Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker

We demonstrated previously elevated caveolin-1 expression in metastatic mouse and human prostate cancer cells both in vitro and in vivo. In this study, we analyzed its prognostic value for progression of clinically confined human prostate cancer. Immunohistochemical staining with a caveolin-1-specific antibody was performed on routinely processed paraffin sections from 189 radical prostatectomy specimens. Caveolin-1 immunoreactivity was evaluated in association with patients' age, race, preoperative prostate-specific antigen, clinical stage, and pathological features including Gleason score, extraprostatic extension, status of surgical margins, and time to disease progression after surgery. Positive caveolin-1 immunostaining was detected in 47 of the 189 cancers (25%) and correlated positively with Gleason score, positive surgical margin, as well as lymph node involvement (P = 0.0071, 0.0267, and 0.0399, respectively). In lymph node-negative cancers (n = 162), caveolin-1 immunoreactivity predicts a shorter time to disease progression after surgery (P = 0.0033, univariate analysis). Multivariate analyses that included caveolin-1 and other prognostic pathological markers identified positive caveolin-1 immunostaining as an independent predictor for time to disease progression (P = 0.0186). Thus, our study establishes caveolin-1 as a novel prognostic marker for clinically confined human prostate cancer.     

Caveolin-1 expression is a predictor of recurrence-free survival in pT2N0 prostate carcinoma diagnosed in Japanese patients

BACKGROUND: The authors previously identified elevated caveolin-1 expression in human prostate carcinoma and determined that caveolin-1 levels as detected by immunohistochemistry of radical prostatectomy specimens offered novel prognostic information. A higher incidence of caveolin-1 expression also was reported in African-American men compared with white men in the U.S. To explore these ethnic/racial differences in caveolin-1 expression further, the authors evaluated caveolin-1 expression as a predictive marker in Japanese men with prostate carcinoma. METHODS: Immunohistochemical staining with a caveolin-1 specific antibody was performed on routinely processed paraffin sections from 152 consecutively collected radical prostatectomy specimens. The mean patient age was 64.3 years (range, 49-74 years; median, 64.5 years) and the mean follow-up period was 49.5 months (range, 1.3-103.3 months; median, 48.2 months). Caveolin-1 immunoreactivity was evaluated in association with patient's age; preoperative prostate specific antigen level; clinical stage; and pathologic features including Gleason score, extraprostatic extension, status of surgical margins, seminal vesicle involvement, lymph node involvement, and time to disease progression after surgery. RESULTS: Positive caveolin-1 immunostaining was detected in 46 of the 152 tumors (30.3%) and was found to be associated significantly with a positive surgical margin (P = 0.022). A higher incidence of caveolin-1 expression tended to be found in patients with poorly differentiated tumors (Gleason score > 7, 6-7, and < 6, 35.0% vs. 34.9% vs. 20.4%, respectively) or in patients with extraprostatic extension versus those without extraprostatic extension (35.4% vs. 24.7%) or patients with lymph node involvement compared with those without lymph node involvement (50% vs. 29.5%), although these differences did not reach statistical significance (P = 0.100, P = 0.150, and P = 0.178, respectively, by the Spearman correlation test). Kaplan-Meier analysis revealed that increased caveolin-1 expression was associated with an increased risk of disease progression at 5 years (P = 0.0122 by the log-rank test). In patients with organ-confined (pT2N0) disease, univariate Cox proportional hazards regression analysis revealed that positive caveolin-1 expression was the only significant predictor of disease recurrence after radical prostatectomy (P = 0.011; hazards ratio = 4.75; and 95% confidence interval, 1.43-15.76). CONCLUSIONS: The results of the current study confirm that positive caveolin-1 expression is associated with clinical markers of disease progression and is predictive of poor clinical outcome after surgery in Japanese patients with pT2N0 prostate carcinoma.     

Overexpression of caveolin-1 in esophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage

BACKGROUND: Caveolin-1 plays a regulatory role in several signaling pathways. Recently caveolin-1 was identified as a metastasis-related gene in prostate carcinoma. However, the clinical impact of caveolin-1 expression in esophageal carcinoma remains unknown. METHODS: One hundred thirty surgical specimens of esophageal squamous cell carcinoma were immunohistochemically assessed for caveolin-1 expression by polyclonal antibody. Caveolin-1 immunoreactivity was correlated with patients' clinicopathologic parameters and outcome. RESULTS: Positive caveolin-1 immunostaining was detected in 58 patients (44.6%). Positive caveolin-1 immunostaining correlated positively with pathologic stage (P = 0.029), pN (P = 0.023), and pM (P = 0.018). The overall survival rate was worse in patients with caveolin-1-positive tumors than in patients with caveolin-1-negative tumors (P = 0.0215). Univariate analyses identified caveolin-1 positivity (P = 0.0238), pT (P = 0.0002), pN (P < 0.0001), pM (P = 0.0002), lymphatic invasion (P = 0.0021), and positive surgical margin (P < 0.0001) as negative prognostic predictors. Multivariate analyses indicated that pT (P = 0.0296), pN (P = 0.0003), and a positive surgical margin (P = 0.0452) were independent prognostic factors. CONCLUSIONS: Over-expression of caveolin-1 is associated with lymph node metastasis and a worse prognosis after surgery in esophageal squamous cell carcinoma.     

Reduced infiltration of class A scavenger receptor positive antigen-presenting cells is associated with prostate cancer progression

The class A macrophage scavenger receptor (SR-A) is expressed in antigen presenting cells and is involved in host immune responses. Germ-line mutation of this gene has been associated with increased risk of human prostate cancer. However, there is little known about its expression in normal or neoplastic human prostate tissues. Double immunofluorescent labeling with monoclonal antibodies to SR-A and specific macrophage and dendritic cell markers was used to identify cells expressing SR-A in human prostate tissues. SR-A immunohistochemical staining was performed on paraffin sections of normal prostate, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancers from radical prostatectomy specimens. SR-A was expressed in a subset of macrophages and dendritic cells that infiltrated prostatic tissues. The majority of SR-A-positive cells coexpressed CD68, and a relatively low percentage expressed S100 protein. The number of SR-A-positive cells was significantly increased in PIN as compared with normal prostatic tissue (P = 0.0176). In contrast, the number of SR-A-positive cells decreased with tumor progression. A lower SR-A-positive cell density was associated with higher clinical stage (rho = -0.26; P = 0.0234). Inverse associations were also found between SR-A density and positive lymph nodes (rho = -0.23; P = 0.0437), tumor size (rho = -0.31; P = 0.0100) and preoperative PSA levels (rho = -0.32; P = 0.0057). SR-A density is a significant predictor of disease-free survival after surgery univariately (P = 0.0003), as well as multivariately, adjusted for known clinical and pathological markers including preoperative prostate-specific antigen, clinical stage, Gleason score, surgical margin, extraprostatic extension, and seminal vesicle invasion, as well as lymph node metastasis (P = 0.0021). The preferential accumulation of SR-A-positive cells in PIN suggests a role for SR-A in the APC response to early malignancy. A reduction in the number of SR-A-positive cells demarcates tumor progression as indicated by clinical and pathological correlations. Our results additionally indicate that systematic measurement of SR-A density is a strong prognostic marker for clinical outcome after surgery.     

Risk of prostate carcinoma death in patients with lymph node metastasis

BACKGROUND: The presence of lymph node metastasis is a poor prognostic sign for patients with prostate carcinoma. Results of published reports on survival among patients with lymph node metastasis are difficult to assess because of treatment selections. The extent to which lymph node status will have an impact on a patient's survival is uncertain. METHODS: The authors analyzed 3463 consecutive Mayo Clinic patients who underwent radical prostatectomy and bilateral pelvic lymphadenectomy for prostate carcinoma between 1987 and 1993. Of these patients, 322 had lymph node metastasis at the time of surgery, and 297 lymph node positive patients also received adjuvant hormonal therapy within 90 days of surgery. The progression free rate and the cancer specific survival rate were used as outcome endpoints in univariate and multivariate Cox proportional hazards models. The median follow-up was 6.3 years. Progression was defined by elevation of serum prostate specific antigen (PSA) > or = 0.4 ng/mL after surgery, development of local recurrence, or distant metastasis documented by biopsy or radiographic examination. RESULTS: The 5-year and 10-year progression free survival rates (+/- standard error [SE]) for patients with lymph node metastasis were 74% +/- 2% and 64% +/- 3%, respectively, compared with 77% +/- 1% and 59% +/- 2%, respectively, for patients without lymph node metastasis. The 5-year and 10-year cancer specific survival rates were 94% +/- 1% and 83% +/- 4%, respectively, compared with 99% +/- 0.1% and 97% +/- 0.5%, respectively, for patients without lymph node metastasis. Among patients with a single lymph node metastasis, the 5-year and 10-year cancer specific survival rates were 99% +/- 1% and 94% +/- 3%, respectively. After adjustment for extraprostatic extension, seminal vesicle invasion, Gleason grade, surgical margins, DNA ploidy, preoperative serum PSA concentration, and adjuvant therapy, the hazard ratio for death from prostate carcinoma among patients with a single lymph node metastasis compared with patients who were without lymph node metastasis was 1.5 (95% confidence interval, 0.5-5.0; P = 0.478), whereas the hazard ratio for death from prostate carcinoma was 6.1 (95% confidence interval, 1.9-19.6; P = 0.002) for those with two positive lymph nodes and 4.3 (95% confidence interval, 1.4-13.0; P = 0.009) for those with three or more positive lymph nodes. There was no significant difference in the progression free survival rate among patients with or without lymph node metastasis in multivariate analysis after controlling for all relevant variables, including treatments (hazard ratio,1.0; 95% CI, 0.7-1.3; P = 0.90). CONCLUSIONS: Patients with prostate carcinoma who have multiple regional lymph node metastases had increased risk of death from disease, whereas patients with single lymph node involvement appeared to have a more favorable prognosis after radical prostatectomy and immediate adjuvant hormonal therapy. Excellent local disease control was achieved by using combined surgery and adjuvant hormonal therapy in patients with positive lymph nodes.     

Metastatic prostate carcinoma to bone: clinical and pathologic features associated with cancer-specific survival

BACKGROUND: The objective of this study was to examine the clinical and pathologic features of metastatic prostate carcinoma to bone in a large cohort of men, and the associations of these features with outcome. METHODS: Sixty-eight men who underwent surgery for metastatic prostate carcinoma to bone for stabilization of a pathologic fracture or impending fracture were studied. Clinical characteristics included the type of treatment for the primary and metastatic prostate carcinoma, age and serum prostate specific antigen (PSA) at the diagnosis of the metastatic prostate carcinoma, radiographic findings of the metastasis (osteoblastic, osteolytic, or mixed), and the number of metastatic sites at the time of the surgery for the metastasis. Pathologic features examined included Gleason score of the metastatic prostate carcinoma. Immunohistochemical stains for MIB-1, cytokeratin, PSA, synaptophysin, chromogranin A, serotonin, estrogen receptor, progesterone receptor, and androgen receptor were performed for all cases. The Kaplan-Meier method was used to estimate cancer-specific survival. The duration of follow-up was defined as the interval from the date of surgery for the metastasis to the date of death or last follow-up. Univariate and multivariate Cox proportional hazards models were fit to assess the features that were associated with death from prostate carcinoma. RESULTS: The average (standard deviation) time from the surgery for the metastasis to death from prostate carcinoma was 1.5 (1.9) years, ranging from 0 days to 10 years, with a median of 1 year. The estimated cancer-specific survival rates at 1 year, 2 years, and 3 years were 54.3%, 28.8%, and 22.9%, respectively. Median cancer-specific survival occurred at 1.1 years. After 4 years of follow-up, there were only seven patients left at risk for death from prostate carcinoma. Features that were found to be significantly associated with death from prostate carcinoma univariately included the interval between the diagnosis of metastasis and the surgery for metastasis (P < 0.001), androgen deprivation therapy before surgery for the metastasis (P = 0.002), presentation with metastasis (P = 0.003), the number of metastatic sites (P = 0.034), Gleason score of the metastasis (P = 0.002), and tumor positivity for chromogranin A (P = 0.041). On multivariate analysis, the interval between the diagnosis of metastasis and the surgery for metastasis (P < 0.001), Gleason score of the metastasis (P < 0.001), and tumor positivity for chromogranin A (P = 0.009) were associated significantly with death from prostate carcinoma. CONCLUSIONS: Although cancer-specific survival for patients after surgery for prostate carcinoma metastatic to bone is poor, assessments of tumor differentiation of the metastasis and chromogranin A positivity provide prognostic information.     

Caveolin-1 overexpression predicts poor disease-free survival of patients with clinically confined renal cell carcinoma

Renal cell carcinomas, although usually apparently fully resected at surgery, commonly recur as distant metastasis. New markers are needed to predict which patients may relapse especially as novel methods of treatment (e.g. laproscopic resection) may make it impossible to assess conventional pathological prognostic markers. The caveolins are a family of proteins that represent the major structural components of caveolae; recent work suggests that these may have influence on several signalling pathways and they are thus potential prognostic markers. Immunohistochemistry for caveolin-1 was performed on sections of peripheral tumour from 114 consecutative nonmetastatic RCCs. Cytoplasmic caveolin-1 immunohistochemical (ICC) reaction was scored on a semiquantative scale of 1-3. Immunohistochemical score was tested for impact on disease-free survival by Kaplan-Meier and Cox regression methods. A total of 50 tumours had ICC score 1; 43 had score 2 and 21 score 3. Larger, higher grade and tumours with vascular invasion had significantly higher scores. On univariate survival analysis (Kaplan-Meier), patients with tumours scoring 1 had a mean disease-free survival of 6.61 years (95% CI 5.76-7.46) compared with 5.4 years (4.53-6.30) and 3.15 years (1.87-4.44) for scores 2 and 3, respectively. This is a significant difference (P=0.0017 log rank test). On multivariate analysis with size, grade and caveolin ICC score as independent covariates, caveolin ICC score 3 was an influential predictor of poor disease-free survival with a hazard ratio of 2.6 (P=0.03). We conclude that cytoplasmic overexpression of caveolin-1 predicts a poor prognosis in RCC; that this is likely to be a useful prognostic marker and that it may have importance in tumour progression.     

人肺鳞癌组织中Caveolin-1的表达及预后意义

  目的   研究Caveolin-1在人肺鳞癌中的表达, 探讨Caveolin-1的表达与人肺鳞癌临床病理特征以及预后的关系。   方法   运用免疫组织化学法检测人肺鳞癌组织中Caveolin-1、PCNA的表达, 并结合患者的临床病理特征和生存情况进行分析。   结果   Caveolin-1在人肺鳞癌中阳性率显著低于正常肺组织(P < 0.001);Caveolin-1的表达与肺鳞癌的TNM分期(P=0.018) 及淋巴结状态(P=0.006) 有关。在人肺鳞癌组织中Caveolin-1与PCNA表达呈正相关(r=0.360, P=0.018)。生存分析显示肺鳞癌中Caveolin-1阳性组的生存时间显著低于阴性组(P=0.007), 在24例淋巴结未转移组中Caveolin-1阳性组的生存时间显著低于阴性组(P=0.002)。多因素Cox分析显示Caveolin-1阳性表达、高临床分期、支气管残端有癌残留的肺鳞癌患者术后生存时间较短。   结论   Caveolin-1的表达与肺鳞癌的恶性演进呈正相关; 其可促进肺癌细胞的增殖。Caveolin-1可作为评估肺鳞癌患者的不良预后指标。      

Survivin expression is associated with features of biologically aggressive prostate carcinoma

BACKGROUND: Survivin counteracts cell death and controls mitotic progression. The objectives of the current study were to compare the expression patterns of survivin in normal prostate, primary prostate carcinoma, and lymph node tissues involved with prostate carcinoma and to determine whether the expression of survivin is associated with prostate carcinoma characteristics and progression. METHODS: Immunohistochemical staining for survivin and for transforming growth factor beta1 (TGF-beta1) and its receptors (types I and II; TGF-betaR1 and TGF-betaR2, respectively) was carried out on archival specimens from 114 consecutive patients who underwent radical prostatectomy (median follow-up, 64.8 months). Punch biopsies of the index carcinoma and normal tissue from each specimen were sectioned onto a single slide and stained. The authors also evaluated the expression of survivin in normal and malignant lymph node tissue from eight patients. RESULTS: Survivin was expressed in 41 of 114 normal prostate specimens (36%) from prostates that contained carcinoma, in 81 of 114 primary prostate carcinoma specimens (71%), in 3 of 8 normal lymphoid specimens (38%), and in 7 of 8 prostate carcinoma lymphoid specimens (88%). Survivin expression was associated with higher final Gleason sum (P = 0.001), loss of TGF-betaR1 and TGF-betaR2 expression (P = 0.041 and P = 0.008, respectively), and an increased risk of biochemical progression on univariate analysis (P = 0.0441). Among patients who had disease progression, survivin was expressed more commonly in those who had tumors with features of aggressive behavior. CONCLUSIONS: The expression of survivin gradually increased from normal prostate tissue, to low-grade primary carcinoma, to high-grade primary carcinoma and was highest in lymph node metastases. Survivin expression was associated further with alteration of the TGF-beta pathway and with overall and aggressive biochemical progression after radical prostatectomy.     

磷酸化小窝蛋白-1在食管鳞癌中的表达及意义

目的:检测磷酸化小窝蛋白-1（PY14caveolin-1,PY14cav-1）在不同食管组织中的表达,探讨PY14cav-1与食管癌发生、发展的关系。方法:收集60例食管鳞状细胞癌患者手术标本,采用免疫组织化学方法分析和检测PY14cav-1在食管癌组织、癌旁组织及正常食管组织中的表达情况,分析PY14cav-1表达水平与食管癌发生、发展的关系。结果:PY14cav-1在食管鳞癌组织中的表达水平明显高于癌旁组织与食管正常组织中的表达水平,差异具有统计学意义(P<0.05)。PY14cav-1与食管癌的临床分期呈正相关性,随着肿瘤临床分期的升高表达增强,差异具有统计学意义(P<0.05)。淋巴结转移组中PY14cav-1的表达明显高于无淋巴结转移组,差异具有统计学意义(P<0.05)。PY14cav-1的表达与肿瘤的分化程度呈负相关性（P=0.034）。结论:PY14cav-1的表达与食管癌分化程度、临床分期和淋巴结转移有关,可能参与了食管癌的侵袭和转移,在食管癌的发生和发展过程中起着重要的作用,很可能成为潜在的治疗靶点及判断食管癌预后有价值的肿瘤标记物。     

Prognostic model of event-free survival for patients with androgen-independent prostate carcinoma

BACKGROUND: The current study was conducted to develop a prognostic model of event-free survival (EFS) in men with androgen-independent prostate carcinoma (AIPC). METHODS: Data from 160 patients diagnosed with AIPC between 1989-2002 were reviewed. No patient had received cytotoxic chemotherapy. A univariate Cox proportional hazards model identified significant predictors of EFS. Recursive partitioning analysis divided these significant variables into prognostic risk groups. The final prognostic model was tested with a Cox proportional hazards model. RESULTS: The final prognostic risk model included the presence of metastatic disease at the time of androgen-independent disease progression (P = 0.040), time to prostate-specific antigen (PSA) recurrence (P = 0.043), and PSA doubling time (P < 0.01). Three highly independent risk groups were identified. The observed median EFSs were 6.1 months (95% confidence interval [95= CI], 3.4-8.8 months), 33.6 months (95= CI, 25.3-41.9 months), and 96.1 months (95= CI, 57.9-134.3 months) for the low-risk, intermediate-risk, and high-risk groups, respectively. Each risk group was found to be independently predictive of EFS (P < 0.01). Patients who died of prostate carcinoma experienced significantly more clinical events than those who died of other causes (P < 0.01). CONCLUSIONS: The prognostic model in the current study stratified patients into three highly significant and independent risk groups for EFS. A detailed PSA history and knowledge of metastatic disease are sufficient to risk-stratify patients with AIPC. One very unique aspect of this model was that it was developed from a patient cohort that never received chemotherapy.     

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.     

Expression of caveolin-1 is associated with poor prognosis of patients with squamous cell carcinoma of the lung

BACKGROUND: Caveolin-1, as a major component of caveolae, is involved in the regulation of cell cycle by impacting various signaling pathways. Previous studies of caveolin-1 in cancer showed two contrary results. In most in vitro studies, caveolin-1 played a role as a tumor suppressor. On the other hand, the elevated expression of caveolin-1 was often reported to be associated with poor clinical outcome in human studies. These results indicate differential biological functions of caveolin-1 depending on the development and progression stage of cancer in vivo. METHODS: To clarify the correlation between the clinicopathologic profiles of pulmonary squamous cell carcinomas and the expression of caveolin-1, 107 cases of formalin-fixed and paraffin-embedded tissues of pulmonary squamous cell carcinomas were immunohistochemically evaluated for the expression of caveolin-1 by the tissue-array method. RESULTS: Caveolin-1 was expressed in 34 cases (31.7%) among 107 cases of pulmonary squamous cell carcinoma. The expression of caveolin-1 was statistically correlated with pathologic stage (stage I and II vs. III; P<0.001), pT (T1 and T2 vs. T3 and T4; P=0.001), and pN (N1 vs. N2 and N3; P=0.0143). The patients with caveolin-1 expression in pulmonary squamous cell carcinomas showed a poorer prognosis than those in caveolin-1-negative group (P=0.0345). CONCLUSION: The expression of caveolin-1 is significantly correlated with advanced pathologic stage and poor prognosis in pulmonary squamous cell carcinoma. The results of current study suggest that the expression level of caveolin-1 may be a candidate factor for predicting prognosis in patients with pulmonary squamous cell carcinoma.     

Estramustine phosphate combined with orchidectomy as first-line therapy in patients with prostate carcinoma. Effect of age on survival

BACKGROUND: The role of age as a prognostic factor for survival remains debatable in patients with prostate carcinoma. METHODS: The authors conducted a retrospective study of the significance of age as a prognostic factor for survival and progression free survival in 386 patients who underwent orchidectomy for locally advanced or metastatic prostate carcinoma, 75% of whom had T0-T4, M1 disease. After undergoing orchidectomy, 192 patients received no further therapeutic intervention, whereas 194 patients received additional treatment with estramustine phosphate (EMP) as first-line therapy. RESULTS: The findings confirmed that age was a significant prognostic factor for survival and progression free survival in patients with prostate carcinoma as well as a predictor of response to chemotherapy. The data also showed that, although combining orchidectomy with EMP appeared to be beneficial in younger patients, using this relatively more aggressive therapeutic approach as first-line therapy in older patients (age > or = 80 years) may shorten their survival. CONCLUSIONS: The current findings call for caution with the additional use of EMP as first-line therapy in older patient with prostate carcinoma.     

Prostate-specific antigen velocity and survival for patients with hormone-refractory metastatic prostate carcinoma

BACKGROUND: The authors investigated whether prostate-specific antigen (PSA) velocity was associated significantly with the time to death after randomization among patients with hormone-refractory metastatic prostate carcinoma (HRMPC) who were treated with cytotoxic, cytotatic, or combination therapy. METHODS: The study cohort included 213 men with HRMPC who were treated on 3 prospective, randomized Phase II studies between February 1996 and October 2001. Cox regression analysis was used to evaluate whether there was a significant association between PSA velocity and the time to death after randomization, controlling for treatment and known prognostic factors. RESULTS: Increasing PSA velocity was associated significantly with shorter survival after randomization (P = 0.005) controlling for treatment and known prognostic factors. The adjusted hazard ratio for death was 1.8 (95% confidence interval [95% CI], 1.3-2.5; P = 0.0004) for men who had a PSA velocity > 0.0 ng/mL per month compared with men who had a PSA velocity < or = 0.0 ng/mL per month. Estimates of survival 2 years after randomization for these men were 16% (95% CI, 7-25%) and 44% (95% CI, 35-53%), respectively. CONCLUSIONS: PSA velocity was associated significantly with the length of survival among men with HRMPC who received cytotoxic, cytostatic, or combination therapy.     

Prognostic value of DNA ploidy and automated assessment of stroma fraction in prostate cancer

The combination of DNA ploidy and automatically estimated stroma fraction has been shown to correlate with recurrence and cancer death in colorectal cancer. We aimed to extend this observation and evaluate the prognostic importance of this combined marker in prostate cancer. DNA ploidy status was determined by image cytometry and the stroma fraction was estimated automatically on hematoxylin and eosin stained sections in three tumor samples from each patient to account for tumor heterogeneity. The optimal threshold for low (≤56%) and high (>56%) stroma fraction was identified in a discovery cohort (n = 253). The combined marker was validated in an independent patient cohort (n = 259) with biochemical recurrence as endpoint. The combined marker predicted biochemical recurrence independently in the validation cohort. Multivariable analysis showed that the highest risk of recurrence was observed for patients with samples that had both non-diploid ploidy status and a high stroma fraction (hazard ratio: 2.51, 95% confidence interval: 1.18–5.34). In conclusion, we suggest the combination of DNA ploidy and automatically estimated stroma fraction as a prognostic marker for the risk stratification of prostate cancer patients. It may also be a potential generic marker as concurrent results have been described in colorectal cancer.     

Body mass index is weakly associated with, and not a helpful predictor of, disease progression in men with clinically localized prostate carcinoma treated with radical prostatectomy

BACKGROUND: Several studies have recently suggested an association between body mass index (BMI) and disease progression after radical prostatectomy. In the current study, the authors examined this association and that between the reciprocal of BMI (INVBMI, 1/BMI) and progression-free probability in men treated with radical retropubic prostatectomy (RRP) for clinically localized prostate carcinoma. METHODS: The authors retrospectively studied 2210 patients who underwent RRP at Memorial Sloan-Kettering Cancer Center between September 1986 and May 2003. Clinicopathologic variables analyzed included BMI (kg/m2), preoperative serum prostate-specific antigen level (ng/mL), clinical T classification, year of surgery, race, biopsy-derived primary and secondary Gleason grades, and INVBMI, known to better correlate with percent body fat than BMI. Cox regression analysis was used to examine the possible association between BMI or its reciprocal with disease progression after controlling for the effects of common prognostic factors. The areas under the receiver operating curve (AUC) for models with and without INVBMI were calculated. RESULTS: Of the 2210 patients analyzed, 251 experienced disease progression in a median follow-up time of 25.9 months (range, 0-143 months). After adjusting for all clinical variables, both BMI (P = 0.071; hazards ratio [HR] = 1.027) and INVBMI (P = 0.041; HR < 0.001) were associated with disease progression. However, the areas under AUC for models with and without INVBMI were similar (range, 0.794-0.798). CONCLUSIONS: Although conflicting evidence has been reported regarding the link between obesity and an increased risk of developing prostate carcinoma, as well as an increased risk of developing aggressive disease and prostate carcinoma-related mortality, the authors found weak associations with disease progression for both BMI and INVBMI. These variables were of negligible prognostic value in men who received surgery. Studies with longer follow-up, that examine alternative end points, and that follow treatment(s) besides surgery are needed.     

Targeting Aurora kinases for the treatment of prostate cancer

Inappropriate expression of the Aurora kinases can induce aberrant mitosis, centrosome irregularities, and chromosomal instability, which lead to anueploidy and cell transformation. Here, we report that Aurora-A and Aurora-B are highly expressed in primary human and mouse prostate cancers and prostate cancer cell lines. In clinical samples, levels of Aurora-A and Aurora-B were significantly elevated in prostatic intraepithelial neoplasia lesions and prostate tumors when compared with the non-neoplastic samples. Interestingly, expression of Aurora-A in non-neoplastic prostates correlated with seminal vesicle invasion (rho = 0.275, P = 0.0169) and in prostate tumor with positive surgical margins (rho = 0.265, P = 0.0161). In addition, nuclear expression of Aurora-B in prostatic intraepithelial neoplasia lesions correlated with clinical staging of the tumor (rho = -0.4, P = 0.0474) whereas cytoplasmic expression in tumors correlated with seminal vesicle invasion (rho = 0.282, P = 0.0098). Cell lines and primary tumors derived from the TRAMP model were also found to express high levels of Aurora-A and Aurora-B. When human PC3, LNCaP, and mouse C1A cells were treated with the potent Aurora kinase inhibitor VX680, which attenuates phosphorylation of histone H3, cancer cell survival was reduced. VX680 could further reduce cell viability >2-fold when used in combination with the chemotherapy drug doxorubicin. Our findings support a functional relationship between Aurora kinase expression and prostate cancer and the application of small-molecule inhibitors in therapeutic modalities.     

Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression

Tumor-associated macrophages (TAMs) are highly active immune effector cells that may either positively or negatively regulate the growth of various malignant cells, depending on the biological context. However, the role of TAMs in human prostate cancer progression is unclear. TAMs were immunohistochemically labeled using a monoclonal (CD68) antibody in radical prostatectomy specimens derived from 81 prostate cancer patients. CD68-positive cells were counted with the aid of a microscope and expressed as macrophage index (MphiI), including TAMs/mm2 total tumor tissue (MphiItotal), TAMs/mm2 tumor stroma (MphiIstroma), and TAMs/mm2 cancer cell area (MphiIcancer). MphiIs were analyzed in association with patients' clinical and pathological stage, recurrence status, and histological grade of the cancer. There were significant inverse relationships between MphiItotal and MphiIstroma and clinical stage (P = 0.016 and P = 0.006, respectively). Reduced MphiItotal was also associated with the presence of positive lymph nodes (P = 0.010). Interestingly, although all of the MphiIs differed between Gleason score groups, only MphiIcancer was positively associated with Gleason score. Univariate analysis of MphiItotal and multivariate analysis of MphiItotal with specific pathological markers revealed that MphiItotal was an independent predictor for disease-free survival after surgery (Cox proportional hazard model, P = 0.044 and P = 0.007, respectively). For patients with high MphiItotal (> or = 185.8, the mean MphiItotal value), the disease-free probability 5 years after surgery was 0.75, which was significantly higher than for those with low MphiItotal (0.31, P = 0.0008). Additional immunohistochemical studies that evaluated cytotoxicity-related biomarkers in stroma-associated mononuclear cells suggested reduced functional activities in highly aggressive prostate cancer compared with less aggressive disease. Our results indicate that reduced MphiItotal is a novel prognostic marker for prostate cancer.