Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen

Angiostatin, a potent inhibitor of angiogenesis, tumour growth and metastasis, is a biologically active fragment of plasminogen, containing the kringle domains 1-4. It is generated from plasminogen by limited proteolysis. We show that prostate-specific antigen (PSA), a serine proteinase secreted by human prostate and human prostate cancer cells, is able to convert Lys-plasminogen to biologically active angiostatin-like fragments, containing kringles 1-4, by limited proteolysis of peptide bond Glu439-Ala440 in vitro. In an in vitro morphogenesis assay, the purified angiostatin-like fragments inhibited proliferation and tubular formation of human umbilical vein endothelial cells with the same efficacy as angiostatin. This finding might help to understand growth characteristics of prostate cancer, which usually has low microvessel density and slow proliferation.     

Angiostatin generation by human tumor cell lines: involvement of plasminogen activators

Angiostatin is a tumor-derived angiogenesis inhibitor consisting of an internal fragment of plasminogen. Little is known about the production of angiostatin by human tumors. In this study, we examined the in vitro angiostatin-generating capacities of a panel of human tumor cell lines (total n = 75) and the proteolytic molecule(s) involved. Angiostatin formation was determined by assessing the level of plasminogen digestion in conditioned medium by Western-blot analysis. We found that the capacity to produce angiostatin is a common feature of many cell lines, depending on the tumor type. All 6 bladder-carcinoma and 6 out of 7 prostate-carcinoma cell lines showed intermediate to potent angiostatin-generating activity. In contrast, only 2 out of 7 colon-carcinoma and 2 out of 9 renal-cell carcinoma cell lines were able to generate angiostatin at intermediate levels. Out of 25 melanoma cell lines, only one line failed to generate angiostatin. In the other cell-line groups (cervix, breast and ovary), angiostatin formation varied. Remarkably, angiostatin bands were not of equal size in all plasminogen digests. Since reported data have indicated that plasminogen activators (uPA and tPA) were able to excise the angiostatin fragment from the plasminogen parent molecule via plasmin generation, we determined levels of uPA and tPA and PAI-1 antigen in the conditioned media, and correlated the results with angiostatin-generating capacity. Whereas prostate- and bladder-carcinoma lines capable of generating high levels of angiostatin showed high uPA levels, angiostatin generation in melanoma cell lines was correlated with tPA levels. Generally, angiostatin non-producers did not express uPA or tPA. In 6 out of 75 cell lines, however, we found angiostatin generation combined with low or absent levels of plasminogen activator, suggesting the involvement of alternative proteolytic pathways in the generation of angiostatin.     

Predicting prostate carcinoma volume and stage at radical prostatectomy by assessing needle biopsy specimens for percent surface area and cores positive for carcinoma, perineural invasion, Gleason score, DNA ploidy and proliferation, and preoperative serum prostate specific antigen: a report of 454 cases

BACKGROUND: DNA ploidy analysis of prostate carcinoma is a generally accepted prognostic marker, particularly when tumors are extraprostatic at the time of surgery. In the past decade, the DNA content of prostate carcinoma frequently has been assessed in needle biopsy specimens based on the assumption that ploidy, in conjunction with serum prostate specific antigen (PSA) and Gleason score, provides valuable pretreatment information. METHODS: Between 1995 and 1998, the authors identified a consecutive series of 454 prostate carcinomas, verified by needle biopsies and followed by radical retropubic prostatectomies (RRP). Based on the needle biopsies, DNA ploidy and MIB-I immunostaining were measured by digital image analysis (DIA). The authors also quantified the percent of nuclei in four categories from the DNA histograms. The DIA data were combined with the age of the patient at diagnosis, the serum PSA, Gleason score, percent cores and percent surface area positive for carcinoma, and status of perineural invasion in multivariate models using tumor volume and risk of extraprostatic extension (EPE) at RRP as the outcome variables. RESULTS: Joint predictors of tumor volume at RRP were the percent cores positive for carcinoma (P < 0.0001), serum PSA (P < 0.0001), the percent surface area positive for carcinoma (P < 0.0001), and the percent nuclei classified by DNA quantification to be in the "S-phase" category (P = 0.03). Joint predictors of risk of EPE were the percent cores positive for carcinoma (P = 0.0004), a Gleason score of 7 (P < 0.0001), a Gleason score of 8 or 9 (P < 0.0001), serum PSA (P = 0.006) and perineural invasion (P = 0.02). CONCLUSIONS: After adjusting for traditional prognostic markers, DNA ploidy interpretation and MIB-I quantitation of prostate carcinoma did not appear to jointly predict either outcome variable in the multivariate models. However, a quantitative measure related to both ploidy and proliferation, the percent of nuclei in the putative "S-phase" category from the DIA histograms, was found to jointly predict for tumor volume.     

Angiostatin and Angiostatin-related Proteins

The study of angiogenesis, and the promise of angiogenesis inhibition as a means of cancer therapy, has dramatically accelerated in the last several years. The discovery and publication of angiostatin by O'Reilly and colleagues in Judah Folkman's lab in 1994 has greatly contributed to this progress. Angiostatin is a kringle-containing fragment of plasminogen, which is a potent inhibitor of angiogenesis in-vivo, and selectively inhibits endothelial cell proliferation and migration in-vitro. There have been a number of proposed proteolytic mechanisms by which plasminogen is cleaved to form angiostatin, and the resulting cleavage products contain different NH₂ and COOH termini of the angiostatin. Therefore, it is possible that there are more than one angiostatin isoforms (or angiostatin-related proteins) which occur in one or more normal or pathophysiological situations. It is also possible that some of the proteolytic processes which can convert plasminogen to angiostatin-like proteins are simply laboratory artifacts. Angiostatin-related proteins exert potent endothelial cell inhibitory activity, including the induction of apoptosis, and inhibition of migration, and the intact kringle structures are believed to be necessary for the antiangiogenic activity. Efforts are now underway to translate the understanding of the biology of angiostatin to clinical practice, which includes phase 1 clinical trials with recombinant angiostatin K1–3 (kringles 1–3) as well as phase 1 trials of an Angiostatin Cocktail, which induces the direct in vivo conversion of plasminogen to angiostatin 4.5 (kringles 1–4, plus most of kringle 5). The translation of the basic science of angiostatin and angiostatin-related proteins to clinical trial promises to provide an important new tool in the treatment of cancer by inhibition of angiogenesis.     

PSA正常的前列腺癌患者临床特点分析北大核心

目的:根据PSA低于4 ng/mL的前列腺患者的临床资料及随访情况,探讨此类前列腺癌患者的临床特点,对PSA正常的前列腺癌患者的诊断及治疗提供临床思路。方法:收集2013年01月至2018年01月西京医院及西安交通大学第二附属医院收治的35例PSA正常的前列腺癌患者的临床资料。观察此类患者的发病情况、临床就诊特征、病理学特征、危险程度分级、Gleason评分、治疗及预后。总结PSA正常的前列腺癌患者的临床诊断及治疗特征。结果:PSA正常的前列腺癌患者占同期确诊前列腺癌的5.72%。35例患者中,28例主要因为排尿困难为症状就诊,血清PSA 0.91~3.96 ng/mL,平均(2.73±0.77)ng/mL。f/tPSA>0.16为5例,占14.3%,前列腺体积平均值为(68.4±36.66)cm^(3),12例患者行磁共振检查,10例报告提示前列腺癌可能,2例报告为前列腺增生,未发现前列腺癌影像学证据。13例患者行B超引导下经直肠前列腺穿刺活检术,11例患者病理诊断为前列腺癌,2例患者未发现肿瘤证据。行经尿道前列腺电切术共24例,其中包括2例穿刺活检未发现肿瘤证据患者,并于术后12周行前列腺癌根治性手术。病理结果显示:29例为前列腺腺癌,2例为肉瘤,2例为小细胞癌,1例为鳞癌,1例为黏液腺癌。切缘阳性10例(28.6%),侵犯精囊9例(25.71%),淋巴结阳性13例(37.14%)。TNM分期:T期6例,T期10例,T期7例,T期12例。危险度分级:低危患者5例(14.28%),中危9例(25.71%),高危21例(60%)。Gleason评分7分以下为6例(20.69%),7分为9例(31.03%),7分以上为14例(48.28%)。随访时间13~72月,术后密切监测PSA水平,术后生化复发共13例(37.14%),21例患者死亡,16例为前列腺特异性死亡。术后1、2、3年的生存率分别为:97.14%,88.57%,77.14%。结论:PSA正常的前列腺癌因无明显的临床就诊特征,精囊侵犯检出率高、Gleason评分及危险程度均偏高,3年生存率仅为77.14%。对于此类患者,不应以惯性思维认为PSA水平低,临床风险小,应更积极的完善检查,调整治疗策略,给此类患者带来更多的生存获益。     

Can initial prostate specific antigen determinations eliminate the need for bone scans in patients with newly diagnosed prostate carcinoma? A multicenter retrospective study in Japan

BACKGROUND: The objective of the current study was to assess rigorously whether serum prostate specific antigen (PSA) determination can eliminate the need for bone scans in Japanese patients with newly diagnosed prostate carcinoma with serum PSA levels < or = 10 ng/mL. METHODS: A retrospective assessment of 1294 patients with newly diagnosed, untreated prostate carcinoma was conducted at the authors' institutions. All patients underwent a bone scan, serum PSA measurement, and core needle biopsy of the prostate. The receiver operating characteristic curve for identifying a positive bone scan based on serum PSA levels and a decision tree were analyzed to determine the expected 10-year cumulative cost and disease specific survival rate. Two competing strategies were used: PSA alone and PSA plus baseline bone scan. For the PSA-alone strategy, a baseline bone scan was performed only when the patient had a serum PSA level > 10 ng/mL. RESULTS: The proportion of positive bone scans in patients with serum PSA levels < or = 10.0 ng/mL was 1.33%. The area under the receiver operating characteristic curve was 0.870. Patients with a Gleason Grade > or = 3 tumors or with a Gleason score > or = 7 had a higher proportion of positive bone scans. The 10-year disease specific survival rates with the PSA-alone strategy and the PSA-plus-bone-scan strategy were the same. The PSA-alone strategy was minimally cost effective, with a savings of $16.00 (U.S.) in the cumulative net cost per patient over the PSA-plus-bone-scan strategy. CONCLUSIONS: The current results suggest that baseline bone scans can be eliminated in patients with newly diagnosed prostate carcinoma in Japan who have serum PSA levels < or = 10 ng/mL. Apparently, it is possible to omit baseline bone scans for patients with a Gleason Grade < or = 2 tumors or with a Gleason score < or =6.     

Prostate specific antigen outcome based on the extent of extracapsular extension and margin status in patients with seminal vesicle negative prostate carcinoma of Gleason score < or = 7

BACKGROUND: Early (< or = 2 years) prostate specific antigen (PSA) failure after radical prostatectomy (RP) has been shown to predict for distant failure. After excluding patients with the pathologic predictors of early PSA failure, an analysis of PSA failure free (bNED) survival was performed to identify patients who may benefit from the use of postprostatectomy radiation therapy (RT). METHODS: Of 1,028 patients treated with RP for clinically localized prostate carcinoma between 1989 and 1999, 862 (84%) had either organ confined (OC), specimen confined (SC), or margin positive disease with negative seminal vesicles (SV) and a prostatectomy Gleason score < or = 7. A Cox regression multivariate analysis was performed in these patients evaluating the ability of the extent of extracapsular extension (ECE) (into but not through the capsule, SC focal ECE, SC established ECE, margin positive) and prostatectomy Gleason score (2-6 vs. 7) to predict time to postoperative PSA failure. RESULTS: SC focal ECE (P = 0.0017), SC established ECE (P < 0.0001), and margin positive disease (P < 0.0001) were significant predictors of time to postoperative PSA failure, whereas prostatectomy Gleason score and disease extending into but not through the capsule were not. Five-year bNED rates were 90%, 88%, 69%, 45%, and 33% for patients with OC, into but not through capsule, SC focal ECE, SC established ECE, and margin positive prostate carcinoma, respectively. CONCLUSIONS: Patients with SC ECE or margin positive prostate carcinoma and a prostatectomy Gleason score < or = 7 with no evidence of SV invasion may benefit from adjuvant postoperative RT.     

The percentage of prostate needle biopsy cores with carcinoma from the more involved side of the biopsy as a predictor of prostate specific antigen recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

BACKGROUND: The authors previously found that, although the total percentage of prostate needle biopsy cores with carcinoma was a significant predictor of prostate specific antigen (PSA) failure among men undergoing radical prostatectomy (RP), there was a trend toward a lower risk of recurrence in patients with positive bilateral biopsies, suggesting that high-volume, unilateral disease was a worse predictor of outcome than an equivalent number of positive cores distributed over two lobes. In the current study, the authors sought to compare the total percentage of cores with carcinoma directly with the percentage of cores from the more involved or dominant side of the prostate with carcinoma for their ability to predict outcome among men who underwent RP. METHODS: A retrospective survey of 535 patients from the Shared Equal Access Regional Cancer Hospital database who underwent RP at 4 different equal-access medical centers between 1988 and 2002 was undertaken. The total percentage of cores positive was compared with the percentage of cores positive from the dominant and nondominant sides for their ability to predict biochemical recurrence after RP. The best predictor then was compared with the standard clinical variables PSA, biopsy Gleason score, and clinical stage in terms of ability to predict time to PSA recurrence after RP using multivariate analysis. RESULTS: The adverse pathologic features of positive surgical margins and extracapsular extension were significantly more likely to be ipsilateral to the dominant side on the prostate biopsy. The percentage of cores positive from the dominant side provided slightly better prediction (concordance index [C] = 0.636) for PSA failure than the total percentage of cores positive (C = 0.596) and markedly better than the percentage of cores from the nondominant side (C = 0.509). Cutoff points for percentage of cores positive from the dominant side were identified (< 34%, 34-67%, and > 67%) that provided significant risk stratification for PSA failure (P < 0.001). On multivariate analysis, the percentage of cores positive from the dominant side was the strongest independent predictor of PSA recurrence (P < 0.001). Biopsy Gleason score (P = 0.017) also was a significant, independent predictor of recurrence. There was a trend, which did not reach statistical significance, toward an association between greater PSA values and biochemical failure (P = 0.052). Combining the PSA level, biopsy Gleason score, and percentage of cores positive from the dominant side of the prostate resulted in a model that provided a high degree of prediction for PSA failure (C = 0.671). CONCLUSIONS: The percentage of cores positive from the dominant side of the prostate was a slightly better predictor of PSA recurrence than was the total percentage of cores positive. Using the percentage of cores from the dominant side along with the PSA level and the biopsy Gleason score provided significant risk stratification for PSA failure.     

前列腺特异性膜抗原和前列腺特异性抗原表达强度与前列腺癌Gleason评分之间的相关性研究

目的研究前列腺特异性膜抗原(PSMA)和前列腺特异性抗原(PSA)的表达强度与前列腺癌Gleason评分之间的相关性。方法制备抗PSMA膜外段表位的单克隆抗体,应用免疫组织化学方法检测前列腺癌中PSMA的表达,统计分析其与Gleason评分之间的相关性,并和PSA与Gleason评分之间的相关性进行对比。结果制备出8株分泌抗PSMA膜外段表位的单抗的杂交瘤细胞株。免疫组化结果表明,PSMA的表达强度与前列腺癌的Gleason评分之间存在相关性。在分化差的前列腺癌中,PSMA水平高于分化中等和分化良好的前列腺癌(P<0.01),而PSA在前列腺癌中的表达无明显差异(P>0.05)。结论PSMA表达水平在分化差的前列腺癌中明显升高,与Gleason评分存在相关性,可以作为前列腺癌的Gleason分级的标记物,提示PSMA可以作为对激素疗法效果不敏感的低分化前列腺癌抗体介导的免疫治疗靶点。     

前列腺癌术后 Gleason 分级与 PSA、P504s、Ki -67蛋白表达相关性分析

目的：探讨前列腺癌 Gleason 分级评分与 PSA、P504s、Ki -67蛋白免疫组化表达的关系。方法：采用免疫组化 SP 法检测45例前列腺癌患者术后石蜡包埋组织中 PSA、P504s、Ki -67的表达，并根据 HE 切片进行 Gleason 分级评分。结果：前列腺癌 Gleason 分值越高，PSA 阳性表达越弱（P ﹤0.05），Ki -67阳性表达越强（P ﹤0.05）；P504s 强表达，与 Gleason 评分无相关性（P ﹥0.05）。结论：PSA 表达越弱、Ki -67表达越强，前列腺癌组织分化程度越差，预后越差。P504s 在前列腺癌中强表达，可应用于诊断，与预后无明显相关性。     

Combined c-Myc and caveolin-1 expression in human prostate carcinoma predicts prostate carcinoma progression

BACKGROUND: Over-expression of the oncogene c-Myc has been implicated in the development and progression of human prostate carcinoma. However, previous assessments of c-Myc expression have not revealed its potential for predicting prostate carcinoma progression. Caveolin-1 is associated with prostate carcinoma progression and is a downstream target gene of c-Myc. The observation that caveolin-1 can suppress c-Myc-induced apoptosis suggested the potential for cooperation between c-Myc and caveolin-1 in malignant progression. In this study, the authors evaluated the prognostic potential of combined c-Myc and caveolin-1 expression in human prostate carcinoma progression. METHODS: Immunostaining with c-Myc and caveolin-1-specific antibodies was performed on paraffin sections from 104 radical prostatectomy specimens from men with lymph node negative prostate carcinoma. Combined c-Myc and caveolin-1 immunostaining scores were related with the clinical and pathologic features and the probability of prostate-specific antigen recurrence after surgery. RESULTS: The combination of c-Myc and caveolin-1 immunopositivity correlated positively with Gleason score (rho = 0.219; P = 0.0253) and positive surgical margin (rho = 0.333; P = 0.0006). The combination of positive c-Myc and caveolin-1 in patients with clinically confined prostate carcinoma was a significant prognostic marker for the time to disease progression after surgery in both univariate analysis (P = 0.0039; hazard ratio, 3.035) and multivariate analysis (P = 0.0114; hazard ratio, 2.916). CONCLUSIONS: The coexpression of c-Myc and caveolin-1 showed potential as a useful prognostic marker for human prostate carcinoma. The current results suggest interactions between c-Myc and caveolin-1 in the progression of human prostate carcinoma.     

Small cell carcinoma of the prostate. II. Immunohistochemical and electron microscopic studies of 18 cases

To evaluate the histogenesis of small cell carcinoma of the prostate, 18 cases of this tumor (9 pure small cell and 9 combined adeno- and small cell carcinoma) were studied using immunohistochemical methods. Seven of the small cell components also were assessed by electron microscopic examination. Using neuron-specific enolase (NSE), prostatic acid phosphatase (PAP), and prostate-specific antigen (PSA) on tissue sections, three distinctive immunostaining patterns of small cell carcinoma components were identified: staining positive for NSE and negative for PSA and PAP (10 cases), staining positive for PSA and PAP and negative for NSE (3 cases), and negative reaction for all three antigens (5 cases). Electron microscopic study demonstrated neurosecretory granules in two cases. Based on the immunostaining and electron microscopic findings, small cell carcinomas of the prostate appear to be a heterogeneous group of tumors. Some of them are neuroendocrine carcinomas whereas others are poorly differentiated adenocarcinomas or, possibly, reserve cell carcinomas. Differences in immunostaining patterns or presence and absence of adenocarcinoma component do not reflect any differences in the uniformly poor prognosis of small cell carcinomas, in which median survivals is 7.7 months. The authors believe that, because of such heterogeneity, small cell carcinomas of the prostate arise from multipotential prostatic epithelium and that an origin from specific neuroendocrine cells need not be implicated.     

Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era

BACKGROUND: To the authors' knowledge, consensus is lacking regarding the relative long-term efficacy of radical prostatectomy (RP) versus conventional-dose external beam radiation therapy (RT) in the treatment of patients with clinically localized prostate carcinoma. METHODS: A retrospective cohort study of 2635 men treated with RP (n = 2254) or conventional-dose RT (n = 381) between 1988-2000 was performed. The primary endpoint was prostate specific antigen (PSA) survival stratified by treatment received and high-risk, intermediate-risk, or low-risk group based on the serum PSA level, biopsy Gleason score, 1992 American Joint Commission on Cancer clinical tumor category, and percent positive prostate biopsies. RESULTS: Estimates of 8-year PSA survival (95% confidence interval [95% CI]) for low-risk patients (T1c,T2a, a PSA level < or = 10 ng/mL, and a Gleason score < or = 6) were 88% (95% CI, 85, 90) versus 78% (95% CI, 72, 83) for RP versus patients treated with RT, respectively. Eight-year estimates of PSA survival also favored RP for intermediate-risk patients (T2b or Gleason score 7 or a PSA level > 10 and < or = 20 ng/mL) with < 34% positive prostate biopsies, being 79% (95% CI, 73, 85) versus 65% (95% CI, 58, 72), respectively. Estimates of PSA survival in high-risk (T2c or PSA level > 20 ng/mL or Gleason score > or = 8) and intermediate-risk patients with at least 34% positive prostate biopsies initially favored RT, but were not significantly different after 8 years. CONCLUSIONS: Intermediate-risk and low-risk patients with a low biopsy tumor volume who were treated with RP appeared to fare significantly better compared with patients who were treated using conventional-dose RT. Intermediate-risk and high-risk patients with a high biopsy tumor volume who were treated with RP or RT had long-term estimates of PSA survival that were not found to be significantly different.     

The expression of metallothioneins on imprint smears of prostate carcinoma: correlation with clinicopathologic parameters and tumor proliferative capacity

AIMS AND BACKGROUND: Metallothioneins are a family of metalbinding cysteine-rich proteins that play an important role in cellular processes such as proliferation and apoptosis, protection against oxidative stress and metal ion homeostasis and detoxification. Recent findings suggest that metallothioneins might play a significant role in the development and progression of prostate cancer. It has been also demonstrated that Ki67 expression may have prognostic value for disease-free survival in cases of prostate carcinoma. STUDY DESIGN: Imprint smears samples obtained from 70 patients immediately after radical prostatectomy for prostatic carcinoma were immunostained with monoclonal antibodies against metallothioneins and Ki-67. Metallothionein expression was correlated with Ki-67 immunostaining, Gleason score, stage, preoperative prostate-specific antigen levels and biochemical recurrence. RESULTS: Metallothionein expression was shown to correlate strongly with Gleason score (P < 0.001) and significantly with pathological staging and Ki-67 immunostaining (P < 0.001, P < 0.05, respectively). In contrast, no significant association between metallothioneins and preoperative PSA was demonstrated. Both of the studied markers (metallothioneins and Ki-67) correlated with recurrence (P = 0.009, P = 0.006, respectively). CONCLUSIONS: The present findings support the independent predictive value of metallothioneins and Ki-67 in prostate cancer. However, additional data are needed in order to reveal the factors that influence the expression of metallothioneins in epithelial neoplastic cells and clarify their mechanism of action.     

A prospective study of the serum prostate specific antigen concentrations and Gleason histologic scores of black and white men with prostate carcinoma.

BACKGROUND: The stage specific survival rates of black American men with prostate carcinoma are less favorable than those of white American men. The authors conducted a prospective study of the serum prostate specific antigen (PSA) concentrations and Gleason histologic scores of black and white men with newly diagnosed prostate carcinoma to determine whether there were racial differences in these prognostic variables. METHODS: At a Veterans Affairs Medical Center between January 1, 1992, and December 31, 1997, clinical stage, Gleason histologic score, serum PSA concentration, prostate volume, and PSA density were determined for 796 consecutive men (465 black and 331 white) who had biopsy-detected prostate carcinoma. RESULTS: The percentages, respectively, of black and white men with local, regional, and metastatic carcinoma were 58 and 72; 22 and 17; and 20 and 11 (P < 0.0001). Of 271 black and 329 white men with local stage cancer, 20% and 12%, respectively, had Gleason 8-10 tumors (P = 0.02), and the age-adjusted risk of Gleason 8-10 cancer was 1.39 times greater for black men (95% confidence interval [CI] = 1.09-2.93). Gleason 8-10 cancer was found in 12 of 68 black (18%) and 5 of 87 white (6%) men with local cancer who were age 65 years or younger (P = 0.02). Among black and white men with local stage cancer, the mean PSA was 12.9 (95% CI = 11.5-14.4) and 8.5 (95% CI = 7.6-9.4) ng/mL, respectively (P < 0.0001), and among black and white men with regional stage cancer the mean PSA was 53.3 (95% CI = 42.7-63.9) and 35.0 (95% CI = 27.3-42.6) ng/mL, respectively (P = 0.02). The mean PSA of black and white men with local cancer who were age 65 years or younger was 11.6 (95% CI = 8.8-14.4) and 6.9 (95% CI = 5.9-8.0) ng/mL, respectively (P = 0.0009). CONCLUSIONS: Disparities in the risk of Gleason score 8-10 cancer for black and white men with local stage disease and in the serum PSA concentrations of black and white men with local and regional stage disease help to explain racial differences in cancer survival. Racial differences in the risk of Gleason 8-10 cancer and in the serum PSA concentrations of men age 65 years or younger have implications regarding the potential benefits of screening for prostate carcinoma in the African American community.     

Optimizing patient selection for prostate monotherapy

PURPOSE: Patients at low risk for prostate-specific antigen (PSA) failure following definitive local therapy are those with PSA of 10 or less, biopsy Gleason Score of 6 or less, and 1992 American Joint Committee on Cancer (AJCC) clinical Stage T1c or T2a. However, low-risk patients managed with radical prostatectomy and found to have prostatectomy Gleason score > or = 3+4 have a less favorable PSA outcome when compared to patients with prostatectomy Gleason score < or = 3+3. This study was performed to determine whether the percentage of positive prostate biopsy cores could predict upgrading from a biopsy Gleason score of 6 or less to a prostatectomy Gleason score > or = 3+4 in low-risk patients to optimize selection for prostate only radiation therapy. METHODS AND MATERIALS: Concordance testing of the biopsy Gleason score and the primary and secondary prostatectomy Gleason grades was performed in 427 prostate cancer patients treated with radical prostatectomy and at low risk for PSA failure. Logistic regression multivariable analysis was performed to test the ability of the established prognostic factors and the percentage of positive prostate biopsies (<34%, 34-50%, >50%) to predict for upgrading from biopsy Gleason score of 6 or less prostatectomy Gleason score > or = 3+4. PSA failure-free survival was reported using the actuarial method of Kaplan and Meier and comparisons were made using a log-rank test. RESULTS: Twenty-nine percent of the 427 study patients were upgraded from a biopsy Gleason score of 6 or less to a prostatectomy Gleason score > or = 3+4. The presence of greater than 50% positive biopsies was the only significant factor for predicting the upgrading from biopsy Gleason score of 6 or less to prostatectomy Gleason score > or = 3+4 on logistic regression multivariable analysis with the variables treated as continuous and categorical. Specifically, upgrading occurred in 26% vs. 59% of patients with 50% or less vs. greater than 50% positive biopsies, respectively. This translated into a 5-year PSA failure-free survival which was significantly higher (92% vs. 62%, p = 0.00001) for men with 50% or less vs. greater than 50% positive prostate biopsies, respectively. CONCLUSION: The presence of greater than 50% positive biopsies was associated with higher rates of pathologic upgrading which translated into lower 5-year PSA failure-free survival following radical prostatectomy (RP). Therefore, the percentage of positive biopsies may be useful in optimizing the selection of low-risk patients for prostate only radiation therapy such as external beam radiation or implant monotherapy.     

Reduction of tumor angiogenesis induced by desmopressin in a breast cancer model

Desmopressin (DDAVP), a synthetic peptide analog of vasopressin, is a safe antidiuretic and hemostatic compound that acts as a selective agonist for the vasopressin V2 membrane receptor. It is known that DDAVP can inhibit progression of residual metastatic cells and also improves chemotherapy effects in preclinical breast cancer models. Here, we explored the effects of DDAVP on tumor angiogenesis using the aggressive F3II mammary carcinoma in syngeneic Balb/c mice. Intravenous administration of the compound (2 μg/kg) markedly decreased vascularization of growing subcutaneous tumors, as well as inhibited the early angiogenic response around intradermal inoculation sites. In vitro studies confirmed the presence of vasopressin V2 receptors on F3II cells and a modest antiproliferative activity of DDAVP. Interestingly, conditioned media from F3II monolayers exposed to low doses of DDAVP (100 nM) significantly increased angiostatin formation in the presence of purified plasminogen. Such increase was associated with an enhancement of tumor-secreted urokinase-type plasminogen activator, suggesting the proteolytic conversion of plasminogen to angiostatin in vitro. Similar results were observed with the MCF-7 human breast carcinoma, a cell line known to express the vasopressin V2 receptor. No direct effects of DDAVP (100 nM–1 μM) were found on capillary-like tube formation by human microvascular cells HMVEC. Our studies showed that DDAVP induces anti-angiogenic effects that may be associated with the generation of angiostatin by tumor cells. Further preclinical studies with DDAVP and other vasopressin analogs are warranted to determine their potential in cancer management.     

HOXB13 overexpression is an independent predictor of early PSA recurrence in prostate cancer treated by radical prostatectomy

HOXB13 is a prostate cancer susceptibility gene which shows a cancer predisposing (G84E) mutation in 0.1–0.6% of males. We analyzed the prognostic impact of HOXB13 expression by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancers. Results were compared to tumor phenotype, biochemical recurrence, androgen receptor (AR) and prostate specific antigen (PSA) as well as molecular subtypes defined by ERG status and genomic deletions of 3p, 5q, 6q, and PTEN. HOXB13 immunostaining was detectable in 51.7% of 10,216 interpretable cancers and considered strong in 9.6%, moderate in 19.7% and weak in 22.3% of cases. HOXB13 expression was linked to advanced pT stage, high Gleason grade, positive lymph node status (p < 0.0001 each), high pre-operative PSA levels (p = 0.01), TMPRSS2:ERG fusion, PTEN deletions, AR expression, cell proliferation, reduced PSA expression and early PSA recurrence (p < 0.0001 each). The prognostic value of HOXB13 was independent from established parameters including Gleason, stage, nodal stage and PSA. Co-expression analysis identified a subset of tumors with high HOXB13 and AR but low PSA expression that had a particularly poor prognosis. HOXB13 appears to be a promising candidate for clinical routine tests either alone or in combination with other markers, including AR and PSA.     

血清PSA及超声引导穿刺活检对前列腺癌病理分期预测价值研究

目的 研究血清前列腺特异性抗原(PSA)及超声引导穿刺活检对前列腺癌病理分期的预测价值.方法 选取200例经直肠超声引导前列腺穿刺活检确诊为前列腺癌的患者的临床资料进行研究.分析患者的血清PSA、穿刺活检阳性百分数及Gleason评分3个参数与前列腺癌病理分期的相关性;同时对比性分析以上3个参数在不同病理分期前列腺癌患者中的差异情况.结果 血清PSA、穿刺活检阳性百分数及Gleason评分均与前列腺癌患者的病理分期呈正相关(P﹤0.001);D期前列腺癌患者的血清PSA水平明显高于A期、B期、C期前列腺癌患者(P﹤0.05),而A期、B期、C期前列腺癌患者的血清PSA水平两两之间比较,差异均无统计学意义(P﹥0.05);C期与D期前列腺癌患者的穿刺活检阳性百分数比较,差异无统计学意义(P﹥0.05),而其他各分期间穿刺活检阳性百分数两两比较,差异均有统计学意义(P﹤0.05);A期与C期、B期与C期、A期与D期、B期与D期前列腺癌患者的Gleason评分比较,差异均有统计学意义(P﹤0.05),而A期与B期、C期与D期前列腺癌患者的Gleason评分比较,差异无统计学意义(P﹥0.05).结论 血清PSA、穿刺活检阳性百分数及Gleason评分均可单独用于前列腺期病理分期的预测,同时该3个参数在区分前列腺癌病理分期方面也发挥一定辅助作用.     

The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer

PURPOSE: An investigation was performed of the clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following external-beam radiation therapy (RT) for men with PSA-detected or clinically palpable prostate cancer. METHODS AND MATERIALS: A Cox regression multivariable analysis was used to determine whether the percent of positive prostate biopsies provided clinically relevant information about PSA outcome following external beam RT in 473 men while accounting for the previously established risk groups based on the pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Commission on Cancer (AJCC) clinical T stage. RESULTS: Controlling for the known prognostic factors, the percent of positive prostate biopsies added clinically significant information (p = 0.02) regarding time to PSA failure following RT. Specifically, 76% of the patients in the intermediate risk group (1992 AJCC T(2b) or biopsy Gleason 7 or PSA > 10 ng/mL and < or = 20 ng/mL) could be classified into either an 30% or 85% 5-year PSA control cohort using the preoperative prostate biopsy data. CONCLUSION: The previously validated stratification of PSA outcome following radical prostatectomy (RP) using the percent of positive prostate biopsies in intermediate-risk patients is also clinically significant for men treated with external beam RT. The percent positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and 1992 AJCC clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome following RP or external beam RT.