Frequency of PSA-mRNA-bearing cells in the peripheral blood of patients after prostate biopsy

Transrectal ultrasound (TRUS) guided prostate biopsy is standard diagnostic procedure for prostate cancer (PCa). However, possibility of dissemination of cancer cells by biopsy is not negligible. To investigate this possibility, we examined prostate specific antigen (PSA)-bearing cells in peripheral blood of the 108 patients before and after prostate biopsy. Peripheral blood samples were obtained from 108 patients with elevated serum PSA (sPSA) levels, who had undergone sextant prostate biopsy using TRUS. The presence of PSA-mRNA bearing cells was examined using the nested RT-PCR method enabling detection of one LNCaP cell diluted in 1 ml of whole blood. Among 108 patients, 62 and 46 were diagnosed with benign prostatic hyperplasia (BPH) and PCa, respectively. PSA-mRNA was detected in 3 PCa cases but in no BPH patients before and after biopsy, and in 16 BPH (25.8%) and in 21 PCa (45.7%) patients only after biopsy (P< 0.01). The patients with positive mRNA before biopsy had higher sPSA (P< 0.001), and those after biopsy had higher sPSA and PSA density (PSAD) levels (P< 0.05). Positive PSA-mRNA cases had more cancer involved biopsy cores than the negative PSA-mRNA cases (P< 0.001). Although further investigations are needed, the present findings suggest that prostate biopsy might scatter prostate cells in the blood stream especially in cases with high sPSA and, thus, might contribute to tumour spreading in the cases of prostate cancer.     

分子标志物在前列腺癌早期诊断中的进展

较多的研究显示,血清PSA值指导前列腺癌(prostate cancer,Pca)早期诊断的优势不足,例如PSA值在4～10 ng/mL.时,Pca穿刺阴性率占70%～80%.然而,阴性的穿刺结果并不能完全排除肿瘤的存在.寻找敏感性和特异性更高的肿瘤生物标志物一直是Pca研究的热点.目前,PSA衍生物、PCA3、TMPRSS2:ETS、GSTP1、AMACR、COLPH2、EPCA和肌氨酸以及多瘤标的联合应用研究受到广泛关注.本文中我们综述了这些分子标志物的研究近况,展望了多瘤标组合在Pca早期诊断中的价值和应用前景,为Pca的早期诊断和预后监测提供参考.     

The clinical utility of measuring total PSA, PSA density, gamma-seminoprotein and gamma-seminoprotein/total PSA in prostate cancer prediction

BACKGROUND: To evaluate whether serum total prostate-specific antigen (PSA), PSA density (serum total PSA level divided by prostate volume), gamma-seminoprotein and gamma-seminoprotein/total PSA ratio could predict prostate cancer (PCa) prior to biopsy. METHODS: A total of 316 consecutive patients who had undergone transrectal prostate biopsy and/or transurethral resection were examined. The prostate volume was determined by transrectal ultrasonography (TRUS) and the ability of the above-mentioned four variables to distinguish PCa from benign prostatic hyperplasia (BPH) was evaluated. RESULTS: PCa was detected in 61 cases. Receiver-operating characteristic (ROC) analysis revealed that both the PSA density and serum total PSA were the most useful predictors of PCa among the four variables. For the patients with a serum total PSA level of 4.1-10.0 ng/ml, PSA density was significantly more accurate than total PSA (p < 0.005). An optimum PSA density value of 0.18 was chosen as a cutoff because it showed the highest sum of sensitivity and specificity, 92 and 54%, respectively. Using this PSA density cutoff, the number of biopsies could have been reduced to 57 from 63% when compared with a PSA density of 0.15. CONCLUSIONS: PSA density was significantly more accurate than other variables in predicting PCa. To avoid unnecessary biopsies, the PSA density cutoff value of 0.18 would be recommendable for determining a prostate biopsy for Japanese males with a serum total PSA level of 4.1-10.0 ng/ml.     

The risk of prostate cancer for men on aspirin,statin or antidiabetic medications

BackgroundA decreased risk of prostate cancer (PCa) has been suggested in men taking aspirin, statins and metformin, although the evidence has been conflicting. We estimated the association between prescribed medications, prostate specific antigen (PSA) levels and the risk of either any PCa or high-grade PCa.MethodsThis population-based cohort study included 185,667 men having a first recorded PSA test and 18,574 men having a first prostate biopsy in Stockholm County, Sweden for the period 2007–2012. Detailed clinical information including PSA levels, biopsy results, comorbidities and educational level were obtained from population-based registers. High-grade prostate cancer was defined as a Gleason score of seven or higher. Differences in PSA levels by medication status were estimated using linear regression on log PSA values. PCa risk was estimated using multivariate logistic regression.ResultsCompared with men who were not on medication, the PSA level at the first PSA test was lower among men using 75 mg/dose aspirin (−3.9% change in PSA concentration; 95% confidence interval (CI): −5.8 to −2.1), statin (−4.6%; 95% CI: −6.2 to −2.9), metformin (−14%; 95% CI: −17 to −12) and insulin (−16%; 95% CI: −18 to −14). Men using any statins had an increased risk of both high-grade PCa (odds ratio (OR) 1.25; 95% CI: 1.10–1.42) and PCa of any grade (OR 1.16; 95% CI 1.04–1.29). There were no significant associations between aspirin or any antidiabetic medication and the risk of PCa.ConclusionWe found no protective effect of aspirin, statins or antidiabetics in terms of risk for any PCa or high-grade PCa. Use of any statins was associated with an elevated risk of being diagnosed with high-grade prostate cancer.     

A comparative study on expression of prostatic inhibin peptide, prostate acid phosphatase and prostate specific antigen in androgen independent human and rat prostate carcinoma cell lines

Prostatic inhibin peptide (PIP), consisting of 94 amino-acid residues is synthesized and secreted by the prostate gland. Previous studies on immuno-histochemical localization of PIP in primary prostatic tumor and their metastasis, have documented the value of this peptide as a tumor marker for diagnosis of prostate cancer (PCa). The present study was undertaken to compare the expression of PIP with that of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) in androgen independent human PCa cell lines (PC-3, DU-145 and TSU-Prl) by immunoperoxidase technique. The results of the study indicated that the staining for PIP was more intense than that of PSA and PAP. The PSA staining was either weakly positive (PC-3) or totally absent (TSU-Prl and DU-145) while PAP staining was intense in PC-3 and moderate in the other two human cell lines. The intense staining observed for PIP in all of the androgen independent cell lines suggests that the synthesis and secretion of PIP is not primarily dependent on androgens. Furthermore, expression of these markers in Dunning rat cultured adenocarcinoma cell lines and tumors were studied. Positive staining for all three human tumor associated antigens (PIP, PSA and PAP) cross-reacting with the Dunning rat PCa cell lines and the tumors, suggest the suitability of this model for preclinical screening of various therapeutic agents.     

Postoperative radiotherapy in prostate cancer: When and how? – An update review

Radical prostatectomy (RP) has been found to be curative in most cases of prostate cancer (PCa); however, 20–40% of patients have a biochemical recurrence (BCR) of the disease. Prostatic specific antigen prostate–specific antigen (PSA) levels are used to assess patient prognosis after surgery; however, there is no consensus about the optimal PSA level that defines BCR. Detection of very low volume disease and early detection of the disease are very important predictors for clinical outcomes in BCR, as early salvage radiation therapy (SRT) provides a possibility of a cure. The aim of this study is to review briefly about important and controversies in radiotherapy after radical prostatectomy. No guideline exists to select ideal patients for each treatment, but there are tools currently being developed; genetic tests and prostate-specific membrane antigen (PSMA) positron emission tomography (PET) may be able to identify patients with worse outcomes who would benefit from more treatment.     

Identification of candidate prostate cancer biomarkers in prostate needle biopsy specimens using proteomic analysis

Although serum prostate specific antigen (PSA) is a well-established diagnostic tool for prostate cancer (PCa) detection, the definitive diagnosis of PCa is based on the information contained in prostate needle biopsy (PNBX) specimens. To define the proteomic features of PNBX specimens to identify candidate biomarkers for PCa, PNBX specimens from patients with PCa or benign prostatic hyperplasia (BPH) were subjected to comparative proteomic analysis. 2-DE revealed that 52 protein spots exhibited statistically significantly changes among PCa and BPH groups. Interesting spots were identified by MALDI-TOF-MS/MS. The 2 most notable groups of proteins identified included latent androgen receptor coregulators [FLNA(7-15) and FKBP4] and enzymes involved in mitochondrial fatty acid beta-oxidation (DCI and ECHS1). An imbalance in the expression of peroxiredoxin subtypes was noted in PCa specimens. Furthermore, different post-translationally modified isoforms of HSP27 and HSP70.1 were identified. Importantly, changes in FLNA(7-15), FKBP4, and PRDX4 expression were confirmed by immunoblot analyses. Our results suggest that a proteomics-based approach is useful for developing a more complete picture of the protein profile of PNBX specimen. The proteins identified by this approach may be useful molecular targets for PCa diagnostics and therapeutics.     

PSAD和游离/总PSA比值在前列腺癌诊断中的意义

 目的　比较研究前列腺特异抗原(PSA)、PSA密度(PSAD)和游离/总PSA比值(F/TPSA)在前列腺癌诊断中的价值。方法　41例前列腺增生和22例前列腺癌患者,术前用放免法测定血清PSA和游离PSA。所有患者经直肠腔内B超测出前列腺体积,求得PSAD,用t检验比较分析。结果　前列腺癌组的PSA、PSAD均显著高于前列腺增生组(PSA：46.3±33.8μg/Lvs7.04±6.91μg/L,P=0.000021;PSAD：1.43±1.21μg。L-1。ml-1vs0.14±0.15ng。ml-1。ml-1,P=0.000055)。两组的F/TPSA比值无显著差异(0.18±0.11vs0.22±0.18,P=0.34)。结果　PSA和PSAD是鉴别前列腺癌的良好指标,对于PSA可疑者,PSAD有助于区分前列腺癌和前列腺增生,本组游离/总PSA比值不能帮助鉴别诊断。     

智能融合成像技术对中低风险前列腺特异性抗原人群的临床显著性前列腺癌诊断研究

目的:探讨核磁联合经直肠超声计算机软件融合成像引导前列腺靶向穿刺活检(software guided magnetic resonance imag?ing-ultrasound fusion targeted biopsies,MRUS-TB)在中低风险前列腺特异性抗原(prostate-specific antig...     

A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue

Prostate-specific antigen (PSA) is a widely used serum marker for prostate cancer (PCa), but in the critical diagnostic range of 4-10 ng/ml it has limited specificity for distinguishing early PCa from benign prostatic hyperplasia (BPH). PSA in serum is comprised of a variety of both "free" and "complexed" forms that have been used to improve the specificity of PSA for prostate cancer detection. We previously reported that pro PSA (pPSA), the zymogen or precursor form of PSA, is a component of free PSA in the serum of PCa patients. In the current study, we examined prostate tissues to understand the origin and specificity of pPSA. PSA was immuno-affinity purified from matched sets of prostate tissues including peripheral zone cancer (PZ-C); peripheral zone noncancer; and benign tissue from the transition zone (TZ), the primary site of BPH within the prostate. We found that pPSA is differentially elevated in PZ-C, but is largely undetectable in TZ. N-terminal sequencing revealed that the pPSA was comprised primarily of [-2]pPSA and minor levels of [-4]pPSA, containing pro leader peptides of 2 and 4 amino acids, respectively. The median value of pPSA was 3% in PZ-C and 0% (undetectable) in TZ (P < 0.0026). No pPSA was detected in 13 of 18 transition zone specimens (72%), but only 2 of the 18 matched cancer specimens (11%) contained no measurable pPSA. These results demonstrate that pPSA is more highly correlated with prostate cancer than with BPH. The pPSA in serum may represent a more cancer-specific form of PSA that could help distinguish prostate cancer from BPH.     

经直肠超声引导前列腺穿刺活检方案的合理选择

目的 分析经直肠超声(TRUS)和前列腺特异性抗原(PSA)及其相关参数在前列腺穿刺活检中的作用,探讨个体化前列腺穿刺方案的可行性。方法 回顾性分析195例患者的首次穿刺活检资料,所有患者均采用系统8点穿刺方案,并对可疑病灶增加1~2点。依据穿刺病理结果,分析前列腺癌(PCa)检出率与TRUS、PSA及其相关参数的关系。结果 195例患者中检出PCa 98例(50.3%),其中PSA 4~10 ng/mL组45例,检出PCa 16例(35.6%),其中TRUS(+)且PSATZ≥0.35 ng/mL² 210例均证实为PCa;PSA＞10 ng/mL组150例,检出PCa 82例(54.7%)。PSA 4~10 ng/mL与PSA＞10 ng/mL两组患者PCa检出率差异有统计学意义(P＜0.05),且两组中TRUS(+)与TRUS(-)患者相较PCa检出率差异均有统计学意义(P＜0.01)。结论 依据TRUS、PSA及其相关参数制定个体化前列腺穿刺方案是可行的。     

A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer

Prostate-specific antigen (PSA) is a widely used serum marker for prostate cancer (PCa) but has limited specificity for distinguishing early PCa from benign prostatic hyperplasia, because both PCa and benign prostatic hyperplasia release PSA into the serum. We have identified previously a truncated form of precursor PSA (pPSA) in prostate tumor extracts consisting of PSA with a serine-arginine pro leader peptide ([-2]pPSA) instead of the normally expressed 7 amino acid pro leader peptide. In the current study we developed monoclonal antibodies to detect [-2]pPSA and other isoforms of pPSA for Western blot analysis. PSA was immunoaffinity purified from 100 to 200 ml of serum from each of five men with biopsy-proven cancer and three biopsy-negative men, all with total PSA levels in the diagnostically relevant range near 10 ng/ml. The truncated [-2]pPSA was estimated to range from 25 to 95% of the free PSA in the five PCa samples but only 6-19% of the free PSA in the biopsy-negative men. Immunohistochemical studies showed positive staining for [-2]pPSA in PCa epithelium and that [-2]pPSA was enriched in cancer cell secretions. In vitro activation studies showed that human kallikrein 2 and trypsin readily activated full-length pPSA but were unable to activate [-2]pPSA to mature PSA. Thus, [-2]pPSA, once formed, is a stable but inactive isoform of PSA. Truncated [-2]pPSA may represent an important new diagnostic marker for the early detection of PCa.     

血清PSA联合PSAD检测对前列腺癌的诊断价值

目的:探讨血清前列腺特异抗原（PSA）、前列腺特异抗原密度（PSAD）对前列腺癌的诊断价值。方法:检测经病理确诊的57例前列腺癌、125例前列腺增生患者的血清PSA。经直肠超声测定其前列腺的体积（PV）并计算PSAD。结果:前列腺癌组患者的PSA、PSAD明显高于前列腺增生组(P<0.05)。PSA值在4.1-10.0,10.1-20.0,>20.0ng/ml区间时PCa诊断率分别为8.8%,36.8%,54.4%。前列腺癌组的ROC曲线图中PSAD的AUC值（0.682）高于PSA的AUC值（0.601）,当取PSAD≥0.18ng/（ml·cm3）时,敏感性为84.5%,特异性为78.6%。比较58例重复穿刺患者的PSA、PSAD,只有PSAD差异有统计学意义(P<0.05)。结论:PSA动态监测结合PSAD是重复穿刺的重要参考指标,PSAD是PSA对前列腺癌诊断的有益补充。     

前列腺癌ADC值与血清IL-6、VEGF、PSA的相关性分析

目的:探讨前列腺癌（prostate cancer,PCa）患者表观扩散系数（apparent diffusion coefficient,ADC）与血清血管内皮生长因子（vascular endothelial growth factor,VEGF)、白细胞介素-6（interleukin-6,IL-6）、前列腺特异性抗原（prostate specific antigen,PSA）的相关性。方法:收集2016年1月至2017年12月经临床病理证实且资料齐全的60例PCa患者,将其分成两组,经SPECT/CT全身骨显像诊断为30例骨转移患者及30例未发生全身骨转移患者。采集全部患者的肘静脉血,利用酶联免疫吸附法（ELISA法）及化学发光法测定血清VEGF、IL-6及PSA水平。结果:60例PCa患者ADC值与血清VEGF、IL-6及PSA存在负相关(r=-0.431,P=0.001＜0.005;r=-0.534,P=0.000<0.005;r=-0.593,P=0.000＜0.005),骨转移组血清VEGF、IL-6及PSA水平明显高于无骨转移组（P＜0.05）。结论:血清VEGF、IL-6及PSA与PCa发生、进展及转移关系密切。PCa患者ADC值与血清VEGF、IL-6、PSA的相关性可以作为评估患者病情进展程度的一个指标。     

Biology of prostate-specific antigen.

Prostate-specific antigen (PSA) is an androgen-regulated serine protease produced by both prostate epithelial cells and prostate cancer (PCa) and is the most commonly used serum marker for cancer. It is a member of the tissue kallikrein family, some of the members of which are also prostate specific. PSA is a major protein in semen, where its function is to cleave semenogelins in the seminal coagulum. PSA is secreted into prostatic ducts as an inactive 244-amino acid proenzyme (proPSA) that is activated by cleavage of seven N-terminal amino acids. PSA that enters the circulation intact is rapidly bound by protease inhibitors, primarily alpha1-antichymotrypsin, although a fraction is inactivated in the lumen by proteolysis and circulates as free PSA. This proteolytic inactivation, as well as the cleavage of proPSA to PSA, is less efficient in PCa. Serum total PSA levels are increased in PCa, and PSA screening has dramatically altered PCa presentation and management. Unfortunately, although high PSA levels are predictive of advanced PCa, a large fraction of organ-confined cancers present with much lower total PSA values that overlap those levels found in men without PCa. Measurement of free versus total PSA can increase specificity for PCa, and tests under development to measure forms of proPSA may further enhance the ability to detect early-stage PCa. PSA is also widely used to monitor responses to therapy and is under investigation as a therapeutic target. Finally, recent data indicate that there may be additional roles for PSA in the pathogenesis of PCa.     

The impact of socioeconomic status on stage specific prostate cancer survival and mortality before and after introduction of PSA test in Finland

Socioeconomic status (SES) has an impact on prostate cancer (PCa) outcomes. Men with high SES have higher incidence and lower mortality of PCa versus lower SES males. PCa cases diagnosed in Finland in 1985–2014 (N = 95,076) were identified from the Finnish Cancer Registry. Information on education level (EL) was obtained from Statistics Finland. EL was assessed with three‐tiered scale: basic, upper secondary and higher education. PCa stage at diagnosis was defined as localized, metastatic or unknown. Years of diagnosis 1985–1994 were defined as pre‐PSA period and thereafter as post‐PSA period. We report PCa‐specific survival (PCSS) and relative risks (RR) for PCa specific mortality (PCSM) among cancer cases in Finland, where healthcare is 100% publicly reimbursed and inequality in healthcare services low. Men with higher EL had markedly better 10‐year PCSS: 68 versus 63% in 1985–1994 and 90 versus 85% in 1995–2004 compared to basic EL in localized PCa. The RR for PCSM among men with localized PCa and higher EL compared to basic EL was 0.76(95%confidence interval (CI) 0.66–0.88) in 1985–1994 and 0.61(95%CI 0.53–0.70) in 1995–2004. Variation in PCSS and PCSM between EL categories was evident in metastatic PCa, too. The difference in PCSM between EL categories was larger in the first 10‐year post‐PSA period than before that but decreased thereafter in localized PCa, suggesting PSA testing became earlier popular among men with high EL. In summary, higher SES/EL benefit PCa survival both in local and disseminated disease and the effect of EL was more pronounced in early post‐PSA period.     

Progression of prostate cancer: diagnostic and prognostic utility of prostate-specific antigen, alpha2-macroglobulin, and their complexes

We previously reported cases of advanced prostate cancer (PCa) in which serum alpha2-macroglobulin (alpha2M) levels were markedly decreased to less than approximately 50 mg/dl whereas serum prostate-specific antigen (PSA) levels were remarkably increased. These cases were not complicated with disseminated intravascular coagulation (DIC). In this study, we measured serum PSA and alpha2M in 108 patients with either benign prostatic hyperplasia (BPH) or PCa to elucidate the relationship between PSA, i.e. the serum protease derived from the prostatic tissue, and alpha2M, i.e. the protease inhibitor that was the most abundantly contained in serum. alpha2M was determined by ELISA, total PSA and PSA-alpha1-antichymotrypsin (PSA-ACT) by EIA, and free-PSA by RIA in 44 patients with untreated BPH and 64 patients with untreated PCa. The ready association of alpha2M and PSA was assessed using Western blotting to identify complexes of the two. Levels of total serum PSA correlated positively with those of PSA-ACT in PCa (r = 0.99, p < 0.001), and both levels increased with advancing stage of disease. In contrast, the serum-free PSA/total PSA ratio (free/total PSA) and alpha2M levels decreased as the disease progressed. However, only the free/total PSA ratio attained significant difference for localized cancer in stage T1,2 versus BPH (p < 0.05). In stage M1b PCa, in which serum PSA levels were very high, there was a negative correlation between the total PSA and alpha2M values (r = -0.57, p < 0.05). In addition, serum alpha2M levels tended to decrease with progression of PCa. Serum total PSA levels correlated tightly with serum PSA-ACT levels. It is suggested that PSA is usually complexed with ACT in the serum. Free/total PSA was useful for differential diagnosis between early cancer and BPH. Levels of serum alpha2M of less than 50 mg/dl in PCa patients may indicate a possibility of bone metastases.