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.     

Neurotrophin receptor p75(NTR) suppresses growth and nerve growth factor-mediated metastasis of human prostate cancer cells

The loss of tumor- and/or metastasis-suppressor gene function contributes to the transformation of human prostate epithelial cells to a malignant pathology. Such a putative tumor-suppressor and metastasis-suppressor gene(s) has been mapped to the region of 17q21, which coincidentally is in the vicinity of the human gene locus for the neurotrophin receptor p75(NTR). The p75(NTR) is expressed in normal human prostate epithelial cells and exhibits an inverse association of p75(NTR) expression with the malignant progression of the prostate, consistent with a pathologic role of the p75(NTR) as a putative tumor and metastasis suppressor. Utilizing stable transfectants of the TSU-pr1 and PC-3 human prostate tumor cell lines that exhibit a rank order (dose-dependent) increase in p75(NTR) protein expression, we investigated the effects of the p75(NTR) in combination with its predominant ligand, nerve growth factor (NGF), on tumor cell growth. A rank order (dose-dependent) increase in p75(NTR) expression was found to suppress the growth of prostate tumors in severe combined immunodeficient (SCID) mice. Treatment of these tumors with NGF stimulated both proliferation as indicated by PCNA expression and apoptosis as indicated by TUNEL assay, the net result of which was no change in the overall growth of the tumors. However, NGF was found to increase the formation of satellite tumors, both contiguous and noncontiguous with respect to the primary tumor mass, indicating dose-dependent induction of metastasis. Significantly, the formation of satellite tumors was suppressed by the expression of p75(NTR). This suggests that p75(NTR) is a tumor suppressor of growth and a metastasis suppressor of NGF-stimulated migration of human prostate tumor cells.     

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.     

Metastatic prostate cancer with a normal prostate-specific antigen level

Prostate-specific antigen (PSA) is the most commonly used tumour marker for prostate cancer; both in screening and in follow-up. However, there are many false positive increases in the presence of other prostate diseases and , currently, there is no consensus regarding sensitivity and specificity of the PSA test, nor what constitutes the upper limit of normality. We report a case of a 67-year-old patient with metastatic prostate cancer who, with increased level of alkaline phosphatase and normal PSA, showed clinical and radiological evidence of progression of the disease     

复合PSA及相关指标在前列腺癌诊断中的应用

Objective:To study the diagnostic value of complex PSA(cPSA),the calculated free/total PSA(f/t PSA) raio and total PSA(tPSA)in the differentiation of prostate cancer from benign prostate hyperplasia.Methods:The tPSA,cPSA and fPSA were measured using the Bayer ACS-180 chemiluminescence immuno-assay.152 patients(21 with prostate cancer and 131 with benign prostate hyperplasia proven by tissue pathology)whose serum total PSA ranged from 0.2-20.0ng/ml were accessed from July 2001 to May 2002 consecutively.The correlation between tPSA and cPSA was analyzed.The re-ceiver operator characteristic curves(ROC curve)were generated by plotting the sensitivity versus specificity.Areas under the curve were calculated for each assay.Logistic regression analysis was used to evaluate the ability of the indices as independent varia-bles to predict prostate cancer.Results:In the experimental group,the areas under the ROC curve of cPSA ,tPSA and fPSA/tPSA ratio were 0.811,0.799 and 0.376 respectively.The specificity for tPSA,fPSA/tPSA ratio and cPSA were 62%,57% and 4.7%,respectively,at cotoff yield-ing 95% sensitivity.Serum cPSA concentration was determined to be the best index among the three through logistic regression analy-sis.Conclusion:The serum levels of cPSA and tPSA are better indices than f/tPSA in the differentiation of prostate cancer from benign prostate hyperplasia.At the same level of sensitivity,cPSA has a higher specificity than tPSA.Serum cPSA may be a better indicator in the prediction of prostate cancer of early stage.     

Obesity is associated with increased risks of prostate cancer metastasis and death after initial cancer diagnosis in middle-aged men

BACKGROUND: Current research is inconclusive regarding the effect of obesity on outcomes after a prostate cancer diagnosis. The objective of this study was to examine associations between obesity and the risks of developing metastasis or prostate cancer-specific mortality in a population-based cohort of men with prostate cancer. METHODS: Seven hundred fifty-two middle-aged men with prostate cancer who were enrolled in a case-control study and remain under long-term follow-up for disease progression and mortality formed the study cohort. Body mass index (BMI) in the year before diagnosis was obtained at the time of initial interview. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of prostate cancer metastasis and mortality associated with obesity, controlling for age, race, smoking status, Gleason score, stage at diagnosis, diagnostic prostate-specific antigen level, and primary treatment. RESULTS: Obesity (BMI >or=30 kg/m(2)) was associated with a significant increase in prostate cancer mortality (HR, 2.64; 95% CI, 1.18-5.92). Among men who were diagnosed with local- or regional-stage disease, obesity also was associated with an increased risk of developing metastasis (HR, 3.61; 95% CI, 1.73-7.51). Associations generally were consistent across strata defined by Gleason score (2-6 or 7 [3 + 4] vs 7 [4 + 3] or 8-10), stage (local vs regional/distant for mortality), and primary treatment (androgen-deprivation therapy use: yes vs no). CONCLUSIONS: Obesity at the time of diagnosis was associated with increased risks of prostate cancer metastasis and death. The increased risk of prostate cancer death or metastasis associated with obesity largely was independent of key clinical prognostic factors at diagnosis.     

Cyclooxygenase-2 (COX-2) expression is an independent predictor of prostate cancer recurrence

Lack of reliable prognostic markers hinders accurate prediction of disease progression in prostate cancer. The inducible proinflammatory enzyme cyclooxygenase-2 (COX-2) is implicated in prostate carcinogenesis, but its role in cancer progression is less clear. We examined whether COX-2 expression evaluated by immunohistochemistry (IHC) in radical prostatectomy (RP) specimens can predict biochemical recurrence. Archival prostate cancer specimens (n = 60) were obtained from patients who underwent RP, but had not received neoadjuvant hormonal therapy. Twenty-three patients had biochemical or clinical recurrence (mean time of recurrence: 38.2 months), and 37 patients were recurrence free (mean follow-up: 95 months). COX-2 expression was determined by IHC, using an anti-COX-2 antibody. Three individuals scored the staining independently, as high- or low-expression. COX-2 was expressed in prostate cancer cells, in adjacent normal glands and in specimens from patients who later progressed. At 62-months follow-up, COX-2 staining predicted progression with 82.4% sensitivity and 81.3% specificity. Sensitivity (86.4%) and specificity (86.7%) improved at > or = 100-months follow-up. In univariate analysis, Gleason score, preoperative PSA, extraprostatic extension, margin, seminal vesicle invasion, and high COX-2 expression were significant predictors of biochemical recurrence (p < 0.05). In multivariate analysis, preoperative PSA (hazard ratio/unit PSA change 1.080; p = 0.0036) and COX-2 expression (hazard ratio 16.442; p < 0.0001) were independent prognostic indicators. Patients with PSA > 7 ng/ml and high COX-2 expression had the highest probability of recurrence (Kaplan-Meier analysis). COX-2 expression is an independent predictor of prostate cancer progression following RP and underscores the significance of inflammatory factors in this process.     

PrLZ expression is associated with the progression of prostate cancer LNCaP cells

PrLZ is a novel recent isolated gene and specific expression in prostate tissues. PrLZ expression was specifically elevated in prostate embryonic tissues and androgen independent prostate cancer cells, suggesting it might be association with the embryonic development and malignancy progression. However, the function and mechanism of PrLZ during the progression of prostate cancer remain blurred. Our present studies showed PrLZ expression might enhance the proliferation and invasion capability in vitro and also increase the tumorigenicity in situ prostate cancer animal model, which is indicated PrLZ expression contributed to the malignancy progression of prostate cancer. In addition, PrLZ also might up regulate androgen receptor (AR) expression and increase the PSA expression, a putative downstream target gene of AR, which indicated PrLZ mediated the malignancy progression of prostate cancer was associated with androgen signals.     

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.     

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。     

Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-kappaB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer.     

Excess cases of prostate cancer and estimated overdiagnosis associated with PSA testing in East Anglia

This study aimed to estimate the extent of 'overdiagnosis' of prostate cancer attributable to prostate-specific antigen (PSA) testing in the Cambridge area between 1996 and 2002. Overdiagnosis was defined conceptually as detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient's lifetime. Records of PSA tests in Addenbrookes Hospital were linked to prostate cancer registrations by NHS number. Differences in prostate cancer registration rates between those receiving and not receiving prediagnosis PSA tests were calculated. The proportion of men aged 40 years or over with a prediagnosis PSA test increased from 1.4 to 5.2% from 1996 to 2002. The rate of diagnosis of prostate cancer was 45% higher (rate ratios (RR)=1.45, 95% confidence intervals (CI) 1.02-2.07) in men with a history of prediagnosis PSA testing. Assuming average lead times of 5-10 years, 40-98% [corrected] of the PSA-detected cases were estimated to be overdiagnosed. In East Anglia, from 1996 to 2000, a 1.6% excess of cases was associated with PSA testing (around a quarter of the 5.3% excess incidence cases observed in East Anglia from 1996 to 2000). Further quantification of the overdiagnosis will result from continued surveillance and from linkage of incidence to testing in other hospitals.     

Algorithms based on prostate-specific antigen (PSA), free PSA, digital rectal examination and prostate volume reduce false-positive PSA results in prostate cancer screening

Our objective was to determine whether multivariate algorithms based on serum total PSA, the free proportion of PSA, age, digital rectal examination and prostate volume can reduce the rate of false-positive PSA results in prostate cancer screening more effectively than the proportion of free PSA alone at 95% sensitivity. A total of 1,775 consecutive 55- to 67-year-old men with a serum PSA of 4-10 microg/l in the European Randomized Study of Screening for Prostate Cancer were included. To predict the presence of cancer, multivariate algorithms were constructed using logistic regression (LR) and a multilayer perceptron neural network with Bayesian regularization (BR-MLP). A prospective setting was simulated by dividing the data set chronologically into one set for training and validation (67%, n = 1,183) and one test set (33%, n = 592). The diagnostic models were calibrated using the training set to obtain 95% sensitivity. When applied to the test set, the LR model, the BR-MLP model and the proportion of free PSA reached 92%, 87% and 94% sensitivity and reduced 29%, 36% and 22% of the false-positive PSA results, respectively. At a fixed sensitivity of 95% in the test set, the LR model eliminated more false-positive PSA results (22%) than the proportion of free PSA alone (17%) (p < 0.001), whereas the BR-MLP model did not (19%) (p = 0.178). The area under the ROC curve was larger for the LR model (0.764, p = 0.030) and the BR-MLP model (0.760, p = 0.049) than for the proportion of free PSA (0.718). A multivariate algorithm can be used to reduce unnecessary prostate biopsies in screening more effectively than the proportion of free PSA alone, but the algorithms will require updating when clinical practice develops with time.     

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.     

Phase II trial of anti-idiotypic p53 peptides (Pentrys) plus granulocyte-macrophage colony-stimulating factor in patients with hormone-refractory prostate cancer

Background: p53 overexpression occurs commonly in hormone‐refractory prostate cancer (HRPC). T‐cell responses against p53 could potentially mediate an antitumor effect. We investigated a novel system of vaccination using three peptides derived from a mouse‐antihuman p53 antibody (Pentrys) in men with HRPC. Patients and methods: A phase II, single‐arm, open‐label study of Pentrys peptides admixed with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was injected intradermally in men with HRPC, rising prostate‐specific antigen (PSA) and minimal symptoms. The primary objective was to determine clinical responses as measured by PSA. Secondary objectives were to determine duration of PSA response, progression‐free survival (PFS), anti‐p53 antibody response, and safety. Patients received study drug on weeks 1, 3, 5, 9, 13 and 17. Patients suitable for ongoing treatment received two more doses at weeks 21 and 25. Tumor status was assessed at baseline, week 17 and 3 months after the final injection. Results: Forty patients entered the study and were evaluable for safety; 39 were evaluable for efficacy. Thirty patients completed at least 16 weeks of treatment. One PSA response was observed that lasted 85 days. Median PFS was 56 days. Treatment was generally well tolerated. Only one dose‐limiting toxicity was observed (allergic rhinitis and urticaria). Five patients had anti‐p53 antibodies at screening. Two patients developed anti‐p53 antibodies during the study, including the patient with the PSA response. Conclusions: Pentrys administered with GM‐CSF by intradermal injection is well tolerated. Only one PSA response was seen and anti‐p53 seroconversion was observed in two patients. Pentrys has minimal clinical activity in this patient population.