不同前列腺组织中雄激素受体的表达研究

目的:研究雄激素受体(AR)在正常前列腺、良性前列腺增生(BPH)和前列腺癌(PCa)组织中的表达,探讨AR与BPH和PCa的关系。方法:采用实时定量PCR、免疫荧光和组织蛋白电泳方法,分析15例正常前列腺、20例BPH与40例PCa标本中AR的表达情况。结果:实时定量PCR和组织蛋白电泳检测BPH组织与正常前列腺组织中AR的表达量差异无统计学意义(P>0.05)。但免疫荧光检测发现BPH组织中AR蛋白表达量增高。3种方法检测PCa组织中AR表达量较正常前列腺组织和BPH组织增高(P<0.05)。高分化PCa的AR表达比低分化PCa高(P<0.05)。随着临床分期的增高,AR的表达降低(P<0.05),激素非依赖性前列腺癌(HRPC)组织中AR表达最低。结论:AR在PCa组织中的表达较正常前列腺和BPH组织中增高,AR的表达与PCa的分级、分期相关。     

Reduced circulating androgen bioactivity in patients with prostate cancer

BACKGROUND: Previous studies on immunoreactive androgen levels in serum have revealed equivocal associations with the risk of prostate cancer (CaP). The aim of this study was to compare serum biological androgen activity between men with newly diagnosed CaP and age-matched men with benign prostatic hyperplasia (BPH). METHODS: Caucasian men with newly diagnosed, untreated CaP (n = 101) and age-matched patients with BPH (n = 103) were investigated. Serum androgen bioactivity (ABA) levels were measured using a recently developed recombinant cell bioassay. RESULTS: In comparison to men with BPH, CaP patients with Gleason score >or=8 (n = 16) had lower serum ABA (P < 0.05), and patients with Gleason score or=8 (P = 0.07) displayed suppressed ABA levels in relation to serum testosterone. As the entire group, men with CaP (n = 101) had significantly lower serum ABA than age-matched men with BPH (n = 103): median 3.0 nM (range, 0.8-6.4 nM) versus 3.2 nM (range, 0.8-7.9 nM) testosterone equivalents, respectively (P < 0.005). By contrast, serum immunoreactive testosterone and SHBG concentrations and free androgen indices did not differ significantly between the two groups. CONCLUSIONS: Patients with CaP have lower serum ABA than controls with BPH, and men with low or high Gleason score display suppressed circulating ABA-to-testosterone ratio. These features may reflect interaction between variables such as the degree of tumor differentiation and tumor volume with androgen metabolism.     

前列腺组织中睾酮含量状态与前列腺生理和增生的关系

目的：检测前列腺组织中总睾酮、结合睾酮和游离睾酮的含量，并分析其与前列腺生理和组织增生的关系。方法：14例相对年轻正常前列腺组织、22例良性前列腺增生(BPH)组织和ll例相应年龄段前列腺对照组织，制备组织脑浆和胞核提取液，乙醚萃取分离游离和结合睾酮，采用^125I标记睾酮放免试剂盒测定睾酮的含量。结果：前列腺组织中睾酮存在结合和游离2种状态，结合态为多，约占2/3；3组比较，总睾酮、游离和结合睾酮含量无显著差异。结论：前列腺组织中睾酮存在游离和结合二种状态，共同维持局部高水平的总睾酮含量，并且随年龄增长而保持稳定，有利于睾酮在前列腺生理和组织增生过程中的作用。     

MRS对可疑前列腺癌鉴别诊断价值的研究

目的探讨3.0T三维磁共振波谱成像(MRS)影像学检查对可疑前列腺癌患者鉴别诊断的价值。方法收集2013年1月至2014年4月在本院就诊怀疑前列腺癌并行MRI及MRS检查患者的临床资料,根据病理结果分为前列腺癌(Pca)组、前列腺增生(BHP)组。观察两组患者MRS参数胆碱(Choline,Cho)+肌酸(Creatine,Cre)/枸橼酸盐(Citrate,Cit)值(CC/C),并与病理Gleason评分(G)对照;评估MRS对Pca诊断效能,分析CC/C值与病理分级的关系。结果 32例Pca的CC/C平均值为2.52±1.42,而52例BHP的为0.70±0.77(P0.01),MRS对前列腺癌诊断效率:灵敏度87.5%、特异度86.3%、阳性预测值80%、阴性预测值91.6%;G≤7患者CC/C平均值为1.81±1.09,G7患者为3.38±0.98(P0.01)。结论 MRS的应用有助于对可疑前列腺癌患者进行鉴别诊断,且其参数对前列腺癌病理分级有参考意义。     

Androgen receptor expression is associated with prostate cancer‐specific survival in castrate patients with metastatic disease

Study Type – Aetiology (case series)
Level of Evidence 4

OBJECTIVE

To investigate whether baseline (before treatment) clinical variables and tumour specimen characteristics (including the androgen receptor, AR) from patients with castrate‐resistant metastatic prostate cancer can be used to predict the time to prostate cancer‐specific mortality and overall survival, as AR levels in prostate cancer have been associated with disease progression, including prostate‐specific antigen (PSA) recurrence and systemic metastasis.

PATIENTS AND METHODS

Haematoxylin and eosin (H&E) slides/blocks and outcome data from a 104 castrate patients with metastatic disease (43 prostatectomy and 61 prostate needle biopsy samples), were independently reviewed; H&E morphometry and quantitative immunofluorescence were used to assess the samples. Sections were analysed with a multiplex quantitative immunofluorescence (IF) assay for cytokeratin‐18 (epithelial cells), 4′,6‐diamidino‐2‐phenylindole (nuclei), p63/high molecular weight keratin (basal cells), AR and α‐methyl CoA‐racemase. Images were acquired with spectral imaging software and processed for quantification with IF algorithms.

RESULTS

The median follow‐up was 12 years from diagnosis; 49 men (47%) baseline PSA levels of ≥ 20 ng/mL, 55 (53%) had a Gleason sum of 8, 63 (60%) died from the disease and 40% were alive (censored). In all, 66 patients had evaluable IF features, and the association with outcome was evaluated by univariate Cox modelling and support‐vector regression. PSA was the only clinical variable associated with outcome (concordance index, CoI, 0.41; P < 0.05, log‐rank test). The amount of AR present within tumour nuclei (regardless of tissue provenance and primary treatment) significantly correlated with a greater risk of a shorter time to prostate cancer‐specific mortality (CoI 0.36; P < 0.05 log‐rank test). There were no H&E features that correlated with mortality.

CONCLUSION

By univariate analysis, increased nuclear AR expression in either the diagnostic biopsy and/or radical prostatectomy specimen, from patients with advanced disease, was associated with a reduced time to prostate cancer‐specific mortality.     

Longitudinal PSA changes in men with and without prostate cancer: assessment of prostate cancer risk

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.     

Oxidised low‐density lipoprotein,a possible distinguishing lipid profile biomolecule between prostate cancer and benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) share common conditions such as lower urinary tract symptoms (LUTS) and dyslipidaemia. Whether an extensive lipid profile analysis could discriminate between BPH and PCa was the objective. Thirty‐six (36) BPH and twenty (20) PCa outpatients of a urology clinic plus forty (40) controls without LUTS, but normal PSA, were recruited. Body mass index (BMI), lipid profile (total cholesterol [CHOL], triglycerides [TG], high‐density lipoprotein [HDL], very‐low‐density lipoprotein [VLDL], low‐density lipoprotein [LDL] and Castelli's risk index I [CR I] [TC/HDL]), oxidised LDL, apolipoprotein E, ceramide and PSA were determined. Mean ages for BPH, PCa and control were 69 ± 13, 67 ± 10 and 53 ± 7 years respectively. Most parameters apart from BMI and HDL were significantly different compared to the control group. oxLDL for BPH versus control, PCa versus control and BPH versus PCa was significant (p < 0.001, p = 0.02 and p < 0.001 respectively). Ceramide showed significant group differences. Between BPH and PCa, total cholesterol, LDL and Apo E were significantly different (p = 0.00, p = 0.01 and p = 0.03 respectively). Apo E could potentially be a discriminating biomarker. Receiver operating characteristic curves for TPSA, Apo E and oxLDL demonstrated sensitivity of 69.44 and specificity of 88.24 for oxLDL, hence more discriminatory.     

Obesity and prostate enlargement in men with localized prostate cancer

Study Type – Prevalence (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Obesity is associated with prostate enlargement in men without prostate cancer. This study demonstrates an association between obesity and prostate enlargement in men with prostate cancer, and leads to possible implications for prostate cancer screening and diagnosis.

OBJECTIVE

? To determine if obesity is associated with prostate size in men with prostate cancer.

PATIENTS AND METHODS

? We examined preoperative body mass index (BMI) and whole prostate weight in a cohort of 16 325 patients undergoing radical prostatectomy for localized prostate cancer from 1975 to 2008 at a single institution. ? We used multivariable regression modelling adjusting for age, year of surgery, preoperative serum prostate‐specific antigen (PSA), pathological stage and Gleason grade.

RESULTS

? Of the entire cohort, 13 343 (82%) patients had a prostate weight of at least 40 g. These men were older (P < 0.001), had a higher preoperative BMI (P < 0.002), higher preoperative PSA (P < 0.001), and were more likely to have pT2 disease (P < 0.001). ? In multivariable regression, preoperative BMI was associated with increased prostate weight: for each 1 kg/m² increase in BMI, prostate weight increased by 0.45 g (95% CI 0.35–0.55, P‐trend < 0.001). ? Compared with men with BMI < 25 kg/m², men with a BMI ≥35 kg/m² had a 40% (odds ratio 1.40, 95% CI 1.01–1.95) increased risk of prostate weight of at least 40 g and a 70% (odds ratio 1.70, 95% CI 1.32–2.20) increased risk of prostate weight of at least 50 g.

CONCLUSIONS

? In men with localized prostate cancer, obesity is associated with an increased risk of prostate enlargement. ? These data validate other observations linking obesity with prostate enlargement and may have important ramifications for prostate cancer diagnosis in obese men.     

雄激素受体CAG重复多态性与BPH和PCa相关性的meta分析

目的:通过meta分析探讨雄激素受体(AR)基因CAG重复多态性与良性前列腺增生(BPH)和前列腺癌(PCa)发病风险的关系。方法:检索国内外大型数据库发表的AR基因CAG重复多态性与BPH和PCa相关性的文献,基于异质性检验的结果,分别采用M-H固定效应模型和随机效应模型合并比值比(OR)效应量,采用Begg和Egger偏倚分析评估本项meta分析的发表偏倚,系统评价AR基因CAG重复多态性与BPH和PCa发病风险的关系,并按种族进行分层分析。结果:检索获得文献29篇,最终纳入4篇符合条件的文献,累计BPH患者485例、PCa患者767例、正常对照组709例。BPH组和正常对照组间不存在异质性,M-H固定效应模型合并效应量后提示低CAG重复多态性与BPH无相关性。PCa组和BPH组及对照组间均存在异质性,随机效应模型提示低CAG重复多态性与PCa的风险呈正相关(OR PCa/对照=1.45,OR PCa/BPH=1.86,OR PCa/(BPH+对照)=1.66)。种族分层的亚组分析提示,低CAG重复多态性与PCa发病风险在种族间存在差异。Begg和Egger偏倚分析显示各组比较中均无显著发表偏倚。结论:AR受体低CAG重复多态性与PCa发病风险呈正相关,与BPH发病风险无相关性。     

精浆前列腺特异性抗原检测的临床意义

目的检测清浆PSA与F-PSA,并探讨其在临床上的应作价值。方法 用化学发光标记免疫技术稀释检测法,检测30例健康男性组,30例BPH患者组和15例PCa患者组精浆PSA与F-PSA浓度水平,用回收试验和重复性试验和重复性试验来验证检测的正确性。并采用计算机SAS软件包(version 8.2)进行统计分析。结果(1)健康男性组精浆中PSA浓度范围为302800～1340000ng/ml,(587240±234394)ng/ml。F-PSA浓度范围为212800～778000ng/ml,(419720±148637)ng/ml。比血清PSA及F-PSA高出几十万倍。(2)BPH组精浆PSA与F-PSA浓度略高于正常对照组,但差异无统计学意义。(3)Pac组精浆PSA及F-PSA浓度低于正常对照组及BPH组,差异有高度显著性,有统计学意义。(4)前列腺癌患者精浆PSA与肿瘤分期Spearman和Kendall等级相关分析结果显示前列腺癌患者精浆PSA含量与肿瘤分期间相关不显著。结论 检测精浆PSA与F-PSA对前列腺癌与良性前列腺增生的鉴别有一定的临床应用价值。     

TRPC6在人良性与恶性前列腺组织中的表达

观察瞬时受体电位通道C6（TRPC6）在人良性与恶性前列腺组织及前列腺癌细胞系中的表达,进一步探讨TRPC6的表达与前列腺癌分期、分级及激素依赖性的关系。利用免疫组织化学技术,检测发现45．0％的前列腺增生和86．6％的前列腺癌病例表达TRPC6,两者比较有显著性差异沪〈0．01）。TRPC6的表达与前列腺癌分级和前列腺外转移有关（P〈0．01）。前列腺癌分期增高,TRPC6表达增多,但在T2、T3和DT4期肿瘤病例中,TRPC6表达无显著差异。此外TRPC6在激素依赖性前列腺癌与激素非依赖性前列腺癌中的表达也无显著差异。应用RT-PCR及Westernblot,检测到TRPC6在前列腺癌细胞系中的表达。本研究发现,TRPC6在良性与恶性前列腺组织及前列腺癌细胞系中表达。TRPC6的表达与前列腺癌的组织分级、Gleason评分及前列腺外转移有关。     

前列腺增大与性功能障碍的临床相关性

前列腺直肠指检可以为了解前列腺的生长状态和发现可疑的外周结节提供有用的信息。本实验的目的在于研究经直肠指检发现前列腺增大与性功能障碍（SD）的临床和生化相关性。对一组2379例患者进行回顾性分析。样本（n=1823；平均年龄为54．7±11．4岁）选自无明显前列腺疾病的人群。对几个指标进行了研究。经过校正后，经直肠指检发现的前列腺增大与代谢终合症（HR=1．346[1．129．1．759]；P=0．030）、二型糖尿病（HR=I．489[1．120．1．980]；P=0．006）、低密度脂蛋白胆固醇增高（〉100mgdl^-1；HR=1．354[1．018—1．801]；P=0．037）及平均血压增高（HR=1．017n．007．1．027]每增加1mmHg；P=0．001）的高发病存在相关性。因此，前列腺增大也与动脉性勃起功能障碍及其他的男科疾病的高发病相关，如精索静脉曲张和早泄。在前列腺增大的人群中PSA水平显著高于非前列腺增大的人群（HR=3-318[2．304；4．799]每增加1单位PSA；P〈0．0001）。根据不同标准，动脉性ED也与PSA水平升高相关。结论：我们的研究结果表明对于ED患者，进行前列腺大小的检查，包括临床（DRE）和生化（PSA）检查是必要的，以此能对患者的性功能障碍和代谢及心血管背景有全面的了解。     

Changes in serum prostate-specific antigen following prostatectomy in patients with benign prostate hyperplasia

PURPOSE: To investigate how prostatectomy for patients with benign prostate hyperplasia (BPH) affected the serum prostate-specific antigen (PSA) levels. METHODS: In 193 patients who underwent prostatectomy for BPH, serum PSA levels were measured before and three months after the operation. The total prostate weight measured by transrectal ultrasonography (TRUS) and the weight of the surgical specimen were examined in relation to the pretreatment PSA value and the changes in PSA levels after the operation. RESULTS: The transition zone volume measured by TRUS could well estimate the weight of the surgical specimen in patients who underwent subcapsular prostatectomy and transurethral resection of the prostate. The concentration of preoperative serum PSA showed a significant correlation with the prostatic volume and with the transition zone volume. Removal of 1 g of BPH tissue reduced serum PSA levels by an average of 0.18 ng/mL. The change in serum PSA levels after the prostatectomy correlated with the total prostatic gland volume and with the transition zone volume. CONCLUSIONS: The elevated PSA levels in patients with BPH were caused by the enlargement of the transition zone. After the resection of the adenoma, PSA levels should be expected to decrease to the normal range.     

Survival of patients with hormone refractory prostate cancer in the prostate specific antigen era

PURPOSE: The historically reported 12 to 18-month duration of survival of patients with hormone refractory prostate cancer is not consistent with current clinical experience. Furthermore, to our knowledge patient survival after serum prostate specific antigen (PSA) progressively increases from a nadir despite castrate testosterone has not been previously reported. For this reason we studied overall survival and the clinical variables that influence survival in patients with hormone refractory prostate cancer. MATERIALS AND METHODS: The study focused on 254 patients with prostate cancer on androgen deprivation therapy. Hormone refractory prostate cancer was defined as the first in a series of PSA elevations despite castrate levels of testosterone. The duration of survival in the hormone refractory phase was calculated from the date of the first PSA elevation to the date of death. RESULTS: Median survival after hormone refractory prostate cancer developed in patients initially staged with and without skeletal metastasis was 40 and 68 months, respectively. Six of more than 25 input variables were retained as significant in the final Cox model. Variables associated with longer survival were lower nadir PSA, younger age, higher pretreatment testosterone, no history of obstructive uropathy, no history of tobacco use (past or current) and lower alkaline phosphatase. CONCLUSIONS: Historical reports of survival in hormone refractory prostate cancer underestimate current survival observations. The likely explanations of this observation include delayed enrollment in clinical trials from which most survival data are derived, PSA lead time in staging and improved supportive care. Models predicting survival in patients with hormone refractory prostate cancer should consider multiple variables.     

前列腺癌与良性前列腺增生患者血清细胞因子差异的蛋白质组学研究

目的:探讨前列腺癌与BPH患者血清细胞因子的差异,为前列腺癌的早期诊断提供血清蛋白质组学依据。方法:应用细胞因子抗体芯片技术,对12例PSA在灰度范围内、经穿刺活检证实的前列腺癌和BPH患者的血清进行细胞因子芯片检测。结果:筛选出19种有明显差异表达的蛋白质(差异>1.5倍),其中前列腺癌组表达明显上调的有IL-3、IL-6、IL-16等16个细胞因子,表达明显下调的有Fas/TNFRSF6、TRALR-3、IGFBP-6等3个细胞因子。其中多个蛋白与细胞的转录、增殖、信号转导和细胞凋亡等生物过程有关。结论:细胞因子抗体芯片技术能够对较小血清样本同时检测多个指标,能够筛选出与癌细胞生物学行为密切相关的"关键细胞因子",有助于寻找用于前列腺癌早期诊断、判断疗效和预后的分子标志物。     

Detection of prostate cancer in males with prostatism

The present study was designed to compare the prostate cancer detection rate, sensitivity, specificity, and positive predictive value of digital rectal examination (DRE) and serum prostatic specific antigen (PSA) in a consecutive cohort of males presenting to a single institution with clinically significant prostatism. The study population was comprised of 224 consecutive males with clinically significant prostatism referred to the Prostate Center at the Medical College of Wisconsin between June 1990 and December 1991. Subjects were considered to have clinically significant prostatism if they elected to pursue medical or surgical therapy following exclusion of carcinoma of the prostate. The initial examination consisted of a Boyarsky symptom score assessment, DRE, uroflowmetry, postvoid residual determination, serum PSA level, and transrectal prostatic ultrasonography. Subjects with an abnormality on DRE or serum PSA > 4 ng/dl were advised to undergo transrectal prostatic biopsy. Of the 224 subjects, 40 (17.9%) had an abnormal DRE and 57 (25.4%) had an elevated serum PSA > 4 ng/dl. The overall detection rate of prostate cancer in the study population was 6.7%. The prostate cancer detection rates for PSA alone and DRE alone were 5.8% and 5.3%, respectively. The sensitivity, specificity, and positive predictive values of PSA alone were 86.7%, 80.9%, and 25.0% and of DRE alone 80.0%, 86.3%, and 30.0%, respectively. Receiver operator characteristic (ROC) curves were constructed for the entire study population in order to compare the screening measures serum PSA and PSA density. The area under the curves was 0.88 for both tests, indicating that these screening tests for prostate cancer were not significantly different. The present study demonstrated that males with clinically significant prostatism represent a high risk cohort for detecting prostate cancer. DRE and PSA are equally effective measures for detecting prostate cancer. PSA density does not offer any advantage over serum PSA in screening for prostate cancer, except in the subset of patients with a normal DRE and serum PSA levels between 4.0 and 9.9 ng/dl. © 1994 Wiley-Liss, Inc.     

Effects of the Bowman-Birk inhibitor on growth, invasion, and clonogenic survival of human prostate epithelial cells and prostate cancer cells

BACKGROUND: The Bowman-Birk inhibitor (BBI) is a soybean-derived serine protease inhibitor with demonstrated anticarcinogenic activity in both in vitro and in vivo systems. METHODS: The effects of BBI and BBI Concentrate (BBIC), a soybean concentrate enriched in BBI, on cell growth, invasion, and/or survival were evaluated by the sulforhodamine B assay, a colony formation assay, the trypan blue dye exclusion assay and an in vitro invasion assay. The cells used in these studies were normal human prostate epithelial cells and prostate epithelial cell lines derived from embryonic prostate tissue (267B1) or benign prostatic hyperplasia (BPH) tissue (BRF-55T) and human prostate cancer cells established by Ki-ras oncogene transfection of 267B1 cells (267B1/Ki-ras) or from metastatic lesions of human prostate cancer (LNCaP and PC-3). RESULTS: BBIC had a statistically significant inhibitory effect on the growth and clonogenic survival of BRF-55T, 267B1/Ki-ras, LNCaP, and PC-3 cells. BBI also inhibited the growth of LNCaP cells and the clonogenic survival of BRF-55T and 267B1/Ki-ras cells and decreased the ability of LNCaP cells to invade across reconstituted basement membrane (Matrigel) when PC-3 cell-conditioned medium was utilized as the chemoattractant. BBI or BBIC did not affect the growth of normal prostate epithelial cells. CONCLUSION: BBI and/or BBIC could be a useful agent for treatment of prostate diseases.