Antibody array profiling reveals serum TSP-1 as a marker to distinguish benign from malignant prostatic disease

BACKGROUND: Blood protein markers that provide more accurate or earlier diagnosis of prostate cancer should have a positive impact on prostate cancer treatment and management. METHODS: Serum samples from control subjects and patients with benign or malignant prostatic disease were analyzed on antibody arrays targeting multiple candidate prostate cancer markers and detected with two-color, rolling-circle amplification (TC-RCA). The measurements of certain antibodies were validated using immunoblots, immunoprecipitation/mass spectrometry, and sandwich immunoassays. RESULTS: Several potential disease-associated protein alterations were uncovered. The most significant was thrombospondin-1, which was strongly elevated in patients with benign prostatic disease and repressed in patients with prostate cancer. Thrombospondin-1 levels did not correlate with prostate-specific antigen (PSA) levels and differentiated benign from malignant disease with 79% sensitivity and 81% specificity. CONCLUSIONS: The measurement of thrombospondin-1 could be used to assist the decision to obtain a biopsy in men with suspected prostate cancer, which could lead to a reduction in the number of unnecessary prostatic biopsies.     

血清PSA、游离PSA与良性前列腺增生临床的相关性研究

目的分析血清前列腺特异性抗原(PSA)及游离前列腺特异性抗原(fPSA)与良性前列腺增生(BPH)临床的相关性。方法应用化学发光微粒子免疫分析法(CMIA)对BPH患者血清PSA、fPSA进行检测。结果入选的40例患者病理均为BPH。PSA>4ng/ml者,术后随访1～3个月,平均2.5个月,PSA值均降至0.02ng/ml以下,可除外前列腺癌(PCa)病例。PSA<4ng/ml者16例(40%),4～10ng/ml者14例(35%),>10ng/ml者10例(25%);fPSA>0.934ng/ml者22例(55%)。血清PSA、fPSA水平与前列腺总体积(PV)、前列腺移行区体积(TZV)、年龄及国际前列腺症状评分(IPSS)呈正相关。结论本组血清fPSA与PV、TZV、年龄、IPSS评分有更强相关性。BPH患者血清PSA、fPSA水平升高的相关因素与前列腺总体积及移行区增大、高龄及高IPSS评分有关。     

Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum PSA and PSA density

OBJECTIVE: Inflammation is a frequent histological finding in prostate biopsies, performed on men without prostatic malignancy or clinical prostatitis. We investigated the relationship between morphological parameters of inflammation in prostatic tissue and total serum prostate-specific antigen (PSA) and prostate-specific antigen density (PSAD) levels to determine if subclinical inflammation can cause elevation of PSA and PSAD. METHODS: We reviewed 268 prostate biopsies, performed on 238 men with elevated PSA and/or abnormal digital rectal examination of the prostate. All premalignant and malignant biopsies and cases of clinical prostatitis were excluded. The inflammation in the remaining 145 prostate biopsies was scored for extent of inflammation and aggressiveness of inflammation, using the four-point scale designed by Irani and co-workers. In this prostatic inflammation scoring system, extent of inflammation is graded from 0 up to 3 according to the degree of invasion of inflammatory cells in prostatic tissue. Aggressiveness of inflammation is graded from 0 up to 3 according to the degree of contact or disruption of prostatic glandular epithelium by inflammatory cells. RESULTS: Each of the studied biopsies showed inflammatory cells. Median PSA levels in grades 1, 2 and 3 of extent of inflammation were, respectively, 5.7, 6.8 and 13. 0. Median PSAD levels in these groups were 0.13, 0.16 and 0.33. There was no significant difference between these grades for PSA nor for PSAD. Median PSA levels in grades 0, 1 and 2 of aggressiveness of inflammation were, respectively, 3.9, 5.9 and 8.9. Median PSAD levels in these groups were 0.12, 0.18 and 0.17. For both parameters, there was a significant difference between grades (respectively, p = 0.0028 and p = 0.0330). CONCLUSION: Inflammation of the prostate is a histological finding in almost every set of prostate biopsies, even when there are no signs of clinical prostatitis. This subclinical inflammation can cause PSA elevation. Not the extent of inflammation is of importance, but the disruption of epithelial integrity caused by the inflammatory infiltrate. When confronted with a patient with an elevated PSA level whose prostate biopsies reveal no malignancy but only inflammation, this concept can help in determining the need for quick repeat biopsies.     

Putative protein markers in the sera of men with prostatic neoplasms

OBJECTIVE: To describe the preliminary identification of serum proteins that may be diagnostic markers in prostate cancer. PATIENTS AND METHODS: The study included 11 men referred for treatment of localized prostate cancer, 12 with benign prostatic hyperplasia (BPH) and 12 disease-free controls. For serum protein analysis, the protein-chip array surface-enhanced laser desorption/ionization (SELDI) technique was used (Ciphergen Biosystems, Fremont, CA). SELDI combines protein-chip technology with time-of-flight mass spectrometry, and offers the advantages of speed, simplicity and sensitivity. RESULTS: Three protein peaks were identified in the serum of men with prostate cancer and BPH, but not in controls, with relative molecular masses of 15.2, 15.9 and 17.5 kDa. These three proteins were significantly associated with BPH and prostate cancer when compared with controls (P = 0.001, 0.004, and 0.011, respectively, Kruskal-Wallis test). Interestingly, the 17.5 kDa protein was more abundant in five men with stage T1 prostate cancer than in eight with stage T2 (P = 0.016, two tailed Mann-Whitney U-test corrected for ties). CONCLUSIONS: These proteins, particularly the 15.9 kDa one, may be used for the diagnosis or monitoring of prostate cancer and differentiation from BPH, and have the potential for antibody-based chip SELDI-TOF technology. Identified proteins may be targets for immunotherapy.     

Significance of preoperative PSA velocity in men with low serum PSA and normal DRE

Objectives  

A PSA velocity (PSAV) >0.35 ng/ml/year approximately 10–15 years prior to diagnosis is associated with a greater risk of lethal prostate cancer. Some have recommended that a PSAV >0.35 ng/ml/year should prompt a prostate biopsy in men with a low serum PSA (<4 ng/ml) and benign DRE. However, less is known about the utility of this PSAV cutpoint for the prediction of treatment outcomes among men undergoing radical prostatectomy (RP).     

血清TPSA与F/T检测在前列腺良、恶性病变诊断中的价值及其影响因素

目的:探讨血清总前列腺特异抗原(TPSA)、游离前列腺特异抗原(FPSA)检测及其比值(F/T)在BPH及前列腺癌(PCa)诊断中的应用价值,并观察各种因素对BPH患者TPSA值变化的影响。方法:对138例BPH患者及35例PCa患者血清TPSA、F/T的差异进行比较;另观察几种因素对298例BPH患者的影响作用。结果:总体比较两组间TPSA及F/T均有统计学意义;而在灰区(4μg/L相似文献   

前列腺增生症中血管内皮生长因子C的表达与血清前列腺特异抗原的相关性

目的探讨不同前列腺特异抗原(PSA)水平组的前列腺组织中血管内皮生长因子C(VEGF-C)的表达有无差异,VEGF-C与PSA、前列腺体积等有无相关性等,为目前临床上常用的PSA分组方法提供依据或提出新的见解。方法收集本院2011年6月至2013年6月住院的前列腺增生症(BPH)患者150例,术前测定血清PSA值,根据总PSA(tPSA)及PSA比值(f/tPSA)分为5组,术后获取前列腺组织,用免疫组化法检测VEGF-C的表达情况。结果在全部组织中,VEGF-C阴性、弱阳性、阳性表达率分别为17.3%、55.3%和27.4%。各PSA组间表达差异有显著性意义,其表达水平与年龄无关,与前列腺体积、血清总PSA及PSA密度呈正相关。结论 VEGF-C可促进前列腺组织增生,从而促进血清PSA分泌,前列腺组织中VEGF-C的表达可作为预测前列腺术后复发及恶变几率的指标之一。     

Correlation of serum PSA and Gleason score in Nigerian men with prostate cancer

Objective  Prostate cancer is an important cause of morbidity and mortality worldwide. While the predisposing factors are not fully understood, African descent is an important risk factor, and prostate cancer has become the number-one cancer in Nigerian men. This was a retrospective study of the correlation between serum prostate specific antigen (PSA) and Gleason grade and score in patients of Nigerian descent. Patients and Methods  The University College Hospital (UCH) Ibadan Cancer Registry was used to identify and quantify the incidence of prostate cancers occurring between 1998 and 2000. The histological slides of appropriate cases were reviewed to confirm the Gleason grade and score. The serum PSA values were retrieved from the patients' case notes and laboratory files. The data obtained were subjected to statistical analysis to look for associations and correlations. Results  The study included 67 men with prostate adenocarcinoma and PSA measurements who were diagnosed and treated at the UCH Ibadan between January 1998 and December 2000. There was a positive correlation between serum PSA and Gleason grade, as well as between serum PSA and Gleason score in our cohort of Nigerian African men with prostate cancer. PSA levels were significantly lower in patients with stage B disease than in patients with stage D disease. Conclusion  Serum PSA is significantly higher in metastatic than in localized disease. Further studies are necessary to determine biomarkers that complement serum PSA and the Gleason grading system in the prognostication of prostate cancer in African patients.     

Comparative study of plasma steroid and steroid glucuronide levels in normal men and in men with benign prostatic hyperplasia

Plasma steroids were analyzed in 16 normal men and in 10 men with prostatic benign hyperplasia (BPH). The steroids measured by radioimmunoassay include pregnenolone, 17-OH-pregnenolone, dehydroepiandrosterone, androst-5-ene-3 beta, 17 beta-diol, testosterone, dihydrotestosterone, androstane-3 alpha, 17 beta-diol, androstane-3 beta, 17 beta-diol, estrone, and estradiol as well as their glucuronide derivatives. In addition, cortisol and the sulphoconjugated form of dehydroepiandrosterone were determined. Whereas the levels of pregnenolone, pregnenolone glucuronide and 17-OH-pregnenolone glucuronide are not different in the two groups, the levels of 17-OH-pregnenolone in the BPH group (0.87 +/- 0.07 ng/ml) exceed by two-fold (p less than 0.01) those observed in normal men. Plasma dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol concentrations are markedly elevated in the BPH group (1.49 +/- 0.23 and 0.55 +/- 0.08 ng/ml vs the control groups 0.43 +/- 0.11 and 0.31 +/- 0.05 ng/ml, respectively). Since the plasma cortisol and pregnenolone levels are comparable in these two groups, our data suggest that the elevation of plasma 17-OH-pregnenolone, dehydroepiandrosterone, and androst-5-ene-3 beta, 17 beta-diol reflects an increase of adrenal 17-hydroxylase activity in patients with BPH. A slight increase of the plasma dihydrotestosterone and androsterone glucuronide concentration is also observed in men with BPH, indicating an increase of 5 alpha-reduced androgen formation. We have also observed, in the BPH group, a 50% decrease (p less than 0.01) of plasma glucuronidated androst-5-ene-3 beta, 17 beta-diol, estrone, and estradiol levels, suggesting that the transformation of unconjugated estrogenic steroids into glucuronide derivative is inhibited in BPH patients. In summary, our data indicate that adrenal C-19 steroids might be involved in the process of BPH. Furthermore, whereas the estrogen glucuronide formation is diminished in men with BPH, the prostatic androgen metabolism as reflected by plasma dihydrotestosterone and androsterone glucuronide concentrations seems to be increased.     

Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: a multicentre study

OBJECTIVES: To evaluate the relationship between prostate specific antigen (PSA) and prostate volume (PV) in Korean men, as PV is a key predictor of both disease progression and response to medical therapy in patients with benign prostatic hyperplasia (BPH), and PSA has been suggested as a proxy marker to estimate the total PV, mainly in Caucasians. PATIENTS AND METHODS: From 1999 to 2004, men aged 50-79 years with lower urinary tract symptoms (LUTS) and BPH were enrolled into this multicentre study. The analyses included 5716 patients presenting to 11 medical centres with LUTS (International Prostate Symptom Score >8, peak urinary flow rate <15 mL/s); they had a mean age of 64.3 years, mean baseline PV of 36.9 mL, and mean baseline PSA level of 2.2 ng/mL. Men with a baseline PSA of >10 ng/mL were excluded, to reduce the likelihood of including occult prostate cancer. A biopsy was taken in those with suspicious findings on a digital rectal examination or serum PSA level of >4 ng/mL, to exclude prostate cancer. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to predict threshold PV in men with BPH. RESULTS: The PV and serum PSA level had an age-dependent log-linear relationship, the strength of which increased with age. The ROC curve analysis showed that PSA had good predictive value for various prostate volume thresholds (30, 40 and 50 mL). CONCLUSIONS: The PSA-PV relationship in Korean men is similar to that in Caucasians, but Korean men have a slightly lower PSA level and a smaller PV than Caucasians. The approximate age-specific criteria for detecting Korean men with a PV of >40 mL were a PSA level of >1.3 ng/mL, >1.7 ng/mL and >2.0 ng/mL for men with BPH in their sixth, seventh and eighth decade, respectively.     

Prostate cancer detection in men with a 'normal' total prostate-specific antigen (PSA) level using percentage free PSA: a prospective screening study

OBJECTIVE: To assess the utility of percentage free/total prostate-specific antigen (f/tPSA) levels for detecting prostate cancer in a prospectively screened population of men with a 'normal' total PSA level. PATIENTS AND METHODS: Men aged 50-65 years were contacted via their general practitioner and invited for prostate cancer screening. All had their total and f/tPSA levels measured; those meeting the biopsy criteria (PSA 1.1-3.99 ng/mL and f/tPSA < or = 20%) were offered a biopsy. The cancer detection rate was then evaluated and compared with other methods of detection. In all, 773 men were screened, of whom 115 met the criteria and agreed to undergo a prostate biopsy. RESULTS: Cancer was detected in 13 of the 115 men (11.3%) of whom most would have been missed by lowering the age-adjusted threshold for total PSA to 2.5 ng/mL. There was no significant difference in total and f/tPSA values in men with and without prostate cancer. Those cancers that could be evaluated were found to be clinically significant. CONCLUSION: In this study prostate cancer was detected solely on the basis of a low f/tPSA value. Most men with cancer would have been missed by simply lowering the age-adjusted threshold for total PSA. Using the f/tPSA level may allow the detection of clinically significant cancer in men at a time when they are most likely to benefit from treatment.     

f/tPSA比值对tPSA值为2.6～4.0ng/ml前列腺癌的诊断意义

目的探讨利用血清游离前列腺特异性抗原(fPSA)和总前列腺特异性抗原(tPSA)的比值(f/tPSA),提高tPSA2.6～4.0ng/ml前列腺癌的诊断率的价值。方法对117例tPSA在2.6～4ng/ml可疑前列腺癌患者行直肠B超引导下前列腺穿刺活检,对患者血清tPSA,fPSA及f/t PSA值及其他临床病理资料进行统计学分析。结果经病理诊断良性前列腺增生(BPH)82例和前列腺癌35例,35例癌中Gleason score≤4分共6例(17%),Gleason score5-7分和8-10分别为22例(63%)和7例(20%)。前列腺癌的f/tPSA明显高于BPH(P＜0.01),以f/tPSA0.22为界值,诊断癌的特异性为83%,敏感性为71%,阳性预测值为68%。结论f/t PSA作为一项辅助检查可提高tPSA 2.6～4.0ng/ml前列腺癌的诊断率。     

Association of polymorphisms within androgen receptor, 5alpha-reductase,and PSA genes with prostate volume,clinical parameters,and endocrine status in elderly men

BACKGROUND: The aim of this study was to assess the impact of polymorphisms of three genes within the androgen pathway on prostate volume, clinical parameters, and endocrine status. METHODS: Elderly men with lower urinary tract symptoms underwent clinical and endocrine work-up. In parallel, polymorphisms within the 5alpha-reductase gene (SRD5A2 V89L and A49T), the androgen receptor gene (AR; number of CAG repeats), and the prostate specific antigen (PSA) gene (A --> G substitution at position-158) were determined by polymerase chain reaction and restriction-length polymorphism analysis by using DNA from peripheral blood. RESULTS: A total of 190 men (66.5 +/- 9.2 yr) were analyzed. The number of CAG repeats within the AR and the PSA polymorphism revealed no associations to clinical and endocrine parameters. Individuals carrying the mutated SRD5A2 A49T allele (5.3% of the total population) had larger prostates (54.1 vs. 39.3 ml), higher PSA levels (12.2 vs. 4.3 ng/ml), and a 35% reduction in prostatic stroma/epithelial cell ratio. Men with the mutated SRD5A2 V89L gene had lower testosterone levels. CONCLUSIONS: In contrast to prostate cancer, polymorphisms within AR and PSA genes do not seem to be of importance for benign prostatic hyperplasia. Polymorphisms within the 5alpha-reductase gene are interesting biomarkers for the development of benign prostatic hyperplasia and benign prostatic enlargement.     

Mitochondrial DNA in serum of patients with prostate cancer: a predictor of biochemical recurrence after prostatectomy

OBJECTIVE

To investigate the role of circulating mitochondrial DNA (mtDNA) in patients with localized prostate cancer, as recent reports show that patients with advanced cancer have increased levels of mtDNA.

PATIENTS AND METHODS

DNA was isolated from the serum of 100 patients with prostate cancer and 18 with benign prostate hyperplasia (BPH). A quantitative real‐time polymerase chain reaction was used to amplify 79 bp and 230 bp fragments of the mitochondrial 16s‐RNA gene, the short fragment representing total mtDNA, including mtDNA truncated by apoptosis, and the long fragment representing mostly mtDNA from other cell death entities. mtDNA integrity was defined as the ratio of long to short mtDNA fragments.

RESULTS

The short and long mtDNA levels, and mtDNA integrity, were similar in patients with BPH and cancer (P = 0.940, 0.211 and 0.441, respectively), and were not correlated with clinical or pathological variables, e.g. age, prostate‐specific antigen (PSA) level, cT stage, pT stage, seminal vesicle infiltration, lymph node invasion, or Gleason score (P = 0.075 to 0.961). However, patients with high levels of short mtDNA (>75th percentile) had a greater risk of PSA progression and this variable was the strongest predictor of PSA recurrence in a multivariate Cox analysis (P = 0.023; hazard ratio 0.31; 95% confidence interval 0.113–0.851).

CONCLUSION

Circulating mtDNA levels did not distinguish between patients with prostate cancer or BPH. However, there was a significant increase in short mtDNA fragments in patients with early PSA recurrence after radical prostatectomy.     

前列腺增生患者前列腺液白细胞数量与血清PSA含量的关系

目的探讨前列腺增生患者前列腺按摩液（EPS）中白细胞含量与血清前列腺特异性抗原（PSA）升高之间的关系。方法 ELISA法测定78例前列腺增生患者的血清PSA含量,术前通过前列腺按摩获取前列腺液,并行前列腺液中的白细胞计数。分析EPS中白细胞含量与血清PSA升高的相关性,并比较不同血清PSA水平间（〈4ng/mL、4~10ng/mL、≥10ng/mL）的EPS中白细胞含量差异。结果前列腺增生患者血清PSA与EPS中白细胞密度和总数呈正相关关系,血清PSA升高组EPS中白细胞含量明显高于血清PSA正常组。结论前列腺增生患者血清PSA与EPS中白细胞的含量呈正相关,前列腺增生患者的PSA值增高可能与前列腺液中的白细胞增高有关。     

前列腺癌患者血清睾酮水平与前列腺穿刺活检阳性的相关性

目的探讨血清总睾酮水平与前列腺穿刺活检阳性之间的相关性,为临床个体化治疗方案的选择提供理论依据。方法 2015年9月至2019年3月期间在汉中市人民医院泌尿外科接受前列腺穿刺活检的患者,收集患者的年龄、血清总前列腺特异性抗原(tPSA)及性激素等相关资料,观察这些指标对前列腺穿刺活检阳性率的影响。结果在113例患者中,前列腺癌(PCa)患者检出率共89例,穿刺阳性率为78.76%。与穿刺阴性组比较,患者血清tPSA[(12.42±4.64)vs.(5.35±1.66)ng/mL,P<0.001]和催乳素水平[(8.55±2.48)vs.(6.91±1.92)ng/L,P=0.003]升高与前列腺穿刺活检阳性有关,而总睾酮激素水平下降与前列腺穿刺活检阳性有关[(12.64±3.28)vs.(16.85±3.37)nmol/L,P<0.001]。多变量分析证实tPSA[P<0.001,OR=3.383(1.924~5.342)]和血清睾酮[P=0.038,OR=1.361(1.124~1.927)]是预测前列腺穿刺活检阳性的独立预测因子。受试者工作曲线(ROC)显示tPSA水平与前列腺穿刺阳性风险呈正相关,曲线下面积(AUC)为0.989,最佳截断值为8.022,敏感度和特异度分别为87.5%和98.88%;总睾酮激素水平与前列腺穿刺阳性风险呈负相关,AUC为0.786,最佳截断值为17.85,敏感度和特异度分别为66.67%和78.65%,差异具有统计学意义(P<0.001)。结论低血清睾酮激素与前列腺穿刺检测PCa的风险有关,这些结果可能揭示了PCa与睾酮两者关系的潜在机制。     

Correlation between serum prostate specific antigen and prostate volume in Taiwanese men with biopsy proven benign prostatic hyperplasia

PURPOSE: We studied the correlation between serum prostate specific antigen and the volume of different zones of the prostate in Taiwanese men with biopsy proven benign prostatic hyperplasia. MATERIALS AND METHODS: A total of 233 patients with a mean age of 71.4 years (range 42 to 89), serum prostate specific antigen less than 10 ng/ml and pathologically confirmed benign prostatic hyperplasia were enrolled in this study. Total prostate and transitional zone volumes were measured with transrectal ultrasonography. Peripheral zone volume was determined by subtracting transitional zone volume from total prostate volume. Correlations between patient age, total serum prostate specific antigen and the volume of each prostate zone were analyzed with the Pearson correlation coefficient. A linear regression model was used to determine the relationship between prostate specific antigen and prostate volume. The prostate specific antigen-prostate volume relationship in our patients was compared with published data on white and Japanese men. RESULTS: Age did not significantly correlate with serum prostate specific antigen and prostate volume. Serum prostate specific antigen significantly correlated with the volume of each prostate zone. After log transformation the Pearson correlation coefficient between total prostate specific antigen and the volume of the whole prostate gland, the transitional zone and the peripheral zone were 0.369, 0.377 and 0.272, respectively (p <0.001). Taiwanese men had lower prostate volume per unit prostate specific antigen comparing with white men, while the prostate specific antigen-total prostate volume relationship between Taiwanese and Japanese men was similar. CONCLUSIONS: In Taiwanese men with biopsy proven benign prostatic hyperplasia the volume of each prostate zone has significantly correlates with serum prostate specific antigen. The prostate specific antigen-total prostate volume relationship in Taiwanese men is different from that in white men. However, the prostate specific antigen-total prostate volume relationship between Taiwanese and Japanese men is similar.