血清FPSA/TPSA 比值在前列腺癌鉴别诊断中的应用

目的：探讨游离前列腺特异性抗原／总前列腺特异性抗原（FPSA／TPSA）比值在鉴别诊断前列腺癌中的应用价值。方法：随机选取我院2005年1月-2006年8月住院的前列腺炎患者44例，良性前列腺增生42例，前列腺癌患者54例，排除前列腺疾病的健康体检者63例，测定血清TPSA和FPSA，并计算FPSA／TPSA比值。应用SPSS10．0软件进行统计学分析。结果：FPSA／TPSA比值界值为≤1．8时对前列腺癌鉴别诊断与只检测TPSA相比在敏感性相近的情况下特异性明显提高（TPSA特异性为57．5％，FPSA／TPSA特异性为81．3％）。结论：FPSA／TPSA比值在敏感性相近的情况可明显提高前列腺癌鉴别诊断的特异性，是较为理想的前列腺癌鉴别诊断新指标。     

Percent free prostate-specific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower

BACKGROUND: Up to 17% of men with a prostate-specific antigen (PSA) level below the accepted prostate biopsy cutoff of 2.5 ng/mL may have prostate cancer. Because identification of these patients represents a difficult task, we assessed the ability of percent free PSA to discriminate between benign and malignant prostate biopsy outcomes in men with PSA < or =2.5 ng/mL. METHODS: Between 1999 and 2006, 543 men with a PSA < or =2.5 ng/mL were referred for initial prostate biopsy. Age, total PSA, percent free PSA, and digital rectal examination findings represented predictors of prostate cancer at biopsy in logistic regression models. The area under the receiver operating characteristics curve (AUC) quantified the discriminative ability of the predictors. The pathological characteristics of the detected cancers were assessed in individuals treated with radical prostatectomy. RESULTS: Of all, 23% had prostate cancer on biopsy, 16.5% of patients treated with radical prostatectomy had pT3 stage, and 35.6% had a pathological Gleason score of 3 + 4 or higher. The most accurate predictor of prostate cancer on biopsy was percent free PSA (0.68) versus age (0.50), total PSA (0.57), or rectal examination findings (0.58). Of patients with percent free PSA below 14%, 59% had prostate cancer. In multivariate models, percent free PSA (P < .001) and rectal examination findings (P = .001) were the only independent predictors of prostate cancer. The combined AUC of all predictors (0.69) was not significantly (P = .7) higher than that of percentage of free PSA alone (0.68). CONCLUSIONS: The risk of prostate cancer is clearly non-negligible in patients with PSA < or =2.5 ng/mL. The percent free PSA can accurately predict the prevalence of prostate cancer at prostate biopsy in these individuals.     

Effect of exogenous testosterone replacement on prostate-specific antigen and prostate-specific membrane antigen levels in hypogonadal men

Previous studies have suggested that serum prostate-specific antigen (PSA) levels are under androgenic influence, especially in patients with adenocarcinoma of the prostate. PSMA (prostate-specific membrane antigen) is thought to reflect hormonal or clonal resistance or an independence with respect to testosterone regulation. The influence of testosterone on serum PSA expression in normal men is not clear. We studied the effect of exogenous testosterone administration on the serum levels of PSA and PSMA in hypogonadal men. Serial serum PSA, serum PSMA by Western blot, and serum total testosterone levels were obtained at intervals of every 2–4 weeks in 10 hypogonadal men undergoing treatment with exogenous testosterone, delivered as testosterone enanthate injection or by testosterone patch. Linear and quadratic orthogonal polynomial scores were calculated for PSMA, PSA, and testosterone. A 2-tailed, paired t-test failed to demonstrate a significant correlation between serum PSA (linear P = 0.432, quadratic P = 0.290) or PSMA (linear P = 0.162, quadratic P = 0.973) and serum testosterone levels. This study suggests that in hypogonadal men, neither PSMA nor PSA expression is testosterone-dependent.     

Measurement of serum total and free prostate-specific antigen in women with colorectal carcinoma

We investigated the diagnostic value and the relationship with clinicopathological features of total and free prostate-specific antigen by measuring the concentrations of these markers in the sera of 75 women with colorectal carcinoma and in 30 healthy women. Measurements were performed by immunoradiometric assay which utilizes monoclonal and polyclonal anti-prostate-specific antigen antibodies; the lowest detection level for both markers was 0.01 ng ml(-1). Free prostate-specific antigen levels were significantly higher in women with colorectal carcinoma than healthy women (P=0.006). The percentage of free prostate-specific antigen predominant (free prostate-specific antigen/total prostate-specific antigen >50%) subjects was 20% in colorectal carcinoma patients and 3.3% in healthy women (P=0.035). Cut-off values were 0.34 ng ml(-1) for total prostate-specific antigen and 0.01 ng ml(-1) for free prostate-specific antigen. In women with colorectal carcinoma, total prostate-specific antigen positivity was 20% and free prostate-specific antigen positivity was 34.6%. When compared to negatives, total prostate-specific antigen positive patients had a lower percentage of well-differentiated (P=0.056) and early stage (stages I and II) tumours (P=0.070). However, patients with predominant free prostate-specific antigen, had a higher percentage of well-differentiated (P=0.014) and early stage tumours (P=0.090) than patients with predominant bound prostate-specific antigen. In conclusion, although the sensitivity of free prostate-specific antigen predominancy is low (20%), in distinguishing women with colorectal carcinoma than healthy women, its specificity is high (96.7%). Free prostate-specific antigen predominancy tends to be present in less aggressive tumours. These findings may indicate clinical significance of preoperative measurement of serum total and free prostate-specific antigen in women with colorectal carcinoma.     

Influence of body mass index on prostate-specific antigen failure after androgen suppression and radiation therapy for localized prostate cancer

BACKGROUND: Increasing body mass index (BMI) is associated with shorter time to prostate-specific antigen (PSA) failure after radical prostatectomy. Whether BMI is associated with time to PSA failure was investigated in men treated with androgen suppression therapy (AST) and radiation therapy (RT) for clinically localized prostate cancer. METHODS: The observational prospective cohort study consisted of 102 men with clinically localized prostate cancer who received 70 Gy RT with 6 months of AST on a single arm of a randomized trial between December 1995 and April 2001. Height and weight data were available at baseline for 99 (97%) of the men, from which BMI was calculated. Adjusting for age (continuous) and known prognostic factors including PSA level (continuous), Gleason score, and T-category, Cox regression analyses were performed to analyze whether BMI (continuous) was associated with time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits). RESULTS: Median age and median BMI (interquartile range [IQR]) at baseline was 72 (69.1-74.7) years and 27.4 (24.8-30.7) kg/m,(2) respectively. In addition to an increasing PSA level (P = .006) and Gleason 8-10 cancer (P = .024), after a median follow-up (IQR) of 6.9 (5.6-8.5) years, an increasing BMI was also significantly associated with a shorter time to PSA failure (adjusted hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.01-1.19; P = .026) after RT and AST. CONCLUSIONS: After adjusting for known prognostic factors, baseline BMI is significantly associated with time to PSA failure after RT and AST for men with clinically localized prostate cancer. Further study is warranted to assess the impact of an increasing BMI after AST administration on PSA failure, prostate cancer-specific, and all-cause mortality.     

Elevated levels of prostate-specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis

The underlying basis for rising levels of prostate-specific antigen (PSA) in prostate cancer is not fully understood, but attention has turned to the possibility that loss of normal p53 function might be directly involved. We have investigated the relationship between p53 function and PSA expression using in vitro and in vivo approaches. Three prostate cancer-derived p53 mutants (F134L, M237L, R273H) were introduced into LNCaP prostate cancer cells and stable transfectants established. Expression of mutant p53 was demonstrated by Western blot analysis, inactivation of wtp53 function, and a loss of p53-dependent responses to DNA damage induced by UV-irradiation and cisplatin. Levels of PSA mRNA and secreted protein were determined by RT-PCR and Western blotting, respectively. Serine protease activity was assessed using an esterase assay. In vivo effects of mutant p53 expression were examined after orthotopic implantation into prostates of nude mice. Expression of all p53 mutants was associated with elevated PSA mRNA and secreted PSA protein. In a representative line, mutant p53 was also associated with increased PSA protease-like activity compared with a control line expressing wildtype p53. Overall PSA levels, and PSA levels in serum from mice bearing tumors derived from cells expressing mutant p53, were increased compared with levels in mice bearing tumors derived from control cells. In addition, the tumors derived from cells with mutant p53 had increased vascularization and induced lymph node metastases. These data provide in vitro and in vivo support for the notion that p53 mutations directly contribute to increased levels of serum PSA, and are associated with more aggressive tumors.     

Evaluation of serum prostate-specific antigen in urologic cancers

Serum prostate-specific antigen (PA), a new tumor marker of prostate cancer, was evaluated with an eznyme immunoassay (EIA) in various urologic cancer patients and benign prostatic diseases in Japanese. Sera of prostate cancer patients before treatment (n = 27) revealed a range of PA concentrations from 0.12-23 ng/ml with a mean (+/- SD) of 5.78 +/- 6.85 ng/ml, while that of patients with benign prostatic hypertrophy (BPH) (n = 27) showed from less than 0.10 to 2.6 ng/ml with 0.84 +/- 0.81 ng/ml (mean +/- SD). The mean serum PA levels in nonprostatic cancers were calculated as follows: bladder cancer (n - 21), 0.77 +/- 0.55 ng/ml; renal pelvis or ureteral cancer (n = 6), 0.46 +/- 0.47 ng/ml; renal adenocarcinoma (n equal to 6), 1.07 +/- 0.77 ng/ml; other urologic cancers (n = 6), 0.55 +/- 0.52 ng/ml. Serum PA ranged from less than 0.10 to 1.1 ng/ml in patients with prostatitis (n = 5). A significant statistical difference in serum PA levels between prostate cancer and other groups was recognized. These results suggested that an elevation of serum PA value was highly specific to prostate cancer in urological malignancies. The evaluation of serum PA may be of great value in the detection of prostate cancer.     

Induction of autoantibodies to syngeneic prostate-specific membrane antigen by xenogeneic vaccination

Prostate-specific membrane antigen (PSMA) is a prototypical differentiation antigen expressed on normal and neoplastic prostate epithelial cells, and on the neovasculature of many solid tumors. Monoclonal antibodies specific for PSMA are in development as therapeutic agents. Methodologies to actively immunize against PSMA may be limited by immunologic ignorance and/or tolerance that restrict the response to self-antigens. Our studies have previously shown that xenogeneic immunization with DNA vaccines encoding melanosomal differentiation antigens induces immunity in a mouse melanoma model. Here we apply this approach to PSMA to establish proof of principle in a mouse model. Immunization with xenogeneic human PSMA protein or DNA induced antibodies to both human and mouse PSMA in mice. Monoclonal antibodies specific for mouse PSMA were generated to analyze antibody isotypes and specificity for native and denatured PSMA at the clonal level. Most antibodies recognized denatured PSMA, but C57BL/6 mice immunized with xenogeneic PSMA DNA followed by a final boost with xenogeneic PSMA protein yielded autoantibodies that reacted with native folded mouse PSMA. Monoclonal antibodies were used to confirm the expression of PSMA protein in normal mouse kidney. These results establish the basis for clinical trials to test PSMA DNA vaccines in patients with solid tumors that either express PSMA directly or that depend on normal endothelial cells expressing PSMA for their continued growth.     

Human kallikrein 2 (hK2), but not prostate-specific antigen (PSA), rapidly complexes with protease inhibitor 6 (PI-6) released from prostate carcinoma cells.

Human kallikrein 2 (hK2) is a secreted, trypsin-like protease that shares 80% amino acid sequence identity with prostate-specific antigen (PSA). hK2 has been shown to be a serum marker for prostate cancer and may also play a role in cancer progression and metastasis. We have previously identified a novel complex between human kallikrein 2 (hK2) and protease inhibitor 6 (PI-6) in prostate cancer tissue. PI-6 is an intracellular serine protease inhibitor with both antitrypsin and antichymotrypsin activity. In the current study we have shown that PI-6 forms a rapid in vitro complex with hK2 but does not complex with PSA. Recombinant mammalian cells expressing both hK2 and PI-6 showed hK2-PI-6 complex in the spent media only after cell death and lysis. Similarly, LNCaP cells expressing endogenous hK2 and PI-6 showed extracellular hK2-PI-6 complex formation concurrently with cell death. Immunostaining of prostate cancer tissues with PI-6 monoclonal antibodies showed a marked preferential staining pattern in cancerous epithelial cells compared with noncancerous tissue. These results indicate that the hK2-PI-6 complex may be a naturally occurring marker of tissue damage and necrosis associated with neoplasia. Both hK2 and PI-6 were shed into the lumen of prostate cancer glands as granular material that appeared to be cellular necrotic debris. The differential staining pattern of PI6 in tissues suggests a complex regulation of PI-6 expression that may play a role in other aspects of neoplastic progression.     

尿PCA3在前列腺癌中的临床价值

目的探讨尿前列腺癌抗原3(PCA3)基因表达水平及与血清前列腺特异性抗原(PSA)的表达水平,及其与肿瘤分化程度的关系。方法选择81例因血清PSA表达升高和(或)直肠指诊异常行前列腺穿刺活检的患者。采用苏木精-伊红(HE)染色及免疫组化鸡尾酒染色明确病理活检结果,定量-实时逆转录聚合酶链反应(qRT-PCR)检测尿PCA3 m RNA表达水平,并分析其与肿瘤分化程度的关系。前列腺癌患者尿PCA3 mRNA和血清PSA表达水平间的相关性采用线性回归分析。结果 81例患者的前列腺活检组织中,诊断前列腺癌阳性53例,阴性28例。前列腺癌患者尿PCA3 mRNA和血清PSA表达水平,均明显高于非前列腺癌患者(P﹤0.01);前列腺癌患者尿PCA3 m RNA表达水平与血清PSA表达水平无线性相关关系(P﹥0.05)。PCA3 mRNA高表达组患者Gleason评分明显高于低表达组患者(P﹤0.01),尿PCA3高表达倾向低、中度分化(P﹤0.01)。尿PCA3 mRNA高表达组患者NME1、NME3和SPARCL1 mRNA表达水平均明显低于低水平组患者(P﹤0.01);SPOCK1和survivin m RNA表达水平均明显高于低表达组患者(P﹤0.01)。结论前列腺癌患者尿PCA3 mRNA及血清PSA表达水平明显升高,但二者间无线性关系。前列腺癌患者尿PCA3 mRNA高表达时,NME1、NME3和SPARCL1mRNA表达水平及分化程度均降低,SPOCK1和survivin mRNA表达水平升高。     

Detection of prostate-specific antigen immunoreactivity in breast tumors

Prostate-specific antigen (PSA) is a glycoprotein produced by the epithelial cells of the prostate. PSA is currently used in clinical practice to facilitate diagnosis and monitoring of prostate carcinoma. The prostate is an organ that possesses androgen, estrogen, and progesterone receptors, and in this respect is similar to the breast. We postulated that breast tumors might also have the ability to produce PSA. We performed these studies on a collection of 525 tumor specimens collected for routine biochemical determination of estrogen and progesterone receptors. Using a highly sensitive immunofluorometric procedure, we measured the p53 tumor suppressor gene product and PSA. Twenty nine percent of the breast tumor extracts contained detectable levels of PSA immunoreactivity (> 0.05 µg/L). The immunoreactive PSA content was associated with estrogen and/or progesterone receptor-positive tumors (P < 0.002). No association was found between PSA immunoreactivity and levels of the p53 tumor suppressor gene product (P = 0.37). High performance liquid chromatography and Western blot analysis revealed that the PSA immunoreactivity in the tumor had a molecular weight of 30 kDa, similar to that of seminal PSA. Immunoreactive PSA-positive tumors were associated with younger women (P = 0.012) and earlier disease stage (P = 0.064). We postulate that PSA immunoreactivity may be an additional marker of steroid hormone receptor-ligand action.     

Transrectal ultrasound in detecting prostate cancer compared with serum total prostate-specific antigen levels

We carried out a retrospective study to review the efficiency of grey-scale transrectal ultrasonography (TRUS) in detecting prostate cancer compared with the data in recent published work, including alternative imaging methods of the prostate gland. Our study group consisted of 830 patients who underwent TRUS-guided biopsy of the prostate between May 2000 and June 2004. The relation between abnormal TRUS findings and serum total prostate-specific antigen (tPSA) levels was evaluated in patients with prostate cancer who were divided into three different groups according to serum tPSA levels. Group I included patients with tPSA levels of 4-9.9 ng/mL, group II included tPSA levels of 10-19.9 ng/mL and group III included patients with tPSA levels of 20 ng/mL or more. In general, TRUS detected 185 (64%) of 291 cancers with a specificity of 89%, a PPV of 76% and an accuracy of 80%. TRUS findings enabled the correct identification of 22 (56%) of the 39 cancers in group I, 28 (30%) of the 93 cancers in group II and 135 (85%) of the 159 cancers in group III. In conclusion, TRUS alone has a limited potential to identify prostate cancer, especially in patients with tPSA levels lower than 20 ng/mL. Therefore, increased numbers of systematically placed biopsy cores must be taken or alternative imaging methods are required to direct TRUS-guided biopsy for improving prostate cancer detection.     

Overdetection, overtreatment and costs in prostate-specific antigen screening for prostate cancer

Background:

Prostate cancer screening with prostate-specific antigen (PSA) has shown to reduce prostate cancer mortality in the European Randomised study of Screening for Prostate Cancer (ERSPC) trial. Overdetection and overtreatment are substantial unfavourable side effects with consequent healthcare costs. In this study the effects of introducing widespread PSA screening is evaluated.

Methods:

The MISCAN model was used to simulate prostate cancer growth and detection in a simulated cohort of 100 000 men (European standard population) over 25 years. PSA screening from age 55 to 70 or 75, with 1, 2 and 4-year-intervals is simulated. Number of diagnoses, PSA tests, biopsies, treatments, deaths and corresponding costs for 100 000 men and for United Kingdom and United States are compared.

Results:

Without screening 2378 men per 100 000 were predicted to be diagnosed with prostate cancer compared with 4956 men after screening at 4-year intervals. By introducing screening, the costs would increase with 100% to €60 695 000. Overdetection is related to 39% of total costs (€23 669 000). Screening until age 75 is relatively most expensive because of the costs of overtreatment.

Conclusion:

Introduction of PSA screening will increase total healthcare costs for prostate cancer substantially, of which the actual screening costs will be a small part.