Heather J. Chalfin

Impact of surgical margin status on prostate-cancer-specific mortality.

Study Type – Diagnostic (exploratory cohort)

Allogeneic versus autologous blood transfusion and survival after radical prostatectomy

Potential adverse effects of blood transfusion (BT) remain controversial, especially for clinical outcomes after curative cancer surgery. Some postulate that immune modulation after allogeneic BT predisposes to recurrence and death, but autologous superiority is not established. This study assessed whether BT is associated with long‐term prostate cancer recurrence and survival with a large single‐institutional radical prostatectomy (RP) database.

The Relationship Between the Extent of Extraprostatic Extension and Survival Following Radical Prostatectomy

BACKGROUND Subclassification of the extent of extraprostatic extension (EPE) in radical prostatectomy (RP) specimens may enhance prognostication for prostate cancer (PCa) patients. Yet optimal criteria for staging, validation within a large cohort, and long-term follow-up are lacking. OBJECTIVE To compare biochemical recurrence-free survival (BRFS), PCa-specific survival (PCSS), and overall survival (OS) for focal EPE (pT3aF) and nonfocal EPE (pT3aNF) in a large tertiary-referral center with the Epstein criteria for EPE extent. DESIGN, SETTING, AND PARTICIPANTS Between 1982 and 2012, 20 434 men underwent RP, and 15 565 men (76.2%) had available pathologic and survival data. A total of 4216 men with isolated EPE were subclassified into pT3aF (1869 men, 44%) and pT3aNF (2347 men, 56%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Predictors of BRFS, PCSS, and OS were identified with multivariate Cox proportional hazard models. Covariates included age, preoperative prostate-specific antigen, body mass index, surgery year, Gleason score, and surgical margin status. RESULTS AND LIMITATIONS With a median follow-up of 9.0 yr (range: 1-27), 314 men died of PCa, with 1300 deaths from any cause. In a multivariate model, pT3aNF compared with pT3aF was an independent predictor of BRFS (hazard ratio [HR]: 1.39; 95% confidence interval [CI], 1.18-1.62; p<0.001), but not of PCSS (HR: 1.38; 95% CI, 0.89-2.11; p=0.146) or OS (HR: 1.13; 95% CI, 0.94-1.36; p=0.197). Ten-year BRFS, PCSS, and OS for pT3aF and pT3aNF were 76% versus 59%, 98% versus 96%, and 95% versus 90%, respectively. CONCLUSIONS In a large RP cohort, subclassification of EPE extent with the Epstein criteria improves correlation with BRFS. PCSS and OS in men with isolated EPE (pT3a) are excellent and are not significantly different between pT3aF and pT3aNF. The EPE extent should be subclassified to identify a subgroup of men with a higher risk of recurrence (pT3aNF) and to consider them for additional therapy. PATIENT SUMMARY Subclassification of extraprostatic extension (EPE) with the Epstein criteria improves correlation with biochemical recurrence-free survival. Prostate cancer-specific survival and overall survival in men with isolated EPE (pT3a) are excellent and are not significantly different between pT3aF and pT3aNF.

New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8–10 Prostate Cancer

BACKGROUND The newly proposed five-tiered prostate cancer grading system (PCGS) divides Gleason score (GS) 8-10 disease into GS 8 and GS 9-10 on the basis of biochemical recurrence (BCR) following radical prostatectomy (RP) as an outcome. However, BCR does not necessarily portend worse survival outcomes. OBJECTIVE To assess the significance of distinguishing GS 8 versus 9-10 disease in terms of long-term survival outcomes for both the preoperative setting using biopsy (Bx) GS and the postoperative setting with RP GS. DESIGN, SETTING, AND PARTICIPANTS Of 23918 men who underwent RP between 1984 and 2014, there were 721 men with biopsy GS 8-10, and 1047 men with RP GS 8-10. OUTCOME MEASURES AND STATISTICAL ANALYSIS Clinicopathologic characteristics were compared between men with GS 8 and those with GS 9-10. We compared all-cause mortality (ACM) and prostate cancer-specific mortality (PCSM) risk between the groups using Cox regression and competing-risks analyses, adjusting for other perioperative variables and death from other causes as the competing event. RESULTS AND LIMITATIONS Compared to men with GS 8, men with GS 9-10 had later RP year and higher pathologic stage. Among men with Bx GS 8-10, 115 died (82 due to PC) with median follow-up of 3 yr (interquartile range [IQR] 1-7) for both overall and cancer-specific survival. Of men with RP GS 8-10, 221 died (151 due to PC) with median follow-up of 4 yr (IQR 2-8) and 4 yr (IQR 2-9) for overall and cancer-specific survival, respectively. PC-specific survival rates were significantly lower for men with GS 9-10 compared to men with GS 8 for both Bx (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.37-3.30; p<0.01) and RP GS (HR 2.38, 95% CI 1.74-3.28; p<0.01). This association persisted in multivariable models after adjusting for perioperative variables. CONCLUSIONS Men with GS 9-10 had higher ACM and PCSM rates compared to those with GS 8. GS 8 and GS 9-10 PC should be considered separately in both the preoperative and postoperative setting as suggested by the new PCGS. PATIENT SUMMARY The prostate cancer grading system can predict mortality risk after radical prostatectomy (RP) for men with Gleason score 8-10 disease based on both biopsy and RP Gleason scores. There are significant differences in all-cause mortality and prostate cancer-specific mortality following surgery between men with Gleason score 8 and those with Gleason score 9-10 disease.

Improving Prostate Cancer Screening and Diagnosis: Health Policy and Biomarkers Beyond PSA

The initial goal of prostate cancer screening with prostatespecific antigen (PSA) was to identify men with early-stage disease according to the general oncologic principle of secondary prevention that early diagnosis and treatment would prevent disease progressionand improve survival. However, 2 randomized clinical trials evaluating PSA screening and a large body of literature have identified unintended harms of overdiagnosis and overtreatment of potentially indolentprostatecancer.1,2TherevisedUSPreventiveServices Task Force grade D recommendation for PSA screening in 2012, stating that there is a lack of evidence that its benefits outweigh itsharms, further thrustprostate cancer screening into the spotlight of health policy in the United States.3 Recently, one of the intended consequences of the US Preventive ServicesTaskForce recommendationwas realized in that fewer men are being screened for and diagnosed with prostate cancer,withanestimated33000fewer incident cases in 2012 than in 2011.4 Although a uniform recommendation against screeningcan reduceoverdiagnosis andovertreatment of low-riskdisease, it also reduces theopportunity todiagnose higher-riskdisease, inwhich treatmenthas beenproven to reduce deaths from prostate cancer. Amore nuanced approach toPSAscreeningbasedona systematic reviewof the literature was proposed in 2013 by theAmericanUrological Association guideline for the earlydetectionof prostate cancer.5Although the review also investigated other serum and urine biomarkersofprostatecancer, suchasPSAisoforms, theProstateHealth Index, prostate cancer antigen 3 assay, and TMPRSS2-ERG fusion,6 the quality of the reviewed data was insufficient for determining their role in screening. In the current prospective cohort study reported in JAMA Oncology,McKiernanand colleagues7 demonstrate thepotential utility of a urine-based 3-gene exosome expression assay utilizing SAM pointed domain containing ETS transcription factor, ERG, and PCA3 (ExoDx Prostate IntelliScore, Exosome Diagnostics) to discriminate prostate cancer with a Gleason score of 7 ormore from that with a Gleason score of 6 and benign disease at initial biopsy. The population forwhich use of the assaywas intended includedmenolder than50yearswith no prior biopsy and a PSA value between 2 and 10 ng/mL (to convert tomicrograms per liter,multiply by 1.0). Similar estimates of the area under the curve were seen in the training (0.74) and validation (0.71) cohorts for the assay, with statistically significant improvements inmodel areaunder thecurve when the test was added to standard-of-care variables alone. Inapracticalapplication,applyingacutoffvalue fromthetraining cohort to serve as a threshold for biopsy in the validation cohort showed that 27% (138 of 519) of initial biopsies could havebeenavoidedat the cost ofmissing8%(12of 148) of prostate cancers of a Gleason score of 7 or more. A cutoff adjustment avoided 37% (192 of 519) of biopsies at a cost ofmissing 13% (19 of 148) of prostate cancers of a Gleason score of 7 or more (only 4 of the 19 patients had prostate cancer with a Gleason score including dominant pattern 4 disease). McKiernan and colleagues7 suggest that this 3-gene expression signature assay and similar tests could provide a route to reducing thediagnosis of low-riskprostate cancer and decreasing the number of unnecessary prostate biopsies. Instead of uniformly halting efforts to screen for early-stage prostate cancer, the focus shifts to detecting clinically significant disease.Notably, thepopulation included23% (55of 237) of menwith digital rectal examinations that raised the suspicionof prostate cancer and25% (64of 255) ofmenwith a familyhistoryofprostatecancer.These factors, combinedwithPSA values, led to the decision to perform a biopsy of the prostate, which resulted in a diagnosis of prostate cancer in almost half of the men in the study population and the finding that more than one-fourth of the study population had a Gleason score of 7 or more. The performance of the 3-gene expressionassay ina randomsampleofmennot scheduled for biopsy is unknown, making it uncertain whether the assay holds promise as an independent screening modality. Longitudinal assessment of the assay in a screening cohort will provide more data. Therefore, the current role of the 3-gene expression signature assay, if validated in external cohorts, would be as a secondary or reflex test for risk stratification in the setting of exercising stewardship with PSA screening, as suggested in theAmericanUrological Association guidelines, rather than as ameans of completely stopping PSA screening. The introduction of an effective reflex test for risk stratification adds an additional procedure to health policy efforts to combat overdiagnosis and overtreatment of prostate cancer. Health policy considerations in these efforts can be listed in downstream order from population-based screening to individualizedmanagementdecisions. The first step in this process includes guideline statements by the American Urological Association advocating shared decision making for men aged 55 to 69 years and PSA screening intervals of 2 years or more,5 resembling the2009USPreventiveServicesTaskForce recommendation for screeningmammography.A second step is effective risk stratification before conducting a diagnostic biopsy by using a validated gene-expression signature, such Related article page 882 Opinion

Predicting the Risk of Non–organ-confined Prostate Cancer When Perineural Invasion Is Found on Biopsy

OBJECTIVE To more precisely define the risk of non-organ-confined (non-OC) prostate cancer among men with perineural invasion (PNI) identified on prostate biopsy. MATERIALS AND METHODS The Johns Hopkins radical prostatectomy database was queried for men with PNI reported on prostate biopsy. Patients with and without non-OC disease were compared for differences in preoperative clinical and pathologic characteristics, including three biopsy-based measures of tumor volume (number of cores with cancer, percentage of cores with cancer, and maximum percent core involvement with cancer). After evaluating the different preoperative variables in univariate analyses, a multivariable logistic regression model was generated, and bootstrap estimates of the risk of non-OC disease were calculated. RESULTS In total, 556 patients with PNI were analyzed, 279 (50.2%) of whom were found to have non-OC prostate cancer. In univariate analyses, preoperative prostate-specific antigen, clinical T stage, biopsy Gleason sum, and the three biopsy-based measures of tumor volume were significantly associated with non-OC disease. Of the three measures of tumor volume, the best fit to the data and highest degree of model discrimination were obtained using maximum percent core involvement with cancer. Incorporating this variable, preoperative prostate-specific antigen, clinical T stage, and biopsy Gleason sum into a multivariable model, the estimated risk of non-OC disease was found to range from 13.8% to 94.4% (bootstrap corrected c-index = 0.735). CONCLUSION Men with PNI on prostate biopsy are at a wide range of risk for non-OC disease. Preoperative estimation of this risk is improved by considering readily available biopsy estimates of tumor volume.

Hospital Charges and Length of Stay Following Radical Cystectomy in the Enhanced Recovery After Surgery Era

OBJECTIVE To report our centers experience with enhanced recovery after surgery (ERAS) pathway for radical cystectomy (RC), specifically evaluating complications, LOS, 30- and 90-day readmissions, and hospital charges. Pathways of this type have been shown to decrease the length of stay (LOS) and postoperative ileus. However, concerns persist that ERAS is costly and increases readmissions. To date, limited studies have evaluated these concerns. MATERIALS AND METHODS Our ERAS protocol was implemented for RC in December 2015. Outcomes in ERAS patients were compared with those in RC patients from the time period before ERAS. Patients were excluded if they underwent concomitant nephroureterectomy. RESULTS Fifty-six consecutive ERAS patients were compared with 54 pre-ERAS patients. The median charge for index hospitalization was

Nucleolin staining may aid in the identification of circulating prostate cancer cells

31,090 in the ERAS group and

Role of biobanking in urology: a review

35,489 in the pre-ERAS group (P = .036). The median LOS was 5.0 days in the ERAS group and 8.5 days in the pre-ERAS group (P = < .001). The pre-ERAS group had a significantly increased use of nasogastric tube (13.8% vs 30.0%) and parenteral nutrition (6.9% vs 20.4%). The overall complication rate (including infectious, renal, deep vein thrombosis and pulmonary embolism, myocardial infarction and stroke, and respiratory and gastrointestinal-related complications) was similar between the 2 groups (51.7% in the ERAS group and 62.0% in the pre-ERAS group, P = .28). Thirty- and 90-day readmissions also remained similar (19.0% vs 14.8%, P = .55, and 31.0% vs 27.7%, P = .64). The most common readmission reason was infection, specifically urinary tract infection. CONCLUSION Implementation of the ERAS pathway at our center resulted in significantly reduced LOS and total hospital charge, with comparable rates of complication and readmission, highlighting the need for ERAS pathways in patients undergoing RC.

Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms

Micro‐Abstract In advanced prostate cancer, there is a need for biomarkers to monitor response to therapy and determine prognosis. Current tests for circulating tumor cells (CTCs) rely on epithelial markers with limited sensitivity and specificity. We showed that the staining pattern of nucleolin, a protein associated with proliferative cells, aids in the classification of prostate cancer CTCs. Introduction: Circulating tumor cells (CTCs) have great potential as circulating biomarkers for solid malignancies. Currently available assays for CTC detection rely on epithelial markers with somewhat limited sensitivity and specificity. We found that the staining pattern of nucleolin, a common nucleolar protein in proliferative cells, separates CTCs from white blood cells (WBCs) in men with metastatic prostate cancer. Patients and Methods: Whole peripheral blood from 3 men with metastatic prostate cancer was processed with the AccuCyte CTC system (RareCyte, Seattle, WA). Slides were immunostained with 4′,6‐diamidino‐2‐phenylindole (DAPI), anti–pan‐cytokeratin, anti‐CD45/CD66b/CD11b/CD14/CD34, and anti‐nucleolin antibodies and detected using the CyteFinder system. DAPI nucleolin colocalization and staining pattern wavelet entropy were measured with novel image analysis software. Results: A total of 33,718 DAPI‐positive cells were analyzed with the novel imaging software, of which 45 (0.13%) were known CTCs based on the established AccuCyte system criteria. Nucleolin staining pattern for segmentable CTCs demonstrated greater wavelet entropy than that of WBCs (median wavelet entropy, 6.86 × 107 and 3.03 × 106, respectively; P = 2.92 × 10−22; approximated z statistic = 9.63). Additionally, the total nucleolin staining of CTCs was greater than that of WBCs (median total pixel intensity, 1.20 × 105 and 2.55 × 104 integrated pixel units, respectively; P = 2.40 × 10−21; approximated z statistic = 9.41). Conclusion: Prostate cancer CTCs displayed unique nucleolin expression and localization compared to WBCs. This finding has the potential to serve as the basis for a sensitive and specific CTC detection method.