Expression and Implication of Hypoxia Inducible Factor-1α in Prostate Neoplasm

Summary: To study the expression of hypoxia inducible factor-1α (HIF-1α) protein in prostate cancer (Pca) and its biological significance, the expression of HIF-1α was assayed by means of immunohistochemical technique in 42 prostate cancer, 12 prostatic intraepithelial neoplasm (PIN) and 9 normal prostate tissue (NP) specimens. Western blot was used to examine the expression of HIF-1α in prostate cancer cell line (PC-3M) induced by different oxygen tension. HIF-1α expression was positive in 33 Pca and 9 PIN specimens, and the positive rate of HIF-1α was higher in distant metastasis patients than in patients without metastasis of prostate cancer (P<0.05), while there was no expression of HIF-1α in NP. The level of HIF-1α in PC-3M significantly increased with the decrease of oxygen tension (P<0.01). Overexpression of HIF-1α is the preliminary event of the formation of Pca, which may induce carcinoma into malignant phenotype. Thus it may serve as an early diagnosis marker and the novel target for Pca treatment.

Prognostic role of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with non-metastatic and metastatic prostate cancer:A meta-analysis and systematic review

Objective: To analyze data available in the literature regarding a possible prognostic value of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in prostate cancer (PCa) patients stratified in non-metastatic and metastatic diseases.Methods: A literature search process was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. In our meta-analysis, the pooled event rate estimated and the pooled hazard ratio were calculated using a random effect model.Results: Forty-two articles were selected for our analysis. The pooled risk difference for non-organ confined PCa between high and low NLR cases was 0.06 (95% confidence interval [CI]: −0.03-0.15) and between high and low PLR cases increased to 0.30 (95% CI: 0.16-0.43). In non-metastatic PCa cases, the pooled hazard ratio for overall mortality between high and low NLR was 1.33 (95% CI: 0.78-1.88) and between high and low PLR was 1.47 (95% CI: 0.91-2.03), whereas in metastatic PCa cases, between high and low NLR was 1.79 (95% CI: 1.44-2.13) and between high and low PLR was 1.05 (95% CI: 0.87-1.24).Conclusion: The prognostic values of NLR and PLR in terms of PCa characteristics and responses after treatment show a high level of heterogeneity of results among studies. These two ratios can represent the inflammatory and immunity status of the patient related to several conditions. A higher predictive value is related to a high NLR in terms of risk for overall mortality in metastatic PCa cases under systemic treatments.

Diagnosis and treatment of primary seminoma of the prostate:A case report and review of literature

BACKGROUND Primary seminoma of the prostate(PSP)is a rare type of extragonadal germ cell tumour that is easily misdiagnosed,owing to the lack of specific clinical features.It is therefore necessary for clinicians to work toward improving the accuracy of PSP diagnosis.CASE SUMMARY A 59-year-old male patient presenting with acute urinary retention was admitted to a local hospital.A misdiagnosis of benign prostatic hyperplasia led to an improper prostatectomy.Histopathology revealed PSP invading the bladder neck and bilateral seminal vesicles.Further radiotherapy treatment for the local lesion was performed,and the patient had a disease-free survival period of 96 mo.This case was analysed along with 13 other cases of PSP identified from the literature.Only four of the cases(28.6%)were initially confirmed by prostate biopsy.In these cases,imaging examinations showed an enlarged prostate(range 6-11 cm)involving the bladder neck(13/14).Of the 14 total cases,11(78.6%)presented typical pure seminoma cell features,staining strongly positive for placental alkaline phosphatase,CD117,and OCT4.The median age at diagnosis was 51(range 27-59)years,and patients had a median progression-free survival time of 48(range 6-156)mo after treatment by cisplatin-based chemotherapy combined with surgery or radiotherapy.The remaining three were cases of mixed embryonal tumours with focal seminoma,which had clinical features similar to those of pure PSP,in addition that they also had elevated serum alpha fetoprotein,beta-human chorionic gonadotropin,and lactose dehydrogenase.CONCLUSION PSP should be considered in patients younger than 60 years with an enlarged prostate invading the bladder neck.Further prostate biopsies may aid in proper PSP diagnosis.Cisplatin-based chemotherapy is still the main primary therapy for PSP.

Altered Expression of Connexin-43 and Impaired Capacity of Gap Junctional Intercellular Communication in Prostate Cancer Cells

Connexin-43 (Cx43) expression in prostate cancer (PCa) cells and the potency of gap junctional intercellular communication (GJIC) in the cells were investigated, with an attempt to elu- cidate the reason why the so-called 'bystander effect' mediated by thymidine kinase (TK) suicide gene therapy on PCa cells is not of significance and to explore the role of GJIC in PCa carcinogenesis. mRNA and protein expression of Cx43 in a PCa cell line PC-3m was detected by re- verse-transcription polymerase chain reaction (RT-PCR) and strapt-avidin-biotin-enzyme complex (SABC) immunohistochemical staining, and inherent GJIC of PC-3m cells was assayed by scrape-loading and dye transfer (SLDT) assay. The expression of Cx43 in human normal and malig- nant prostate tissues was determined by SABC immunohistochemistry as well. It was found that Cx43 mRNA and protein expression in PC-3m cells was slightly reduced as compared with positive controls and the location of Cx43 protein was aberrant in cytoplasm rather than on membrane. As- sessment of paraffin sections demonstrated that the expression of Cx43 protein in PCa cells was ab- normally located and markedly diminished as compared with normal prostatic epithelial ones, dis- playing a negative correlation to the pathological grade (χ2=4.025, P<0.05). Additionally, capacity of inherent GJIC in PC-3m cells was disrupted, which was semi-quantified as (+) or (-). It was indi- cated that both down-regulated expression of Cx43 mRNA and aberrant location of Cx43 protein par- ticipated in the mechanisms leading to deficient GJIC in PC-3m cells. Lack of efficient GJIC is a molecular event, which may contribute not only to limited extent of 'bystander effect', but also to initiation and progression of prostatic neoplasm.

Cognitive magnetic resonance imaging-ultrasound fusion transperineal targeted biopsy combined with randomized biopsy in detection of prostate cancer

BACKGROUND Prostate cancer(PCa)is one of the most common cancers among men.Various strategies for targeted biopsy based on multiparametric magnetic resonance imaging(mp-MRI)have emerged,which may improve the accuracy of detecting clinically significant PCa in recent years.AIM To investigate the diagnostic efficiency of a template for cognitive MRIultrasound fusion transperineal targeted plus randomized biopsy in detecting PCa.METHODS Data from patients with an increasing prostate-specific antigen(PSA)level but less than 20 ng/mL and at least one lesion suspicious for PCa on MRI from December 2015 to June 2018 were retrospectively analyzed.All patients underwent cognitive fusion transperineal template-guided targeted biopsy followed by randomized biopsy outside the targeted area.A total of 127 patients with complete data were included in the final analysis.A multivariable logistic regression analysis was conducted,and a two-sided P<0.05 was considered statistically significant.RESULTS PCa was detected in 66 of 127 patients,and 56 cases presented clinically significant PCa.Cognitive fusion targeted biopsy alone detected 59/127 cases of PCa,specifically 52/59 cases with clinically significant PCa and 7/59 cases with clinically insignificant PCa.A randomized biopsy detected seven cases of PCa negative on targeted biopsy,and four cases had clinically significant PCa.PSA density(OR:1.008,95%CI:1.003-1.012,P=0.001;OR:1.006,95%CI:1.002-1.010,P=0.004)and Prostate Imaging-Reporting and Data System(PI-RADS)scores(both P<0.001)were independently associated with the results of cognitive fusion targeted biopsy combined with randomized biopsy and targeted biopsy alone.CONCLUSION This single-centered study proposed a feasible template for cognitive MRIultrasound fusion transperineal targeted plus randomized biopsy.Patients with higher PSAD and PI-RADS scores were more likely to be diagnosed with PCa.

Screening of Differently Expressed Genes in Human Prostate Cancer Cell Lines with Different Metastasis Potentials

In order to screen the genes differentially expressed in two human prostate cancer cells with different metastasis potentials, suppression subtractive hybridization （SSH） was done twice on human prostate cancer cell line with high potential of metastasis PC3M-IE8 and its synogenetic cell line PC3M-2B4 with low metastasis potential. In the first subtraction PC3M-2B4 was used as tester and PC3M-1E8 as driver and the forward subtractive library was constructed. In the second one the tester and driver were interchanged and the reverse subtractive library was constructed. The screened clones of both libraries were sequenced and Gene Bank homology search was performed. Some clones were confirmed by quantitative real-time PCR. The results showed that two subtractive libraries containing 238 positive clones were constructed. Analysis of 16 sequenced clones randomly picked from two libraries showed that 4 differentially expressed gene fragments were identified as new EST with unknown functions. It was concluded that two subtractive libraries of human prostate cancer cell lines with different metastasis potentials were constructed successfully.

Reduced expression of α-tocopherol-associated protein is associated with tumor cell proliferation and the-increased risk of prostate cancer recurrence

Aim： To examine the impact and prognostic significance of α-tocopherol associated protein （TAP） expression in a series of prostate cancer patients. Methods： Tissues from 87 patients underwent radical prostatectomy were examined for TAP expression by immunohistochemistry. The relationships of the staining results, the clinic pathological characteristics and the recurrence times were analyzed. Results： Compared with the adjacent areas of normal and benign glands, immunoreactivity of TAP was reduced in areas of prostate cancer. A lower TAP-positive cell number per mm^2 of the largest cancer area （defined as TAP-PN） was associated with higher clinical stage （r = -0.248, P = 0.0322）. Inverse associations were found among the TAP-PN and positive lymph nodes （r = -0.231, P = 0.0325）, preoperative prostatespecific antigen （PSA） levels （r = -0.423, P = 0.0043）, tumor size （r = -0.315, P = 0.0210） and elevated tumor cell proliferation, which was indicated by the staining of Ki-67 （r = -0.308, P = 0.0026）. TAP-PN was a significant predictor of recurrence univariately （P = 0.0006）, as well as multivariately, adjusted for known markers including preoperative PSA, clinical stage, Gleason score, surgical margin, extra-prostatic extension, seminal vesicle invasion and lymph node metastasis （P = 0.0012）. Conclusion： Reduced expression of TAP was associated with the cell proliferation status of prostate cancer, adverse pathological parameters and the increased risk of recurrence.

Analysis on chromosome 8 heterozygosity loss in humanprostate carcinoma and high grade prostaticintraepithelial neoplasia

Objective: To analysis the chromosome 8 heterozygosity loss in human prostate carcinoma and high grade prostatic intraepithelial neoplasia. Methods: Pure DNA was obtained from prostate neoplasms and normal tissues by tissue microdissection. The chromosome 8 heterozygosity loss was detected by PCR based micro-satellite polymorphism analysis technique using 14 pairs of microsatellite primers in 10 samples of prostate carcinoma and 10 samples of high grade prostatic intraepithelial neoplasia. Results: There were different frequencies of chromosome 8 heterozygosity loss in 10 samples of prostate carcinoma. 8p23.1-p23.2 and p21-p22 were two high frequency heterozygosity loss regions. Chromosome 8 heterozygosity loss was detected in 3 samples of high grade prostatic intraepithelial neoplasia. Conclusion: There were high frequency heterozygosity loss regions on chromosome 8 of prostate carcinoma, located at 8p23.1-p23.2 and p21-p22. The high grade prostatic intraepithelial neoplasia and prostate carcinoma share the same allelic loss on 8p. Tumor suppressor genes located at these two regions may be potentially involved in the initiation and progression of prostate carcinoma.

Effect of androgen withdrawal on activation of ERKs and expression of cell cycle regulation molecules in human prostate carcinoma cells

Objective: To explore the possible mechanisms of growth regression of human androgen dependent prostate carcinoma cells caused by androgen withdrawal. Methods: After 24 h of treatment with 1 × 10-9 mol/L dihydrotestosterone (DHT), the expression of phosphorylated ERK proteins and cell cycle regulation molecules including CDK2, CDK4, CDK6 and P27kip1 in human androgen dependent prostate carcinoma cell line LNCaP was measured by Western blot analysis 0 h, 8 h and 24 h of after androgen withdrawal. Human androgen independent prostate carcinoma cell line PC-3 was also examined as control. Results: Down-regulation of phosphorylated ERK, CDK2, CDK4 and CDK6 and up-regulation of P27kip1 were found initially in LNCaP cell line 8 h after androgen withdrawal. The levels of phosphorylated ERK and CDKs decreased continuously and reached the lowest after 24 h, while continuous elevation of P27kip1 was detected thereafter to 24 h. No expression change of phosphorylated ERK, CDKs and P27kip1 were detected in PC-3 cell line. Conclusion: The androgen withdrawal can cause ERKs activation decrease and cell cycle regulation molecules changes, which may be one of the mechanisms for inhibited growth of androgen dependent prostate carcinoma after androgen ablation by either operative or medicine methods.

Commentary on: Mobley AJ, Lam YW, Lau KM, Pais VM, Lesperance JO, Steadman B, et al. Monitoring the serological Proteome Colon, the latest modality in prostate cancer detection. J Urol 2004; 172: 331-7.

This manuscript examines the utility, utilizing the Ciphergen Protein Biosystem II, to develop a fingerprint for the diagnosis of prostate cancer. The investigators compared samples from control individuals as well as those with prostate cancer. In doing so, they utilize several chip platforms on which to examine the resulting

Individualized prostate biopsy strategy for Chinese patients with different prostate-specific antigen levels

Aim： To evaluate the best individualized prostate biopsy strategies for Chinese patients with suspected prostate cancer. Methods： The present study included 221 Chinese patients who underwent transrectal ultrasound guided prostate biopsies for the first time. All patients underwent the same 10-core biopsy protocol. In addition to the Hodge sextant technique, four more biopsies were obtained from the base and middle regions of bilateral peripheral zones. The differences between 10-core and sextant strategies in cancer detection among patients with different prostate specific anitgen （PSA） levels were evaluated. The relationship between PSA level, number of positive biopsy cores and organ-confined cancer rate in prostate cancer patients was also analyzed. Results： The overall prostate cancer detection rate was 40.7% in the 221 patients. The 10-core strategy increased cancer detection by 6.67% （6/90） in our patients （P 〈 0.05）. The increased cancer detection rates decreased significantly when the patient PSA level increased from 0-20 ng/mL to 20.1-50 ng/mL and 〉 50 ng/mL （P 〈 0.01）. The number of positive biopsy cores in prostate cancer patients increased significantly with increasing patient PSA level （P 〈 0.01）. The rate of organ-confined prostate cancer decreased significantly with increasing patient PSA level （P 〈 0.01）. Conclusion： The extended 10- core strategy is recommended for Chinese patients with PSA 〈 20 ng/mL and the sextant strategy is recommended for those with PSA〉 50 ng/mL. For patients with PSA ranging from 20.1 ng/mL to 50 ng/mL, the 10-core strategy should be applied in patients with life expectancy 〉 10 years and the sextant strategy should be applied in those with life expectancy 〈 10 years. （Asian J Androl 2008 Mar; 10： 325-331）

Stroma-epithelium crosstalk in prostate cancer

The critical role played by stroma-epithelium crosstalk in carcinogenesis and progression of prostate cancer has been increasingly recognized. These interactions are mediated by a variety of paracrine factors secreted by cancer cells and/or stromal cells. In human prostate cancer, reactive stroma is characterized by an increase in myofibroblasts and a corresponding amplification of extracellular matrix production and angiogenesis. Permanent genetic mutations have been reported in stromal cells as well as in tumour cells. Transforming growth factor-J3, vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor signalling pathways are involved in the process of angiogenesis, whereas hepatocyte growth factor, insulin-like growth factor-l, epidermal growth factor, CXC12 and Interleukin-6 play active roles in the progression, androgen-independent conversion and distal metastasis of prostate cancer. Some soluble factors have reciprocal interactions with androgens and the androgen receptor （AR）, and can even activate AR in the absence of the androgen ligand. In this article, we review the complex interactions between cancer cells and the surrounding microenvironment, and discuss the potential therapeutic targets in the stromal compartment of prostate cancer.

An elevated serum miR-141 level in patients with bone-metastatic prostate cancer is correlated with more bone lesions

The skeleton is the most common metastatic organ in patients with prostate cancer （PCa）. Non-invasive biomarkers that can facilitate the detection and monitoring of bone metastases are highly desirable. We designed this study to assess the expression patterns of serum miR-141 in patients with bone-metastatic PCa. Serum samples were collected to measure the miR-141 level in 56 patients, including six with benign prostatic hyperplasia （BPH）, 20 with localized PCa and 30 with bone-metastatic PCa （10 with hormone-naive PCa, 10 with hormone-sensitive PCa and 10 with hormone-refractory PCa）. A bone scan was performed for each patient with PCa to assess the number of bone lesions. The quantification of serum miR-141 levels was assayed by specific TaqMan qRT-PCR. The results showed that serum miR-141 levels were elevated in patients with bone metastasis （P〈O.O01）. There was no statistically significant difference in the serum miR-141 levels between patients with BPH and patients with localized PCa. Using Kendall＇s bivariate correlation test, both the Gleason score and the number of bone-metastatic lesions were found to correlate with serum miR-141 levels （P=0.012 and P〈O.O01, respectively）. The serum miR-141 level was found to be positively correlated with alkaline phosphatase （ALP） level in patients with skeletal metastasis, using Pearson＇s bivariate correlation test. No relationship was found between the serum miR-141 level and the serum prostate-specific antigen （PSA） level. We concluded that serum miR-141 levels are elevated in patients with bone-metastatic PCa and that patients with higher levels of serum miR-141 developed more bone lesions. Furthermore, serum miR-141 levels are correlated with serum ALP levels but not serum PSA levels.

Radioiodine therapy for castration-resistant prostate cancer following prostate-specific membrane antigen promoter-mediated transfer of the human sodium iodide symporter

Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of the thyroid-specific expression of the human sodium iodide symporter （hNIS）. Here, we explore the efficacy of a novel form of gene therapy using prostate-specific membrane antigen （PSMA） promoter-mediated hNIS gene transfer followed by radioiodine administration for the treatment of castration-resistant prostate cancer （CRPC）. The androgen-dependent C33 LNCaP cell line and the androgen-independent C81 LNCaP cell line were transfected by adenovirus. PSMA promoter-hNIS （Ad.PSMApro-hNIS） or adenovirus.cytomegalovirus-hNIS containing the cytomegalovirus promoter （Ad.CMM-hNIS） or a control virus. The iodide uptake was measured in vitro. The in vivo iodide uptake by C81 cell xenografts in nude mice injected with an adenovirus carrying the hNIS gene linked to PSMA and the corresponding tumor volume fluctuation were assessed. Iodide accumulation was shown in different LNCaP cell lines after Ad.PSMApro-hNIS and Ad.CMV-hNIS infection, but not in different LNCaP cell lines after adenovirus.cytomegalovirus （Ad.CMV） infection. At each time point, higher iodide uptake was shown in the C81 cells infected with Ad.PSMApro-hNIS than in the C33 cells （P 〈 0.05）. An in vivo animal model showed a significant difference in 1311 radioiodine uptake in the tumors infected with Ad.PSMApro-hNIS, Ad.CMV-hNIS and control virus （P 〈 0.05） and a maximum reduction of tumor volume in mice infected with Ad.PSMApro-hNIS. These results show prostate-specific expression of the hNIS gene delivered by the PSMA promoter and effective radioiodine therapy of CRPC by the PSMA promoter-driven hNIS transfection.

KAI1/CD82 gene expression in benign prostatic hyperplasia and late-stage prostate cancer in Chinese

Aim: To evaluate KAII/CD82 expression in Chinese patients with benign prostatic hyperplasia (BPH) and late-stage carcinoma of prostate (CaP). Methods: Thirty Chinese patients with benign prostatic hyperplasia and 34 withCaP (adenocarcinoma clinical stage C and D) were analyzed by means of immunohistochemical methods. Results:The KAII/CD82 expression in BPH tissue was all positive, which was uniformly located on the glandular cell mem-brane at the cell-to-cell borders, but KAII/CD82 expression in metastasis CaP tissues was either significantly lower thanthat of BPH or negative, and the immunostaining pattern was not continuous. In late-stage CAP KAII/CD82 expressionwas correlated inversely to the pathological grade ( P < 0.05), but not to clinical stage ( P > 0.05). Conclusion:The authors believe that decreased and negative KAII/CD82 expression in late-stage CaP may be related to tumor pro-gression and metastasis, and appears to be a prognostic marker.

Clinical significance of the leptin and leptin receptor expressions in prostate tissues

Aim： To evaluate the expression of leptin and leptin receptor in benign prostatic hyperplasia （BPH） and prostate cancer （PCa）, and to investigate whether they are associated with the development and progression of PCa. Methods： hnmunohistochemical staining was performed to examine the expression of leptin and leptin receptor in BPH and PCa. PCa was divided into three groups： localized PCa, locally advanced PCa and metastatic PCa. The positive staining was identified and the percentage of the positive staining was graded. We also assessed the relationship between both the Gleason score and body mass index （BMI） and PCa. Results： The percentage of the leptin expression in PCa was significantly higher than that in BPH （P 〈 0.01）. For the PCa group, the expressed levels of leptin showed a considerable correlation with localized PCa and metastatic PCa （P 〈 0.05）. Leptin receptor, however, did not reveal a definite difference between BPH and PCa. The expression of leptin indicated a significant difference between well-differentiated PCa （Gleason score ≤6） and poorly differentiated PCa （Gleason score 8-10） （P 〈 0.05）. The relation between the leptin expression level in PCa and the BMI was not remarkable （P = 0.447）. Conclusion： Our results suggest that leptin might have a promoting effect on the carcinogenesis and progression of PCa.

Cyclooxygenase-2 expression is dependent upon epidermal growth factor receptor expression or activation in androgen independent prostate cancer

Aim： To investigate the expression of cyclooxygenase-2 （COX-2） and epidermal growth factor receptor （EGFR） and the possible mechanism in the development in androgen independent prostate cancer （AIPC）. Methods： Immunohistochemistry was performed on paraffin-embedded sections with goat polyclonal against COX-2 and mouse monoclonal antibody against EGFR in 30 AIPC and 18 androgen dependent prostate cancer （ADPC） specimens. The effect of epidermal growth factor （EGF） treatments on the expression of COX-2 and signal pathway in PC-3 and DU-145 cells was studied using reverse transcription-polymerase chain reaction （RT-PCR） and Western blot analysis. ELISA was used to measure prostaglandin E2 （PGE2） levels in the media of PC-3 and DU-145 incubated with EGF for 24 h. Results： COX-2 was positively expressed in AIPC and ADPC, which were predominantly in endochylema of prostate cancer （PCa） cells. Intense staining was seen in AIPC （80%） and in ADPC （55.5%）, but there was no significant association between the two groups. EGFR expression was also positive in the two groups （61.8% in ADPC and 90% in AIPC, P 〈 0.01）. A significant association was found between EGFR expression and a higher Gleason score （P 〈 0.05） or tumor stage （P 〈 0.05）. The expression of PGE2 was increased in PC-3 and DU-145 cells after being incubated with EGF. Both p38MAPK and PI-3K pathway were involved in the PC-3 cell COX-2 upregulation course. In DU- 145, only p38MAPK pathway was associated with COX-2 upregulation. Conclusion： EGFR activation induces COX-2 expression through PI-3K and/or p38MAPK pathways. COX-2 and EGFR inhibitors might have a cooperative anti-tumor effect in PCa.

Prostate calculi in cancer and BPH in a cohort of Korean men：presence of calculi did not correlate with cancer risk

Prostatic calculi are common and are associated with inflammation of the prostate. Recently,it has been suggested that this inflammation may be associated with prostate carcinogenesis. The aim of this study was to investigate the relationship between prostatic calculi and prostate cancer （PCa） in prostate biopsy specimens. We retrospectively analyzed 417 consecutive patients who underwent transrectal ultrasonography （TRUS） and prostate biopsies between January 2005 and January 2008. Based on the biopsy findings,patients were divided into benign prostatic hyperplasia and PCa groups. TRUS was used to detect prostatic calculi and to measure prostate volume.The correlations between PCa risk and age,serum total PSA levels,prostate volume,and prostatic calculi were analyzed. Patient age and PSA,as well as the frequency of prostatic calculi in the biopsy specimens,differed significantly between both the groups （P〈0.05）. In the PCa group,the Gleason scores （GSs） were higher in patients with prostatic calculi than in patients without prostatic calculi （P = 0.023）. Using multivariate logistic regression analysis,we found that patient age,serum total PSA and prostate volume were risk factors for PCa （P = 0.001）,but that the presence of prostatic calculi was not associated with an increased risk of PCa （P = 0.13）. In conclusion,although the presence of prostatic calculi was not shown to be a risk factor for PCa,prostatic calculi were more common in patients with PCa and were associated with a higher GS among these men.

Increased expressions of vascular endothelial growth factor(VEGF),VEGF-C and VEGF receptor-3 in prostate cancer tissue are associated with tumor progression

Aim： To investigate the differences in microvessel densities （MVD） and the expressions of vascular endothelial growth factor （VEGF）, VEGF-C and VEGF receptor-3 （VEGFR-3） between prostate cancer （PCa） tissues and adjacent benign tissues, and to explore the correlations among MVD, Jewett-Whitmore staging, Gleason scores and expressions of VEGF, VEGF-C and VEGFR-3 in the progression of PCa. Methods： An immunohistochemical approach was adopted to detect the expressions of CD34, VEGF, VEGF-C and VEGFR-3 in both cancer areas and peripheral benign areas of 71 primary prostatic adenocarcinoma specimens. A statistic analysis was then performed according to the experimental and clinic data. Results： Significantly upregulated expressions of VEGF, VEGF-C and VEGFR-3 were all found in malignant epithelium/cancer cells compared with adjacent benign epithelium （P 〈 0.01）. Patients in stage D had a significantly higher score than patients in stage A, B or C when comparing the expression of VEGF-C or VEGFR-3 in the tumor area （P 〈 0.01）. In addition, significant correlations were observed between Jewett-Whitmore staging and VEGF-C （rs = 0.738, P 〈 0.01）, clinical staging and VEGFR-3 （rs = 0.410, P 〈 0.01）, VEGF-C and Gleason scores （rs = 0.401, P 〈 0.01）, VEGFR-3 and Gleason scores （rs = 0.581, P 〈 0.001） and MVD and VEGF （rs = 0.492, P 〈 0.001）. Conclusion： Increased expressions of VEGF and VEGF-C were closely associ- ated with progression of PCa. The main contribution of increased VEGF expression for PCa progression was to upregulate MVD, which maintained the growth advantage of tumor tissue. However, the chief role of increased expressions of VEGF-C and VEGFR-3 was to enhance lymphangiogenesis and provide a main pathway for cancer cells to disseminate. （Asian J Androl 2006 Mar; 8： 169-175）

Serum prostate-specific antigen value adjusted for non-cancerous prostate tissue volume in patients undergoing radical prostatectomy： a new predictor of biochemical recurrence in localized or locally advanced prostate cancer

The aim of this study was to investigate the significance of serum prostate-specific antigen （PSA） value adjusted for total tumor volume （PSA/tumor volume） and serum PSA value adjusted for non-cancerous prostate tissue volume （NCPV） （PSA/NCPV） as a predictor of pathological findings and clinical outcome after radical prostatectomy. Clinical and pathological data of 407 patients （median age： 66.5 years; range： 41.8--85.7 years） were reviewed retrospectively. The median follow-up period was 18. I months （range： 1.0- 107.8 months）. Biochemical recurrence was defined as detectable PSA levels （greater than 0.2 ng ml-1） and the time of biochemical recurrence was taken to be the first time PSA became detectable. In the multivariate model, PSA/NCPV was an independent predictor of extracapsular extension and positive surgical margin （P〈O.05）, but PSA/tumor volume was not. Kaplan-Meier curves revealed that PSA/NCPV correlated with biochemical recurrence-free survival （P〈O.O01; log-rank test） but PSA/tumor volume did not （P=0.275; log-rank test）. PSA/NCPV was also a significant independent prognostic factor for biochemical recurrence-free survival on multivariate Cox proportional hazard analysis （P=0.004, relative risk=2.42）. Our findings suggest that PSA/NCPV is associated independently with extracapsular extension and surgical margin status and may be an independent prognostic variable of PSA recurrence after radical prostatectomy.