Carlo Andrea Bravi

Development and Internal Validation of a Novel Model to Identify the Candidates for Extended Pelvic Lymph Node Dissection in Prostate Cancer

BACKGROUND Preoperative assessment of the risk of lymph node invasion (LNI) is mandatory to identify prostate cancer (PCa) patients who should receive an extended pelvic lymph node dissection (ePLND). OBJECTIVE To update a nomogram predicting LNI in contemporary PCa patients with detailed biopsy reports. DESIGN, SETTING, AND PARTICIPANTS Overall, 681 patients with detailed biopsy information, evaluated by a high-volume uropathologist, treated with radical prostatectomy and ePLND between 2011 and 2016 were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS A multivariable logistic regression model predicting LNI was fitted and represented the basis for a coefficient-based nomogram. The model was evaluated using the receiver operating characteristic-derived area under the curve (AUC), calibration plot, and decision-curve analyses (DCAs). RESULTS AND LIMITATIONS The median number of nodes removed was 16. Overall, 79 (12%) patients had LNI. A multivariable model that included prostate-specific antigen, clinical stage, biopsy Gleason grade group, percentage of cores with highest-grade PCa, and percentage of cores with lower-grade disease represented the basis for the nomogram. After cross validation, the predictive accuracy of these predictors in our cohort was 90.8% and the DCA demonstrated improved risk prediction against threshold probabilities of LNI ≤20%. Using a cutoff of 7%, 471 (69%) ePLNDs would be spared and LNI would be missed in seven (1.5%) patients. As compared with the Briganti and Memorial Sloan Kettering Cancer Center nomograms, the novel model showed higher AUC (90.8% vs 89.5% vs 89.5%), better calibration characteristics, and a higher net benefit at DCA. CONCLUSIONS An ePLND should be avoided in patients with detailed biopsy information and a risk of nodal involvement below 7%, in order to spare approximately 70% ePLNDs at the cost of missing only 1.5% LNIs. PATIENT SUMMARY We developed a novel nomogram to predict lymph node invasion (LNI) in patients with clinically localized prostate cancer based on detailed biopsy reports. A lymph node dissection exclusively in men with a risk of LNI >7% according to this model would significantly reduce the number of unnecessary pelvic nodal dissections with a risk of missing only 1.5% of patients with LNI.

IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.IL-23 produced by myeloid-derived suppressor cells regulates castration resistance in prostate cancer by sustaining androgen receptor signalling.

The Impact of Implementation of the European Association of Urology Guidelines Panel Recommendations on Reporting and Grading Complications on Perioperative Outcomes after Robot-assisted Radical Prostatectomy

The rate of postoperative complications might vary according to the method used to collect perioperative data. We aimed at assessing the impact of the prospective implementation of the European Association of Urology (EAU) guidelines on reporting and grading of complications in prostate cancer patients undergoing robot-assisted radical prostatectomy (RARP). From September 2016, an integrated method for reporting surgical morbidity based on the EAU guidelines was implemented at a single, tertiary center. Perioperative data were prospectively and systematically collected during a patient interview at 30 d after surgery as recommended by the EAU Guidelines Panel Recommendations on Reporting and Grading Complications. The rate and grading of complications of 167 patients who underwent RARP±pelvic lymph node dissection (PLND) after the implementation of the prospective collection system (Group 1) were compared with 316 patients treated between January 2015 and August 2016 (Group 2) when a system based on patient chart review was used. No differences were observed in disease characteristics and PLND between the two groups (all p≥0.1). Postoperative complications were graded according to the Clavien-Dindo classification system. Overall, the complication rate was higher when the prospective collection system based on the EAU guidelines was used (29%) than when retrospective chart review (10%; p<0.001) was used. In particular, a substantially higher rate of grade 1 (8.4% vs 4.7%) and 2 (14% vs 2.8%) complications was detected in Group 1 versus Group 2 (p<0.001). Although the rate of complications occurred during hospitalization did not differ (13% vs 10%; p=0.3), 31 (19%) complications after discharge were detected in Group 1. This resulted into a readmission rate of 16%. Conversely, no complications after discharge and readmissions were recorded for Group 2. The implementation of the EAU guidelines on reporting perioperative outcomes roughly doubled the complication rate after RARP and allowed for the detection of complications after discharge in more than 15% of patients that would have been otherwise missed, where patients assessed with the EAU implemented protocol had a threefold higher likelihood of reporting complications. PATIENT SUMMARY The implementation of the European Association of Urology guidelines on reporting and grading of complications after urologic procedures in prostate cancer patients roughly doubled the complication rate after robot-assisted radical prostatectomy compared to retrospective patient chart review. Moreover, it allowed for the detection of complications after discharge in more than 15% of patients that would have been otherwise missed.

Impact of implementation of the EAU guidelines panel recommendations on reporting and grading of complications on perioperative outcomes after robot-assisted radical prostatectomy

word count: 298; Word count: 1,239; References: 11; Tables: 2; Supplementary files: 1; Pages: 9 Corresponding author: Alberto Briganti Division of Oncology/Unit of Urology; URI San Raffaele Hospital Milan, Italy Tel. +390226437286 Email: briganti.alberto@hsr.it 1

MP03-04 DOES THE INCLUSION OF NON-INDEX LESIONS AT BIOPSY IMPROVE OUR ABILITY TO PREDICT ADVERSE PATHOLOGIC OUTCOMES AT RADICAL PROSTATECTOMY? IMPLICATIONS FOR TARGETED PLUS SYSTEMATIC BIOPSY SCHEMES

METHODS: A review was performed of a prospectively maintained database of patients undergoing mpMRI followed by fusion biopsy (Fbx) and systematic biopsy (Sbx) from 2007 to 2016. The patients were stratified based on the timing of first biopsy in 3 groups. Cohort 1 included patients biopsied between 7/2007 to 12/ 2010, accounting for learning curve at our institution. Cohort 2 included patients biopsied from 1/2011 up to the debut of UroNav (Invivo) platform in 5/2013. Cohort 3 included patients biopsied after 5/ 2013. Clinically significant (CS) disease was defined as Gleason 7 (3+4) or higher. Cancer detection rates (CDR) between Sbx and Fbx during different time periods were compared using McNemar test. Age and PSA standardized CDRs were calculated for comparison between 3 cohorts. RESULTS: 1528 patients were included in the study with 219, 549 and 761 patients included in 3 respective cohorts. Mean age, PSA and race distribution were similar across 3 cohorts. In cohort 1 there was no significant difference between CDR of CS disease by Fbx (24.7%) vs Sbx (21.5%), p1⁄40.377. Fbx was significantly better than Sbx in detection of CS disease in cohort 2 and cohort 3 (31.5% vs 25.3%, p1⁄40.001; 36.5% vs 30.2%, p<0.001, respectively). There was significant decline in the detection of low risk disease by Fbx when compared to Sbx in the same period (cohort 2: 14.2% vs 20.9%, p<0.001; cohort 3: 12.5% vs 19.5%, p<0.001). Age and PSA standardized CDR of CS cancer by Fbx increased significantly between each successive cohort (cohort 1 and 2: 5.2%, 95% CI [2.1-8.5]), 2 and 3 (5.2%, 95% CI [1.88.6]). While CS CDR in patients with a prior negative biopsy was not significantly different between Fbx and Sbx in cohort 1, it was significantly different in cohorts 2 and 3 (p1⁄40.388, p>0.001, p1⁄40.036, respectively). CONCLUSIONS: Our results show that after an early learning period using Fbx, CS prostate cancer was detected at significantly higher rates with Fbx than with Sbx, and low risk disease was detected at lower rates. Advances in software allowed for even greater detection of CS disease in the last cohort. This study shows that accuracy of Fbx is dependent on multiple factors; surgeon/radiologist experience and software improvements together produce improved accuracy.

PD51-10 SURVIVAL AFTER RADICAL PROSTATECTOMY IN PATIENTS WITH PSA PERSISTENCE: THE IMPACT OF COMPETING CAUSES OF MORTALITY

INTRODUCTION AND OBJECTIVES: Data on the oncologic outcomes of high-risk prostate cancer (HRPCa) patients at 20 years after radical prostatectomy (RP) are lacking. The aim of our investigation was to evaluate the long-term patterns of biochemical (BCR), clinical recurrence (CR), cancer specific mortality (CSM) and othercause mortality (OCM) in a multi-institutional database of surgicallytreated HRPCa patients. METHODS: We evaluated 2280 patients with HRPCa treated with RP and pelvic lymph node dissection at 3 tertiary care centers between 1986 and 2015. High-risk prostate cancer was defined according to D’Amico criteria. We estimated BCR and CR rates using the Kaplan-Meier method. The CSM and OCM rates were obtained using competing risk analyses. BCR, CR, and CSM were assessed after 20 years from surgery. Cox regression analyses assessed predictors of long-term oncological outcomes. RESULTS: Median follow-up was 210 months. Median age was 66 years. The 20-year overall BCR-free survival and CR-free survival rates were 36.7% and 76.3%. Overall, 1050 experienced BCR. The latest BCR was registered at 237 months after RP. Out of 1230 patients who experienced BCR, 394 (37.5%) developed CF, while 656 (62.5%) were CF-free at last follow-up. The latest CF was registered at 244 months from RP. Overall, 394 and 172 patients experienced OCM and CSM. The competing risk 20 years CSM and OCM rates were 12.4 and 30.8%. Overall, 74 patients (3.5%) had a follow up 20 years. Of those, 7 (9.2%) and 1 (1.3%) experienced CSM and OCM. The 25-year competing-risks OCM and CSM-free survival rates were 77.9 and 98.5%. Age at RP (HR1⁄40.97), pathological Gleason score 6 (HR1⁄43.73), time to BCR (HR1⁄41.01) and number of nodes removed (HR1⁄41.06) were predictors of being free from overall mortality at 20year follow up (all p 0.04). Among patients with a follow-up 20 years (n1⁄474), 39 (51.3%) experienced BCR at a median follow-up of 214 months. No patient developed BCR after 20 years from RP. Moreover, 12 (33.3%) developed CF within 20 years (median follow-up 231 months), while only 1 (1.5%) developed CF after 20 years from RP. CONCLUSIONS: Among HRPCa patients, CSM may still occur even after 20 years from RP. Therefore, long monitoring and follow-up should be prolonged even after this time point. Moreover, time to BCR was a strong predictor of reaching a long follow-up after surgery and should be considered as a main criterion to further stratify patients according to their risk of CF and mortality over time.