Evaluation of PSF1 as a prognostic biomarker for prostate cancer.

BACKGROUND: Partner of SLD5 1 (PSF1) is an evolutionarily conserved DNA replication factor. Previous studies have suggested that transcriptional activity of the PSF1 gene correlated with malignancy of cancer cells. The objective of the current study was to evaluate the relationship between PSF1 expression and the clinical features of prostate cancer. METHODS: We determined the expression of PSF1 in 120 needle biopsy samples of prostate cancer by immunohistochemistry. We divided patients into PSF1-positive or -negative groups and analyzed the relationships between the expression of PSF1, the Gleason score, PSA level, TNM classification and prognosis. RESULTS: Our results showed that the PSF1 expression correlated significantly with PSA values at diagnosis (P=0.0028), with tumor grade (P<0.0001), and with clinical stage (P=0.0005). Moreover, the PSF1 expression correlated significantly with overall survival (hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.17-15.8; P=0.003) and progression-free survival in 99 consecutive patients with prostate cancer. Noteworthy, the prognosis of PSF1-positive cases was also worse in patients with a Gleason score of 8-10 (HR 3.7; 95% CI 1.28-13.43; P=0.0143). Limitations include that this study had a retrospective design, that patients in the study were heterogeneous and included those with early and advanced cancer, and that small tumor fragments may not be representative of the entire carcinoma. CONCLUSIONS: PSF1 is expressed in high-grade prostate cancer and may be a useful biomarker to identify patients with a poor prognosis at the time of diagnosis.

The beneficial effect of propolis on fat accumulation and lipid metabolism in rats fed a high-fat diet.

This study examined whether propolis, which had many biological activities, affected body fat and lipid metabolism. Four-week-old Wistar rats were fed a control or propolis diet for 8 wk. The control group was fed a high-fat diet, the low and the high group were fed a high-fat diet supplemented with 0.5% (w/w) and 0.05% (w/w) propolis, respectively. The weight of total white adipose tissue of the high group was lower than that of the control group. The level of PPARgamma protein in the adipose tissues of the high group was significantly lower than that of the control group. In plasma and the liver, the high group showed a significantly reduced level of cholesterol and triglyceride compared to the control group. The liver PPARalpha protein level of the high group was significantly higher than that of the control group. The liver HMG-CoA reductase protein in the high group was also significantly lower than that in the control group. Results from rats on an olive oil loading test were used to investigate whether propolis inhibited triglyceride absorption. The serum triglyceride level of the group, which received propolis corresponding to the daily dose of the high group, was significantly lower than that of the control group. It is possible that the administration of propolis improves the accumulation of body fat and dyslipidemia via the change of the expression of proteins involved in adipose depot and lipid metabolism.

Topical application of royal jelly has a healing effect for 5-fluorouracil-induced experimental oral mucositis in hamsters.

The aim of this study was to evaluate the effects of bee products such as honey, royal jelly and propolis on 5-fluorouracil-induced experimental oral mucositis in hamsters. Oral mucositis was induced in hamsters through a combination of 5-fluorouracil and mild abrasions that were made on the cheek pouch. Honey, royal jelly and propolis were thereafter topically administered to the oral mucosa, and then the healing process was examined by measuring the size of the mucositis. Honey (1%, 10% and 100%) and propolis (0.3%, 1% and 3%) ointments did not reduce the size of the mucositis in comparison to the vaseline-treated control group. However, the royal jelly (3%, 10% and 30%) ointments significantly improved the recovery from 5-fluorouracil-induced damage in a dose-dependent manner. These results suggest the possibility that the topical application of royal jelly has a healing effect on severe oral mucositis induced by chemotherapy.

Possible use of transrectal power Doppler imaging as an indicator of microvascular density of prostate cancer.

OBJECTIVES: To reveal the possible use of transrectal power Doppler imaging (PDI) of the prostate in the assessment of the microvascular density (MVD) of cancer lesions. METHODS: In 22 patients with clinically organ-confined prostate cancer, PDI was performed before radical prostatectomy and the degree of vascularity of the cancer lesions as evaluated by PDI was compared with the MVD determined on the surgical specimens. The vascularity by PDI of each cancer lesion was graded on a scale of DS0 to DS2, according to the degree of Doppler signal accumulation. MVD was obtained using factor VIII immunohistochemistry. RESULTS: The vascularity of the PDI of 46 cancer lesions categorized 23 (50%), 10 (22%), and 13 (28%) cancer lesions as DS0, DS1, and DS2, respectively. Significant differences were found in the MVD between DS0 (46.6 +/- 26.8) and DS2 (89.0 +/- 18.1, P <0.005) lesions and between DS1 (50.9 +/- 25.4) and DS2 (P <0.001) lesions. The MVD of 30 cancer lesions in 13 patients without neoadjuvant therapy was significantly higher than that of the 16 lesions in 9 patients with therapy (70.2 +/- 28.2 versus 39.5 +/- 23.9, P <0.001). In the 13 patients without neoadjuvant therapy, the MVD of the DS2 lesions (89.1 +/- 18.9) was significantly higher than that of the DS0 lesions (59.3 +/- 32.5, P <0.01) and DS1 lesions (55.9 +/- 20.9, P <0.005). CONCLUSIONS: The semiquantitative assessment of Doppler flow signals using PDI appears to be of clinical value as an indicator of MVD.

Can complexed prostate specific antigen and prostatic volume enhance prostate cancer detection in men with total prostate specific antigen between 2.5 and 4.0 ng./ml.

PURPOSE: We assessed whether complexed prostate specific antigen (PSA) and complexed PSA referenced variables would enhance prostate cancer detection in men with serum total PSA between 2.5 and 4.0 ng./ml. MATERIALS AND METHODS: Transition zone and total prostate gland volumes were determined in 151 men who underwent prostate biopsy using an 11 core biopsy strategy. In addition to measuring the Bayer section sign complexed PSA assay, we also calculated 2 computed complexed PSA values (Hybritech parallel total PSA--Hybritech free PSA and Bayer total PSA--Hybritech free PSA). We calculated 8 volume referenced variables using total and complexed PSA, and 2 computed complexed PSA values by dividing each value by the total prostate and transition zone volumes. RESULTS: Of the 151 patients 37 (24.5%) had cancer. In 10 of the 37 men with cancer (27%) a positive core was present in only 1 or more of the 5 alternate regions not sampled by conventional sextant biopsies. At 92% sensitivity a cutoff value of 2.3 ng./ml. for complexed and 31% for free-to-total PSA provided 42% and 11% specificity, respectively (p <0.001). In the 116 men with a total prostate volume of 30 cc or greater at 92% sensitivity the specificity of complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (52%) were better than that of complexed (40%) and free-to-total (11%) PSA. In the 35 men with a total prostate volume of less than 30 cc at 92% sensitivity the specificity of complexed PSA (50%), complexed PSA density (55%) and complexed PSA adjusted for transition zone volume (55%) were significantly better than that of free-to-total PSA (8%, p <0.001). The area under the curve of complexed PSA was almost identical to that of the 2 computed complexed PSA calculations. CONCLUSIONS: A substantial proportion of men with total PSA values between 2.5 and 4.0 ng./ml. had prostate cancer. Complexed and computed complexed PSA were more specific than the free-to-total PSA ratio when total PSA was between 2.5 and 4.0 ng./ml. A 2.3 ng./ml. threshold for complexed and computed complexed PSA appears to stratify prostate biopsy results in men with total PSA between 2.5 and 4.0 ng./ml. The computed complexed PSA calculation appears to be equivalent to the complexed PSA serum assay for detecting cancer. Volume referenced complexed PSA performed better than complexed PSA in men with a total prostate volume of 30 cc or greater compared to men with a total prostate volume of less than 30 cc.

Early detection of prostate cancer: is PSA a reliable option?

A close relationship exists between prostate volume and prostate-specific antigen (PSA). Clinical decisions must be determined based on the variability of PSA. Screening with the PSA assay has contributed to early detection of prostate cancer. Some important undetermined issues are the optimal cutoff values of PSA, the proportion of free to total PSA, and the clinical usefulness of complexed PSA. Current articles demonstrating novel markers (human kallikrein-2, BPSA, and pro PSA) and artificial neural networks are introduced.

Immunohistochemical localization of platelet-derived endothelial cell growth factor expression and its relation to angiogenesis in prostate.

OBJECTIVES: Tumor angiogenesis has been reported as a predictor for prognosis in patients with prostate cancer. The aim of this study was to determine the localization of one angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), in benign and malignant prostatic tissues and the correlation between PD-ECGF expression and microvessel density (MVD) in prostate cancer. METHODS: Forty cases of prostate cancer, 3 cases of benign prostatic hyperplasia, and 5 young autopsy cases without prostatic disease were processed with immunohistochemistry, using an anti-PD-ECGF antibody and anti-factor VIII-related antigen antibody. The PD-ECGF expression intensity and MVD were evaluated in each case. RESULTS: In the 40 cases with prostate cancer, the expression of PD-ECGF was noted in the stromal cells within cancer tissues in 80% of cases. Additionally, noncancerous glands next to cancer lesions were positive for PD-ECGF in 85% of cases. However, cancer cells were negative for PD-ECGF in all cases. In the 8 cases without cancer, both the prostatic glands and their surrounding stroma were positive for PD-ECGF only when they were accompanied by inflammation. There was a significant positive correlation (r = 0.636, P <0.001) between the intensity of PD-ECGF expression and MVD. MVD was significantly different when comparing the intensity of PD-ECGF expression of grade 0 versus grade 1 (P <0.05), grade 1 versus grade 2 (P <0.05), and grade 0 versus grade 2 (P <0.01). CONCLUSIONS: This study suggested that PD-ECGF expression in the stromal cells within cancer tissues might play an important role in tumor angiogenesis in prostate cancer.

Complexed prostate-specific antigen improvement in detecting prostate cancer.

This article presents the current reports of complexed prostate-specific antigen (PSA) aimed for the enhancement of prostate cancer detection. Further studies are needed to ascertain the variability of complexed PSA. Comparisons of percent free PSA, potential additive value of alpha(1)-antichymotripsin-bound PSA (PSA-ACT) and Bayer complexed PSA (cPSA) remains controversial in men with intermediate elevated total PSA concentration. Volume-referenced complexed PSA (PSA-ACT and cPSA) can enhance prostate cancer detection. Preliminary results show that PSA-alpha(2)-macrobloblin (PSA-a(2)M) and PSA-alpha(1)-protease inhibitor (PSA-API) are promising assays for improving cancer detection.

Transrectal power Doppler imaging in the detection of prostate cancer.

OBJECTIVES: To evaluate the clinical utility of transrectal power Doppler imaging (PDI) of the prostate for detecting prostate cancer in patients with abnormally high serum levels of prostate specific antigen (PSA). PATIENTS AND METHODS: Patients (107) with abnormally high serum PSA levels were assessed using a digital rectal examination (DRE), transrectal ultrasonography (TRUS) and PDI. Any hypervascular lesion on PDI was graded on a scale of 0-3, where grade 1-3 was considered positive and grade 0 negative. Patients were then diagnosed by prostatic needle biopsy and the results compared with the other detection methods. RESULTS: Needle biopsy confirmed prostate cancer in 41 (24%) of the 170 patients. PDI was positive in 68, of whom 40 (59%) had prostate cancer; all those but one having prostate cancer were positive on PDI. Thus, PDI had a high sensitivity of 98% (40/41) and a negative predictive value of 99% (101/102). PDI could have saved a significant number of patients from undergoing unnecessary biopsies, compared with DRE and TRUS (P < 0.001). CONCLUSION: The use of PDI in detecting prostate cancer might reduce the number of unnecessary needle biopsies of the prostate in patients with abnormally high serum PSA levels.

Doppler resistive index in benign prostatic hyperplasia: correlation with ultrasonic appearance of the prostate and infravesical obstruction.

OBJECTIVE: This study was designed to characterize the resistive index (RI) of prostatic blood flows obtained by transrectal power Doppler sonography (TRPDS) in benign prostatic hyperplasia (BPH). METHOD: In 140 patients with lower urinary tract symptoms, the RI was measured using TRPDS and compared with age and planimetric parameters of the prostate obtained by conventional transrectal sonography. In addition, the RI was related with pressure flow studies. RESULTS: The RI was significantly higher in patients with BPH (0.72+/-0.06, p<0.0001) than those with a normal prostate (0. 64+/-0.04). Although the RI correlated significantly with age and all prostatic planimetric parameters, multiple regression analysis revealed that age and presumed circle area ratio were independent predictors for RI. The RI was also higher in patients with infravesical obstruction than those without (0.74+/-0.06 vs. 0. 70+/-0.05, p<0.005). There was a significant correlation between RI and urodynamic parameters obtained in pressure flow studies. Out of 33 patients with obstruction, 28 (85%) had an RI of 0.7 or more, while 11 out of 24 patients (46%) without obstruction had an RI less than 0.7. CONCLUSION: The RI is promising as a new parameter to estimate the intraprostatic pressure to investigate BPH. Its value to represent urodynamic information during voiding remains to be studied.

Significant changes in transrectal ultrasonic measurements of the prostate in relation to the degree of rectal wall distension.

The present study was conducted to reveal the possible changes in transrectal ultrasonic measurements of the prostate in relation to the degree of rectal wall distension. When analyzed together for 51 men, all measurements but area changed statistically significantly as the rectal wall was distended by a balloon covering a probe. Ultrasonic measurements concerning the prostatic shape changed more remarkably than those concerning its size. More importantly, changes in ultrasonic measurements were much more remarkable in patients with a healthy prostate than in those with an advanced BPH. These results suggest that possible changes in prostatic shape with the rectal wall distension has to be taken into account when evaluating transrectal prostatic ultrasonograms in terms of changes in shape, especially in patients with a healthy prostate. This is also the case when the diagnosis of BPH is made based on the change in shape, such as presumed circle area ratio, which is a parameter representing the roundness of the horizontal sonogram of the prostate.

[Ultrasound in urodynamics].

Recent developments of ultrasound imaging have contributed much to the understanding of urodynamics in patients with lower urinary tract symptoms (LUTS). These include ultrasound estimated bladder weight (UEBW), transrectal power Doppler imaging of the prostate and transrectal ultrasonography during voiding (voiding TRUS). UEBW, which is obtained by measuring the thickness of the anterior bladder wall using a 7.5 MHz probe, represents well the degree of bladder hypertrophy caused by obstruction. This parameter is, accordingly, of clinical use in the evaluation of obstruction. The UEBW predicted the presence of obstruction as determined by pressure-flow study with a diagnostic accuracy of 73%. Transrectal power Doppler imaging of the prostate has made it easy to detect prostatic vessels and furthermore to obtain their resistive index (RI). Accumulating data suggest strongly that RI reflects the intraprostatic pressure. More interestingly, RI decreases significantly during voiding in normal subjects but not in patients with benign prostatic hyperplasia. Thus, this method is of particular use in monitoring noninvasively the dynamic change in intraprostatic pressure during voiding. Voiding TRUS makes it possible to monitor the movement of not only the posterior urethra but also the prostate during voiding. Based on our recent study, the anterior fibromuscular stroma (AFMS) seems to contract to open the urethra. Although the physiological function of the AFMS in the prostate remains unknown, AFMS may play a significant role in normal micturition. Due to its noninvasiveness and ease of application, ultrasound imaging would play a vital role in the diagnostic process for patients with LUTS in future.

[The role of power Doppler-guided prostatic biopsy in the diagnosis of prostate cancer].

Between March 1997 and December 1998, a total of 170 cases with an abnormal serum prostate specific antigen (PSA) level (range: 4.1-200, mean: 20.5 +/- 31.0) were chosen for this study. Following the evaluation of the prostate using power Doppler imaging (PDI) with a 7.5 MHz transrectal probe, the hypervascular lesion (HVL) was biopsied transperineally under PDI real-time guidance. Thereafter, when gray-scale transrectal sonography revealed a hypoechoic lesion, additional samples were taken from them. Finally, sextant systematic biopsy was performed in all cases. Prostatic biopsy was positive for cancer in 41 cases (24%). The positive biopsy rate was 59% (40/68) in cases with HVL, compared to 1% (1/102) in cases with no HVL (p < 0.0001). In 107 patients with serum PSA 4.1 to 10.0 ng/ml, biopsy was positive in 13 cases (12%). The positive biopsy rate was 38% (12/32) in cases with HVL, compared to 1% (1/75) in cases with no HVL (p < 0.0001). These results imply that HVL represents the neovascularity or increased perfusion of blood in the cancer lesion. Power Doppler-guided prostatic biopsy could be promising as a new biopsy technique in patients with abnormal PSA levels including moderately elevated PSA levels (4.1-10.0 ng/ml).

Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis.

Beta2-Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. beta2-Adrenergic and chemokine receptors belong to the G-protein-coupled receptor family whose responsiveness is turned off by the G-protein-coupled receptor kinase family (GRK-1 to 6). GRKs phosphorylate receptors in an agonist-dependent manner resulting in receptor/G-protein uncoupling via subsequent binding of arrestin proteins. We assessed the activity of GRKs in lymphocytes of rheumatoid arthritis (RA) patients by rhodopsin phosphorylation. We found a significant decrease in GRK activity in RA subjects that is mirrored by a decrease in GRK-2 protein expression. Moreover, GRK-6 protein expression is reduced in RA patients whereas GRK-5 protein levels were unchanged. In search of an underlying mechanism, we demonstrated that proinflammatory cytokines induce a decrease in GRK-2 protein levels in leukocytes from healthy donors. Since proinflammatory cytokines are abundantly expressed in RA, it may provide an explanation for the decrease in GRK-2 expression and activity in patients. No changes in beta2-adrenergic receptor number and Kd were detected. However, RA patients showed a significantly increased cAMP production and inhibition of TNF-alpha production by beta2-adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to beta2-adrenergic activation.

Kinetic study of tumor blood flow in prostatic cancer using power Doppler imaging.

We examined the changes in tumor Doppler flow signals as well as prostatic volume in 11 cases of prostatic cancer, before and after castration, by using power Doppler imaging, and compared the changes in vascular resistance (RI) and prostatic volume (PV) in 11 cases. RI, except for one case, and PV decreased after castration in all cases without exception. In both, the manner of decrease showed an exponential curve. However, the reduction time of RI fell in an extremely narrow range compared with that of PV. Tumor vascular flow was influenced by castration, resulting in a decrease of RI. The dynamic change of vascular flow occurred earlier than that of PV. Analysis of changes in tumor blood flow signals could offer valuable information on early therapeutic effects in patients with prostatic cancer; however, it might not be a useful parameter for the prediction of prognosis.

[Clinical utility of the free prostate specific antigen (PSA), alpha 1-antichymotrypsin-complexed PSA, and free/total PSA ratio using the specific and sensitive enzyme-linked immunosorbent assay "E-plate EIKEN PSA"].

We studied the clinical significance of serum prostate specific antigen (PSA) ratio: free-PSA/total-PSA and free-PSA/complex-PSA to discriminate between prostate cancer (PC) and prostate benign disease (non-PCa) by using total-PSA, alpha 1-antichymotrypsin complexed (complex)-PSA and free-PSA enzyme-linked immunosorbent assay (ELISA) kits newly developed at EIKEN Chemical Co, Ltd. Fre-PSA and complex-PSA ELISA kits demonstrated high sensitivity and specificity. Total-PSA ELISA kit also demonstrated equimolarity for free-PSA and complex-PSA. On the total-PSA range of 4-10 ng/ml, free-PSA/total-PSA% (f/t%) and free-PSA/complex-PSA% (f/c%) were very useful to discriminate between PCa and non-PCa by receiver operating characteristic curve analysis as well as PSA density (PSA-D) but not free-PSA level. F/t% and f/c% were even useful to discriminate early stage PCa (i.e. A1 or B0) from non-PCa by the Mann-Whitney U-test.

[Predictability of Gleason score and reduction time (tau) of prostatic volume after castration for the prognosis of prostatic cancer].

PURPOSE: The efficacy of the reduction time (tau) after castration as a prognostic factor was examined by comparing to Gleason score. MATERIALS AND METHODS: The change of prostatic volume after castration was observed from the castration to 3 months after in 24 cases of prostatic cancer. Prostatic volume was examined by transrectal ultrasonography of the prostate. Survival curves was calculated by Kaplan-Meier method. Differences among survival curves were analyzed using Cox-Mantel test. RESULTS: tau had a close relationship to the prognosis of each case (Wilcoxon test: p < 0.05, Cox-Mantel test: p < 0.05). Gleason score had a weak relationship to prognosis (Wilcoxon test: N. S., Cox-Mantel test: p < 0.05). CONCLUSIONS: tau was efficient as prognostic factor compared to Gleason score.

[Progress of clinical application for prostatic ultrasound].

In 1967, in our laboratory the first clinically available prostatic sonogram was obtained from the rectal cavity with a patient in the lithotomy position. Thereafter, transrectal sonography (TRS) visualized the internal architecture as well as the entire contour of the prostate, and was readily applied to the investigation of prostatic diseases. Currently, TRS occupies a central position among the diagnostic modalities for the prostate. Along with accumulating evidences indicating the clinical usefulness of TRS in the diagnosis of prostatic diseases, recent development has confirmed it to be indispensable for daily practice in urology clinics. This chapter will describe an overall review of the development and diagnostic criteria of TRS.

Kinetic analysis of prostatic volume and prostate specific antigen (PSA) in patients with advanced prostatic cancer treated by castration.

The clinical usefulness of the kinetic analysis of prostate specific antigen (PSA) in patients with advanced prostatic cancer treated by castration has not yet been evaluated. The reduction of both prostatic volume and PSA was monitored in 37 patients with Stage C and Stage D prostatic cancer. The change of prostatic volume was measured frequently by transrectal ultrasonography (TRS) after castration, as was the change of PSA. A kinetic analysis of both prostatic volume and PSA was made by comparing the reduction time tau(PSA) (speed of the reduction of PSA) and tau prostatic volume (PV). There was a statistically significant correlation between tau(PSA) and tau(PV) in patients with a tau(PV) of less than 30 days. However, no correlation was observed in patients with a tau(PV) of more than 30 days, because the tau(PSA) in this group fell into a relatively low range similar to the group with a tau(PV) of less than 30 days. It was assumed that the change of PSA after castration reflected mainly the response of the hormone dependent portion of the total cancer volume. However, all data of tau(PV) with a tau(PSA) less than 10 days were within 30 days. In conclusion, tau(PSA) might be promising as a prognostic factor after castration in patient with advanced prostatic cancer, although tau(PSA) was not a direct substitute for tau(PV).

Ultrasonic power Doppler imaging for prostatic cancer: a preliminary report.

This study was conducted to characterize Doppler blood flow signals in prostatic cancer using power Doppler imaging with a transrectal probe. Both the localization and vascularity of blood flow in the prostate were compared between patients with prostatic cancer and those with benign prostatic hyperplasia (BPH). The prominent accumulation of blood flow signals (hypervascular lesion) was recognized in all the cases with prostatic cancer, compared to only 2 (4%) of 47 with BPH (p < 0.001). Power Doppler imaging is promising for the detection of prostatic cancer.