Two-stage classifiers that minimize PCA3 and the PSA proteolytic activity testing in the prediction of prostate cancer recurrence after radical prostatectomy.

INTRODUCTION: Early biochemical recurrence after prostate cancer surgery is associated with higher risk of aggressive disease and cancer specific death. Many new tests are being developed that will predict the presence of indicators of aggressive disease like early biochemical recurrence. Since recurrence occurs in less than 10% of patients treated for prostate cancer, validation of such tests will require expensive testing on large patient groups. Moreover, clinical application of the validated test requires that each new patient be tested. In this report we introduce a two-stage classifier system that minimizes the number of patients that must be tested in both the validation and clinical application of any new test for recurrence. MATERIALS AND METHODS: Expressed prostatic secretion specimens were prospectively collected from 450 patients prior to robot-assisted radical prostatectomy for prostate cancer. Patients were followed for 2.5 years for evidence of biochemical recurrence. Standard clinical parameters, the levels proteolytic activity of prostate specific antigen (PSA) and the levels of PCA3 RNA, PSA RNA and TMPRSS2:ERG fusion RNA were determined in each prospective patient specimen for subsequent correlation with biochemical recurrence. RESULTS: While levels of PCA3 and PSA proteolytic activity (PPA) in prostatic secretions provided an effective pre-surgical predictor of early biochemical recurrence in prostate cancer, application of the two-stage classifier shows that only 60% of the patients need these tests. CONCLUSION: Two-stage classifiers can provide a parsimonious approach to both the validation and clinical application of biomarker-based tests. Adoption of the two-stage neutral zone classifier can reduce unnecessary testing in prostate cancer treatment.

NCCN Guidelines Insights: Prostate Cancer Early Detection, Version 2.2016.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection provide recommendations for prostate cancer screening in healthy men who have elected to participate in an early detection program. The NCCN Guidelines focus on minimizing unnecessary procedures and limiting the detection of indolent disease. These NCCN Guidelines Insights summarize the NCCN Prostate Cancer Early Detection Panel's most significant discussions for the 2016 guideline update, which included issues surrounding screening in high-risk populations (ie, African Americans, BRCA1/2 mutation carriers), approaches to refine patient selection for initial and repeat biopsies, and approaches to improve biopsy specificity.

Prostate Cancer, Version 1.2016.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.

NCCN Clinical Practice Guidelines Prostate Cancer Early Detection, Version 2.2015.

Prostate cancer represents a spectrum of disease that ranges from nonaggressive, slow-growing disease that may not require treatment to aggressive, fast-growing disease that does. The NCCN Guidelines for Prostate Cancer Early Detection provide a set of sequential recommendations detailing a screening and evaluation strategy for maximizing the detection of prostate cancer that is potentially curable and that, if left undetected, represents a risk to the patient. The guidelines were developed for healthy men who have elected to participate in the early detection of prostate cancer, and they focus on minimizing unnecessary procedures and limiting the detection of indolent disease.

Early and late complications of robot-assisted radical cystectomy: a standardized analysis by urinary diversion type.

PURPOSE: Minimally invasive surgical treatment for bladder cancer has gained popularity but standardized data on complications are lacking. Urinary diversion type contributes to complications and to our knowledge diversion types after minimally invasive cystectomy have not yet been compared. We evaluated perioperative complications stratified by urinary diversion type in patients treated with robot-assisted radical cystectomy. MATERIALS AND METHODS: We analyzed the records of 209 consecutive patients who underwent robot-assisted radical cystectomy at our institution from 2003 to 2012 with respect to perioperative complications, including severity, time period (early and late) and diversion type. All complications were reviewed by academic urologists. Urinary diversion was also done. As outcome measurements and statistical analysis, univariate and multivariate logistic regression models were used to determine predictors of various complications. RESULTS: The American Society of Anesthesiologists(®) (ASA) score was 3 or greater in 80% of patients and continent diversion was performed in 68%. Median followup was 35 months. Within 90 days 77.5% of patients experienced any complication and 32% experienced a major complication. The 90-day mortality rate was 5.3%. Most complications were gastrointestinal, infectious and hematological. On multivariate analysis patients with ileal conduit diversion had a decreased likelihood of complications compared to patients with Indiana pouch and orthotopic bladder substitute diversion despite the selection of a more comorbid population for conduit diversion. Continent diversion was associated with a higher likelihood of urinary tract infection. Our results are comparable to those of previously reported open and minimally invasive cystectomy series. CONCLUSIONS: Open or minimally invasive cystectomy is a complex, morbid procedure. Urinary diversion is a significant contributor to complications, as is patient comorbidity. Although patients with an ileal conduit had more comorbidities, they experienced fewer complications than those with an orthotopic bladder substitute or Indiana pouch diversion.

Expressed prostatic secretion biomarkers improve stratification of NCCN active surveillance candidates: performance of secretion capacity and TMPRSS2:ERG models.

PURPOSE: Active surveillance is a viable patient option for prostate cancer provided that a clinical determination of low risk and presumably organ confined disease can be made. To standardize risk stratification schemes the NCCN (National Comprehensive Cancer Network®) provides guidelines for the active surveillance option. We determined the effectiveness of expressed prostatic secretion biomarkers for detecting occult risk factors in NCCN active surveillance candidates. MATERIALS AND METHODS: Expressed prostatic secretion specimens were obtained before robot-assisted radical prostatectomy. Secretion capacity biomarkers, including total RNA and expressed prostatic secretion specimen volume, were measured by standard techniques. RNA expression biomarkers, including TXNRD1 mRNA, prostate specific antigen mRNA, TMPRSS2:ERG fusion mRNA and PCA3 mRNA, were measured by quantitative reverse-transcription polymerase chain reaction. RESULTS: Of the 528 patients from whom expressed prostatic secretions were collected 216 were eligible for active surveillance under NCCN guidelines. Variable selection on logistic regression identified 2 models, including one featuring types III and VI TMPRSS2:ERG variants, and one featuring 2 secretion capacity biomarkers. Of the 2 high performing models the secretion capacity model was most effective for detecting cases in this group that were up-staged or up-staged plus upgraded. It decreased the risk of up-staging in patients with a negative test almost eightfold and decreased the risk of up-staging plus upgrading about fivefold while doubling the prevalence of up-staging in the positive test group. CONCLUSIONS: Noninvasive expressed prostatic secretion testing may improve patient acceptance of active surveillance by dramatically reducing the presence of occult risk factors among those eligible for active surveillance under NCCN guidelines.

Complications and outcomes of salvage robot-assisted radical prostatectomy: a single-institution experience.

OBJECTIVE: To determine the peri-operative outcomes of men undergoing salvage robot-assisted prostatectomy (RARP) and to examine the complications, functional consequences and need for additional treatments after salvage RARP. PATIENTS AND METHODS: At total of 51 consecutive patients underwent salvage RARP after previous failed local therapy. Biochemical recurrence (BCR) was defined as two postoperative PSA measurements ≥0.2 ng/mL. Complications at any time postoperatively were recorded prospectively using a modified Clavien system. The Kaplan-Meier method was used for survival estimation, and regression models were used to identify the predictors of BCR or progression-free survival (PFS) and complications. RESULTS: The median age at salvage RARP was 68 years and a median of 68 months had elapsed from the time of primary treatment. The median follow-up was 36 months. The median operation duration was 179 min with a median estimated blood loss of 175 mL. In all, 50% of patients had pathological stage 3 disease and positive surgical margins were found in 31% of patients. The estimated 3-year BCR-free or PFS was 57%. The overall complication rate was 47%, with a 35% major complication rate (Grade III-V). Potency was maintained in 23% of preoperatively potent patients and 45% of all patients regained urinary control. No clinical variables were predictive of major complications, but all patients with postoperative bladder neck contracture were incontinent. A higher PSA level and extracapsular extension were significantly associated with BCR or progression (P < 0.01). CONCLUSIONS: Salvage RARP provides oncological control with potential avoidance of systemic non-curative therapy. Complication, incontinence and erectile dysfunction rates are significant but frequently correctable. This reinforces the need for proper patient counselling and selection.

Prostate cancer early detection, version 1.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for men choosing to participate in an early detection program for prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Overall, the 2014 update represents a more streamlined and concise set of recommendations. The panel stratified the age ranges at which initiating testing for prostate cancer should be considered. Indications for biopsy include both a cutpoint and the use of multiple risk variables in combination. In addition to other biomarkers of specificity, the Prostate Health Index has been included to aid biopsy decisions in certain men, given recent FDA approvals.

Prostate cancer, version 2.2014.

Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.

Prostate cancer, version 1.2014.

The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.

The influence of PSA-RNA yield on the analysis of expressed prostatic secretions (EPS) for prostate cancer diagnosis.

INTRODUCTION: In patients with prostate cancer, luminal prostate-specific antigen (PSA) enters the circulation because the basement membrane and glandular epithelium are damaged. Given that excess mobilization of prostate cells during prostatic massage can influence normalization in diagnostic testing, we studied PSA mRNA levels in expressed prostatic secretions (EPS) from patients undergoing biopsy for prostate cancer to determine if prostate cells are preferentially mobilized from patients with prostate cancer during prostatic massage. MATERIALS AND METHODS: Quantitative Reverse-Transcription PCR (qRT-PCR) was used to measure the RNA levels of GAPDH, PSA, TMPRSS2:ERG and PCA3 in EPS specimens obtained from patients undergoing biopsy for prostate cancer. RESULTS: The level of PSA mRNA is significantly elevated in EPS specimens obtained from patients with a subsequent diagnosis of prostate cancer. This correlation influenced diagnostic testing results from EPS in two ways. First, when used as an exclusion parameter it appears to improve the diagnostic performance of TMPRSS2:ERG in EPS. Second, when used as a normalization parameter it appears to decrease the performance of these same tests. CONCLUSION: When comparing the results of mRNA based prostate cancer diagnostics in EPS it will be essential to consider PSA mRNA as a prostate specific gene and not a housekeeping gene.

Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer provide multidisciplinary recommendations for the clinical management of patients with prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Abiraterone acetate is a first-in-class hormonal agent that represents a new standard of care for patients with metastatic castration-recurrent prostate cancer who have previously received docetaxel (category 1 recommendation). Abiraterone acetate also received category 2B recommendations in the prechemotherapy setting for asymptomatic patients or symptomatic patients who are not candidates for docetaxel. The NCCN Prostate Cancer Panel also added new indications for existing agents, including the option of sipuleucel-T as second-line therapy. In addition, brachytherapy in combination with external beam radiation therapy with or without androgen deprivation therapy is now an alternative for patients with high-risk localized tumors or locally advanced disease.

Controlling the dorsal venous complex during robotic prostatectomy.

INTRODUCTION: The objective of our study was to determine whether dorsal venous complex (DVC) control technique influences positive apical margins following robotic assisted laparoscopic radical prostatectomy (RALRP). MATERIALS AND METHODS: One thousand fifty-eight patients who underwent RALRP at City of Hope from June 2007 to October 2009 were assessed. Endoscopic stapling and suture ligature of the DVC were compared. Positive apical margins were identified and compared based on DVC-control technique. Recurrence probability was estimated using the Kaplan-Meier method, and logistic regression analysis was used to predict the odds of positive apical margins. RESULTS: Of 1058 patients, 633 (60%) underwent endoscopic stapling, and 425 (40%) had suture ligature. The groups had similar baseline characteristics including age and body mass index. We observed a statistically different PSA (5.4 ng/mL versus 5.2 ng/mL, p = 0.03) and operative time (2.8 hours versus 2.7 hours, p = 0.02) between stapling and suture groups, but the actual difference was small. Operative time, Gleason score, pathologic stage, and overall positive margin rates were not significantly different between groups. Positive apical margins were observed in 39 (6%) and 27 (6%) patients in the staple and suture groups, respectively. Multivariate analysis showed that the positive apical margin rate was greater in patients with higher pathologic stage and final pathological Gleason score. CONCLUSIONS: During RALRP, there is no difference in positive apical margin rate when the DVC is controlled using either endoscopic stapling or suture ligature. However, patients with a higher pathologic stage and final pathologic Gleason score are at higher risk for positive apical surgical margins.

Robotic assisted laparoscopic salvage prostatectomy for radiation resistant prostate cancer.

PURPOSE: We report on outcomes of robotic assisted laparoscopic radical prostatectomy as salvage local therapy for radiation resistant prostate cancer. MATERIALS AND METHODS: We retrospectively reviewed the charts of all patients who underwent robotic assisted laparoscopic radical prostatectomy for biopsy proven prostate cancer after primary radiation treatment. Patient characteristics, intraoperative and perioperative data, and oncological and functional outcomes were assessed. RESULTS: A total of 18 patients were identified with a median followup of 18 months (range 4.5 to 40). Primary treatment was brachytherapy in 8 patients and external beam radiation in 8, while 2 underwent proton beam therapy. Median age at salvage robotic assisted laparoscopic radical prostatectomy was 67 years (range 53 to 76). Median preoperative prostate specific antigen was 6.8 ng/ml (range 1 to 28.9) and median time to surgery after primary treatment with radiation was 79 months (range 7 to 146). Median operative parameters for estimated blood loss, surgery length and hospital stay were 150 ml, 2.6 hours and 2 days, respectively. No patient required conversion to open surgery or a blood transfusion, or experienced a rectal injury. Perioperative complications occurred in 7 patients (39%) of which the most common was urine leak identified by postoperative cystogram. Five patients (28%) had a positive surgical margin. Although some patients had limited followup, 6 (33%) were continent and 67% were free of biochemical progression. CONCLUSIONS: Robotic assisted laparoscopic radical prostatectomy can be performed safely as salvage local therapy after failed radiation therapy. Outcomes are comparable to those of large series of open salvage prostatectomy.

Assessment of low prostate weight as a determinant of a higher positive margin rate after laparoscopic radical prostatectomy: a prospective pathologic study of 1,500 cases.

BACKGROUND: The assessment of prostate weight as a determinant of a high prostate margin rate after laparoscopic radical prostatectomy has not been studied. METHODS: Prospective pathologic findings of 1,500 patients who underwent laparoscopic radical prostatectomy (LRP, 399 cases) and da Vinci prostatectomy (DVP, 1,101 cases) between December 2000 to June 2006 at City of Hope National Medical Center were evaluated. Gleason score, pathologic stage, the presence or absence of positive margins, extraprostatic tumor extension, and seminal vesicle involvement by tumor were recorded in all patients. Preoperational serum prostate specific antigen (PSA) levels were recorded in all but 13 cases. These parameters were then correlated with prostate weight. RESULTS: Of 1,500 patients, 345 had one or more positive margins (23%). Patients with low median prostate weight (49 g) had a significantly higher positive margin rate (p < 0.0001) and incidence of extraprostatic extension by tumor (p = 0.04), and were 1.523 times more likely to have positive margins [95% confidence interval (CI) 1.167-1.985]. CONCLUSION: We conclude that low prostate weight may be a determinant of a higher recurrence rate and more aggressive disease.

Performance of a single assay for both type III and type VI TMPRSS2:ERG fusions in noninvasive prediction of prostate biopsy outcome.

BACKGROUND: TMPRSS2:ERG fusions are promising prostate cancer biomarkers. Because they can occur in multiple forms in a single cancer specimen, we developed a quantitative PCR test that detects both type III and type VI TMPRSS2:ERG fusions. The assay is quantified from a standard curve determined with a plasmid-cloned type III TMPRSS2:ERG fusion target. METHODS: We collected expressed prostatic secretion (EPS) under an institutional review board-approved, blinded, prospective study from 74 patients undergoing transrectal ultrasound-guided biopsy for prostate cancer. We compared the characteristic performance of the test for type III and type VI TMPRSS2:ERG fusions in predicting biopsy outcome and distinguishing between high and low Gleason scores with similar tests for the expression of PCA3 and DNA methylation levels of the APC, RARB, RASSF1, and GSTP1 genes. We used logistic regression to analyze the effects of multiple biomarkers in linear combinations. RESULTS: Each test provided a significant improvement in characteristic performance over baseline digital rectal examination (DRE) plus serum prostate-specific antigen (PSA); however, the test for type III and type VI TMPRSS2:ERG fusions yielded the best performance in predicting biopsy outcome [area under the curve (AUC) 0.823, 95% CI 0.728-0.919, P < 0.001] and Gleason grade >7 (AUC 0.844, 95% CI 0.740-0.948, P < 0.001). CONCLUSIONS: Although each test appears to have diagnostic value, PSA plus DRE plus type III and type VI TMPRSS2:ERG provided the best diagnostic performance in EPS specimens.

The impact of prostate gland weight in robot assisted laparoscopic radical prostatectomy.

PURPOSE: We determined whether prostate weight has an impact on the pathological and operative outcomes of robot assisted laparoscopic radical prostatectomy. MATERIALS AND METHODS: We reviewed the records of 1,847 consecutive patients who underwent robot assisted laparoscopic radical prostatectomy at our institution. Variables were compared across quartile distributions of prostate size as defined by weight, including group 1-less than 30 gm, group 2-30 to 49.9, group 3-50 to 69.9 and group 4-70 or greater. Factors assessed in this analysis were patient age, body mass index, prostate specific antigen, Gleason score, pathological stage, margin status, operative time, blood loss, transfusion rate, length of stay and rehospitalization rate. RESULTS: Patients with a larger prostate (group 4) were older (mean age 66.2 years), had higher pretreatment prostate specific antigen (median 6.5 ng/ml), lower Gleason score (mean 6.3), longer operative time (mean 3.2 hours), higher estimated blood loss (median 250 cc) and longer hospital stay (p = 0.0002). There was a trend toward higher risk disease based on D'Amico risk stratification and positive margin status in group 1, although evidence of extracapsular extension was more common in groups 2 and 3. There was no association between prostate size and body mass index, lymph node status, blood transfusion rate, seminal vesicle involvement and rehospitalization rate. CONCLUSIONS: Robot assisted laparoscopic radical prostatectomy in patients with an enlarged prostate is feasible with slightly longer operative time, urinary leakage rates and hospital stay. Pathologically larger prostates are generally associated with lower Gleason score and risk group stratification. One-year continence rates and biochemical recurrence rates are similar across all groups.

Paint-only is equivalent to scrub-and-paint in preoperative preparation of abdominal surgery sites.

BACKGROUND: Antiseptic preoperative skin site preparation is used to prepare the operative site before making a surgical incision. The goal of this preparation is a reduction in postoperative wound infection. The most straightforward technique necessary to achieve this goal remains controversial. STUDY DESIGN: A prospective randomized trial was designed to prove equivalency for two commonly used techniques of surgical skin site preparation. Two hundred thirty-four patients undergoing nonlaparoscopic abdominal operations were consented for the trial. Exclusion criteria included presence of active infection at the time of operation, neutropenia, history of skin reaction to iodine, or anticipated insertion of prosthetic material at the time of operation. Patients were randomized to receive either a vigorous 5-minute scrub with povidone-iodine soap, followed by absorption with a sterile towel, and a paint with aqueous povidone-iodine or surgical site preparation with a povidone-iodine paint only. The primary end point of the study was wound infection rate at 30 days, defined as presence of clinical signs of infection requiring therapeutic intervention. RESULTS: Patients randomized to the scrub-and-paint arm (n = 115) and the paint-only arm (n = 119) matched at baseline with respect to age, comorbidity, wound classification, mean operative time, placement of drains, prophylactic antibiotic use, and surgical procedure (all p > 0.09). Wound infection occurred in 12 (10%) scrub-and-paint patients, and 12 (10%) paint-only patients. Based on our predefined equivalency parameters, we conclude equivalence of infection rates between the two preparations. CONCLUSIONS: Preoperative preparation of the abdomen with a scrub with povidone-iodine soap followed by a paint with aqueous povidone-iodine can be abandoned in favor of a paint with aqueous povidone-iodine alone. This change will result in reductions in operative times and costs.

Detection and phenotyping of circulating tumor cells in high-risk localized prostate cancer.

BACKGROUND: In this study, we aimed to determine the feasibility of identifying CTCs in patients with HRLPC, using a modified isolation procedure using the CellSearch (Veridex) platform, and to assess the expression of stem cell and epithelial-mesenchymal transition (EMT) markers on the CTCs. PATIENTS AND METHODS: Thirty-five patients with HRLPC who had chosen prostatectomy for definitive management were prospectively identified. After obtaining consent, four 30-mL blood draws were performed, 2 before surgery and 2 after surgery. The CTC-containing fraction was Ficoll-purified and transferred to a CellSave (Veridex) tube containing dilution buffer before standard enumeration using the CellSearch system. Loss of E-cadherin expression, a marker of EMT, and CD133, a putative prostate cancer stem cell marker, were characterized using the open channel of the CellSearch platform. CTC fragments were also enumerated. RESULTS: Using the modified methodology, CTCs were detectable in 49% of patients before surgery. Although no correlation between CTC count and biochemical recurrence (BR) was observed, the percentages of CD133 and E-cadherin-positive CTC fragments were associated with BR at 1 year. CONCLUSION: Our results suggest that further research into the development of CTCs as prognostic biomarkers in HRLPC is warranted.

Effect of alvimopan on return of bowel function after robot-assisted radical cystectomy.

INTRODUCTION: Alvimopan has been shown to improve time to return of bowel function in patients undergoing bowel resection. The objective of this study is to determine if alvimopan has similar benefits for patients undergoing robot-assisted radical cystectomy (RARC). MATERIALS AND METHODS: All RARC cases were reviewed from January 2008 to March 2012. All patients during this time were administered alvimopan unless they had been receiving narcotics preoperatively. Patients receiving alvimopan received a preoperative dose of 12 mg perorally and then were dosed twice daily for 7 days or until first bowel movement. Clinicopathologic outcomes were summarized and compared, and functional outcomes of treated patients were compared with outcomes of untreated patients. RESULTS: One hundred seventeen RARCs meeting study criteria were performed. All urinary diversions used an extracorporeal approach. Urinary diversions consisted of 50 Studer neobladders, 22 Indiana pouches, and 45 ileal conduits. Fifty-four patients received alvimopan, and 63 did not. The median time to first bowel movement was 5 days in the alvimopan group and 6 days in the untreated group (P=.03). Median time to solid diet was 6 days in the treated group and 7 days in the untreated group (P=.03). There was a trend toward fewer hospital days in the alvimopan group (alvimopan, 8 days; untreated, 9 days; P=.1). CONCLUSIONS: Alvimopan administration appears to reduce the time to return of bowel function and initiation of diet following RARC. This was a trend toward shorter hospitalization in the alvimopan group. Alvimopan should be considered in ongoing research into protocols to aid in shorter convalescence following RARC.