PSA Recurrence-free Survival Research Articles

未治療高リスク限局性前立腺癌における根治的前立腺全摘除術および拡大骨盤内リンパ節郭清の治療成績

We assessed the outcome after radical prostatectomy and extended pelvic lymphadenectomy in patients with untreated high-risk clinically localized prostate cancer, retrospectively. Between 2001 and 2010, 89 patients for untreated high-risk clinically localized prostate cancer on the risk classification as defined by D'Amico, underwent retropubic radical prostatectomy and extended pelvic lymphadenectomy. Boundaries of the pelvic lymph node dissection field divided into external iliac vessels, obturator fossa, and internal iliac vessels. We investigated mainly the postoperative outcome of 84 patients without any adjuvant therapies. PSA recurrence-free survival among the pretreatment variables was estimated using Kaplan-Meier plots, and the statistical significance was determined by log rank test. In 89 high-risk patients, 32.7% had pT3-pT4 tumors, 16.9% positive surgical margin, 6.7% positive lymph node metastases and 30.3% Gleason score 8-10 at the pathological examination. A median of 13 nodes (mean 14.0, range 9-25 nodes) were removed per patient. In 96.6% cases, postoperative PSA values decreased less than 0.2 ng/ml. The median observation period after operation was 1,819 days. Median PSA recurrence-free survival rates, overall survival and cancer cause-specific survival rates at 5 year, in 84 high-risk patients without any adjuvant therapies, were 73.8%, 100% and 100%, respectively. Median PSA recurrence-free survival rates according to pathological T stage and surgical margin status were statistically significant, but that according to preoperative 3 factors (clinical T stage, Gleason score at biopsy, preoperative PSA values) were statistically insignificant. Moreover, that according to both the number of positive preoperative 3 factors (1 vs. 2 positive factors) and the number of removed lymph nodes (< or =13 vs. > or = 14), were statistically insignificant. The median PSA recurrence-free survival rates at 5 year for positive margin cases were 0%. Radical prostatectomy and extended pelvic lymphadenectomy is feasible in patients with high-risk clinically localized prostate cancer. We suggest that both wide resection and extended pelvic lymphadenectomy may improve the postoperative outcome for high-risk clinically localized prostate cancer.

Preoperative predictors of pathologic stage T2a and pathologic Gleason score ≤ 6 in men with clinical low-risk prostate cancer treated with radical prostatectomy: reference for active surveillance

To assess preoperative parameters that may be predictive of pathologic stage T2a (pT2a) and pathologic Gleason score (pGS) ≤ 6 disease in low-risk prostate cancer patients considering active surveillance. A cohort of 1,495 men with low-risk prostate cancer between 1993 and 2009 was utilized. Preoperative assessment focused on patient age, race, diagnostic PSA level, clinical stage, diagnostic biopsy Gleason score, and prostate cancer laterality. Kaplan-Meier curves and a Cox regression model were used for analysis of PSA recurrence. Preoperative parameters were analyzed by univariate and multivariate logistic regression methods. Of 1,495 patients, 187 (12.5 %) were identified with pT2a and pGS ≤ 6 disease. Of the 187 men with pT2a and pGS ≤ 6 disease, only 6 (3.2 %) cases had PSA recurrence. Kaplan-Meier PSA recurrence-free survival curves identified a difference between prostate cancers with pT2a and pGS ≤ 6 and prostate cancers with >pT2a or pGS ≥ 7 disease (p = 0.002). Only biopsy tumor unilaterality (OR, 10.452; p ≤ 0.001) and low diagnostic PSA levels (OR, 0.887; p = 0.003) were independent predictors of prostate cancers with pT2a and pGS ≤ 6 disease on univariate and multivariate logistic regression. Biopsy tumor unilaterality and low diagnostic PSA levels are the independent predictors of pT2a and pGS ≤ 6 disease in low-risk prostate cancer patients. Unilateral cancer by prostate biopsy and low diagnostic PSA level may be the reference to improving the selection of appropriate candidates for active surveillance within a low-risk prostate cancer cohort.

Metformin and Prostate Cancer: Reduced Development of Castration-resistant Disease and Prostate Cancer Mortality

BackgroundIn vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC). ObjectiveTo determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC. Design, setting, and participantsData from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States. InterventionUse of metformin in localized prostate cancer. Outcome measurements and statistical analysisUnivariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer–specific mortality (PCSM), overall survival (OS), and development of CRPC. Results and limitationsWith a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24–3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78–7.62]; p<0.001), and PCSM (HR: 5.15 [1.53–17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83–119.89]; p=0.01). The retrospective study design was the primary limitation of the study. ConclusionsTo our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.

Impact of the adaptor protein GIPC1/Synectin on radioresistance and survival after irradiation of prostate cancer

Studies have shown that GIPC1/Synectin is an essential adaptor protein of receptors that play an important role in cancer progression and therapy resistance. This is the first study to explore the role of GIPC1/Synectin in radioresistance of prostate cancer and as a possible predictive marker for outcome of primary radiation therapy. The effect of RNA interference-mediated GIPC1/Synectin depletion on clonogenic cell survival after irradiation with 0, 2, 4, or 6 Gy was assayed in two different GIPC1/Synectin-expressing human prostate cancer cell lines. The clinical outcome data of 358 men who underwent radiotherapy of prostate cancer with a curative intention were analyzed retrospectively. Uni- and multivariate analysis was performed of prostate-specific antigen recurrence-free survival and overall survival in correlation with protein expression in pretreatment biopsy specimens. Protein expression was evaluated by standard immunohistochemistry methods. In cell culture experiments, no change was detected in radiosensitivity after depletion of GIPC1/Synectin in GIPC1/Synectin-expressing prostate cancer cell lines. Furthermore, there was no correlation between GIPC1/Synectin expression in human pretreatment biopsy samples and overall or biochemical recurrence-free survival after radiotherapy in a retrospective analysis of the study cohort. Our results do not show a predictive or prognostic function of GIPC1/Synectin expression for the outcome of radiotherapy in prostate cancer. Furthermore, our in vitro results do not support a role of GIPC1 in the cellular radiation response. However, the role of GIPC1 in the progression of prostate cancer and its precursors should be subject to further research.

25-Year Disease-Free Survival Rate After Irradiation for Prostate Cancer Calculated with the Prostate Specific Antigen Definition of Recurrence Used for Radical Prostatectomy

We addressed whether there is durable control of prostate cancer, defined as a prostate specific antigen cutoff of less than 0.2 ng/ml, greater than 20 years after irradiation for this disease. We also evaluated late recurrence, defined as recurrence after 10-year followup. A total of 3,546 consecutive hormone naïve men were treated with a (125)I prostate implant (retropubic and later transperineal), followed by external beam irradiation, from 1984 to 2000. Recurrence was defined as a prostate specific antigen increase of greater than 0.20 ng/ml or a prostate specific antigen nadir of greater than 0.20 ng/ml. Median followup was 11 years (range 3 months to 26 years). In all men 10, 15, 20 and 25-year disease-free survival rates were 75%, 73%, 73% and 73%, respectively. Longest time to recurrence was at the 15.5-year followup. In 313 men with recurrence who were treated 16 to 25 years ago 5% of recurrences were late. In men implanted by the transperineal method since 1995 the 15-year disease-free survival rate was 79%. With this irradiation program cancer control, defined using the recurrence definition for radical prostatectomy, was durable with no further recurrence between 15.5 and 25 years of followup. This study also suggests that at least 15 years of followup are necessary to fully evaluate any prostate cancer treatment. Furthermore, if prostate specific antigen is less than 0.20 ng/ml 15 years after treatment, later recurrence should be unlikely.

Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

Preoperative Predictors of Pathologic Stage T2a in Low-Risk Prostate Cancer: Implications for Focal Therapy

Objective: To assess preoperative parameters that may be predictive of pathologic stage T2a disease in low-risk prostate cancer patients. Methods: Data from a cohort of 1,495 consecutive men with low-risk prostate cancer who underwent a radical prostatectomy between 1993 and 2009 were evaluated. Preoperative parameter assessment focused on age, race, clinical stage, diagnostic PSA level, biopsy tumor laterality and diagnostic Gleason score. Preoperative parameters were analyzed by univariate and multivariate methods. Kaplan-Meier method was used to evaluate the biochemical disease-free survival. Results: Among the 1,495 men, 236 (15.8%) had pT2a disease. In univariate analysis, biopsy tumor unilaterality (p < 0.001), diagnostic PSA ≤4 ng/ml (p < 0.001) and non-African-American race (p = 0.009) were significant variables. In multivariate analysis, biopsy tumor laterality (OR 0.377; p < 0.001), diagnostic PSA ≤4 ng/ml (OR 0.621; p = 0.002) and race (OR 0.583; p = 0.029) were independent predictors. Low-risk patients with pT2a disease showed a better PSA recurrence-free survival rate, compared with men with >pT2a diseases (p = 0.012). Conclusions: Biopsy tumor unilaterality, diagnostic PSA ≤4 ng/ml and race are independent predictors of pT2a in low-risk prostate cancer. These three preclinical variables may be a useful reference to begin the selection process for focal therapy in men with low-risk prostate cancer.

Intratumoral T but not B lymphocytes are related to clinical outcome in prostate cancer

The number of tumor-infiltrating lymphocytes is functionally important and correlates with clinical outcome in several tumor entities. Herein we explore the impact of the density of T and B lymphocytes in prostate cancer tissue on prostate-specific antigen (PSA) recurrence after prostatectomy in 3261 prostate cancer tissue samples. The number of prostate cancer-infiltrating CD3-positive T cells and CD20-positive B cells per tissue spot in a tissue microarray format was determined by immunohistochemistry and was correlated with clinical and pathological data from the same patient cohort. Patients with very low and very high numbers of CD3-positive T cells per tissue spot had a significantly shorter PSA recurrence-free survival compared to patients with intermediate numbers of T cells (p = 0.0188). Furthermore, a high number of CD3-positive T cells per tissue spot was associated with fusion type prostate cancer identified by ERG expression analysis. The number of CD20-positive B cells per tissue spot was not associated with other clinical and histopathological parameters. This study indicates that the density of T but not B cells plays a functional role in the biology of prostate cancer and may have an impact on clinical outcome in this frequent neoplasia.

Association between percentage of tumor involvement and Gleason score upgrading in low-risk prostate cancer

To find the predictors of Gleason score upgrading in a cohort of low-risk prostate cancer patients, data were analyzed comprising 1,632 consecutive men with low-risk prostate cancer who underwent radical prostatectomy between 1993 and 2009. Assessment focused on preoperative parameters including patient age, race, diagnostic prostate-specific antigen (PSA) levels, clinical stage and biopsy Gleason score, along with pathological parameters including percentage of tumor involvement (PTI), tumor laterality, pathological stage, extra-capsular extension, seminal vesicle invasion, and surgical margins. These parameters were analyzed using univariate and multivariate methods. Kaplan-Meier curves compared differences in biochemical disease-free survival in men having cancers with and without Gleason score upgrading. Cases involving pathological Gleason score upgrading were identified in 723 (44.3 %) of 1,632 patients. Kaplan-Meier PSA recurrence-free survival curves showed a difference in outcome between men with and without Gleason score upgrading (p < 0.001). Of Gleason score upgraded patients, 35 (4.8 %) men had PTI of <5 %, 237 (32.8 %) had PTI of 5-9.9 %, 177 (24.5 %) had PTI of 10-14.9 %, and 274 (37.9 %) had PTI ≥ 15 % (p < 0.001). PTI (p < 0.001) along with diagnostic PSA, patient age, diagnostic biopsy Gleason score, pathologic stage, and surgical margin status were independent predictors of pathological Gleason score upgrading on multivariate logistic regression. PTI correlates closely with Gleason score upgrading in a low-risk prostate cancer cohort. Low-risk prostate cancer patients with clinical findings suggestive of high PTI or large volume cancers should not benefit from active surveillance strategies.

Abstract 3291: Defining the role of the cellular polarity regulator Scrib in epithelial tumorigenesis

Abstract In recent years, loss of cell polarity and tissue architecture has been defined as a hallmark of epithelial cancer yet the molecular mechanisms underlying this predisposition are not fully understood. Two distinct polarity programs are required for the correct assembly and function of all mammalian epithelial tissues; apical-basal polarity and non-canonical Wnt/planar cell polarity (1). The Scribble complex functions to establish and maintain both aspects of epithelial polarity and has been shown to mediate cell adhesion, migration and asymmetric cell division (2). In human colorectal, breast, and cervical cancers, expression of the Scribble complex member SCRIB is often mislocalised and deregulated, suggesting that polarity regulators plays a role in maintaining homeostasis of epithelial tissues (1,3). Scrib null mice are neonatal lethal owing to a neural tube closure defect. To determine the tumor suppressive role of Scrib within epithelial tissues, we have employed tissue specific Cre-LoxP technology to deplete Scrib specifically within the prostate, mammary or lung. Scrib depletion in these epithelial tissues results in tumor initiation, supporting previous work in Drosophila (1). We and others have previously shown that SCRIB loss stimulates Ras/MAPK signaling in vitro, suggesting that SCRIB negatively regulates the Ras/MAPK cascade to suppress tumorigenesis (4,5). We now show elevated p-ERK1/2 expression is a common feature of Scrib deficient tumors in vivo. Accordingly, administration of the MEK inhibitor PD0325901 in Scrib+/− mice partially rescued the hyperplastic prostate phenotype. Together, these studies establish that depletion of the polarity regulator Scrib can initiate murine tumorigenesis in several epithelial tissues in a process involving deregulation of the Ras/MAPK cascade. Interestingly, tissue specific activation of oncogenic K-ras in combination with Scrib depletion accelerated tumor progression in both the prostate and lung. Thus, K-ras activation and Scrib deficiency synergise to facilitate tumor growth, demonstrating that Scrib depletion can contribute to tumor progression in the presence of an additional oncogenic mutation. The clinical relevance of this research is highlighted by our observation that SCRIB deregulation strongly correlated with PSA recurrence free survival in human prostate cancer (3). Together, our findings suggest that the polarity network may hold prognostic value or provide a novel route for therapeutic intervention. (1) Humbert PO et al (2008) Oncogene 27(55):6888-6907 (2) Kallay LM et al (2006) J Cell Biochem 99: 647-64 (3) Pearson HB et al (2011) J Clin Invest 121(11):4257-4267 (4) Dow LE et al (2008) Oncogene 27(46):5988-6001 (5) Nagasaka K et al (2010) Oncogene 29(38):5311-5321 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3291. doi:1538-7445.AM2012-3291

968 REGULATION OF MCP-1 EXPRESSION THROUGH ANGIOTENSIN II TYPE 1 RECEPTOR IN CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2012968 REGULATION OF MCP-1 EXPRESSION THROUGH ANGIOTENSIN II TYPE 1 RECEPTOR IN CASTRATION-RESISTANT PROSTATE CANCER Suguru Shirotake, Akira Miyajima, Takeo Kosaka, Nobuyuki Tanaka, Eiji Kikuchi, and Mototsugu Oya Suguru ShirotakeSuguru Shirotake Tokyo, Japan More articles by this author , Akira MiyajimaAkira Miyajima Tokyo, Japan More articles by this author , Takeo KosakaTakeo Kosaka Tokyo, Japan More articles by this author , Nobuyuki TanakaNobuyuki Tanaka Tokyo, Japan More articles by this author , Eiji KikuchiEiji Kikuchi Tokyo, Japan More articles by this author , and Mototsugu OyaMototsugu Oya Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1067AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Tumor associated macrophage infiltration and the main regulator, monocyte chemoattractant protein-1 (MCP-1) expression, have been reported to be associated with a poor prognosis in prostate cancer (CaP). However, the mechanism of regulation of MCP-1 in CaP is still unclear. Since angiotensin II (AngII) type 1 receptor (AT1R) is known to be one of the regulators of MCP-1 in hypertensive disease and we have already investigated the correlation between AT1R and tumor angiogenesis in CaP, here we examined the regulation of MCP-1 through AT1R in CaP. METHODS Specimens were obtained from 138 CaP patients; androgen dependent CaP in 121 cases obtained by prostatectomy and castration resistant CaP (CRPC) in 17 cases obtained by autopsy. All specimens were immunostained for MCP-1 and CD68+ macrophages (Mφ). Clinicopathological characteristics were reviewed retrospectively. We also investigated the regulation of MCP-1 expression through AT1R using 3 human CaP cell lines; LNCaP, C4-2, and C4-2AT6. CV11974 and TCV116 are active metabolites of candesartan and were used for the in vitro and in vivo experiments. RESULTS Specimens with a high Gleason score (7≤) and advanced stage (pT3≤), and those of CRPC had significantly higher MCP-1 expression and higher Mφ infiltration than low malignant CaP. Kaplan-Meier curves showed that the 5-year PSA recurrence-free survival rate was 77.0% in the low MCP-1 group vs 54.5% in the high MCP-1 group (p=0.017). Multivariate analysis revealed that preoperative high PSA (15≤) (risk ratio, 2.48) and high MCP-1 (risk ratio, 2.20) were independent risk factors for PSA recurrence. Higher expression of MCP-1 and AT1R in C4-2 and C4-2AT6 cells than in LNCaP cells was observed. AngII induced significantly higher MCP-1 in C4-2AT6 cells than in LNCaP cells, while MCP-1 expression was reduced by CV11974. C4-2AT6 tumors treated with TCV116 also exhibited significantly lower MCP-1 expression and Mφ infiltration than the control tumors. In C4-2AT6 cells, immunoblotting demonstrated that CV11974 inhibited the phosphorylation of Akt by AngII stimulation, but that the MAPK and JAK/STAT pathways were not activated by AngII. MCP-1 induced by AngII was suppressed by PI3K inhibitor in C4-2AT6 cells. CONCLUSIONS Both high MCP-1 and high Mφ in CaP specimens correlated with a high PSA recurrence rate. AT1R blockade inhibited MCP-1 expression through the PI3K/Akt pathway and also suppressed Mφ infiltration in CRPC. AT1R is one of the regulators of MCP-1 expression, and may potentially become a new therapeutic target molecule for the treatment of CRPC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e394 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Suguru Shirotake Tokyo, Japan More articles by this author Akira Miyajima Tokyo, Japan More articles by this author Takeo Kosaka Tokyo, Japan More articles by this author Nobuyuki Tanaka Tokyo, Japan More articles by this author Eiji Kikuchi Tokyo, Japan More articles by this author Mototsugu Oya Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Quantitative RT‐PCR analysis of PSA and prostate‐specific membrane antigen mRNA to detect circulating tumor cells improves recurrence‐free survival nomogram prediction after radical prostatectomy

Circulating tumor cell (CTC) analysis is a potential new biomarker in prostate cancer. We hypothesize that quantitative detection of CTCs in patients pre- and post-radical prostatectomy (RP) using quantitative TaqMan® fluorogenic RT-PCR will improve the accuracy of the Kattan nomogram to predict the probability of recurrence-free survival (RFS) post-RP. Ninty-two patients who underwent RP between 2004 and 2009 had venous blood samples taken pre- (Day - 1) and post-operatively (Day + 7). We performed quantitative Taqman® RT-PCR to detect circulating prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) mRNA. We calculated both the logarithmic ratio of Day + 7/Day - 1 for PSA (PSAr) and PSMA (PSMAr) expression (log(Day+7/Day-1) ) and the Kattan nomogram predicted probability of disease recurrence for each patient. We then analyzed how the AUC-ROC analysis for the Kattan nomogram prediction alone (K) compared to the addition of the PSAr and PSMAr in predicting 5-year RFS. The mean age (years), PSA (ng/ml), and follow-up (mo) was 65.1, 9.13, and 72, respectively. The AUCs for K, PSAr + K, and PSMAr + K were 0.752 (95%CI 0.620-0.860), 0.830 (95%CI 0.740-0.911), and 0.837 (95%CI 0.613-0.923), respectively (P = 0.03). The Kattan 5-year PSA RFS was 75%. The actual 5-year PSA RFS survival rate was 77%. Data from modern quantitative RT-PCR to detect circulating prostate-derived PSA and PSM mRNA pre- and post-RP improves the accuracy of the Kattan nomogram to predict biochemical recurrence.

Projecting the clinical benefits of adjuvant radiotherapy versus observation and selective salvage radiotherapy after radical prostatectomy: a decision analysis

Our purpose was to project and compare clinical and quality-adjusted life year (QALY) outcomes of adjuvant radiotherapy (ART) versus salvage RT (SRT) after radical prostatectomy for men with locally advanced prostate cancer. We constructed a Markov model to simulate the randomized studies of observation versus ART, assuming 75% of observation patients would receive SRT at PSA recurrence. Transition probabilities and utility inputs were drawn from randomized trials of ART and cohort studies of SRT. We projected 10-year PSA recurrence-free survival, metastasis-free survival and overall survival. We found that observation with selective SRT yielded slightly worse outcomes than ART for post-RT PSA recurrence-free survival (47 and 52%), metastasis-free survival (69 and 70%) and overall survival (72 and 73%). Findings were robust to sensitivity analyses. After adjusting for the disutility of RT, observation plus SRT yielded better QALYs at 10 years than ART (6.80 and 6.13 QALYs). Thus, observation plus SRT may be optimal for men likely to comply with surveillance who wish to minimize side effects of the treatment. These findings reflect outcomes for the average patient given the current level of evidence and are meant to help inform current decision-making as we await future clinical studies of comparative effectiveness.

Relationship of T lymphocytes, T regulatory cells, and B lymphocytes to clinical outcome in prostate cancer.

4632 Background: Tumor-infiltrating lymphocytes are functionally important and correlate with clinical outcome in several tumor entities. In prostate cancer, systematic profiling of the number and subtype of lymphatic cells in the tumor tissue based on large patient cohorts are lacking. Methods: We explored the prognostic significance of the density of T and B lymphocytes in prostate cancer tissue in 3,261 prostate cancer tissue samples. The number of prostate cancer-infiltrating CD3-positive T cells, FOX-P3-positive T-regulatory cells (Tregs), and CD20-positive B cells per tissue spot in a tissue microarray format was determined by immunohistochemistry and was correlated with clinical and functional pathological data from the same patient cohort. Results: Patients with very low and very high numbers of CD3-positive T cells per tissue spot had a significantly shorter PSA recurrence-free survival compared to patients with intermediate numbers of T cells. The number of intraepithelial CD3-positive T cells and the number of CD20-positive B cells per tissue spot was not associated with other clinical and histopathological parameters. PSA recurrence-free survival was significantly reduced in patients with higher numbers of Tregs. Further, a higher number of intratumoral FOXP3+ Tregs was associated with a more advanced tumor stage and higher Ki67 labeling index. The tissue density of Tregs was unrelated to other clinical parameters such as spread to lymph nodes, preoperative PSA level, and Gleason score. Conclusions: Our study suggests for the first time that both the intratumoral absence or presence of T cells and T regulatory cells is functionally relevant and may have an impact on the clinical course in prostate cancer.

Long-Term Results of a Prospective Dose Escalation Phase-II Trial: Interstitial Pulsed-Dose-Rate Brachytherapy as Boost for Prostate Cancer

Purpose: We reviewed our ten-year single institution experience with pulsed dose rate brachytherapy by dose escalation Phase-II study in patients with intermediateand high-risk prostate cancer (according the definition by d’Amico). Materials andMethods:We treated a total of 130 patients for intermediate and high risk prostate cancer between 2000 and 2007 using PDRbrachytherapy as a boost after conformal external beam radiation therapy to 45-50 Gy. Boost brachytherapy doses ranged from 25 to 35 Gy e 33 pts. received 25 Gy (total dose 70 Gy), 63 pts. 30 Gy (total dose 75-80 Gy) and 34 pts. 35 Gy,(total dose 85 Gy) given in one session (dose per pulse was 0.60 -0.70 Gy delivered for 24 h per day, night and day, with a time interval of 1 h between two pulses, total time 48-50 hours). PSArecurrence-free survival according to Kaplan-Meier was calculated and changes in American Urological Association symptom scores and also acute and chronic toxicities according Common Toxicity Criteria scale were assessed. Results: At the time of analysis with a median followup of 66 months local control according to the Phoenix definition was achieved by 88% of patients e only 16/130 patients (12,3%) developed a biochemical relapse. A strong correlation between frequency of a local control according to the Phoenix definition and the brachytherapy dose has been documented: At time of analysis 82%, 86% and 97% of our patients were disease-free for boost doses in values of 25 Gy, 30 Gy and 35 Gy, respectively. The side effects of therapy were negligible: There were 18 cases (14%) of grade 1/2 rectal proctitis, one case (0.8%) grade 3 proctitis, 18 cases (14%) of grade 1/2 cystitis, no cases (0%) with dysuria grade 3. No patient had new onset incontinence or a bulbourethral stricture requiring dilation. Conclusions: Image-guided conformal PDR-brachytherapy as boost after external beam radiation therapy is a very effective treatment option with very lowmorbidity by patientswith intermediate or high risk prostate cancer.

2337 PREOPERATIVE SERUM LEVELS OF INTERLEUKIN-6 AND INTERLEUKIN-12 PREDICT BIOCHEMICAL RECURRENCE IN PATIENTS WITH PROSTATE CANCER TREATED USING RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Markers1 Apr 20112337 PREOPERATIVE SERUM LEVELS OF INTERLEUKIN-6 AND INTERLEUKIN-12 PREDICT BIOCHEMICAL RECURRENCE IN PATIENTS WITH PROSTATE CANCER TREATED USING RADICAL PROSTATECTOMY Shintaro Narita, Norihiko Tsuchiya, Shinya Maita, Takashi Obara, Kazuyuki Numakura, Hiroshi Tsuruta, Takamitsu Inoue, Yohei Horikawa, Shigeru Satoh, and Tomonori Habuchi Shintaro NaritaShintaro Narita Akita, Akita, Japan More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya Akita, Akita, Japan More articles by this author , Shinya MaitaShinya Maita Akita, Akita, Japan More articles by this author , Takashi ObaraTakashi Obara Akita, Akita, Japan More articles by this author , Kazuyuki NumakuraKazuyuki Numakura Akita, Akita, Japan More articles by this author , Hiroshi TsurutaHiroshi Tsuruta Akita, Akita, Japan More articles by this author , Takamitsu InoueTakamitsu Inoue Akita, Akita, Japan More articles by this author , Yohei HorikawaYohei Horikawa Akita, Akita, Japan More articles by this author , Shigeru SatohShigeru Satoh Akita, Akita, Japan More articles by this author , and Tomonori HabuchiTomonori Habuchi Akita, Akita, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2584AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Circulating cytokine levels are known to be related to disease progression in prostate cancer. This study aimed to evaluate the clinical significance of preoperative serum levels of inflammatory cytokines as prognostic markers in patients treated using radical prostatectomy. METHODS One hundred and seventeen prostate cancer patients who underwent radical prostatectomy at our institute were enrolled in this study. Preoperative serum levels of six inflammatory cytokines [interleukin (IL)-10, IL-6, tumor necrosis factor-α, IL-1b, IL-8, and IL-12p70] were measured using the BD™ Cytometric Bead Array. Statistical interactions between levels of prostate-specific antigen (PSA) and predictive factors, including clinical parameters and levels of inflammatory cytokines, were assessed. RESULTS Overall, 12% (14/117) patients had PSA recurrence with a median follow-up of 14.9 months. In univariate analysis, patients with IL-12p70 ≤ 1.5 pg/mL in their serum had a significantly higher recurrence rate of PSA than those with higher values (p = 0.019). Furthermore, patients with IL-6 > 2.2 pg/mL in their serum tended to have a higher recurrence rate of PSA (p = 0.068). Preoperative PSA level, biopsy Gleason score, and T stage were also associated with PSA recurrence. Multivariate analysis revealed that preoperative serum level of PSA, IL-6, and IL-12p70 were independent predictors for PSA recurrence-free survival [odds ratio (OR) 5.4, 95% confidence interval (CI) 1.7–17.0, p = 0.004; OR 4.3, 95% CI 1.1–16.3, p = 0.034; and OR 9.0, 95% CI 1.1–75.4, p = 0.044]. CONCLUSIONS Preoperative serum levels of IL-6 and IL-12p70 are associated with biochemical recurrence in patients with prostate cancer treated using radical prostatectomy. Circulating cytokine levels may be potential predictors of outcome in patients with localized prostate cancer. Factors causing high levels of cytokines and their influence on progression of prostate cancer remain to be elucidated.α © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e937 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shintaro Narita Akita, Akita, Japan More articles by this author Norihiko Tsuchiya Akita, Akita, Japan More articles by this author Shinya Maita Akita, Akita, Japan More articles by this author Takashi Obara Akita, Akita, Japan More articles by this author Kazuyuki Numakura Akita, Akita, Japan More articles by this author Hiroshi Tsuruta Akita, Akita, Japan More articles by this author Takamitsu Inoue Akita, Akita, Japan More articles by this author Yohei Horikawa Akita, Akita, Japan More articles by this author Shigeru Satoh Akita, Akita, Japan More articles by this author Tomonori Habuchi Akita, Akita, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Pathological findings and oncological control afforded by radical prostatectomy in men with high-risk prostate cancer: a single-centre study

To assess pathological findings and oncological control afforded by radical prostatectomy (RP) in high-risk prostate cancers (PCa) at our institution. We performed a retrospective review of prostate cancer patients who underwent RP between 1995 and 2006 for a high-risk prostate cancer (i.e., PSA >20 or biopsy Gleason ≥8 or clinical stage ≥T2c). Biochemical recurrence was defined as a single rise in PSA levels over 0.2 ng/ml after surgery. Survival curves were elaborated by the Kaplan-Meier method and Cox proportional hazard regression analysis. For each patient, a prognostic score for recurrence was estimated, and a prediction model was then constructed. Overall, 138 patients were included and followed for a median time of 53 months. Mean age at diagnosis was 63.4 years (range 39-80) and mean pre-operative PSA was 15.5 ng/ml (range 7.4-31). The median follow-up was 53 months (range 6-166). Overall, 82 patients (59%) had biochemical recurrence. The five-year PSA recurrence-free survival rate was 40%. In univariate analysis, clinically palpable tumours (T2-T3) (P = 0.032), biopsy Gleason score ≥8 (P = 0.031), seminal vesicle invasion (pT3b), positive margins and positive lymph nodes (P < 0.001) were significantly associated with recurrence. In multivariate analysis, the biopsy Gleason score ≥8, seminal vesicle invasion, positive margins and positive lymph nodes predicted recurrence (P < 0.05). RP affords an acceptable oncological control at first-line treatment of selected patients with high-risk PCa. However, in certain cases, surgery alone might not be sufficient and may be part of a multimodal treatment including either adjuvant radiotherapy or androgen deprivation.

Differential expression of peroxiredoxins in prostate cancer: Consistent upregulation of PRDX3 and PRDX4

The peroxiredoxins (PRDXs) are emerging as regulators of antioxidant defense, apoptosis, and therapy resistance in cancer. Because their significance in prostate cancer (PCa) is unclear, we investigated their expression and clinical associations in PCa. Transcript expression of PRDX1-6 in PCa was evaluated in cancer gene microarray datasets, whereas protein expression was evaluated by immunoblotting in prostate cell lines, and by immunohistochemistry (IHC) in prostate tissue microarrays (TMAs) containing tumor (n = 80) and control (n = 17) tissues. PRDX3 was also analyzed in TMAs containing PCa tissues from African-American and Caucasian patients (n = 150 per group). PRDX expression was correlated with patients' clinicopathologic characteristics. Analysis of PRDX expression in cancer microarray datasets revealed consistent upregulation (tumor vs. normal) of PRDX3 and 4. All PRDXs exhibited elevated protein expression in PCa cell lines, compared with non-tumor cells. IHC revealed significant overexpression of PRDX3 and 4 in PCa, associated with age, increased prostate specific antigen (PSA), tumor stage, or Gleason score. High PRDX3 staining was associated with early age and elevated Gleason score at time of radical prostatectomy in African-American but not in Caucasian patients with PCa. PSA recurrence free survival in patients with low PRDX3 tumor expression was significantly longer in Caucasians compared to African-Americans, but no difference was detected for high expression. PRDXs exhibit differential expression in prostate tumors, with PRDX3 and 4 consistently upregulated. Their role in PCa development, and their potential as biological determinants of PCa health disparities and novel therapeutic targets, deserve further investigation.

Abstract A108: Differential expression of peroxiredoxins in prostate cancer: Ethnic differences in the association of PRDX3 expression with clinical outcomes

Abstract Prostate cancer (PCa) is the most frequently diagnosed male cancer and the second leading cause of cancer death in men in the United States. This growing public health challenge is aggravated by disparities in the incidence and mortality of PCa among African-American (AA) men, compared to Caucasian (CC) men and other ethnic groups. The reasons for these disparities are not completely understood, although available evidence points to the convergence of multiple, interrelated factors, such as socioeconomics, unequal access to health care and screening, unhealthy lifestyle and diet, ancestry, and genetic susceptibility. Emerging evidence suggests that chronic inflammation of the prostate contributes to PCa development by inducing oxidative molecular damage, which in turns lead to the upregulation of stress and redox proteins that protect tumor cells against apoptosis and therapeutic interventions. Evaluation of the expression and role of these proteins in prostate tumors from different ethnic populations would help define molecular and cellular factors associated with prostate tumor aggressiveness and therapy resistance, and uncover potential biological determinants of PCa health disparities. The peroxiredoxin (PRDX) protein family consists of six anti-oxidant enzymes (PRDX1-6) that are emerging as key regulators of cellular anti-oxidant defense, and are being increasingly implicated in malignant transformation and therapy resistance. Very little is known about their role in prostate cancer. In this study we investigated their expression and association with clinical outcomes in prostate cancer (PCa). The expression of PRDX1-6 in PCa was evaluated in 14 cancer gene microarray datasets (from Oncomine and SPECS), by immunoblotting in a panel of 11 prostate cell lines, and by immunohistochemistry (IHC) in prostate tissue microarrays (TMA) containing tumor (n=80) and control (n=17) tissues. PRDX3 was also analyzed in TMA containing PCa tissues from AA and CC patients (n=150 per group). PRDX expression was correlated with patients’ clinicopathologic characteristics. Analysis of PRDX expression in cancer microarray databases revealed consistent upregulation (tumor vs normal) of PRDX3 and 4. All PRDXs exhibited elevated protein expression in PCa cell lines, compared with non-tumor cells. IHC revealed significant overexpression of PRDX3 and 4 in PCa, associated with increased prostate specific antigen (PSA), tumor stage, or Gleason score. High PRDX3 expression was associated with early age and elevated Gleason score at time of radical prostatectomy in AA but not in CC patients with PCa. PSA recurrence free survival in patients with low PRDX3 tumor expression was significantly longer in CC compared to AA patients, but no difference was detected for high expression. We conclude that PRDXs exhibit differential expression in prostate tumors, with PRDX3 and 4 consistently upregulated. The role of these two proteins in PCa development, and their potential as biological determinants of PCa health disparities and novel therapeutic targets, deserve further investigation. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A108.

Abstract 2715: Peroxiredoxin 3: A potential biological determinant of prostate cancer health disparities

Abstract Prostate Cancer (PCa) is the most frequently diagnosed male cancer and presents the greatest racial disparity of any cancer in the U.S., with high incidence and mortality among African American (AA) men. Eliminating these disparities requires a multi-prong approach that includes, in addition to aggressive social and public health interventions, a better understanding of the biology of prostate tumors from different ethnic groups, and the development of effective treatments for castration-resistant prostate cancer (CRPC). Our interest is to define the contribution of antioxidant and stress proteins induced by environmental factors to tumor aggressiveness and health disparities in PCa. We analyzed the expression of the peroxiredoxin (PRDX) protein family in prostate cell lines and prostate tissue microarrays (TMA), and observed a dramatic upregulation of PRDX3 in androgen responsive metastatic cell lines, particularly the AA-derived cell line MDA-PCa-2b. There was also a significant correlation between high PRDX3 tissue expression and PCa (when compared to normal tissues), advanced tumor stage, and elevated PSA (P&amp;lt;0.05). These observations prompted an analysis of PRDX3 protein expression in ethnicity PCa TMAs containing 150 cases from AA PCa patients and 150 cases from Caucasian (CC) PCa patients, plus normal prostate tissues. Although we did not observe significant differences in the percent of PRDX3-positive immunostained prostate tumor tissues when comparing AA vs CC tissues, high PRDX3 expression correlated with early age at diagnosis (P&amp;lt;0.01) and elevated Gleason score (P&amp;lt;0.05) in the AA group but not in the CC group (P=0.459 and P=0.3394, respectively). We also examined the association between PRDX3 prostate tumor tissue expression and PSA recurrence free survival in AA and CC patients for which disease progression data was available. PSA recurrence free survival in patients with low PRDX3 tumor expression was longer in the CC group than in the AA group (P&amp;lt;0.05, log rank test), suggesting a correlation with a more favorable prognosis for the CC patients. However, no statistically significant difference in PSA recurrence free survival was detected in patients with high PRDX3 expression, when both groups were compared (P=0.159). These results could be interpreted as that high PRDX3 expression in prostate tumors is associated with a less favorable prognosis regardless of ethnicity, whereas low PRDX3 expression is associated with a less favorable prognosis in AA patients compared to CC patients. The contribution of PRDX3 to these differences is unclear, but taken together the data suggest that the presence of PRDX3 (low or high) in prostate tumors from AA patients could be associated with a more aggressive disease phenotype. These results warrant further investigation of the significance of PRDX3 expression in prostate tumors, and exploiting PRDX3 as a novel therapeutic target for CRPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2715.