality with a risk ratio of 0.70 (95% confidence interval 0.57, 0.87) for Tyrol, and for Austria excluding Tyrol a moderate reduction with a risk ratio of 0.92 (95% confidence interval 0.87, 0.97), each compared to the mortality rate in the period 1989-1993. CONCLUSIONS: This update strengthens our previously published results, namely that PSA testing offered to a population at no charge can reduce prostate cancer mortality. The extent of mortality reduction is in line with that reported in the other recent publications. However, our data do not permit us to fully assess the harms associated with PCA screening, and no recommendation for PSA screening can be made without a careful evaluation of overdiagnosis and overtreatment.
Abstract: The genetic etiology of prostate cancer, the most common form of male cancer in western countries, is complex and the interplay of disease genes with environmental factors is far from being understood. Studies on somatic mitochondrial DNA (mtDNA) mutations have become an important aspect of cancer research because these mutations might have functional consequences and/or might serve as biosensors for tumor detection and progression. We sequenced the entire mitochondrial genome (16,569 bp) from 30 prospectively collected pairs of macrodissected cancerous and benign cells from prostate cancer patients and compared their genetic variability. Given recent concerns regarding the authenticity of newly discovered mtDNA mutations, we implemented a high-quality procedure for mtDNA whole-genome sequencing. In addition, the mitochondrial genes MT-CO2, MT-CO3, MT-ATP6, and MT-ND6 were sequenced in further 35 paired samples from prostate cancer patients. We identified a total of 41 somatic mutations in 22 out of 30 patients: the majority of these mutations have not previously been observed in the human phylogeny. The presence of somatic mutations in transfer RNAs (tRNAs) was found to be associated with elevated PSA levels (14.25 ± 5.44 versus 7.15 ± 4.32 ng/ml; p = 0.004). The level and degree of heteroplasmy increased with increasing tumor activity. In summary, somatic mutations in the mitochondrial genome are frequent events in prostate cancer. Mutations mapping to mitochondrial tRNAs, ribosomal RNAs, and protein coding genes might impair processes that occur within the mitochondrial compartment (e.g., transcription, RNA processing, and translation) and might finally affect oxidative phosphorylation.
Abstract: Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA=tPSA/fPSA) lack diagnostic specificity.
Abstract: It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.
Abstract: PURPOSE: We sought to evaluate the efficacy of transdermal dihydrotestosterone treatment based on the results of hypospadias repair in children with primary hypospadias. MATERIALS AND METHODS: A total of 75 randomized consecutive children who were a mean of 33.4 +/- 3.7 months old and had primary hypospadias were included in the study between September 2004 and April 2006. While 37 children were treated with 2.5% transdermal gel daily, applied directly onto the penile shaft and glans for 3 months (group 1), 38 children did not receive any treatment preoperatively (group 2). All children underwent hypospadias repair using tubularized incised plate urethroplasty. Postoperative complications were analyzed using the Mann-Whitney U test with respect to fistulas, urethral strictures, diverticula, meatal stenosis, glanular dehiscence and scar formation according to the results at 1-year followup. RESULTS: Mean ages of the children in groups 1 and 2 were similar (30.8 +/- 5.4 months and 35.1 +/- 5.1 months, respectively). The urethral meatus was coronal in 70%, penile in 24% and penoscrotal in 5% of the patients in group 1, while it was coronal in 84% and penile in 16% of the patients in group 2. Postoperative complications included urethrocutaneous fistula in 4 patients (11%) in group 2, compared to 1 patient (3%) in group 1 (p >0.05). While 3 patients (8%) in group 2 had glanular dehiscence, no patient in the dihydrotestosterone group had this complication (p <0.05). There were 2 patients with meatal stenosis in group 2 (5%), and no patient with meatal stenosis in group 1 (p >0.05). In addition, there were 16 patients (42%) with moderate to severe postoperative scar formation in group 2, compared to only 2 patients (5%) in the dihydrotestosterone group (p <0.05). Finally, there was a significant difference between the overall reoperation rates of group 2 (9 patients, 24%) and group 1 (1 patient, 3%, p <0.05). None of our patients had signs or symptoms of urethral stricture or urethral diverticulum. CONCLUSIONS: Pretreatment with dihydrotestosterone transdermal gel was effective in decreasing the complications and improving the cosmetic results after hypospadias repair.
Abstract: OBJECTIVE: To assess the pathological features of Gleason score 6 prostate cancers after radical prostatectomy in the low (<4 ng/mL) and intermediate range of prostate-specific antigen level (4-10 ng/mL), as such prostate cancers are considered to be well differentiated tumours with a low risk for recurrence after therapy. PATIENTS AND METHODS: In all, 1354 patients with T1c prostate cancer and PSA levels of <10.0 ng/mL had a radical retropubic prostatectomy. Patients with Gleason score 6 tumours were divided into two groups, those with PSA levels of <4 and 4.0-10.0 ng/mL. Extracapsular extension, positive surgical margins, biochemical recurrence (BCR) and mean time to BCR were evaluated. RESULTS: Of the 1354 patients, there were 437 (32.3%) with Gleason score 6 prostate cancers. Patients in the low PSA group had less extraprostatic disease than those with a higher level (5.9% vs 14.5%) and both groups had an almost equal proportion of positive surgical margins (9.4% vs 11.0%). In the low PSA group there was statistically significantly shorter BCR than in the high PSA group, with a mean time to BCR of 1.7 vs 3.1 years. CONCLUSIONS: These results show a statistically significantly higher rate of extraprostatic disease and earlier BCR in men with a high than a low PSA level even in Gleason score 6 prostate cancer. As the rate of BCR and extracapsular extension are significantly related to prostate cancer mortality, these findings further support the concept of screening using low PSA levels.
Abstract: OBJECTIVE: To evaluate the clinical and pathological characteristics of screen vs non-screen-detected prostate cancers, to determine if there is a difference in the same prostate-specific antigen (PSA) range. PATIENTS AND METHODS: In all, 997 patients who had had a radical prostatectomy were evaluated; 806 were Tyrolean screening volunteers, and 191 were from outside Tyrol, representing the 'referred prostate cancer' group. PSA level, age, prostate volume and pathological characteristics were assessed, as was the amount of over- and under-diagnosis. RESULTS: There were no statistically significant differences in patient age or PSA levels in the two groups. Even in the same PSA range there were statistically significantly more extraprostatic cancers in the referral group, at 31.7% and 17.4%, respectively. In the referred and screening groups there was over-diagnosis in 7.9% and 16.8%, and under-diagnosis in 40.8% and 27.8%, respectively. CONCLUSION: This study suggests that screening volunteers have a statistically significantly higher rate of organ-confined prostate cancers, and a statistically significantly lower rate of extracapsular extension and positive surgical margins than their counterparts in the referral group even in the same PSA range. As the pathological stage and surgical margin status are significant predictors of recurrence, these findings support the concept of PSA screening.
Abstract: OBJECTIVE: To evaluate the effectiveness of a well-controlled programme of early detection and treatment of prostate cancer in the population of Tyrol, Austria, where such a programme of early detection and treatment was initiated in 1988 and where prostate-specific antigen (PSA) testing was offered for free to all men aged 45-75 years from 1993. SUBJECTS AND METHODS: Comparison of prostate cancer mortality rates in Tyrol and the rest of Austria was accomplished through a generalized additive model. A piecewise linear change-point Poisson regression model was used to compare mortality rates in Tyrol and the rest of Austria. Standardized mortality ratios were calculated with reference to the mortality rates in 1986-1990. RESULTS: In all, 86.6% of eligible men have been tested at least once since 1993. Cancer deaths in Tyrol in 2005 were 54% (95% confidence interval [CI] 34-69%) lower than expected compared with 29% (95% CI 22-35%) in the rest of Austria. The decreasing trend in prostate cancer mortality was significantly greater in Tyrol compared with the rest of Austria (P = 0.001). A significant migration to lower stage disease occurred and radical prostatectomy was associated with low morbidity. CONCLUSIONS: In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer.
Abstract: OBJECTIVES: To evaluate possible over- and under-diagnosis of prostate cancer in a screened vs a referral population in the same range of prostate-specific antigen (PSA). PATIENTS AND METHODS: In all, 1445 patients undergoing radical prostatectomy and with a PSA level of <10 ng/mL were evaluated; 237 were from outside Tyrol (Austria) and represented the unscreened group, and 1208 were Tyrolean screening volunteers. Over-diagnosis was defined as a pathological stage of pT2a and a Gleason score of <7 with no positive surgical margins. Under-diagnosis was defined as a pathological stage of >or=pT3a or positive surgical margins. The chi-square test was used to assess the differences, with P < 0.05 considered to indicate statistical significance. RESULTS: There were no significant differences in patient age or PSA levels between the study groups. There was over-diagnosis in the screening and referral groups in 17.4% and 8.9%, respectively, and under-diagnosis in 18.6% and 42.2%, respectively. CONCLUSION: This study suggests that patients with prostate cancer participating in a screening programme are less likely to be under-diagnosed or have extracapsular disease than their counterparts in a referral population, even in the same PSA range, after radical prostatectomy. Furthermore, there was more under-diagnosis in the referral group than over-diagnosis in the screened group.
Abstract: OBJECTIVES: To assess the longitudinal prostate-specific antigen (PSA) changes in a screening population with or without prostate cancer during a 10-year period. METHODS: Serial PSA measurements performed during a 10-year period were evaluated in 4272 participants of a screening program who had no evidence of prostate malignancy and 528 men who eventually developed prostate cancer. RESULTS: Of the 4272 men with no evidence of prostate cancer, the mean total PSA level increased from 1.16 to 1.49 ng/mL during the 10 years, corresponding to a PSA velocity (PSAV) of 0.03 ng/mL/yr. Younger men had lower total PSA values throughout the 10-year period. Of the 528 patients with prostate cancer, the total PSA level increased from 2.19 at 10 years before diagnosis to 6.09 ng/mL at the time of positive biopsy findings, corresponding to a PSAV of 0.39 ng/mL/yr. The PSAV increased in the years before diagnosis (0.225 ng/mL/yr in the 8 to 10 years before diagnosis compared with 0.98 ng/mL/yr in the 2 years before diagnosis). The PSAV was greater in patients with Stage pT3-T4 cancer than in men with organ-confined tumors (median 0.53 versus 0.32 ng/mL/yr; P <0.001). CONCLUSIONS: In men with prostate cancer, the PSAV was significantly greater than in those without prostate cancer and correlated with pathologic stage and Gleason score but not with prostate volume. In the patients with prostate cancer, the PSAV increased in the years before the diagnosis. In contrast, men without prostate cancer had only slight PSA changes over time. Hence, PSA kinetics may help identify men with potentially curable prostate cancer.
Abstract: PURPOSE: Since the implementation of widespread serum total prostate specific antigen based screening, the risk of prostate cancer over diagnosis has become a concern. We evaluated the amount of possible over and under diagnosis of prostate cancer in an asymptomatic screening population with a total prostate specific antigen of 2.0 to 3.9 (lower range) and 4.0 to 10.0 ng/ml (higher range). MATERIALS AND METHODS: A total of 680 patients with prostate cancer were included. Possible over diagnosis was defined as Gleason score less than 7, pathological stage pT2a and negative surgical margins. Under diagnosis was defined as pathological stage pT3 or greater, or positive surgical margins. Furthermore, insignificant tumors according to the Epstein criteria were evaluated in a small subset of patients for whom cancer volume information was available. RESULTS: In the lower and higher total prostate specific antigen ranges there was an over diagnosis rate of 19.7% and 16.5%, and an under diagnosis rate of 18.9%* and 36.7%, respectively (p<0.05). In the prostate specific antigen range of 2.0 to 10.0 ng/ml combined the rates of over and under diagnosis were 17.6% and 30.3%, respectively. In addition, 8.7% of tumors with total prostate specific antigen 2.0 to 10.0 ng/ml met the Epstein criteria for insignificance. CONCLUSIONS: These data show that the reported estimates of over diagnosis in the low total prostate specific antigen group are exaggerated in a screening population. Using our criteria prostate cancer under diagnosis occurs more frequently than over diagnosis in the total prostate specific antigen range of 4.0 to 10 ng/ml.
Abstract: OBJECTIVE: To evaluate the influence of prostate volume (PV) on the detection of prostate cancer using a combined approach of contrast-enhanced ultrasonography (CEUS) and grey-scale US-guided systematic biopsy (SB). PATIENTS AND METHODS: We evaluated 345 patients with prostate cancer and a total prostate-specific antigen (PSA) level of >/= 1.32 ng/mL (1.32-35.3, mean 6.6). Biopsies were taken by two independent examiners; one took five CEUS (Doppler) targeted biopsies of hypervascular regions in the peripheral zone, and subsequently the other took 10 systematic prostate biopsies. We assessed the cancer detection rates for the five different subgroups of prostate volumes, i.e. <20, 20-30, 30-40, 40-50 and > 50 mL. RESULTS: Each technique, SB and CEUS, detected 73.4% and 77.1% of all detected cancers, respectively, but there were statistically significant differences in detection rate only in small glands. Only 69.0% and 70.4% of all cancers were detected by SB in glands of <20 and 20-30 mL, respectively, whereas 88.1% and 80.8% were detected by CEUS. CONCLUSION: The prostate cancer detection rate for CEUS was significantly higher in prostates of <30 mL (48.1% of the study population) than for SB. Therefore the combined approach of CEUS and SB allows improved cancer detection in patients with small glands and low total PSA values.
Abstract: Highly active antiretroviral therapy including HIV protease inhibitors has led to a marked reduction of clinically relevant mucosal candidiasis. We have previously shown that HIV protease inhibitors directly inhibit adhesion of Candida albicans to epithelial cells at concentrations that are reached in vivo during antiretroviral therapy. The aim of this study was to establish whether HIV protease inhibitors also inhibit adhesion of Candida to endothelial cells, which play a major role in systemic fungal disease. Three C. albicans strains were incubated with human umbilical vein endothelial cells or an endothelial cell line in the presence of either Ritonavir, Saquinavir or Indinavir. Subsequently, adherence was determined by counting colony-forming units. The results were comparable and revealed that Ritonavir and Saquinavir significantly inhibited adherence to endothelial cells at only very high concentrations which are likely not reached in vivo, and Indinavir did not even inhibit then. Inhibition of adhesion of C. albicans to human cells by HIV protease inhibitors is not a general feature, but strongly cell type-dependent, and clearly not observed for endothelial cells in vitro, which are a main target of systemic candidiasis in vivo.
Abstract: OBJECTIVE: To describe the influence of blood sampling/sampling tubes on mass spectrometric and clustering results, and on clinical blood variables, in blood samples collected from healthy volunteers and patients with prostate cancer. PATIENTS, SUBJECTS AND METHODS: Two venous blood samples were taken from 12 healthy volunteers and 12 patients with localized prostate cancer. Two blood samples were taken from each participant using two different venepuncture systems (group A and group B). The Kolmogorov-Smirnov test was used to identify the peaks distinguishing the different groups. In a 10-fold cross-validation study, decision trees for identifying discriminatory peaks that separate the benign from the malignant were constructed. RESULTS: The decision tree separated samples measured by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) from healthy volunteers from those of patients with prostate cancer, with a sensitivity of 93.6% and a specificity of 91.6%. Of special interest is that one peak at 6941 m/z was produced during blood sample preparation and had a very powerful influence on the results of the classification. CONCLUSION: The results clearly showed that blood-sampling systems have a great influence on the recorded MALDI MS traces, and thus can markedly influence and confound the results of the MS analysis, whereas clinical variables might remain unchanged. MS profiling is a promising method of marker discovery, but as it could be shown well-designed studies are critical to allow proper interpretation for the identification of key variables as well as for the clinical use.
Abstract: OBJECTIVES: To evaluate, in a screening population, the impact of tumor volume and prostate volume on prostate-specific antigen (PSA) velocity (PSAV) and to find predictors of biochemical failure after radical prostatectomy. Longitudinal PSA changes in men with prostate cancer have been reported to be significantly different from those without prostate cancer. METHODS: PSAV was assessed in 102 men undergoing radical retropubic prostatectomy. The pathologic findings of specimens obtained at radical retropubic prostatectomy and pelvic lymph node dissection were analyzed separately for all patients. RESULTS: The median preoperative PSA in the 102 patients was 6.4 ng/mL, the median prostate volume was 32.8 cm3, and the median tumor volume was 1.27 cm3. The PSAV correlated significantly with tumor volume (P <0.05) but not with prostate volume (P = 0.142). The median tumor volume in men with biochemical progression after radical retropubic prostatectomy was 2.55 cm3 versus 0.94 cm3 in men who were free of disease 5 years after surgery. The median PSAV in the year before diagnosis in men with relapse after radical prostatectomy was 1.98 ng/mL/yr versus 1.05 ng/mL/yr in men who had no evidence of disease. CONCLUSIONS: The results of our study have shown that the main factor contributing to the PSAV in patients with prostate cancer is cancer load and that prostate volume is not significantly associated with the PSAV. Men with a PSAV of more than 2 ng/mL/yr in the year before cancer diagnosis are at a high risk of relapse. The PSAV may be helpful in identifying patients with small tumors and thus increase the detection rate of potentially curable prostate cancers.
Abstract: The aim of this study was to identify amplified oncogenes in endometrial cancer using array-based comparative genomic hybridization (array CGH). Despite its prevalence, the molecular mechanisms of endometrial carcinogenesis are still poorly understood. The selected array CGH allows the simultaneous examination of 58 oncogenes commonly amplified in human cancers and is capable of achieving increased mapping resolution compared with conventional CGH. A subset of 8 specimens from a bank of 60 malignant and normal specimens was selected for array analysis to identify potential genes of interest. TaqMan polymerase chain reaction was carried out on the 60 specimens to examine if aberrations at the genomic level correlated with gene expression and to compare expression in normal and malignant samples. Oncogenes amplified in the endometrial cancers included AR, PIK3CA, MET, HRAS, NRAS, D17S1670, FGFR1, CTSB, RPS6KB1, LAMC2, MYC, PDGFRA, FGF4/FGF3, PAKI, and FGR. Three genes were examined at the messenger RNA level. AR and PIK3CA were higher in normal specimens, and MET was higher in malignant samples, suggesting a role for MET in endometrial cancer. Newer arrays examining more genes and larger sample numbers are necessary to elucidate the carcinogenic pathway in endometrial cancer.
Abstract: BACKGROUND: Interleukin-6 (IL-6) is a multifunctional regulator of cellular events in prostate cancer. LNCaP-IL-6+ cells selected in the presence of IL-6 were taken for assessment of effects of the chimeric monoclonal anti-IL-6 antibody CNTO 328. METHODS: Cell viability was assessed after treatment with CNTO 328 by the ATP assay. Expression of Bcl-2 and Bax and activation of signaling pathways were evaluated by Western analysis. Nude mice were inoculated with LNCaP-IL-6+ cells and treated with CNTO 328. The tumors were analyzed by immunohistochemistry for expression of Ki-67, tissue transglutaminase, and vascular endothelial growth factor. RESULTS: CNTO 328 caused a statistically significant inhibition of cell viability. The protein levels of Bcl-2 and the phosphorylation of ERK1/2 mitogen-activated protein kinases were decreased by the anti-IL-6 antibody. Treatment with CNTO 328 yielded an increase in the phosphorylation of signal transducers and activators of transcription factor 3. The mean tumor volume in animals inoculated with LNCaP-IL-6+ cells and treated with CNTO 328 was insignificantly lower than that in animals treated with the control antibody. There was a statistically significant decrease in the percentage of Ki-67-positive cells in CNTO 328-treated tumors. CONCLUSION: CNTO 328 has a potential in prostate cancer therapy and could be further tested in various combination experimental treatments.
Abstract: OBJECTIVE: To evaluate prostatic vascular resistance by measuring the resistive index (RI), and flow velocity using colour Doppler ultrasonography (CDUS), in normal prostates and in patients with benign prostatic hyperplasia (BPH) or prostate cancer, as BPH is considered to be a result of urogenital ageing and studies suggest that hyperplasia in the stromal and glandular compartments might be induced by stromal growth secondary to hypoxia, which in turn results from abnormal blood flow patterns. PATIENTS, SUBJECTS AND METHODS: Ninety-two men (22 with normal prostates, 45 with BPH and 25 with prostate cancer; mean age 56 years) were prospectively evaluated by CDUS. The RI values for the peripheral, central and transition zones were assessed by one investigator. The diagnosis of BPH and prostate cancer was established from histological findings. RESULTS: The mean (sd) RI in the transition zone was significantly higher only in patients with BPH, at 0.77 (0.05), vs 0.65 (0.05) in the other two groups. In the peripheral and central zones there was no significant difference in the RI among the three groups. Arterial CDUS flow velocity was increased in the transition zone of patients with BPH, but not in the peripheral and central zones. CONCLUSIONS: The present results support the hypothesis that an age-related impairment of blood supply to the lower urinary tract might have a role in the development of BPH. Although prostate cancer cannot be excluded by measuring RI, high RI values (>0.75) in the transition zone are indicative of BPH.
Abstract: PURPOSE: ATF3 is a member of the basic leucine zipper/cyclic adenosine monophosphate responsive element binding protein family of transcription factors. There is overwhelming evidence that it is a stress inducible factor acting in a signal-type and cell-type dependent manner, and it is involved in cell proliferation and survival. We found that ATF3 was differently expressed in an in vitro prostate cancer tumor progression model and we investigated the possible role of ATF3 in prostate cancer. MATERIALS AND METHODS: ATF3 up-regulation in vivo/in vitro and androgen regulation were assessed by immunohistochemistry and immunoblot analysis. Results after forced ATF3 transfection were evaluated by proliferation assay and cell cycle analysis. RESULTS: Immunohistochemistry and immunoblot analysis revealed ATF3 up-regulation in prostate cancer in vitro and in vivo, and stimulation of expression by androgens. Antiandrogen treatment decreased ATF3 expression in androgen sensitive cells but acted as a stimulator in long-term androgen ablated cells representing a model for therapy refractory disease. Expression in tumors increased with higher Gleason scores and highest expression was observed in samples of therapy refractory tumor tissue. Forced ATF3 over expression in a prostate cancer cell line induced cell proliferation and accelerated cell cycle progression from G1 to S-phase. CONCLUSIONS: These data provide new insight into the role of ATF3 in prostate cancer development and/or progression. They indicate that ATF3 is an androgen regulated gene that is highly expressed in prostate tumors and stimulating cell proliferation. It represents a possible target for prostate cancer therapy.
Abstract: BACKGROUND: RhoE/Rnd3, a recently described novel member of the Rho GTPases family, was discussed as a possible antagonist of the RhoA protein that stimulates cell cycle progression and is overexpressed and/or overactivated in prostate cancer. We investigated the expression of RhoE and its role in cell cycle regulation and apoptosis in the human prostate. METHODS: RhoE expression in cell lines and tissue specimens was assessed by immunoblot analysis, real-time PCR (RT-PCR), and immunohistochemistry. To elucidate RhoE effects on the prostate, RhoE was cloned and overexpressed in DU-145 prostate cancer. Cell cycle modulation and apoptosis was investigated by immunoblot and FACS analysis. RESULTS: Immunoblot analysis showed a strong RhoE signal in both, benign epithelial and stromal cells. In contrast, almost no protein was detected in various prostate cancer cells. On RT-PCR and microarray analysis, RhoE mRNA expression was significantly reduced in malignant tissue when compared to benign samples. RhoE immunostaining was strong in benign tissue, especially in prostate epithelial cells, whereas it was minimal or absent in malignant tissue. Forced RhoE overexpression in a prostate cancer cell line inhibits the expression of two proteins essential for G2/M transition, namely CDC2 and cyclin B1, and induces G2/M arrest. In addition, apoptotic cell death as measured by a cleavage product of caspase 3 is significantly increased in RhoE-overexpressing cells. CONCLUSION: In conclusion, our findings suggest RhoE as a tumor suppressor gene that is downregulated early in the development of prostate cancer.
Abstract: BACKGROUND: To determine longitudinal PSA changes over a period of 10 years in patients with and without prostate cancer. METHODS: Serial PSA measurements performed over 10 years were evaluated in 353 men who eventually developed prostate cancer and in 2.462 participants of a screening program without prostatic malignancy. RESULTS: In men with cancer, mean tPSA increased from 2.28 ng/ml at 10 years before diagnosis to 6.37 ng/ml at the time of postive biopsy (PSA velocity: 0.409 ng/ml/year). PSA velocity was significantly associated with Gleason scores and pathologic stage. In the benign group (n=2.462), mean tPSA increased from 1.18 to 1.49 ng/ml over a period of 10 years (PSA velocity of 0.03 ng/ml/year). Of the subjects with tPSA levels of 2 ng/ml or less, 2 years prior to cancer diagnosis, 11.4% had tPSA values of more than 4 ng/ml at the time of biopsy. Of the 972 men with tPSA below 1 ng/ml 2 years before the most recent measurement was obtained, 966 (99.4%) had no evidence of prostate cancer 2 years later, while six were found to have malignancies (0.6%). CONCLUSIONS: Longitudinal PSA changes in men with and without prostate cancer are significantly different. Annual testing may not be required in men with baseline tPSA levels of 1 ng/ml or below, whereas in patients with levels higher than 1 ng/ml, it seems to be indicated because of the significant percentage of men presenting with tPSA levels of more than 4 ng/ml two years later.
Abstract: AIMS/HYPOTHESIS: The aim of this study was to evaluate the relationship between benign prostatic hyperplasia (BPH) and arteriosclerosis shown in a model of type 2 diabetes in a trans-sectional population study using contrast-enhanced colour Doppler ultrasound for exact assessment of prostatic blood flow. METHODS: Contrast-enhanced transrectal colour Doppler ultrasound was performed using a microbubble-based ultrasound enhancer SonoVue for evaluating prostate vascularity (transitional zone [TZ] and peripheral zone [PZ]) in diabetic BPH patients, non-diabetic BPH patients and healthy subjects. Computer-assisted quantification of colour pixel intensity (CPI) was used to objectively evaluate the prostate vascularity. Resistive index measurements were obtained in the TZ and the PZ. Findings were compared between these three groups. RESULTS: TZ-CPI was significantly lower in diabetic patients than in non-diabetic BPH men (p=0.001), whereas the CPI of the PZ showed no difference between these two groups (p=0.978). TZ-CPI of patients with diabetic and non-diabetic BPH were significantly lower than in controls (p<0.001), but no difference was found between diabetic and healthy patients in the PZ (p=0.022) and borderline significance was seen when comparing patients of the BPH group with the control patients (p=0.019). Resistive index values of the TZ in diabetic patients showed significantly higher values (p<0.001) than the BPH and control groups. CONCLUSIONS/INTERPRETATION: The significantly lower CPI and higher resistive index values of the TZ in diabetic patients compared with patients with non-diabetic BPH and healthy subjects indicate considerable vascular damage in the TZ of these patients. Diabetic vascular damage may cause hypoxia and may contribute to the pathogenesis of BPH.
Abstract: OBJECTIVE: To evaluate the prostate cancer detection rate at low total prostate-specific antigen (tPSA) ranges of 2.6-4 and 4.1-10 ng/mL, according to different percentage free (f/t) PSA levels in a screening population. SUBJECTS AND METHODS: In all, 1809 consecutive screening volunteers with a tPSA level of 2.6-10.0 ng/mL were assessed. Ten systematic ultrasonography-guided prostate biopsies and, since 2000, an additional five Doppler-enhanced targeted biopsies were taken on the basis of age-specific tPSA reference ranges. We analysed the detection rate of prostate cancer according to f/tPSA ranges of 0-9%, 10-14%, 15-18% and >18%. RESULTS: The detection rates for the subgroups with tPSA levels of 2.6-4.0 and 4.1-10.0 ng/mL were 20.2% and 27.0%, respectively. The cancer detection rate in the first group (2.6-4.0 ng/mL) at 0-10% fPSA was 22.9%, and that in the second group (4.1-10.0 ng/mL) at 0-10% was 36.9%. There were significant differences between these groups. If the f/tPSA was 10-15%, the cancer detection rate for the two groups were 22.6% and 32.5%, respectively (P < 0.05). There was no statistically significant difference in the cancer detecting rates at an f/tPSA of 15-18% or >18%. CONCLUSION: There is a statistically significantly higher cancer detection rate when the f/tPSA is <15% than in groups of men with a f/tPSA of >15% in screening population assessed primarily using tPSA level.
Abstract: Differences in diet have been proposed to be at least partially responsible for the low rate of prostate cancer in Asian populations compared with men in Western countries. One of the compounds that occurs in a greater quantity in the Eastern diet is genistein, an isoflavonoid found in high concentrations in serum after ingestion of soy-rich foods. Extensive molecular studies have been performed to determine its potential health benefits. The mechanism of action of genistein is complex and includes several cellular pathways. In addition to its estrogenic and/or antiestrogenic activities, genistein has been reported to inhibit steroidogenesis and block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases. Moreover, it arrests the cell cycle, induces apoptosis, and has antiangiogenic and antimetastatic properties and antioxidant activity. Herein, we review the current literature on the molecular mechanisms of genistein in relation to its effects on prostate cancer cells.
Abstract: OBJECTIVES: The present retrospective study was designed to investigate the value of transition zone (TZ) biopsies for prostate cancer (PC) detection rate in a combined contrast enhanced color Doppler targeted (CECD) and gray-scale systematic biopsy (SB) approach. METHODS: PSA screening participants totalling 1475 with tPSA of >1.25 ng/ml (fPSA< or =18%) were assessed. Ten SB and additionally 5 or fewer CECD were performed. The impact of TZ biopsies on the PC detection rate and the biological significance of the detected TZ-cancers were analyzed. RESULTS: Out of 1475 biopsied patients, 395 (26.8%) were identified as PC patients; 5925 biopsy cores from these patients were analyzed. In 86 patients (21.8% of PC), we found 102 PC- positive cores in the TZ, and only in 9 of them solitary TZ-cancers without any other PC-location (2.3% of PC or 0.6% of all investigated patients). Pathologic findings after retropubic prostatectomy (RPE) revealed multifocal adenocarcinoma including involved peripheral zone (PZ) in eight of these nine patients, and solitary TZ-cancer in one patient. There was no positive correlation between prostate volume and TZ-detection rate and no patient with solitary TZ-PC after rebiopsy. CONCLUSION: Biopsy revealed 9 solitary TZ cancers (1.8%) and RPE revealed only one of them to be truly TZ-confined cancer (0.6%). Furthermore PC-detection did not improve, even in patients with rebiopsy, and there was no correlation between detection of TZ-cancers and prostate volume. A combined use of CECD and SB to investigate participants of a PSA-screening program suggests that TZ-biopsies do not improve PC detection rate and are therefore unnecessary.
Abstract: OBJECTIVE: To assess benign prostatic hyperplasia (BPH) and erectile dysfunction (ED), both considered to be associated with urogenital ageing, in ageing men in a cross-sectional population study, comparing them with healthy controls by using symptom scores and contrast-enhanced colour Doppler ultrasonography (CDUS). PATIENTS, SUBJECTS AND METHODS: Transrectal CDUS and quantitative measurement of colour pixel intensity (CPI) are excellent minimally invasive techniques for assessing normal and pathological blood flow. CDUS was performed using the microbubble-based ultrasound enhancer for evaluating prostate, bladder neck and corpus cavernosum vascularity in young healthy men, men with BPH, and men with severe vascular damage (diabetes mellitus type 2). Resistive index measurements and computer-assisted quantification of CPI were used to objectively evaluate perfusion. The International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF) were applied to quantify the symptoms. RESULTS: In patients with BPH, perfusion of the transition zone (TZ) of the prostate was significantly lower and the resistive index of the TZ significantly higher (both P < 0.001) than in healthy controls. The perfusion patterns of men with BPH and those who also had severe vascular damage (diabetes mellitus type 2) showed that vascularity in the latter group was lower in the prostatic TZ and the corpora cavernosa. In patients with BPH the IPSS, quality-of-life and IIEF scores were significantly worse than in the control group. Men with concomitant atherosclerosis had even worse symptom scores. CONCLUSION: These results strongly support the hypothesis that age-related impairment of blood supply to the lower urinary tract is important in the development of BPH and ED. Vascular damage may cause chronic ischaemia and thus be a contributing factor in the pathogenesis of BPH and ED.
Abstract: OBJECTIVES: To investigate the prostate cancer (PCa) detection rates and Gleason scores in patients with serum prostate-specific antigen (PSA) levels of 2.0 to 3.9 ng/mL and 4.0 to 10 ng/mL (free PSA 18% or less), in a population-based screening project. With the use of prostate-specific antigen (PSA) screening, more PCa is being diagnosed at PSA values of less than 4 ng/mL. METHODS: A total of 3446 consecutive screening volunteers with a PSA level of 2.0 to 10.0 ng/mL (free PSA 18% or less) were assessed. Ten systematic prostate biopsies and an additional five Doppler-enhanced targeted biopsies were performed on the basis of age-specific PSA reference ranges. The cumulative frequency of detection and the Gleason scores were analyzed. RESULTS: The PCa detection rate for patients with a PSA value of 2.0 to 3.9 ng/mL (n = 1522, group 1) and 4.0 to 10.0 ng/mL (n = 1924, group 2) was 21% (n = 320) and 30% (n = 572), respectively. Of the PCa cases detected, 37% were in men with a PSA level of 2 to 4 ng/mL. Statistically significant differences were found in age and prostate volume between groups 1 and 2, with patients in the lower PSA group younger and having a smaller mean prostate volume (P = 0.0001). Of 313 patients with PCa and a PSA value of 2 to 3.9 ng/mL, 24% had a Gleason score of 7 or greater compared with 33% of 560 patients with a PSA value of 4.0 to 10.0 ng/mL (P = 0.004). CONCLUSIONS: Our data suggest that in a screening population, more than one third of PCa cases in men with a PSA level of 2 to 10 ng/mL will occur in those with a PSA value of 2 to 3.9 ng/mL. Also, PCa cases with a low PSA level occur in younger patients and at lower stages with a smaller prostate volume.
Abstract: PURPOSE: Transrectal gray scale ultrasound guided biopsy is the standard method for diagnosing prostate cancer (PC). Improved cancer detection with ultrasound contrast agents is related to better detection of tumor vascularity. We evaluated the impact of a combined approach of contrast enhanced, color Doppler targeted biopsy (CECD) and systematic biopsy (SB) for the PC detection rate in men with prostate specific antigen (PSA) 4.0 to 10 ng/ml. MATERIALS AND METHODS: We examined 380 screening volunteers with a total PSA of 4.0 to 10 ng/ml (percent free PSA less than 18). CECD was always performed before SB. Another investigator blinded to contrast enhanced findings performed 10 SBs. The cancer detection rate for the CECD, SB and combined approaches was assessed. RESULTS: PC was detected in 143 of 380 patients (37.6%, mean total PSA 6.2 ng/ml). The PC detection rate for CECD and for SB was 27.4% and 27.6%, respectively. The overall cancer detection rate with the 2 methods combined was 37.6%. For targeted biopsy cores the detection rate was significantly better than for SB cores (32.6% vs 17.9%, p <0.01). CECD in a patient with cancer was 3.1-fold more likely to detect PC than SB. CONCLUSIONS: CECD allows for the detection of lesions that cannot be found on gray scale ultrasound or SB. CECD allows for assessment of neovascularity associated with PC. However, the combined use of CECD and SB allows for maximal detection of PC with a detection rate of 37.6% in our patients with PSA 4 to 10 ng/ml.
Abstract: We investigated the effects of androgen receptor (AR) down regulation with a small interference RNA molecule (siRNA_AR(start)) on androgen sensitive LNCaP and androgen independent LNCaPabl prostate cancer cells, the latter representing an in vitro model for the development of therapy resistance in prostate cancer. Although LNCaPabl cells express increased levels of AR in comparison with androgen sensitive LNCaP cells, the protein was significantly down regulated in response to siRNA_AR(start) treatment. This AR down regulation resulted in a marked cell growth inhibition in both cell lines. By contrast, DU-145 prostate cancer cells, which lack AR expression, were not inhibited by the siRNA_AR(start). In consequence to AR down regulation, both cell lines, LNCaP and LNCaPabl, shared a highly similar gene expression profile in terms of major changes in cell cycle regulatory genes. The cell cycle inhibitor p21(Waf1/Cip1) as well as cyclin D1 were significantly up regulated by siRNA_AR(start) treatment, considering a switch in cyclin expression towards cell cycle retardation. Control molecules had moderate effects on cell proliferation and gene expression, respectively. In summary, we found that AR inhibition with siRNA induces cell growth retardation in androgen sensitive as well as in androgen independent prostate cancer cells and thus may represent an interesting approach to combat hormone-refractory prostate cancer.
Abstract: Prostatic carcinoma is the most frequent malignant disease in men and associated with very high mortality. The diagnostic work-up of prostatic carcinoma is based on tests to determine the level of prostate-specific antigen (PSA), digital rectal examination, and transrectal sonography. Due to diagnostic limitations, ultrasound-guided prostate biopsy is the method of choice for diagnosis of prostatic carcinoma. New imaging technologies allow detection of prostatic carcinoma, thus facilitating removal of specific biopsy specimens from these regions. Introduction of ultrasound contrast agents ("echo signal enhancers") significantly increased the diagnostic potential of this method, making it possible to visualize tumor vascularization.
Abstract: PURPOSE: Transurethral resection of the prostate (TURP) is still the gold standard for the surgical treatment of symptomatic benign prostatic hyperplasia. However, the associated morbidity and blood loss remain concerns. A coagulating intermittent cutting (CIC) device with constant voltage pulses and controlled pulse intervals was recently developed. The impact of CIC on bleeding and blood transfusion rates as well as the occurrence of the TUR syndrome were investigated. MATERIALS AND METHODS: From January 2000 to July 2002, 271 consecutive patients with symptomatic benign prostatic hyperplasia underwent TURP with the CIC device. In addition to blood transfusion rates, serum hemoglobin and electrolytes were determined in all patients immediately before and after TURP. RESULTS: The mortality rate in the 271 patients subjected to TURP was 0.0%. Mean decrease in hemoglobin after TURP was 1.08 mg/dl. Intraoperative and postoperative blood transfusions were required in 7 patients (2.6%), and clinical signs of the transurethral resection syndrome were noted in 1.1% of patients. CONCLUSIONS: Coagulating intermittent cutting dramatically improves the safety of TURP by decreasing intraoperative and postoperative blood loss, and the rate of blood transfusions. With this blood sparing device we anticipate a lower incidence of hemostatic complications from TURP.
Abstract: Because of the heterogeneity of prostate cancer knowledge about the genes involved in prostate carcinogenesis is still very limited. Previously, the use of novel high-throughput technologies offered the possibility to investigate broad gene expression profiles and thus helped to improve understanding of the molecular basis of prostate disease. Many candidate genes have been identified so far which have a more or less strong effect on prostate cancer. This vast number of gene expression changes show that it is unlikely that only one gene promotes prostate cancer. Conversely, it seems more likely that a broad network of molecular changes is involved in the complex cascade of events which lead to tumour formation and progression, respectively. A few of these novel molecular targets are currently under clinical evaluation. This paper gives an overview of several interesting candidate genes which may be useful as improved biomarkers for diagnosis or as targets for developing novel treatment methods.
Abstract: PURPOSE: Phytoestrogens are nonsteroidal plant derived compounds with estrogenic activity that have been implicated in protecting against prostate cancer progression. We hypothesized that these compounds would alter cell number and increase the ability of antiandrogens to induce cell death in prostate cancer cells. MATERIALS AND METHODS: RWPE-1, LNCaP and PC-3 cells were treated with or without an extract of Belamcanda chinensis, 2 purified phytoestrogens derived from this extract (irigenin and tectorigenin) and the antiandrogen bicalutamide. We assessed the effect on cell number, proliferation and apoptosis. RESULTS: Phytoestrogens (50 to 100 microM) and bicalutamide (10 to 50 microM) alone decreased the cell number in all 3 cell lines. Phytoestrogens (50 microM) combined with bicalutamide (10 microM) further decreased the number of RWPE-1 and PC-3 cells compared to these agents alone. Tectorigenin and irigenin inhibited the proliferation of RWPE-1, LNCaP and PC-3 cells, causing G1 arrest and the induction of p21WAF1 or p27 protein expression, whereas bicalutamide induced apoptosis in a dose dependent manner in all 3 cell lines. Phytoestrogens did not have antiandrogenic activity. CONCLUSIONS: These in vitro studies demonstrate a role for tectorigenin and irigenin in regulating prostate cancer cell number by inhibiting proliferation through cell cycle regulation.
Abstract: OBJECTIVES: Isoflavonoids are discussed for use in chemoprevention and treatment of prostate cancer. We investigated the potential of genistein to modulate androgen receptor (AR) expression and transcriptional activity in the human androgen-sensitive prostate cancer cell line LNCaP. MATERIALS AND METHODS: AR expression at mRNA and protein level was analyzed by real-time RT-PCR and immunoblot, respectively. In conditioned media PSA was measured by a microparticle enzyme immunoassay (MEIA). Binding of genistein to the AR was tested in a radioligand-binding assay and reporter gene co-transfection assay was employed to investigate AR activity. RESULTS: Using concentrations of genistein that have been detected in sera of Asian men on regular soy-diet we found down-regulation of androgen receptor at both mRNA and protein level. The relative binding affinity to the AR was below 4% when compared to methyltrienologe (R1881) and there was no modulation of AR transcriptional activity by genistein concentrations up to 1 microM. We also demonstrated inhibition of PSA secretion after genistein treatment. As the anti-estrogen ICI 164 384 abolished the inhibitory effect of genistein and ER-beta, but not ER-alpha is expressed in LNCaP cells we postulate that the mechanism of genistein action on androgen receptor is mediated through ER-beta. CONCLUSION: Using physiological concentrations of genistein we showed AR down-regulation by genistein in prostate cancer cells occurring via ER-beta. This likely results in a modified response to hormonal stimuli and may help to explain the low incidence of prostate cancer in the Asian population.
Abstract: Estrogens have profound effects on the developing prostate and are suspected to contribute to the development of benign prostatic hyperplasia, but the mechanism by which this hormone elicits its regulatory function still remains largely unknown. Using complementary RNA microarrays comprising approximately 10,000 oligonucleotide gene targets we compared differences in mRNA expression of estradiol-treated and untreated prostatic stromal cells in vitro. Based on a threshold of greater than twofold change, 228, 241, and 464 of the expressed genes were found to be regulated by estradiol after 10, 24, and 48 h of treatment, respectively. The secondary analysis of one estradiol-activated transcript, namely lipopolysaccharide-binding protein, and four estradiol-repressed genes, namely ras homolog gene family member E (RhoE/Rnd3), ubiquitin thiolesterase, interleukin 6, and interleukin 8 (IL-8), by real-time quantitative PCR confirmed the results of the microarray analysis. Moreover, IL-8 and RhoE were found to be down-regulated by estradiol at the protein level as well. We identified a set of genes involved in a wide range of cellular functions that are potentially important for understanding the molecular basis of estradiol action in the prostate.
Abstract: We have shown recently that inhibition of androgen receptor (AR) expression with an antisense AR oligonucleotide (ODN) inhibits LNCaP prostate tumor cells in vitro as well as in vivo. In this study, we investigated gene expression changes that occur after AR signaling blockade, either through AR elimination by antisense treatment or through complete androgen receptor inhibition by androgen deprivation combined with the antiandrogen bicalutamide, in order to search for genes that are directly or indirectly regulated through the AR. Gene expression changes were investigated with cDNA NIH 10K gene microarrays in response to treatment over 48 h. Expression of selected genes was further analyzed by real-time reverse transcriptase (RT)-polymerase chain reaction (PCR), Western blotting, and radioimmunoassay. A comparison of antisense-treated and androgen-deprived cells revealed several concordances such as significant downregulation of prostate-specific genes, cell-cycle regulatory genes, genes of the cholesterol biosynthesis pathway, and several cytoskeletal genes. However, there were also several genes that were differentially regulated. Among the genes that were exclusively changed by treatment with the antisense AR ODN were the insulin-like growth factor binding protein 2 (IGFBP2) and the phosphatidylinositol-4-phosphate 5-kinase type I alpha (PIP5KIA). On the other hand, complete androgen receptor blockade induced changes in the expression of the prostate overexpressed gene 1 and the S100 calcium binding protein P. In summary, we identified a cohort of interesting genes whose expression was highly affected by elimination of the AR in LNCaP prostate cancer cells. Further investigations are warranted to clarify their role in the AR signaling pathway and their susceptibility as a target for the treatment of prostate cancer.
Abstract: BACKGROUND: Local hypoxia may be one of the triggers of embryonic reawakening of the stroma and subsequent hyperplastic growth in the prostate. Using a cell culture model of human prostatic stromal cells, we investigated the effects of hypoxia on activation of hypoxia-inducible factor 1 (HIF 1) and on the production of growth factors. METHODS: Primary prostatic stromal cells were grown in normal and hypoxic (1% O(2)) atmosphere. Activation of HIF 1 was evaluated after different time intervals by Western blot. Induced secretion of growth factors VEGF, FGF-7, TGF-beta, IL 8, and FGF-2 were analyzed by ELISA. To confirm the in vitro findings we also performed immunohistochemistry of HIF 1alpha as well as pro-collagen I, collagens I, III, and IV in the benign tissue of radical prostatectomy specimens. RESULTS: HIF 1 is activated in a time-dependent manner, already starting 1 hr after exposure of stromal cells to hypoxic conditions. Secretion of VEGF, FGF-7, TGF-beta, FGF-2, and IL 8 is increased under hypoxic in vitro conditions in comparison to normoxia. Levels of TGF-beta, VEGF, and IL 8 were rapidly and statistically significantly increased in the supernatant of hypoxic cells. Consistent with the in vitro findings, immunohistochemistry of HIF 1alpha in (benign prostatic hyperplasia) BPH tissue revealed strong HIF 1alpha nuclear staining in hyperplastic areas. No difference was observed in the collagen pattern between hyperplastic and normal prostate tissue. CONCLUSIONS: Prostatic stromal cells respond to hypoxia by upregulation of secretion of several growth factors suggesting that hypoxia can trigger prostatic growth. Therefore, hypoxia might be a key factor contributing to the pathogenesis of BPH.
Abstract: Oropharyngeal candidiasis is one of the first and most commonly reported opportunistic infections of untreated AIDS patients. With the introduction of the new antiviral HAART therapy, including HIV protease inhibitors, this mucocutaneous infection is nowadays only rarely observed in treated patients. It was recently shown that HIV protease inhibitors have a direct attenuating effect on Candida albicans secreted aspartic proteinases (Saps), an investigation prompted by the fact that both Sap and HIV protease belong to the superfamily of aspartic proteinases and by the observation that mucocutaneous infections sometimes resolve even in the absence of an immunological improvement of the host. As these Saps are important fungal virulence factors and play a key role in adhesion to human epithelial cells we tried to assess the effect of the HIV protease inhibitors Ritonavir, Indinavir and Saquinavir on fungal adhesion to these cells. The effect on phagocytosis by polymorphonuclear leukocytes was also assessed. Ritonavir was found to be the most potent inhibitor of fungal adhesion. A dose-dependent inhibition of adhesion to epithelial cells was found already at 0.8 microM and was significant at 4 microM or higher, at 500 microM the inhibition was about 55%. Indinavir and Saquinavir inhibited significantly at 4 microM or 20 microM, respectively; at 500 microM the inhibition was 30% or 50%. In contrast, no protease inhibitor was able to modulate phagocytosis of Candida by polymorphonuclear leukocytes. In conclusion, inhibition of Saps by HIV protease inhibitors may directly help to ease the resolution of mucosal candidiasis. In future, derivatives of HIV protease inhibitors, being more specific for the fungal Saps, may form an alternative in the treatment of mucosal candidiasis insensitive to currently available antimycotics.
