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1.  PSA density is superior than PSA and Gleason score for adverse pathologic features prediction in patients with clinically localized prostate cancer 
Introduction:
Prostate-specific antigen (PSA) and its kinetics have changed prostate cancer screening and diagnosis. The aim of the present study was to evaluate their value in prostate cancer prognosis by determining the predictive potential of PSA density for adverse pathologic features after radical prostatectomy, in terms of positive surgical margins (PSM), extracapsular disease (ECD), seminal vesicle invasion (SVI) and/or lymph node invasion (LNI), and to compare their predictive ability with preoperative PSA and biopsy Gleason score.
Methods:
We retrospectively analysed 285 patients diagnosed with prostate cancer and underwent a retropubic radical prostatectomy for clinically localized disease. Data concerning preoperative PSA, biopsy Gleason score and PSA density were collected and analyzed. PSA density was calculated by dividing preoperative PSA and the pathological volume of the prostate.
Results:
There was a significant difference in PSA density values between patients with PSM, ECD, SVI and LNI. Areas under the curve for PSA density were higher than those of PSA and Gleason score for all parameters of adverse pathology. In multivariate analyses, it was shown that PSA density and Gleason score were the only statistically significant predictors for PSM and ECD, PSA density and PSA for SVI and only PSA density for LNI.
Conclusion:
PSA density is an accurate predictor for adverse pathology prediction in patients undergoing radical prostatectomy. These results demonstrate that this parameter is useful to determine the aggressiveness of prostate cancer and can be used as an adjunct in predicting outcomes after surgery.
doi:10.5489/cuaj.11079
PMCID: PMC3289697  PMID: 22396369
2.  Prediction of pathological and oncological outcomes based on extended prostate biopsy results in patients with prostate cancer receiving radical prostatectomy: a single institution study 
Diagnostic Pathology  2012;7:68.
Background
The prediction of pathological outcomes prior to surgery remains a challenging problem for the appropriate surgical indication of prostate cancer. This study was performed to identify preoperative values predictive of pathological and oncological outcomes based on standardized extended prostate biopsies with core histological results diagrammed/mapped in patients receiving radical prostatectomy for prostate cancer clinically diagnosed as localized or locally advanced disease.
Methods
In 124 patients with clinically localized or locally advanced prostate cancer (cT1c–cT3a) without prior treatment, pathological outcomes on the surgical specimen including seminal vesicle involvement (SVI), positive surgical margin (PSM), and perineural invasion (PNI) were studied in comparison with clinical parameters based on the results of 14-core prostate biopsies comprising sextant, laterally-directed sextant, and bilateral transition zone (TZ) sampling.
Results
Concerning the association of pathological outcomes with oncological outcomes, patients with PSM and PNI on surgical specimens had poorer biochemical-progression-free survival than those without PSM (logrank p = 0.002) and PNI (p = 0.003); it was also poorer concerning SVI, although the difference was not significant (p = 0.120). Concerning the impact of clinical parameters on these pathological outcomes, positive TZ and multiple positive biopsy cores in the prostatic middle were independent values predictive of SVI with multivariate analyses (p = 0.020 and p = 0.025, respectively); both positive TZ and multiple positive prostatic middle biopsies were associated with larger tumor volume (p < 0.001 in both). The percentage of positive biopsy cores (%positive cores) and biopsy Gleason score were independent values predictive of PSM (p = 0.001) and PNI (p = 0.001), respectively. Multiple positive cores in the prostatic base were associated with proximal/bladder-side PSM (p < 0.001), and also linked to poorer biochemical-progression-free survival (p = 0.004). Clinical T stage had no association with these pathological outcomes.
Conclusions
%positive cores and Gleason score in extended biopsies were independent values predictive of PSM and PNI in prostate cancer clinically diagnosed as localized or locally advanced disease, respectively, which were associated with poorer oncological outcomes. When diagramming biopsy-core results, extended biopsy may provide additional information for predicting oncological and pathological outcomes including SVI in patients clinically diagnosed as having localized or locally advanced disease.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8790262771042628
doi:10.1186/1746-1596-7-68
PMCID: PMC3449198  PMID: 22697234
Extended prostate biopsy; Seminal vesicle involvement; Positive surgical margin; Perineural invasion
3.  Do Positive Surgical Margins Predict Biochemical Recurrence in All Patients Without Adjuvant Therapy After Radical Prostatectomy? 
Korean Journal of Urology  2013;54(8):510-515.
Purpose
The objective was to study whether positive surgical margins (PSMs) predict biochemical recurrence (BCR) in all patients without adjuvant therapy after radical prostatectomy (RP).
Materials and Methods
We retrospectively reviewed the medical records of patients who underwent RP for prostate cancer at Veterans Health Service Medical Center from 2005 to 2011. BCR was defined by a prostate-specific antigen (PSA) value ≥0.2 ng/mL. The clinicopathological factors of the PSM group were compared with those of the negative surgical margin (NSM) group, and the predictive impact of a PSM for BCR-free survival were evaluated. In addition, we analyzed the prognostic difference for BCR-free survival between solitary and multiple PSMs.
Results
A PSM was noted in 167 patients (45.5%). BCR was reported in 101 men in total (27.5%). The BCR-free survival rate of the PSM group was lower than that of the NSM group (p<0.001). In a multivariate analysis for the total patients, PSM was significantly associated with BCR-free survival (p<0.001). After stratification by pathological T stage, Gleason score (GS), and preoperative PSA value, PSM was significantly predictive for BCR-free survival in men with pT2 and/or GS ≤6 or 7 and/or a PSA value <10 or 10-20 ng/mL (all p<0.05). Multiple PSMs were more predictive of BCR-free survival than was a solitary PSM (p=0.001).
Conclusions
A PSM is a significant predictor of postoperative BCR in patients with pT2 and/or GS ≤7 and/or preoperative PSA <20 ng/mL. Multiple PSMs are considered a stronger prognostic factor for prediction of BCR than is a solitary PSM.
doi:10.4111/kju.2013.54.8.510
PMCID: PMC3742902  PMID: 23956825
Prostatectomy; Prostatic neoplasms; Recurrence
4.  Predicting Prostate Cancer Biochemical Recurrence Using a Panel of Serum Proteomic Biomarkers 
The Journal of urology  2009;181(3):1407-1414.
Purpose
The pathological state of the prostate may be reflected by serum proteome in a man. We hypothesized that biomarkers are present in preoperative serum, which may be used to predict the probability of biochemical recurrence following radical prostatectomy.
Materials and Methods
Mass spectrometry analysis was used to compare 52 men who experienced biochemical recurrence with 52 who remained biochemical recurrence-free for approximately 5 years after radical retropubic prostatectomy. A total of 30 matched pairs of recurrent and nonrecurrent serum samples were randomly selected as a training set for biomarker discovery and model development. Selected mass spectrometry peaks were combined with pre-radical retropubic prostatectomy prostate specific antigen in a multivariate algorithm to predict recurrence. The algorithm was evaluated using the remaining 22 recurrent and 22 nonrecurrent subjects as test samples. Protein identities of the selected mass spectrometry peaks were investigated.
Results
Two serum biomarkers for recurrence, P1 and P2, were combined with preoperative prostate specific antigen to predict biochemical recurrence. The ROC AUC for prostate specific antigen and the predicted outcome was 0.606 and 0.691 in the testing data, respectively. Using a single cutoff the samples were divided into 2 groups that were predictive of biochemical recurrence (p = 0.026). In contrast, preoperative prostate specific antigen did not differ between recurrent and nonrecurrent cases (Wilcoxon matched pairs test p = 0.07). The protein identity of P1 was determined to be a truncated form of C4a (C4a des-Arg). Preliminary data indicated that P2 was an N-terminal fragment of protein C inhibitor.
Conclusions
In the current study population, which was matched on Gleason score and TNM staging, pre-radical retropubic prostatectomy prostate specific antigen retained no independent power to predict recurrence. However, by adding 2 proteomic biomarkers to preoperative prostate specific antigen the combined model demonstrated statistically significant value for predicting prostate cancer recurrence in men who underwent radical retropubic prostatectomy.
doi:10.1016/j.juro.2008.10.142
PMCID: PMC4130150  PMID: 19157448
prostate; prostatic neoplasms; neoplasm recurrence; complement C4a; protein C inhibitor
5.  Younger patients have poorer biochemical outcome after radical prostatectomy in high-risk prostate cancer 
Asian Journal of Andrology  2011;13(5):719-723.
The aim of this study was to investigate the prognostic significance of patient age with respect to tumour aggressiveness in men who underwent radical prostatectomy (RP) for prostate cancer. In this study, we reviewed the records of 743 patients who received RP without neoadjuvant or adjuvant therapy at our institution and were followed up for >2 years postoperatively. For our analyses, the patients were divided into two groups according to age: younger (<60 years) and older (≥60 years). Through uni- and multivariate analyses, associations of various clinicopathological parameters, including biochemical recurrence-free survival, with patient age, were evaluated among all patients, and the patients were stratified according to their D'Amico risk classification. Among all subjects, younger (n=126) and older (n=617) patients showed no significant differences regarding pathological parameters and biochemical recurrence-free survival (P=0.288). For the high-risk group (n=206), younger patients had a lower rate of biochemical recurrence-free survival following surgery than older patients (P=0.017), despite the fact that no significant differences were observed regarding various known prognostic parameters between the two age groups. In addition, multivariate analysis revealed that age was an independent predictor of biochemical recurrence-free survival among the high-risk group (P=0.003). Our results showed that relatively younger patients have a comparable biochemical outcome compared with their older counterparts following RP performed for prostate cancer. However, among patients with high-risk disease, younger patients have a worse biochemical outcome following RP compared with older patients.
doi:10.1038/aja.2011.39
PMCID: PMC3739588  PMID: 21706038
age factors; biochemical outcome; prostate; prostatic neoplasms; prostatectomy
6.  Independent predictors of biochemical recurrence after radical prostatectomy: a single center experience 
Introduction
The aim of study was to establish pretreatment and postoperative factors which could predict the early biochemical recurrence after radical prostatectomy.
Materials and method
754 patients had undergone radical prostatectomy since January 2002 to December 2008 in our department and were included in this prospective study. Exclusion criteria were: neoadjuvant or adjuvant treatment (radiation or hormonal treatment) and N+. Following parameters were evaluated: age, PSA at time of biopsy, time period from biopsy to operation, biopsy and postoperative Gleason score, stage, high grade intraepithelial neoplasias, perineural invasion. Biochemical recurrence was detected if PSA value after radical prostatectomy was ≥0.2 ng/ml. All factors likely to be predictive were evaluated by univariate analysis (Log-rank test). Multivariate analysis using Cox model was completed for all factors with p value <0.1 at univariate analysis.
Results
Final analysis was done using data of 496 patients. We detected 53 (10.7%) biochemical recurrences. Calculated actuarial biochemical recurrence free survival reached 64%. Multivariate analysis highlighted that PSA >10 ng/ml (HR 2.45, p = 0.008), pathological stage ≥pT3 (HR 2.371, p = 0.02), postoperative Gleason score ≥7 (HR 2.149, p = 0.049), positive surgical margins (HR 2.482, p = 0.014) and absence of high grade intraepithelial neoplasia in removed prostate (HR 0.358, p = 0.006) are independent factors influencing biochemical recurrence after radical prostatectomy.
Conclusion
Patients with higher PSA, locally advanced disease, positive surgical margins, and Gleason score ≥7 are at the highest risk for biochemical recurrence.
doi:10.5173/ceju.2011.01.art4
PMCID: PMC3921706  PMID: 24578855
prostate; prostate cancer; radical prostatectomy; biochemical recurrence
7.  Undetectable ultrasensitive PSA after radical prostatectomy for prostate cancer predicts relapse-free survival 
British Journal of Cancer  2000;83(11):1432-1436.
Radical retropubic prostatectomy is considered by many centres to be the treatment of choice for men aged less than 70 years with localized prostate cancer. A rise in serum prostate-specific antigen after radical prostatectomy occurs in 10–40% of cases. This study evaluates the usefulness of novel ultrasensitive PSA assays in the early detection of biochemical relapse. 200 patients of mean age 61.2 years underwent radical retropubic prostatectomy. Levels ≤ 0.01 ng ml–1 were considered undetectable. Mean pre-operative prostate-specific antigen was 13.3 ng ml–1. Biochemical relapse was defined as 3 consecutive rises. The 2-year biochemical disease-free survival for the 134 patients with evaluable prostate-specific antigen nadir data was 61.1% (95% CI: 51.6–70.6%). Only 2 patients with an undetectable prostate-specific antigen after radical retropubic prostatectomy biochemically relapsed (3%), compared to 47 relapses out of 61 patients (75%) who did not reach this level. Cox multivariate analysis confirms prostate-specific antigen nadir ≤ 0.01 ng ml–1 to be a superb independent variable predicting a favourable biochemical disease-free survival (P < 0.0001). Early diagnosis of biochemical relapse is feasible with sensitive prostate-specific antigen assays. These assays more accurately measure the prostate-specific antigen nadir, which is an excellent predictor of biochemical disease-free survival. Thus, sensitive prostate-specific antigen assays offer accurate prognostic information and expedite decision-making regarding the use of salvage prostate-bed radiotherapy or hormone therapy. © 2000 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1474
PMCID: PMC2363433  PMID: 11076649
prostate cancer; PSA nadir; radical retropubic prostatectomy
8.  Can p53, Ki-67 and bcl-2 predict biochemical failure after radical prostatectomy? 
Background and Objective
To analyze p53, Ki-67 and bcl-2 expressions immunohistochemically and their predictive role in biochemical recurrence after radical prostatectomy.
Materials and Methods
Seventy one patients who had undergone radical prostatectomy between 1992 and 2001 were randomly selected. Tissue microarrays were constructed from their radical prostatectomy specimens. They contained four cores from neoplastic and additional four cores from corresponding non-neoplastic regions. Gleason score ranged from 6-9, and pathological stage ranged from T2N0Mx to T3BN1. Staining for bcl-2 was scored visually taking percent negative, weak, moderate and strong positivity into consideration. Strong immunoreactivity was considered positive for p53. Ki-67 index was measured as the percentage of positive nuclei among tumor cells. Statistical analysis was performed to explore correlations between staining patterns and clinicopathological prognostic parameters.
Results
The follow-up period extended from 13 to 112 months with a mean 60 (48 ± 23, 2) months. Of all, 38.02% had no evidence of disease, 52.1% were alive with disease and 9.8% were died during follow-up. The expression of p53, Ki-67 and bcl-2 in tumors were 39%, 76% and 5% respectively. While the secretory layer showed negative or weak bcl-2 staining in most cases, expression in basal cells was often stronger. Statistical analysis revealed differences in staining between normal and carcinoma for all three markers. There was no correlation between staining patterns and time to biochemical relapse. On the other hand, cases with higher Gleason sum showed the tendency for over expression of p53, Ki-67 and bcl-2 although the differences were not statistically different. Multivariate analysis revealed CMS group and seminal vesicle invasion as the independent predictors of PSA failure (log rank P = 0.0039 and P = 0.001, respectively).
Conclusion
The proteins bcl-2, p53 and Ki-67 were expressed at a different rate in normal and neoplastic prostate tissue. Bcl-2 was mainly expressed by basal cells in normal glands. p53 and Ki-67 expression were increased in most prostate carcinomas. However, overall expression levels did not correlate with biochemical recurrence in this study.
doi:10.4103/0970-1591.65390
PMCID: PMC2938544  PMID: 20877598
Bcl-2; ki-67; microarray; p53; prostate cancer
9.  Differences in Postoperative Pathological Outcomes between Prostate Cancers Diagnosed at Initial and Repeat Biopsy 
Korean Journal of Urology  2012;53(8):531-535.
Purpose
We evaluated the differences in pathological outcomes between prostate cancers (PCas) diagnosed at initial and repeat biopsy.
Materials and Methods
We retrospectively reviewed the medical records of 287 patients who underwent radical retropubic prostatectomy from 2005 to 2010. We investigated preoperative factors, such as age, serum prostate-specific antigen (PSA), prostate volume (PV), digital rectal examination (DRE) results, biopsy schema, clinical stage, and number of prior biopsies, and postoperative pathological outcomes, including specimen volume, percent tumor volume, Gleason score (GS), tumor bilaterality, pathological stage, positive surgical margin (PSM), lymphovascular invasion (LVI), and perineural invasion (PNI). Patients were then classified into two groups by the number of prior biopsies (initial biopsy vs. repeat biopsy). We compared preoperative factors and postoperative pathological outcomes between the two groups.
Results
Of the 287 patients, 246 (85.7%) were diagnosed with cancer at the initial biopsy and 41 (14.3%) at the repeat biopsy. The repeat biopsy group was older (p=0.048), had a larger PV (p=0.009), had a significantly different biopsy schema (p<0.001), and had a lower (<10%) percentage tumor volume (p=0.016). In the multivariate analysis (after adjustment for biopsy schema, age, serum PSA, PV, and DRE), repeat biopsy was not an independent predictor of GS, tumor bilaterality, pathological stage, PSM, LVI, or PNI (p=0.212, 0.456, 0.459, 0.917, 0.991 and 0.827, respectively), but repeat biopsy could predict lower percentage tumor volume (p=0.037).
Conclusions
The pathological outcomes of PCas detected at repeat biopsy were not significantly different from those of PCas detected at initial biopsy except for a lower (<10%) percentage tumor volume.
doi:10.4111/kju.2012.53.8.531
PMCID: PMC3427836  PMID: 22949996
Biopsy; Prostatectomy; Prostatic neoplasms; Tumor burden
10.  What are the Factors Associated With Short Prostate Specific Antigen Doubling Time After Radical Prostatectomy? A Report From the SEARCH Database Group 
The Journal of urology  2008;180(5):1980-1985.
Purpose
Short prostate specific antigen doubling time following recurrence after radical prostatectomy portends a poor prognosis in men with prostate cancer. We determined which demographic and clinicopathological variables were predictive of a short prostate specific antigen doubling time in a cohort of men with clinically localized prostate cancer treated with radical prostatectomy.
Materials and Methods
Data on 856 men from the Shared Equal Access Regional Cancer Hospital database who underwent radical prostatectomy for node negative prostate cancer between 1988 and 2003 were included in the analysis. We used logistic regression analysis to determine the independent factors associated with a short prostate specific antigen doubling time of less than 9 months vs a longer doubling time of 9 months or greater, or no recurrence. The variables analyzed were patient age, race, logarithmically transformed preoperative prostate specific antigen, body mass index, year of surgery, pathological Gleason sum, extraprostatic extension, surgical margin status and seminal vesicle invasion.
Results
On multivariate analysis higher preoperative prostate specific antigen (OR 2.20, 95% CI 1.52–3.19, p <0.001), pathological Gleason sum 8–10 (OR 4.70, 95% CI 2.11–10.43, p <0.001) and 7 (OR 2.11, 95% CI 1.09–4.08, p = 0.026), tumors with extraprostatic extension and/or positive surgical margins (OR 2.08, 95% CI 1.48–3.91, p = 0.023), and seminal vesicle invasion (OR 3.26, 95% CI 1.48–7.21, p = 0.003) were independent predictors of a short prostate specific antigen doubling time. Based on these risk factors we developed a table to estimate the risk of recurrence with a prostate specific antigen doubling time of less than 9 months.
Conclusions
The factors that are invariably used to predict overall biochemical recurrence following radical prostatectomy, including high prostate specific antigen, high grade and adverse pathological findings, also predict aggressive recurrence.
doi:10.1016/j.juro.2008.07.031
PMCID: PMC3182520  PMID: 18801519
prostate; prostatic neoplasms; prostate-specific antigen; neoplasm recurrence; local; tumor markers; biological
11.  Chemokine markers predict biochemical recurrence of prostate cancer following prostatectomy 
Purpose
Stratifying patients who have a high-risk of prostate cancer recurrence following prostatectomy can potentiate the use of adjuvant therapy at an early stage. Inflammation has emerged as a mediator of prostate cancer metastatic progression. We hypothesized that chemokines can be biomarkers for distinguishing patients with high risk for biochemical recurrence of prostate cancer.
Experimental Design
In a nested case controlled study 82 subjects developed biochemical recurrence within five years of prostatectomy. Prostate tissues from 98 age-matched subjects who were recurrent-free following prostatectomy in the same period of time were the controls. A high-throughput lectin-based enrichment of prostate tissue enabled multiplex-ELISA to identify the expression of three chemokines to discriminate the two patient populations.
Results
The expression of CX3CL1 and IL-15 in prostate tissue was associated with five-year biochemical recurrent-free survival following prostatectomy. However the expression of CCL4 was associated with biochemical recurrence. Multivariable logistic regression model combining pre-operative PSA, Gleason score, surgical margin and seminal vesicle status with the three chemokines doubled the specificity of prediction at 90% sensitivity compared to use of the clinicopathologic variables alone (P < 0.0001). Survival analysis yielded a nomogram that supported the use of CX3CL1, IL-15, and CCL4 in predicting 1-, 3-, and 5-year recurrence-free survival after prostatectomy.
Conclusion
Each of the three chemokines can serve as independent predictors of biochemical recurrence. However, the combination of chemokine biomarkers plus clinicopathologic variables discriminated prostatectomy subjects for the probability of biochemical recurrence significantly better than clinicopathologic variables alone.
doi:10.1158/1078-0432.CCR-08-1716
PMCID: PMC3050736  PMID: 19047106
prostate cancer; biochemical recurrence; chemokine
12.  Prognostic relevance of number and bilaterality of positive surgical margins after radical prostatectomy 
World Journal of Urology  2011;30(1):105-110.
Purpose
Positive surgical margin (PSM) status following radical prostatectomy (RP) is a well-established prognostic factor. The aim of the present study is to evaluate whether number of PSMs or bilaterality of PSMs might have prognostic significance for biochemical recurrence (BCR) in the population with a PSM status following RP.
Methods
We evaluated 1,395 RP pathology reports from our center between 1980 and 2006. All patients who underwent (neo)-adjuvant therapy were excluded, leaving a cohort of 1,009 patients, with 249 (24.7%) subjects having a PSM at RP of whom 29.4% had multiple PSMs (≥ 2 sites), while 13.6% had bilateral PSMs. Median follow-up was 40 months (range 0–258 months). We used BCR-free survival as the primary study outcome. BCR was defined as any rise in PSA above or equal to 0.2 ng/ml.
Results
Of patients with a PSM status, 41% (95% CI: 33–49%) developed BCR within 5 years, compared to 12% (95% CI: 9–15%) in the population without a PSM. Multivariable analysis identified PSA at diagnosis and RP Gleason score as independent predictive factors for BCR. Increasing number and/or bilaterality of PSM did not lead to significant higher rates of BCR.
Conclusion
In patients with a PSM, the number of positive sites or bilaterality of PSM status does not add prognostic information for risk of BCR. Survival curve slopes were different for patients with bilateral PSM, showing a significant tendency to progress to BCR earlier during follow-up than patients with unilateral PSM.
doi:10.1007/s00345-010-0641-4
PMCID: PMC3264849  PMID: 21240506
Prostate cancer; Surgical margin; Biochemical recurrence; Bilateral; Number; Prognosis
13.  Contemporaneous comparison of open vs minimally-invasive radical prostatectomy for high-risk prostate cancer 
BJU international  2013;112(6):751-757.
Objectives
• To analyze pathological and short-term oncological outcomes in men undergoing open and minimally-invasive radical prostatectomy (MIRP) for high-risk prostate cancer (HRPC; prostate-specific antigen level [PSA] >20 ng/mL, ≥cT2c, Gleason score 8–10) in a contemporaneous series.
Patients and Methods
• In total, 913 patients with HRPC were identified in the Johns Hopkins Radical Prostatectomy Database subsequent to the inception of MIRP at this institution (2002–2011)
• Of these, 743 (81.4%) underwent open radical retropubic prostatectomy (ORRP), 105 (11.5%) underwent robot-assisted laparoscopic radical prostatectomy (RALRP) and 65 (7.1%) underwent laparoscopic radical prostatectomy (LRP) for HRPC.
• Appropriate comparative tests were used to evaluate patient and prostate cancer characteristics.
• Proportional hazards regression models were used to predict biochemical recurrence.
Results
• Age, race, body mass index, preoperative PSA level, clinical stage, number of positive cores and Gleason score at final pathology were similar between ORRP and MIRP.
• On average, men undergoing MIRP had smaller prostates and more organ-confined (pT2) disease (P = 0.02).
• The number of surgeons and surgeon experience were greatest for the ORRP cohort.
• Overall surgical margin rate was 29.4%, 34.3% and 27.7% (P = 0.52) and 1.9%, 2.9% and 6.2% (P = 0.39) for pT2 disease in men undergoing ORRP, RALRP and LRP, respectively.
• Biochemical recurrence-free survival among ORRP, RALRP and LRP was 56.3%, 67.8% and 41.1%, respectively, at 3 years (P = 0.6) and the approach employed did not predict biochemical recurrence in regression models.
Conclusions
• At an experienced centre, MIRP is comparable to open radical prostatectomy for HRPC with respect to surgical margin status and biochemical recurrence.
doi:10.1111/j.1464-410X.2012.11757.x
PMCID: PMC3978171  PMID: 23356390
high-risk; minimally-invasive surgery; prostate cancer; radical prostatectomy
14.  Blood Storage Duration and Biochemical Recurrence of Cancer After Radical Prostatectomy 
Mayo Clinic Proceedings  2011;86(2):120-127.
OBJECTIVE: To test the hypothesis that perioperative transfusion of allogeneic and autologous red blood cells (RBCs) stored for a prolonged period speeds biochemical recurrence of prostate cancer after prostatectomy.
PATIENTS AND METHODS: We evaluated biochemical prostate cancer recurrence in men who had undergone radical prostatectomy and perioperative blood transfusions from July 6, 1998, through December 27, 2007. Those who received allogeneic blood transfusions were assigned to nonoverlapping “younger,” “middle,” and “older” RBC storage duration groups. Those who received autologous RBC transfusions were analyzed using the maximum storage duration as the primary exposure. We evaluated the association between RBC storage duration and biochemical recurrence using multivariable Cox proportional hazards regression.
RESULTS: A total of 405 patients received allogeneic transfusions. At 5 years, the biochemical recurrence–free survival rate was 74%, 71%, and 76% for patients who received younger, middle, and older RBCs, respectively; our Cox model indicated no significant differences in biochemical recurrence rates between the groups (P=.82; Wald test). Among patients who received autologous transfusions (n=350), maximum RBC age was not significantly associated with biochemical cancer recurrence (P=.95). At 5 years, the biochemical recurrence–free survival rate was 85% and 81% for patients who received younger and older than 21-day-old RBCs, respectively.
CONCLUSION: In patients undergoing radical prostatectomy who require RBC transfusion, recurrence risk does not appear to be independently associated with blood storage duration.
The authors evaluated the association between duration of red blood cell storage and biochemical recurrence of cancer in men who had undergone radical prostatectomy and perioperative blood transfusions. Recurrence risk does not appear to be independently associated with blood storage duration.
doi:10.4065/mcp.2010.0313
PMCID: PMC3031436  PMID: 21282486
15.  Positive surgical margins during robotic radical prostatectomy: a contemporary analysis of risk factors 
BJU international  2008;102(5):603-608.
Objective
To determine the risk factors (clinical, pathological and technical) for positive surgical margins (PSMs) after robotically assisted radical prostatectomy (RARP), as a PSM is associated with an increased risk of biochemical recurrence and often responsible for significant patient anxiety.
Patients and Methods
Between November 2003 and March 2007, 216 consecutive patients had an RARP by one fellowship-trained urological oncologist. The surgical pathological specimens were fixed and processed using standard techniques, and assessed by a pathologist at the same institution. A PSM was defined as the presence of cancer adjacent to the inked margin. The clinical charts were reviewed retrospectively under an approved institutional review board protocol. Univariable and multivariable methods, including logistic regression models, were used to analyse the clinical, pathological and technical risk factors for PSM.
Results
The overall prevalence of PSM was 14.8% (32/216), and 5.4% (8/149) for pT2 cancers. The only preoperative factor that was associated with a greater risk of a PSM was the serum prostate-specific antigen (PSA) level (P = 0.012) and PSA density (P = 0.005). Age, clinical stage and clinical Gleason grade were not predictors of a PSM. The overall and pT2 PSM rate remained constant throughout the series of 216 patients (P = 0.371), indicating that the initial experience for RARP was not associated with a significantly greater risk of a PSM. However, there was a small independent ‘learning curve’ effect, with a lower rate of PSM associated with each increment of 25 patients (odds ratio 0.8, 95% confidence interval 0.6–1.0), supported by the significantly decreasing trend in PSM for pT3 cancers over time (P = 0.031) Although there was no significant increase over time in PSM with the use of an endostapler to control the dorsal venous complex (DVC), there was a significant learning effect, with a decrease in the PSM rate specifically in pT3 cancers using the suture technique (P = 0.005). A nerve-sparing procedure increased the risk of PSM in multivariable analysis (P = 0.03). As expected, pathological stage and pathological Gleason grade were the strongest predictors of PSM (P < 0.001).
Conclusion
The most important risk factors for a PSM after RARP are the preoperative PSA level, PSA density, pathological stage and Gleason grade. PSM rates for a surgeon in their initial experience can be comparable to that of a surgeon experienced in RARP. Using a stapling device to control the DVC does not appear to increase the risk of a PSM, although nerve-sparing increases the rates of PSM in extraprostatic prostate cancer.
doi:10.1111/j.1464-410X.2008.07672.x
PMCID: PMC4041686  PMID: 18435807
prostate cancer; surgical margins; robotic; PSA
16.  Impact of Prostate Size on Pathologic Outcomes and Prognosis after Radical Prostatectomy 
Korean Journal of Urology  2012;53(7):463-466.
Purpose
We investigated prostate size and its correlation with final pathologic outcomes and prognosis.
Materials and Methods
From 1993 to 2009, 830 consecutive patients who underwent radical prostatectomy with follow-up duration of 12 months or more were included in this study. Patients were categorized according to prostate size as follows: group 1, prostate size ≤40 g (n=458), and group 2, prostate size >40 g (n=472). Preoperative parameters and postoperative pathologic outcomes were compared between groups. Multivariate analysis with Cox proportional hazards regression model was used to identify the pathologic and clinical factors affecting biochemical recurrence.
Results
Patients in group 1 had higher pathologic T stage (pT2a=17.7% vs. 23.9%, pT2b=1.1% vs. 0%, pT2c=40.4% vs. 39.8%, pT3a=29.5% vs. 21.0%, pT3b=10.7% vs. 13.2%, p=0.003) and higher positive surgical margin (40.3% vs. 33.1%, p=0.033) than did patients in group 2. Pathologic Gleason score was not significantly different between the two groups. The 5-year biochemical-recurrence-free survival was 62.3% for patients in group 1 and 73.2% for patients in group 2 (p=0.005). Multivariate Cox regression analysis showed that prostate size of 40 g or less (hazard ratio [HR], 1.378; 95% confidence interval [CI], 1.027 to 1.848; p=0.032), extracapsular extension (HR, 1.592; 95% CI, 1.147 to 2.209; p=0.005), positive surgical margin (HR, 2.348; 95% CI, 1.701 to 3.242; p<0.001), and pathologic Gleason sum (HR, 1.507; 95% CI, 1.292 to 1.758; p<0.001) were independent predictors of biochemical recurrence.
Conclusions
Smaller prostate size was associated with increased risk of higher pT stage and positive surgical margin after radical prostatectomy. Also, prostate size less than 40 g was an independent prognostic factor for biochemical recurrence.
doi:10.4111/kju.2012.53.7.463
PMCID: PMC3406191  PMID: 22866216
Prognosis; Prostate; Prostatectomy
17.  Bcl-2 as a Predictive Factor for Biochemical Recurrence after Radical Prostatectomy: An Interim Analysis 
Purpose
The objective of this study was to determine Bcl-2 expression in localized prostate cancer and its potential role as a predictive factor for biochemical recurrence (BCR).
Materials and Methods
This study included 171 Korean patients with newly diagnosed adenocarcinoma of the prostate who underwent radical prostatectomy (RP) without neoadjuvant therapy at a single center between February 2005 and May 2009. RP specimens obtained from these patients were analyzed for the expression of Bcl-2 using tissue microarray. The values of Bcl-2 and other clinicopathologic factors were evaluated. Statistical analysis was performed with contingency table analysis, chi-square tests, and a Cox proportional hazard model.
Results
Bcl-2 expression was immunohistologically-confirmed in 42 patients (24.6%). Bcl-2 expression was not associated with conventional clinicopathologic factors. Bcl-2 negative patients had a significantly longer mean BCR-free survival than Bcl-2-positive patients (p=0.036). Among several variables, a high Gleason score in the RP specimen (≥8), extraprostatic extension, seminal vesicle invasion (SVI), lymphovascular invasion (LVI), and Bcl-2 expression were significant predictors of BCR based on univariate analysis. Multivariate Cox proportional hazards analysis revealed that BCR was significantly associated with a high prostate specific antigen level (p=0.047), SVI (p<0.001), a positive surgical margin (p=0.004) and Bcl-2 expression (p=0.012).
Conclusion
Bcl-2 expression in RP specimens is associated with a significantly worse outcome, suggesting a potential clinical role for Bcl-2. Post-operative Bcl-2 could be a significant predictor of outcome after RP.
doi:10.4143/crt.2010.42.3.157
PMCID: PMC2953779  PMID: 20948921
Prostatic neoplasms; Proto-oncogene proteins; B-cell leukemia/lymphoma 2; Recurrence; Prostatectomy
18.  Impact of surgical technique (open vs laparoscopic vs robotic-assisted) on pathological and biochemical outcomes following radical prostatectomy: an analysis using propensity score matching 
BJU international  2010;107(12):1956-1962.
OBJECTIVES
To investigate a single institution experience with radical retropubic prostatectomy (RRP), laparoscopic radical prostatectomy (LRP) and robot-assisted radical prostatectomy (RARP) with respect to pathological and biochemical outcomes.
SUBJECTS AND METHODS
A group of 522 consecutive patients who underwent RARP between 2003 and 2008 were matched by propensity scoring on the basis of patient age, race, preoperative prostate-specific antigen (PSA), biopsy Gleason score and clinical stage with an equal number of patients who underwent LRP and RRP at our institution. Pathological and biochemical outcomes of the three cohorts were examined.
RESULTS
Overall positive surgical margin rates were lower among patients who underwent RRP (14.4%) and LRP (13.0%) compared to patients who underwent RARP (19.5%) (P = 0.010). There were no statistically significant differences in positive margin rates between the three surgical techniques for pT2 disease (P = 0.264). In multivariate logistic regression analysis, surgical technique (P = 0.016), biopsy Gleason score (P < 0.001) and preoperative PSA (P < 0.001) were predictors of positive surgical margins. Kaplan–Meier analysis did not show any statistically significant differences with respect to biochemical recurrence for the three surgical groups.
CONCLUSIONS
RRP, LRP and RARP represent effective surgical approaches for the treatment for clinically localized prostate cancer. A higher overall positive SM rate was observed for the RARP group compared to RRP and LRP; however, there was no difference with respect to biochemical recurrence-free survival between groups. Further prospective studies are warranted to determine whether any particular technique is superior with regard to long-term clinical outcomes.
doi:10.1111/j.1464-410X.2010.09795.x
PMCID: PMC3105164  PMID: 21044243
prostate cancer; biochemical recurrence; radical prostatectomy; robotic prostatectomy; laparoscopic prostatectomy
19.  Epidural Analgesia during Open Radical Prostatectomy Does Not Improve Long-Term Cancer-Related Outcome: A Retrospective Study in Patients with Advanced Prostate Cancer 
PLoS ONE  2013;8(8):e72873.
Background
A beneficial effect of regional anesthesia on cancer related outcome in various solid tumors has been proposed. The data on prostate cancer is conflicting and reports on long-term cancer specific survival are lacking.
Methods
In a retrospective, single-center study, outcomes of 148 consecutive patients with locally advanced prostate cancer pT3/4 who underwent retropubic radical prostatectomy (RRP) with general anesthesia combined with intra- and postoperative epidural analgesia (n=67) or with postoperative ketorolac-morphine analgesia (n=81) were reviewed. The median observation time was 14.00 years (range 10.87-17.75 yrs). Biochemical recurrence (BCR)-free, local and distant recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier technique. Multivariate Cox proportional-hazards regression models were used to analyze clinicopathologic variables associated with disease progression and death.
Results
The survival estimates for BCR-free, local and distant recurrence-free, cancer-specific survival and overall survival did not differ between the two groups (P=0.64, P=0.75, P=0.18, P=0.32 and P=0.07). For both groups, higher preoperative PSA (hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.02, P<0.0001), increased specimen Gleason score (HR 1.24, 95% CI 1.06-1.46, P=0.007) and positive nodal status (HR 1.66, 95% CI 1.03-2.67, P=0.04) were associated with higher risk of BCR. Increased specimen Gleason score predicted death from prostate cancer (HR 2.46, 95% CI 1.65-3.68, P<0.0001).
Conclusions
General anaesthesia combined with epidural analgesia did not reduce the risk of cancer progression or improve survival after RRP for prostate cancer in this group of patients at high risk for disease progression with a median observation time of 14.00 yrs.
doi:10.1371/journal.pone.0072873
PMCID: PMC3747085  PMID: 23977366
20.  Ultra-early versus early salvage androgen deprivation therapy for post-prostatectomy biochemical recurrence in pT2-4N0M0 prostate cancer 
BMC Urology  2014;14(1):81.
Background
The optimal timing of salvage androgen deprivation therapy (ADT) for biochemical recurrence after radical prostatectomy is controversial. We compared the outcomes of ultra-early versus early salvage ADT.
Methods
Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 121 with adjuvant-treatment-naïve pT2-4N0M0 prostate cancer who received salvage ADT for biochemical recurrence. These patients were divided into an ultra-early salvage ADT group (n = 51), who started salvage ADT before meeting the standardized definition of biochemical recurrence in Japan (two consecutive prostate-specific antigen [PSA] values ≥0.2 ng/ml), and an early salvage ADT group (n = 70) who started salvage ADT when they met the definition. The ultra-early ADT group consisted of those who started salvage ADT with a single PSA value ≥0.2 ng/ml (n = 30) or with two consecutive PSA values >0.1 ng/ml and rising (n = 21). The primary endpoint was biochemical recurrence after salvage ADT, defined as a single PSA value ≥0.2 ng/ml after PSA nadir following salvage ADT. Secondary endpoints were clinical metastasis and cancer-specific survival. A Cox proportional hazards model was used for multivariate analysis. The median follow-up was 65.5 months.
Results
Biochemical recurrence occurred in one patient (2.0%) in the ultra-early group and in 12 (17.1%) in the early salvage ADT group. Multivariate analysis identified ultra-early salvage ADT and preoperative Gleason score ≤7 as independent negative predictors of biochemical recurrence after salvage ADT. Only one patient in the early salvage ADT group developed clinical metastasis to a left supraclavicular lymph node, and no patient died from prostate cancer during follow-up. The major limitations of this study were its retrospective design, selection bias, and the possibility that the ultra-early salvage ADT group may have included patients without biochemical recurrence.
Conclusions
Ultra-early salvage ADT was an independent negative predictor of biochemical recurrence after salvage ADT in post-prostatectomy patients. Further consideration should be given to the use of salvage ADT before meeting the current definition of biochemical recurrence.
doi:10.1186/1471-2490-14-81
PMCID: PMC4203971  PMID: 25323845
Androgen deprivation therapy; Biochemical recurrence; Prostate cancer; Radical prostatectomy; Salvage androgen deprivation therapy
21.  The prognostic significance of percentage of tumour involvement according to disease risk group in men treated with radical prostatectomy 
Asian Journal of Andrology  2011;13(6):828-832.
We investigated the prognostic significance of percentage of tumour involvement (PTI) according to the clinicopathological features of prostate cancer among patients who underwent radical prostatectomy (RP). A retrospective study of 534 patients who underwent RP between September 2003 and March 2008 without any neoadjuvant or adjuvant therapy was performed. The associations of PTI with various clinicopathological features and biochemical recurrence-free survival were examined via uni- and multivariate analyses. The predictive accuracy of the multivariate model was assessed with a receiver operating characteristics-derived area under the curve. PTI was demonstrated to be significantly associated with preoperative prostate-specific antigen (PSA) level (P=0.001), pathological Gleason score (P<0.001), extraprostatic tumour extension (P<0.001), seminal vesicle invasion (P<0.001) and positive surgical margin (P<0.001) in univariate analyses. When patients were stratified into disease risk groups, PTI was an independent predictor of biochemical recurrence-free survival in multivariate analysis only among the low-risk group (P=0.033) but not the intermediate- (P=0.287) or the high-risk groups (P=0.828). The addition of the PTI did not significantly increase the accuracy of the multivariate model devised for the prediction of biochemical recurrence-free survival among both total patients (P=0.459) and the low-risk group (P=0.268), respectively. In conclusion, although PTI appeared to be a more significant prognostic factor among patients with low-risk disease than among those with higher risk diseases, overall, the PTI may not provide additional prognostic information beyond what can already be obtained via established prognostic factors.
doi:10.1038/aja.2011.111
PMCID: PMC3739551  PMID: 21946230
biochemical recurrence-free survival; percentage of tumour involvement; prognosis; prostate cancer; prostatectomy
22.  Positive surgical margins at radical prostatectomy predict prostate cancer-specific mortality: support for optimizing surgical technique and pathological evaluation at radical prostatectomy 
The Journal of urology  2010;183(6):2213-2218.
Purpose
Positive surgical margins (PSM) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa) are associated with an increased risk of biochemical recurrence. Little data have evaluated the role of PSM in PCa-specific mortality (PCSM). Using a large, population-based national cancer registry, we evaluate the risk of PCSM associated with margin status.
Methods
The SEER cancer registry data for patients diagnosed in 1998–2006 were used to identify men undergoing RP for PCa. Margin status, pathologic stage, Gleason grade and post-operative radiation therapy were recorded along with demographic data. Multivariate Cox regression analysis was used to estimate the risk of PCSM associated with PSMs.
Results
A total of 65,633 patients comprised the cohort in which 291 (0.44%) PCa-specific deaths occurred over an average follow-up of 50 months. PSMs were reported in 21.2% and were more common in pT3a than pT2 tumors (44% vs. 18%, p<0.001) and higher grade tumors (28% vs. 18%, p<0.001). The 7-year disease-specific survival rates for those at highest risk of PCSM (higher grade pT3a) were 97.3% for cases with negative surgical margins and 92.4% for those with PSMs. PSMs were associated with a 2.9-fold increased risk of PCSM (HR 2.55, 95% CI 2.02 – 3.21). PSM remained an independent predictor of PCSM in the multivariate analysis (HR 1.70, 95% CI 1.32 – 2.18).
Conclusion
These data demonstrate the independent role of positive surgical margin in PCSM. These finding support the importance of optimizing surgical technique to achieve a sound oncologic surgical outcome with negative surgical margins when possible.
doi:10.1016/j.juro.2010.02.017
PMCID: PMC2903223  PMID: 20399459
prostate cancer; surgical margin; survival; population-based; radical prostatectomy
23.  Evaluating PSA Density as a Predictor of Biochemical Failure after Radical Prostatectomy: Results of a Prospective Study after a Median Follow-Up of 36 Months 
ISRN Urology  2013;2013:984951.
Purpose. To evaluate the predictive ability of PSA density for biochemical relapse after radical prostatectomy in patients operated for clinically localized disease and to compare its predictive strength with preoperative PSA and Gleason score. Patients and Methods. The study evaluated 244 patients with localized disease who underwent an open retropubic radical prostatectomy between February 2007 and April 2011. PSA was measured every 3 months after surgery with a mean follow-up period of 36 months. Two consecutive rises >0.2 ng/mL were considered as biochemical relapse. Results. Biochemical recurrence was observed in 71 (29.1%). A great correlation was found between relapse and PSA (P = 0.005), PSA density (P = 0.002), Gleason score (P = 0.015), pathological stage (P = 0.001), positive surgical margins (P = 0.021), and invasion of seminal vesicles (P < 0.001) and lymph nodes (P < 0.001). We also found that PSA density was associated with adverse pathological findings. In univariate and multivariate analysis both PSA (P = 0.006) and PSA density (P = 0.009) were found to be significant predictors for relapse in contrast to tumor grade. Conclusion. PSA density is a valuable parameter in estimating the danger of biochemical failure and it may increase predictive potential through the incorporation in preoperative nomograms.
doi:10.1155/2013/984951
PMCID: PMC3671563  PMID: 23762630
24.  Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy 
BJU international  2012;110(8):1122-1128.
OBJECTIVE
To investigate preoperative characteristics that distinguish favourable and unfavourable pathological and clinical outcomes in men with high biopsy Gleason sum (8 – 10) prostate cancer to better select men who will most benefit from radical prostatectomy (RP).
PATIENTS AND METHODS
The Institutional Review Board-approved institutional RP database (1982 – 2010) was analysed for men with high-Gleason prostate cancer on biopsy; 842 men were identified.
The 10-year biochemical-free (BFS), metastasis-free (MFS) and prostate cancer-specific survival (CSS) were calculated using the Kaplan – Meier method to verify favourable pathology as men with Gleason <8 at RP or ≤ pT3a compared with men with unfavourable pathology with Gleason 8 – 10 and pT3b or N1.
Preoperative characteristics were compared using appropriate comparative tests.
Logistic regression determined preoperative predictors of unfavourable pathology.
RESULTS
There was favourable pathology in 656 (77.9%) men. The 10-year BFS, MFS and CSS were 31.0%, 60.9% and 74.8%, respectively.
In contrast, men with unfavourable pathological findings had significantly worse 10-year BFS, MFS and CSS, at 4.3%, 29.1% and 52.3%, respectively (all P < 0.001).
In multivariable logistic regression, a prostate-specific antigen (PSA) concentration of > 10 ng/mL (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.38 – 3.62, P = 0.001), advanced clinical stage (≥ cT2b; OR 2.55, 95% CI 1.55 – 4.21, P < 0.001), Gleason pattern 9 or 10 at biopsy (OR 2.55, 95% CI 1.59 – 4.09, P < 0.001), increasing number of cores positive with high-grade cancer (OR 1.16, 95% CI 1.01 – 1.34, P = 0.04) and > 50% positive core involvement (OR 2.25, 95% CI 1.17 – 4.35, P = 0.015) were predictive of unfavourable pathology.
CONCLUSIONS
Men with high-Gleason sum at biopsy are at high risk for biochemical recurrence, metastasis and death after RP; men with high Gleason sum and advanced pathological stage (pT3b or N1) have the worst prognosis.
Among men with high-Gleason sum at biopsy, a PSA concentration of > 10 ng/mL, clinical stage ≥ T2b, Gleason pattern 9 or 10, increasing number of cores with high-grade cancer and > 50% core involvement are predictive of unfavourable pathology.
doi:10.1111/j.1464-410X.2012.10986.x
PMCID: PMC4124597  PMID: 22373045
prostate cancer; high-risk; Gleason sum; outcomes
25.  Aberrant Methylation of Protocadherin 17 and its Clinical Significance in Patients with Prostate Cancer after Radical Prostatectomy 
Background
Aberrant methylation of protocadherin 17 (PCDH17) has been reported in several human cancers. However, the methylation status of PCDH17 in prostate cancer and its clinical significance remains unclear. The aim of this study was to investigate the methylation status of PCDH17 and its clinical significance in patients with prostate cancer after radical prostatectomy.
Material/Methods
The methylation status of PCDH17 in 152 prostate cancer tissues and 51 non-tumoral prostate tissues was examined by methylation-specific PCR (MSP). Then the association between PCDH17 methylation and clinicopathologic parameters was analyzed. Kaplan-Meier survival analysis, log-rank test and multivariate Cox proportional hazard model analysis were used to analyze the correlation between PCDH17 methylation and prognosis of patients with prostate cancer.
Results
Our data demonstrated that PCDH17 methylation occurred frequently in prostate cancer. PCDH17 methylation was significantly associated with higher pathological Gleason score (P=0.0315), advanced pathological stage (P=0.0260), higher level of preoperative PSA (P=0.0354), positive angiolymphatic invasion (P=0.0461), positive lymph node metastasis (P=0.0362), and biochemical recurrence (BCR) (P=0.0018). In addition, PCDH17 methylation was an independent predictor of poor biochemical recurrence-free (BCR-free) survival and overall survival for patients with prostate cancer.
Conclusions
PCDH17 methylation is a frequent tumor-specific event in prostate cancer, and is significantly correlated with shorter BCR-free survival and overall survival of patients with prostate cancer after radical prostatectomy. PCDH17 methylation in tumor samples after radical prostatectomy may be used as an independent prognostic biomarker.
doi:10.12659/MSM.891247
PMCID: PMC4136940  PMID: 25091018
Cadherins; DNA Methylation; Urologic Neoplasms

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