Risk Of Prostate-specific Antigen Recurrence Research Articles

Post-prostatectomy adjuvant androgen deprivation therapy- Current opinions and practices of Canadian urologists.

Despite the proven benefit of adjuvant androgen deprivation therapy (ADT) for patients receiving primary radiation, there are few studies evaluating adjuvant ADT after prostatectomy. In the absence of evidence, opinions and practice patterns vary. We surveyed Canadian prostate cancer surgeons about their use of adjuvant ADT and their opinions on the design of a potential adjuvant ADT trial. An electronic survey was devised and distributed using a modified Dillman approach. The survey was sent to 38 Canadian urologists that perform radical prostatectomy and representing all 17 major academic institutions in Canada and all 10 Canadian provinces. Reminders were sent three and four weeks following the original request. In addition to demographic information, we asked surgeons about their current use of postoperative adjuvant ADT and their opinion about the need for a clinical trial. To inform trial design, we asked respondents their opinions about which patients should be eligible, what duration of ADT was most appropriate, and which outcomes are clinically meaningful. The survey was sent in February 2020 and all responses were received by March 2020. All 38 (100%) invited urologists completed the survey. Only 3 (7%) respondents currently offer postoperative adjuvant ADT as an option for patients without metastases. 35 (92%) urologists believed that a trial is needed before short-term adjuvant treatment should be offered to prevent recurrence. 15 (45%) urologists believed an adjuvant ADT trial was most appropriate for patients with an estimated PSA recurrence risk of >25% and 16 (42%) believed a recurrence risk of >50% was most appropriate. 25 (66%) respondents believed 12-month was the optimal duration of treatment with adjuvant ADT for a randomized trial. 37 (97%) respondents felt that prolonging the time to PSA recurrence and/or pelvic radiation was a clinically important outcome. The majority (20; 53%) of respondents would recommend 12 months of adjuvant ADT in their practice if a randomized trial showed a 50% relative risk reduction in PSA recurrence at 5-year postoperative. The vast majority of Canadian prostate cancer surgeons do not offer adjuvant ADT following prostatectomy in patients without metastases. Based on the results from this survey, a randomized trial was considered warranted and feasible, and would influence patient care.

SPOP and CHD1 alterations in prostate cancer: Relationship with PTEN loss, tumor grade, perineural infiltration, and PSA recurrence.

In the non-ETS fusion of prostate cancer (PCa) pathway, SPOP mutations emerge as a distinct oncogenic driver subclass. Both SPOP downregulation and mutation can lead to SPOP target stabilization promoting dysregulation of key regulatory pathways. CHD1 gene is commonly deleted in PCa. CHD1 loss significantly co-occurs with SPOP mutations, resulting in a PCa subclass with increased AR transcriptional activity and with a specific epigenetic pattern. In this study, SPOP alterations at mutational and protein levels and CHD1 copy number alterations have been analyzed and correlated with ERG and PTEN protein expression and with the clinical pathological features of the patients. SPOP protein loss has been detected in 42.9% of the cases, and it has been strongly associated with PTEN protein loss (p < .001). CHD1 gene loss has been detected in 24.5% and SPOP mutations in 5.9% of the cases. Loss of CHD1 has been strongly associated with SPOP mutations (p = .003) and has shown a trend to be associated with ERG wt cancers (p = .08). The loss of SPOP protein (p = .01) and the combination of PTEN and SPOP protein loss (p = .002) were both statistically more common in grade group 5 cancers, with a prevalence of 60% and 37.5%, respectively. Furthermore, SPOP loss/PTEN loss and SPOP wt/PTEN loss phenotypes were strongly associated with extraprostatic perineural infiltration (p = .007). Strong CHD1 loss was associated with a shorter time to PSA recurrence in the univariate (p = .04), and showed a trend to be associated with the PSA recurrence risk in the multivariate analysis (p = .058). The results of the present study suggest that the loss of SPOP protein expression, either alone or in combination with loss of PTEN and, on the other hand, a marked loss of the CHD1 gene are very promising prognostic biomarkers in PCa.

Choosing a treatment method for post-catheterization pseudoaneurysms guided by the late to early velocity index

Ultrasound-guided thrombin injection (UGTI) is often the first-line treatment for iatrogenic post-catheterization pseudoaneurysms (psA). There are also first reports of the use of biologically derived tissue glues (TG) instead of sole thrombin especially when UGTI was unsuccessful or in case of psA recurrence. Previously, we have established that a late to early velocity index (LEVI) < 0.2 could be a predictor of an increased risk of psA recurrence after standard UGTI. In this paper, we report our first experiences when the choice of the first-line treatment method was based on LEVI assessment. From May 2017 till January 2020 we included 36 patients with psA. Of them, 10 had LEVI < 0.2 and they underwent ultrasound-guided tissue glue injection (UGTGI) with biological TG and 26 had LEVI > 0.2 and they underwent UGTI. The injection set containing human thrombin and fibrinogen was used for UGTGI. Bovine thrombin was used for UGTI. The success rate was 100% and no psA recurrence was detected during a 2-week follow-up. It was significantly better when compared to the expected recurrence rates based on our previous 14 years of experience (0% vs. 13%, p = 0.01). All complications (10% in the UGTGI group and 15% in the UGTI group) were mild and transient and included clinical symptoms of paresthesia, numbness, tingling, or pain. Their rates were comparable to the rates we previously reported. No significant differences in other characteristics were observed. The approach to choose the first-line treatment method for iatrogenic psA based on LEVI is encouraging. It may increase the success rate and avoid unnecessary repetition of the procedure, without increasing complication rate while keeping costs of the procedure reasonable.

A new approach to the treatment of post-catheterization pseudoaneurysms by ultrasound-guided tissue glue injection or ultrasound-guided thrombin injection depending on a late to early velocity index

Abstract Background Ultrasound-guided thrombin injection (UGTI) is often the first-line treatment for iatrogenic post-catheterization pseudoaneurysms (psA). There are reports of the use of biologically-derived tissue glues (TG) instead of sole thrombin especially when UGTI was unsuccessful or in case of psA recurrence. TG are more potent procoagulants and may increase the procedure success rates at the cost of higher risk of complications in case too much substance escape into the patient's circulation during the procedure. TG are also more expensive than thrombin so they are often reserved for selected patients. We have previously identified a late to early velocity index (LEVI) &amp;lt;0.2 as a predictor of an increased risk of psA recurrence after standard UGTI. In the current paper we report our first experiences when the choice of the first-line treatment method was based on LEVI. Methods From May 2017 till January 2020 we included 36 patients with psA. Of them, 10 had LEVI &amp;lt;0.2 and they underwent ultrasound-guided tissue glue injection (UGTGI) and 26 had LEVI &amp;gt;0.2 and underwent UGTI. The injection set (containing human thrombin and fibrinogen) was used for UGTGI. Bovine thrombin was used for UGTI. Results The success rate was 100% and no psA recurrence was detected during 2-week follow-up. It was significantly better when compared to the expected recurrence rates based on our previous 15 years of experience (0% vs. 13%, p=0.02). All complications were mild and transient and included clinical symptoms of paraesthesia, numbness, tingling, or pain. Their rates were comparable to the rates we previously reported. No significant differences in other characteristics were observed. Conclusion The approach to choose the first-line treatment method for iatrogenic psA based on LEVI is encouraging. Two examples of LEVI calculations Funding Acknowledgement Type of funding source: None

Claudin-1 upregulation is associated with favorable tumor features and a reduced risk for biochemical recurrence in ERG-positive prostate cancer.

Claudin-1 is a membrane-tight junction protein and important for the sealing of the paracellular cleft in epithelial and endothelial cells. Differential expression of Claudin-1 is linked to disease outcome in various cancers. To evaluate the potential relevance of Claudin-1 expression in prostate cancer, a tissue microarray containing samples of 17,747 tumors with annotated clinico-pathological and molecular data was immunohistochemically analyzed for Claudin-1 expression. In normal prostate, glandular cells were always Claudin-1-negative while there was a strong staining of gland-surrounding basal cells. In contrast to normal prostatic glands, a positive Claudin-1 immunostaining, was found, however, in 38.7% of 12,441 interpretable cancers and was considered weak in 12.7%, moderate in 13.2%, and strong in 12.8% of cases. Positive Claudin-1 immunostaining was associated with favorable tumor features like low pT (p = 0.0032), low Gleason grade (p< 0.0001), and a reduced risk of PSA recurrence (p = 0.0005). A positive Claudin-1 staining was markedly more frequent in ERG-positive (63%) than in ERG-negative cancers (23%; p < 0.0001). Subset analyses revealed that all associations of Claudin-1 expression and favorable phenotype and prognosis were driven by ERG-positive cancers. Multivariate analyses revealed, however, that even in ERG-positive cancers, the prognostic impact of high Claudin-1 expression was not independent of established clinico-pathological parameters. Comparison with 12 previously analyzed chromosomal deletions identified conspicuous associations with PTEN and 12p13 deletions potentially indicating functional interactions. These data identify a peculiar role for Claudin-1 in prostate cancer. The protein is overexpressed in a fraction of prostate cancers and increased Claudin-1 expression levels predict a favorable prognosis in ERG-positive cancer.

Prognostic significance of a novel indicator (PSApostd3/PSApre) for PSA recurrence in patients after radical prostatectomy.

PurposeRadical prostatectomy (RP) is a common treatment for prostate cancer, but a fraction of patients may experience PSA recurrence after surgery, manifesting as an elevation in prostate specific antigen (PSA). Vast literature has reported different prognostic factors for PSA recurrence without reaching a consensus. This retrospective study investigated the efficacy of a new indicator in predicting PSA recurrence in patients after RP.Patients and methodsFrom October 2000 to December 2015, 102 PCa patients who underwent laparoscopic prostatectomy in the Urology Department of Peking Union Medical College Hospital were analyzed. We calculated PSApostd3/PSApre, defined as the ratio of the PSA on day 3 postop as the numerator and the pre-operative PSA as the denominator, in these patients to represent PSA decrement after surgery, and investigated its relationship with PSA recurrence during follow-up.ResultsThe receiver operating characteristic (ROC) curve of PSApostd3/PSApre derived a cut-off at 0.453 (sensitivity=0.704, specificity=0.853, P<0.0001), suggesting an increased risk of PSA recurrence in patients whose PSA on day 3 postop did not decrease to approximately half of their preoperative levels. Among several factors, PSApostd3/PSApre (P<0.0001), pathological T stage (P=0.042) and Gleason Grade (P=0.021) were determined to be significantly associated with PSA recurrence by Fisher’s exact test, while only PSApostd3/PSApre (P<0.001) was significantly related to PSA recurrence-free survival (PRFS) by multivariate logistic regression analysis.ConclusionThese results imply that PSApostd3/PSApre could provide substantial information for PSA recurrence prediction in patients after RP.

MP12-02 EFFECTS OF INITIAL GLEASON GRADE ON OUTCOMES DURING ACTIVE SURVEILLANCE FOR PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Localized: Active Surveillance I1 Apr 2018MP12-02 EFFECTS OF INITIAL GLEASON GRADE ON OUTCOMES DURING ACTIVE SURVEILLANCE FOR PROSTATE CANCER Selma Masic, Janet Cowan, Hao Nguyen, Katsuto Shinohara, Matthew Cooperberg, and Peter Carroll Selma MasicSelma Masic More articles by this author , Janet CowanJanet Cowan More articles by this author , Hao NguyenHao Nguyen More articles by this author , Katsuto ShinoharaKatsuto Shinohara More articles by this author , Matthew CooperbergMatthew Cooperberg More articles by this author , and Peter CarrollPeter Carroll More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.389AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Whether men with GS 3+4 disease are appropriate active surveillance (AS) candidates remains a matter of debate. We evaluated the effects of the initial Gleason grade on biopsy reclassification, treatment and outcomes after radical prostatectomy (RP). METHODS We followed men on AS between 1990 and 2016. Those diagnosed with Gleason 3+3 or 3+4 were included. Outcomes were biopsy reclassification (increase in Gleason grade =3+4 for those starting with Gleason 3+3 or = 4+3 for those with Gleason 3+4, or volume >33% positive cores), treatment, metastasis, adverse pathology (Gleason =4+3 or stage =pT3a or pN1), and prostate specific antigen (PSA) recurrence after deferred RP. Multivariate Cox proportional hazards regression was used to determine risk factors for outcome events. A sensitivity analysis was performed to evaluate outcomes for patients with limited amount of Gleason 3+4. Models were adjusted for age, PSA, PSA density (PSAD), internal versus external diagnostic biopsy, and percentage of cores positive at diagnosis; PSA recurrence-free survival after surgery was also for pathologic stage and positive surgical margins. RESULTS 1,243 men met inclusion criteria with Gleason 3+3 or 3+4 on initial biopsy. A total of 1,119 (90%) had Gleason 3+3 and 124 (10%) 3+4. Patients with Gleason 3+4 had lower reclassification-free survival (17% vs 39%, p<0.01) and treatment-free survival (49% vs 64%, p<0.01) at 5 years. On multivariate analysis, diagnostic grade was not a risk factor for biopsy reclassification (HR 1.21 95% CI 0.94-1.58), but was a risk factor for treatment (HR 1.37 95% CI 1.01-1.85). Among 367 men who underwent deferred RP, patients with Gleason 3+4 had a higher risk of adverse pathology on univariate analysis (HR 1.96 95% CI 1.25-3.08) but not multivariate analysis (HR 1.32 95% CI 0.80-2.18). At three years, patients starting with Gleason 3+4 had lower unadjusted PSA recurrence-free survival (69% vs 91%, p<0.01); the finding was significant on multivariate analysis (HR 3.67 95% CI 1.30-10.36). A sensitivity model showed that grade was associated with risk of PSA recurrence, however, only for patients with more than one high-grade core. Diagnostic grade was not a risk factor for metastasis on univariate or multivariate analyses. CONCLUSIONS Gleason 3+4 at initial biopsy was a risk factor for treatment and PSA recurrence but was not associated with higher risk of biopsy reclassification, metastasis, or adverse pathology. Sensitivity analysis showed that patients with a single core of Gleason 3+4 at diagnosis have outcomes similar to those with Gleason 3+3. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e135 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Selma Masic More articles by this author Janet Cowan More articles by this author Hao Nguyen More articles by this author Katsuto Shinohara More articles by this author Matthew Cooperberg More articles by this author Peter Carroll More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Testosterone nadir and PSA recurrence-free survival in men with intermediate and high-risk localized prostate cancer undergoing definitive radiotherapy and androgen deprivation therapy.

100 Background: There is limited data on the relationship between testosterone level during androgen deprivation and clinical outcomes of localized prostate cancer treated with hormone therapy and radiation therapy (RT). Here we investigate the association between testosterone nadir during androgen deprivation therapy and prostate-specific antigen (PSA) response and survival. Methods: Using a nationwide Veterans Affairs database, we identified 899 patients with intermediate- or high-risk localized prostate adenocarcinoma diagnosed between 2000 and 2015 and treated with gonadotropin-releasing hormone agonists and RT. All patients had total testosterone measurements while receiving hormone therapy and between 6 weeks and 6 months after the start of hormone therapy. Using univariable and multivariable models we examined the effect of testosterone nadir on 3-month post-treatment PSA, PSA recurrence-free survival, and prostate cancer-specific survival. Multivariable models included age at diagnosis, Gleason score, tumor stage, anti-androgen therapy, hormone therapy duration, comorbidity, BMI, and pre-treatment PSA. Results: Of the 899 patients with testosterone data, 481 patients had a testosterone nadir of &lt; 20 ng/dL, 305 had a nadir between 20 and 49 ng/dL, and 113 had a nadir ≥50 ng/dL. Higher testosterone nadir was associated with higher 3-month post-treatment PSA on univariable (Spearman rho = 0.22, p &lt; 0.001, n = 651) and multivariable (ß = 0.03, 95% CI 0.01-0.05, p = 0.004) analysis. In multivariable Cox regression, higher testosterone nadir was associated with an increased risk of PSA recurrence (hazard ratio [HR] 1.43 per 10-fold increase in testosterone nadir, 95% CI 1.07-1.90, p = 0.01, n = 715) but not prostate cancer-specific mortality (HR 1.45, 95% CI 0.87-2.42, p = 0.16, n = 891). Conclusions: Higher nadir testosterone levels in intermediate- or high-risk localized prostate cancer patients undergoing hormone therapy is associated with higher 3-month post-treatment PSA and inferior PSA recurrence-free survival, though there was no significant effect on prostate cancer-specific mortality.

High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma of the prostate

Many prostate lesions have 'large gland' morphology with gland size similar to or larger than benign glands, complex glandular architecture including papillary, cribriform, and solid, and significant cytological atypia in glandular epithelium with nucleomegaly, prominent nucleoli, or anisonucleosis. The most common and clinically important lesions with 'large gland' morphology include high-grade prostatic intraepithelial neoplasia (HGPIN), PIN-like carcinoma, ductal adenocarcinoma, and intraductal carcinoma. These lesions have diverse clinical significance and management implications. HGPIN refers to proliferation of glandular epithelium that displays severe cytological atypia within the confines of prostatic ducts and acini. A HGPIN diagnosis in biopsies connotes ~25% risk of detection of cancer in repeat biopsies. It has been accepted as the main precursor lesion to invasive carcinoma. PIN-like carcinoma is a variant of acinar carcinoma that is morphologically reminiscent of HGPIN and is composed of large cancer glands lined with pseudostratified epithelium. Its clinical outcome is similar to that of usual acinar carcinomas and is graded as Gleason score 3+3=6. Ductal adenocarcinoma comprises large glands lined with tall columnar and pseudostratified epithelium. It is more aggressive than acinar carcinomas and is associated with higher stage disease and greater risk of PSA recurrence and mortality. Intraductal carcinoma is an intraglandular/ductal neoplastic proliferation of glandular epithelial cells that results in marked expansion of glandular architecture and nuclear atypia that often exceeds that in invasive carcinomas. In majority of cases, it is thought to represent retrograde extension of invasive carcinoma into pre-existing ducts and acini. Rarely it may represent a peculiar form of carcinoma with predilection for intraductal location. It is considered an adverse pathological feature and is seen almost always in high-grade and volume carcinoma and harbingers worse clinical outcomes. This article reviews 'new' information on the clinical and pathological features of HGPIN, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma, and focuses morphological features that aid the differential diagnosis.

BMI and serum lipid parameters predict increasing risk and aggressive prostate cancer in Chinese people.

ObjectivesTo determine if obesity and serum lipid parameters are associated with increased risk and more aggressive prostate cancer in Chinese populationMaterials and MethodsWe conducted a retrospective cohort analysis including 3102 patients. Kruskal-Wallis test for continuous variables and the chi-squared tests for categorical variables were used for univariate comparison of the differences in patient characteristics across BMI categories between different groups. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the association between prostate cancer and the various patient characteristics. Multivariable Cox proportional hazards regression was performed to assess the risk of prostate cancer recurrenceResults974 consecutive men were diagnosed as prostate cancer and 700 patients subsequently received radical prostatectomy immediately, and 1031 patients were pathologically diagnosed as biopsy negative. The level of low-density-lipoprotein cholesterol (LDL-c) and total cholesterol was significantly higher and the high-density-lipoprotein cholesterol (HDL-c) level is much lower in prostate cancer patients. Patients with low level of HDL-c, who subsequently received radical prostatectomy, had increased risk of high risk disease. In addition, patients with normal weight were less likely to develop a biochemical recurrence. Combined analysis revealed that obese patients had significantly higher rates of PSA recurrence over time than nonobese patients.ConclusionsIn our study, lipid parameters are supposed to be associated with prostate cancer risk and aggressiveness. Obese men are at increased risk of PSA recurrence after radical prostatectomy.

Increased ERCC1 expression is linked to chromosomal aberrations and adverse tumor biology in prostate cancer

BackgroundAnimal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression.MethodsTo better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p).ResultsERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability.ConclusionThe results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors.

Integrating Tertiary Gleason 5 Patterns into Quantitative Gleason Grading in Prostate Biopsies and Prostatectomy Specimens

Presence of small (tertiary) Gleason 5 pattern is linked to a higher risk of biochemical recurrence in prostate cancer. It is unclear, however, how to integrate small Gleason 5 elements into clinically relevant Gleason grade groups. To analyze the prognostic impact of Gleason 5 patterns in prostate cancer and to develop a method for integrating tertiary Gleason 5 patterns into a quantitative Gleason grading system. Prostatectomy specimens from 13 261 consecutive patients and of 3295 matched preoperative biopsies were available. Percentages of Gleason 3, 4, and 5 had been recorded for each cancer. Outcome measurements and statistical analysis: RESULTS AND LIMITATIONS: Our data demonstrate that minimal Gleason 5 areas have strong prognostic impact in Gleason 7 carcinomas, while further expansion of the Gleason 5 pattern population has less impact. We thus defined an integrated quantitative Gleason score (IQ-Gleason) by adding a lump score of 10 to the percentage of unfavorable Gleason pattern (Gleason 4/5) if any Gleason 5 was present and by adding another 7.5 points in case of a Gleason 5 fraction >20%. There was a continuous increase of the risk of prostate-specific antigen recurrence with increasing IQ-Gleason. This was also true for subgroups with identical Cancer of the Prostate Risk Assessment Postsurgical scores (p<0.0001) or Gleason grade groups (p<0.0001). The IQ-Gleason represents a simple and efficient approach for combining both quantitative Gleason grading and tertiary Gleason grades in one highly prognostic numerical variable. Prostatectomy specimens (13 261) were analyzed to estimate the relevance of small Gleason 5 elements in prostate cancers. Even the smallest Gleason 5 areas markedly increased the risk of prostate-specific antigen recurrence after surgery. Larger fractions of Gleason 5 patterns had less further impact on prognosis. Based on this, a numerical Gleason score (integrated quantitative Gleason score) was defined by the percentages of Gleason 4 and 5 patterns, enabling a refined estimate of patient prognosis.

The Combination of DNA Ploidy Status and PTEN/6q15 Deletions Provides Strong and Independent Prognostic Information in Prostate Cancer.

Aberrant DNA content has been discussed as a potential prognostic feature in prostate cancer. We analyzed the clinical significance of DNA ploidy in combination with prognostic relevant deletions of PTEN and 6q15 in 3,845 prostate cancers. The DNA status was diploid in 67.8%, tetraploid in 25.6%, and aneuploid in 6.8% of tumors, and deletions of PTEN and 6q15 occurred in 17.8% and 20.3% of tumors. Abnormal DNA content and deletions were linked to high Gleason score, advanced tumor stage, and positive nodal stage (P < 0.0001 each). The risk of PSA recurrence increased from diploid to tetraploid and from tetraploid to aneuploid DNA status (P < 0.0001 each). However, 40% of patients with Gleason score ≥4+4 and 55% of patients with PSA recurrence had diploid cancers. This fraction decreased to 21% (Gleason ≥4+4) and 29% (PSA recurrence) if PTEN and/or 6q deletion data were added to ploidy data to identify cancers with an aberrant DNA status. The significance of combining both deletions and ploidy was further demonstrated in a combined recurrence analysis. Presence of deletions increased the risk of PSA recurrence in diploid (P < 0.0001), tetraploid (P < 0.0001), and aneuploid cancers (P = 0.0049), and the combination of ploidy data and deletions provided clinically relevant information beyond the CAPRA-S nomogram. Multivariate modeling including preoperatively and postoperatively available parameters identified the "combined DNA status" as a strong independent predictor of poor patient outcome. The combinatorial DNA content analysis involving general (ploidy) and specific events (deletions) has the potential for clinical utility in prostate cancer. Clin Cancer Res; 22(11); 2802-11. ©2016 AACR.

Statin use and risk of disease recurrence and death after radical prostatectomy.

Statins have been linked with improved prostate cancer survival and lower risk of recurrence in men treated with radiation therapy. However, the association is unclear for surgically-treated men. We studied the risk of prostate cancer recurrence and death by statin usage after radical prostatectomy in a cohort of prostate cancer patients treated with radical prostatectomy. A cohort of 1,314 men who underwent curative-intent radical prostatectomy at the Tampere University Hospital, Tampere, Finland during 1995-2009 were linked to national prescription database to obtain detailed information on statin purchases. The risk of PSA recurrence and death (overall and prostate cancer-specific) by statin use before and after the surgery were evaluated using Cox regression with model adjustment for tumor characteristics, total cholesterol and simultaneous use of antidiabetic and antihypertensive drugs. Tissue expression of putative prognostic markers were measured from a subgroup of 323 men. During the median follow-up of 8.6 years after surgery 484 men recurred, while 244 men died (32 due to prostate cancer). In general statin use before or after prostatectomy was not associated with risk of disease recurrence or death. Tissue expression of Ki-67 and ERG modified the association between statin use and risk of disease recurrence; the risk estimates were lower in men with Ki-67 expression above the median (P for interaction 0.001 and 0.004 for statin use before and after prostatectomy, respectively) and no ERG expression in the tumor tissue (P for interaction 0.006 and 0.011). Statin use generally did not affect prostate cancer prognosis after prostatectomy. The effect on disease recurrence may depend on tumor properties, such as proliferation activity. Thus possible future prospective studies should recognize and enroll subgroups of prostate cancer patients most likely to benefit from statins.

Clinical Utility of Quantitative Gleason Grading in Prostate Biopsies and Prostatectomy Specimens

Gleason grading is the strongest prognostic parameter in prostate cancer. Gleason grading is categorized as Gleason ≤ 6, 3 + 4, 4 + 3, 8, and 9-10, but there is variability within these subgroups. For example, Gleason 4 components may range from 5-45% in a Gleason 3 + 4 = 7 cancer. To assess the clinical relevance of the fractions of Gleason patterns. Prostatectomy specimens from 12823 consecutive patients and of 2971 matched preoperative biopsies for which clinical data with an annual follow-up between 2005 and 2014 were available from the Martini-Klinik database. To evaluate the utility of quantitative grading, the fraction of Gleason 3, 4, and 5 patterns seen in biopsies and prostatectomies were recorded. Gleason grade fractions were compared with prostatectomy findings and prostate-specific antigen recurrence. Our data suggest a striking utility of quantitative Gleason grading. In prostatectomy specimens, there was a continuous increase of the risk of prostate-specific antigen recurrence with increasing percentage of Gleason 4 fractions with remarkably small differences in outcome at clinically important thresholds (0% vs 5%; 40% vs 60% Gleason 4), distinguishing traditionally established prognostic groups. Also, in biopsies, the quantitative Gleason scoring identified various intermediate risk groups with respect to Gleason findings in corresponding prostatectomies. Quantitative grading may also reduce the clinical impact of interobserver variability because borderline findings such as tumors with 5%, 40%, or 60% Gleason 4 fractions and very small Gleason 5 fractions (with pivotal impact on the Gleason score) are disclaimed. Quantitative Gleason pattern data should routinely be provided in addition to Gleason score categories, both in biopsies and in prostatectomy specimens. Gleason score is the most important prognostic parameter in prostate cancer, but prone to interobserver variation. The results of our study show that morphological aspects that define the Gleason grade in prostate cancer represent a continuum. Quantitation of Gleason patterns provides clinically relevant information beyond the traditional Gleason grading categories ≤ 3 + 3, 3 + 4, 4 + 3, 8, 9 -1 0. Quantitative Gleason scoring can help to minimize variations between different pathologists and substantially aid in optimized therapy decision-making.

Evaluation of an epithelial plasticity biomarker panel in men with localized prostate cancer.

BackgroundGiven the potential importance of epithelial plasticity (EP) to cancer metastasis, we sought to investigate biomarkers related to EP in men with localized prostate cancer (PC) for the association with time to PSA recurrence and other clinical outcomes after surgery.MethodsMen with localized PC treated with radical prostatectomy at the Durham VA medical center and whose prostatectomy tissues were included in a tissue microarray (TMA) linked to long-term outcomes. We performed immunohistochemical studies using validated antibodies against E-cadherin and Ki-67 and mesenchymal biomarkers including N-cadherin, vimentin, SNAIL, ZEB1, and TWIST. Association studies were conducted for each biomarker with baseline clinical/pathologic characteristics and risk of PSA recurrence over time.ResultsTwo hundred and five men contributed TMA tissue and had long-term follow-up (median 11 years). Forty-three percent had PSA recurrence; 3 died of PC. The majority had high E-cadherin expression (86%); 14% had low/absent E-cadherin expression. N-cadherin was rarely expressed (<4%) and we were unable to identify an E-to-N cadherin switch as independently prognostic. No associations with clinical risk group, PSA recurrence, or Gleason sum were noted for SNAIL, ZEB1, vimentin, or TWIST, despite heterogeneous expression between patients. We observed an association of higher Ki-67 expression with Gleason sum (p=0.043), NCCN risk (p=0.013), and PSA recurrence (HR 1.08, p=0.0095).ConclusionsThe expression of EP biomarkers in this cohort of men with a low risk of PC-specific mortality was not associated with aggressive features or PSA relapse after surgery.

MP62-14 LONG-TERM RESULTS OF POST-PROSTATECTOMY RADIOTHERAPY: A LARGE INSTITUTIONAL EXPERIENCE

You have accessJournal of UrologyProstate Cancer: Localized V1 Apr 2015MP62-14 LONG-TERM RESULTS OF POST-PROSTATECTOMY RADIOTHERAPY: A LARGE INSTITUTIONAL EXPERIENCE Rebecca Clayman, Adam Feldman, Sigolene Galland, Douglas Dahl, Francis McGovern, Aria Olumi, Alec Eidelman, Andrzej Niemierko, William Shipley, Anthony Zietman, and Jason Efstathiou Rebecca ClaymanRebecca Clayman More articles by this author , Adam FeldmanAdam Feldman More articles by this author , Sigolene GallandSigolene Galland More articles by this author , Douglas DahlDouglas Dahl More articles by this author , Francis McGovernFrancis McGovern More articles by this author , Aria OlumiAria Olumi More articles by this author , Alec EidelmanAlec Eidelman More articles by this author , Andrzej NiemierkoAndrzej Niemierko More articles by this author , William ShipleyWilliam Shipley More articles by this author , Anthony ZietmanAnthony Zietman More articles by this author , and Jason EfstathiouJason Efstathiou More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2388AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Randomized trials and consensus statements support the consideration of adjuvant radiation therapy (RT) following prostatectomy for adverse pathologic features (pT3 or positive margins) although its use remains low. Whether early salvage RT is as effective as immediate adjuvant therapy remains unknown. METHODS A retrospective single institutional analysis of 728 post-prostatectomy patients receiving RT between 1993 and 2012 was performed. Early salvage RT was defined as radiation received for a biochemical recurrence with postoperative PSA ≤0.5ng/ml. A Cox regression multivariable analysis (MVA) was used to identify clinical and treatment-related risk factors associated with biochemical recurrence-free survival, freedom from salvage androgen deprivation therapy (ADT), distant metastasis (DM), and overall survival (OS). RESULTS 187 patients were treated with adjuvant RT for adverse pathologic features, while 541 patients received salvage RT (184 of whom received early salvage and had initial pT3 disease and/or positive margins). Median follow-up from surgery was 7.0 and 8.9 years in the adjuvant and salvage cohorts, respectively. Median time from surgery to adjuvant RT was 4.5 months, and median time to first detectable PSA in the salvage cohort was 1.98 years (Range 0.014–15.4 years). In MVA, higher Gleason score, pT-stage, seminal vesicle involvement, and shorter interval between surgery and first detectable PSA were associated with increased risk of biochemical failure, DM, and subsequent need for ADT. Younger age (P<0.0001), lower pre-op PSA (p=0.005), and longer interval between surgery and first detectable PSA (P=0.007) were associated with increased OS. When compared to early salvage, adjuvant RT was associated with significantly improved 10-year freedom from biochemical failure (73.9% vs 59.5%, HR 0.60 (95%CI: 0.4-0.9), P=0.01); however there were no statistically significant differences in terms of 10-yr freedom from ADT (91.2% vs 83.2%, HR 0.67 (95%CI: 0.36-1.2), P=0.2), DM (95.8% vs 91.8%, HR 0.86 (95%CI: 0.3-2.2), P=0.8), and OS (97.8% vs 95.2%, HR 1.7 (95%CI: 0.6-4.6), P=0.3). CONCLUSIONS Postoperative RT confers excellent long-term disease control, a finding validated by the long follow-up in this series. Adjuvant RT is associated with reduced risk of PSA recurrence though not DM, OS, or need for subsequent ADT when compared to early salvage. Rational optimal timing of postoperative RT awaits report of the results of large ongoing randomized trials. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e786 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rebecca Clayman More articles by this author Adam Feldman More articles by this author Sigolene Galland More articles by this author Douglas Dahl More articles by this author Francis McGovern More articles by this author Aria Olumi More articles by this author Alec Eidelman More articles by this author Andrzej Niemierko More articles by this author William Shipley More articles by this author Anthony Zietman More articles by this author Jason Efstathiou More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Maximum Tumor Diameter and the Risk of Prostate-Specific Antigen Recurrence After Radical Prostatectomy

The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features. The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (> 0.1 ng/mL and verified), adjusting for known predictors. After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.23-6.10; P = .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA > 4 ng/mL (P < .001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA ≤ 4 ng/mL (P = .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P = .004) between PSA and MTD. Moreover, in men with a pre-RP PSA > 4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score ≥ 8) was present at RP (P = .01; 5-year estimate: 46.6% vs. 100%) versus none (P = .09; 5-year estimate: 93.4% vs. 98.9%). Men with a low MTD (≤ 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART.

Upregulation of RASGRP3 expression in prostate cancer correlates with aggressive capabilities and predicts biochemical recurrence after radical prostatectomy

Background:This study was undertaken to investigate the expression of guanyl nucleotide-releasing protein for Ras 3 (RasGRP3) in the cell lines and tissues in BPH and prostate cancer (PCa), as well as its associations with cancer invasion and prognosis in prostate carcinomas.Methods:Expression analysis of RasGRP3 was accomplished using immunohistochemical staining of PCa and BPH tissues. Pearson's χ2 test was used to analyze the association between RasGRP3 expression and specific clinical parameters. Survival and PSA relapse curves were evaluated using the Kaplan–Meier curves and log-rank tests, and the differences were assessed using the Cox regression methods. In addition, human PCa cell lines PC-3, DU145, LNCaP, PC3M-1E8, PC3M-2B4 and BPH-1 were examined for expression of RasGRP3 using western blot and quantitative polymerase chain reaction (Q-PCR) analysis. After PC-3 cells were transfected by small interfering RNA targeting RasGRP3, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and migratory assays were employed to determine the vitality and aggressive capability of tumor cell in vitro.Results:Expression of RasGRP3 was significantly correlated (P=0.038 and P=0.021) with Gleason score (⩽6 versus ⩾7) and T stage (T1–T2 versus T3–T4), respectively. PCa with RasGRP3-positive expression may increase the risk of PSA recurrence and decrease cancer-specific survival (P=0.0291 and P=0.0044). The expression of RasGRP3 was also associated with PSA recurrence and cancer-specific survival in univariate (P<0.001 and P<0.001) and multivariate analyses (P<0.001 and P=0.003). RasGRP3 mRNA and proteins were found to be positively expressed in PCa cell lines. There was higher expression of RasGRP3 in PC-3, DU145 and PC3M-1E8 than in LNCaP, PC3M-2B4 and BPH-1. Knockdown of RasGRP3 inhibited the proliferation, migration and invasion capabilities of PC-3 cells.Conclusions:These data suggested that elevated RasGRP3 expression may play a key role in the malignant progression of PCa, especially in invasion and metastasis, and may be a potential marker of biochemical recurrence.

Intratumoral inflammation is associated with more aggressive prostate cancer

Inflammation may play a role in the development and progression of many cancers, including prostate cancer. We sought to test whether histological inflammation within prostate cancer was associated with more aggressive disease. The slides of prostatectomy specimens were reviewed by a board-certified pathologist on 287 men from a Veterans Affairs Medical Center treated with radical prostatectomy from 1992 to 2004. The area with the greatest tumor burden was scored in a blinded manner for the degree of inflammation: absent, mild, or marked. We used logistic and Cox proportional hazards regression analysis to examine whether categorically coded inflammation score was associated with adverse pathology and biochemical progression, respectively. No inflammation was found in 49 men (17%), while 153 (53%) and 85 (30%) had mild and marked inflammation. During a median follow-up of 77 months, biochemical recurrence occurred among 126 (44%) men. On multivariate analysis, more inflammation was associated with greater risk of positive margins, capsular penetration, and seminal vesicle invasion (all p < 0.05). Marked inflammation was associated with increased PSA recurrence risk when adjusting for preoperative features only (HR 2.08, 95% CI 1.02-4.24), but not after adjusting for pathologic features. Inflammation within prostate cancer was associated with more advanced disease, although it is unclear whether aggressive disease caused increased inflammation or inflammation caused aggressive disease.