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Ability to predict the risk of intraoperative adverse events (IOAEs) for patients undergoing partial nephrectomy (PN) can be of great clinical significance.To develop and internally validate a preoperative nomogram predicting IOAEs for robot-assisted PN (RAPN).In this observational study, data for demographic, preoperative, and postoperative variables for patients who underwent RAPN were extracted from the Vattikuti Collective Quality Initiative (VCQI) database.IOAEs were defined as the occurrence of intraoperative surgical complications, blood transfusion, or conversion to open surgery/radical nephrectomy. Backward stepwise logistic regression analysis was used to identify predictors of IOAEs. The nomogram was validated using bootstrapping, the area under the receiver operating characteristic curve (AUC), and the goodness of fit. Decision curve analysis (DCA) was used to determine the clinical utility of the model.Among the 2114 patients in the study cohort, IOAEs were noted in 158 (7.5%). Multivariable analysis identified five variables as independent predictors of IOAEs: RENAL nephrometry score (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.02-1.25); clinical tumor size (OR 1.01, 95% CI 1.001-1.024); PN indication as absolute versus elective (OR 3.9, 95% CI 2.6-5.7) and relative versus elective (OR 4.2, 95% CI 2.2-8); Charlson comorbidity index (OR 1.17, 95% CI 1.05-1.30); and multifocal tumors (OR 8.8, 95% CI 5.4-14.1). A nomogram was developed using these five variables. The model was internally valid on bootstrapping and goodness of fit. The AUC estimated was 0.76 (95% CI 0.72-0.80). DCA revealed that the model was clinically useful at threshold probabilities5%. Limitations include the lack of external validation and selection bias.We developed and internally validated a nomogram predicting IOAEs during RAPN.We developed a preoperative model than can predict complications that might occur during robotic surgery for partial removal of a kidney. Tests showed that our model is fairly accurate and it could be useful in identifying patients with kidney cancer for whom this type of surgery is suitable.

Differential classification of prostate cancer (CaP) grade group (GG) 2 and 3 tumors remains challenging, likely due to the subjective quantification of percentage of Gleason pattern 4 (%GP4). Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-assessed %GP4 is associated with biochemical recurrence (BCR) risk in intermediate risk GG 2 and 3 tumors. The study was conducted in a radical prostatectomy cohort (1999–2012) of African American men from the Henry Ford Health System (Detroit, Michigan). A CNN model that could discriminate four tissue types (stroma, benign glands, GP3 glands, and GP4 glands) was developed using histopathologic images containing GG 1 (n = 45) and 4 (n = 20) tumor foci. The CNN model was applied to GG 2 (n = 153) and 3 (n = 62) for %GP4 estimation, and Cox proportional hazard modeling was used to assess the association of %GP4 and BCR, accounting for other clinicopathologic features including GG. The CNN model achieved an overall accuracy of 86% in distinguishing the four tissue types. Further, CNN-assessed %GP4 was significantly higher in GG 3 compared with GG 2 tumors (p = 7.2*10− 11). %GP4 was associated with an increased risk of BCR (adjusted HR = 1.09 per 10% increase in %GP4, p = 0.010) in GG 2 and 3 tumors. Within GG 2 tumors specifically, %GP4 was more strongly associated with BCR (adjusted HR = 1.12, p = 0.006). Our findings demonstrate the feasibility of CNN-assessed %GP4 estimation, which is associated with BCR risk. This objective approach could be added to the standard pathological assessment for patients with GG 2 and 3 tumors and act as a surrogate for specialist genitourinary pathologist evaluation when such consultation is not available.

Introduction: Prostate cancer is a heterogenous multifocal disease. We hypothesize that different tumor foci may harbor distinct driver molecular aberrations, making it a more complex disease and difficult to manage. To avoid overlooking smaller tumor foci with clinical and biological significance, we used an innovative approach to understand the genetic underpinnings of each tumor foci based on the molecular analysis of whole-mount radical prostatectomy specimens rather than a systematic sampling of dominant nodules alone. Our study aimed to identify distinct molecular subsets of prostate cancer, if any, and correlate them with clinical outcomes in Caucasians (CA) and African Americans (AA). Method: We randomly selected 834 whole-mount radical prostatectomy tissues including 463 (56%) CA and 371 (44%) AA. We used combined dual immunohistochemistry (IHC) for ERG and SPINK1 and dual RNA in-situ hybridization (ISH) for ETV1 and ETV4. The racial disparity in aberrant oncogene expression was analyzed by the Chi-squared test. The recurrence-free survival (RFS) of patients with distinct molecular subsets of prostate cancer was examined by the Kaplan-Meier method and cox-ph models. The Gleason’s grades of prostate biopsies were summarized by spaghetti plot and compared by linear mixed models. Results: Patients with localized prostate cancer expressing none, one, two, and three of four oncogenes were 16.4%, 58.4%, 21.7%, and 3.5%, respectively. The expression of ERG and SPINK1 was negatively correlated (odds ratio (OR)=0.38, 95% CI 0.29-0.51, p Conclusion: Our findings showed the molecular heterogeneity between CA and AA who had localized prostate cancer, and supported ETV1 and ETV4 as prognostic markers that can be incorporated into clinical practice to better predict prostate cancer recurrence after radical prostatectomy in CA and AA, respectively. Citation Format: Wei Zhao, Pin Li, Shannon Carskadon, Craig Rogers, James Peabody, Mani Menon, Dhananjay Chitale, Sean Williamson, Nilesh Gupta, Nallasivam Palanisamy. New perspective on racial disparities in prostate cancer: identification of new molecular subsets using whole-mount radical prostatectomy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5762.

Introduction: African Americans (AA) had a higher mortality from prostate cancer than Caucasian Americans (CA). The racial disparity in the outcome of prostate cancer is explained by socioeconomic factors. However, if equally accessible to standard care, whether AA with prostate cancer have an inferior outcome than CAs remains unknown. To understand the biochemical recurrence free survival (RFS) after radical prostatectomy in a racial disparity perspective, we analyzed a large cohort of patients and made important observations. Method: AA (n=1020) and CA (n=1263) who received prostatectomy for prostate cancer were included. Their demographic and clinicopathologic characteristics were compared using the Chi-squared test and the Wilcox-rank test. RFS between AA and CA was compared using Kaplan-Meier curves with stratified log-rank test and cox-ph models. The Gleason grade across multiple biopsies was summarized by spaghetti plot and compared by linear mixed models. Results: Compared with CA, AA were younger at the time of prostatectomy (60.5 vs 62 years), had higher pre-operative PSA levels (5.7 vs 5.3 ng/mL), were fewer with Gleason grade of 5 (7.9% vs 13.3%) and lymph node metastasis (6.1% vs 9.5%), and waited longer from biopsy to prostatectomy (3 vs 2.3 months)(all p Conclusion: Our data showed that contrary to common belief, AA had a better RFS than CA after receiving prostatectomy. This study further supported the underlying biological difference of prostate cancer between AA and CA that requires future studies to elucidate. RFS Summary HR Race African American 1020 (44.7) - Caucasian 1263 (55.3) 1.25 (1.00-1.58, p=0.05) Pre-operative PSA (ng/mL) Mean (SD) 7.5 (9.0) 1.01 (1.01-1.02, p Citation Format: Pin Li, Wei Zhao, Shannon Carskadon, Craig Rogers, James Peabody, Mani Menon, Dhananjay Chitale, Sean Williamson, Nilesh Gupta, Nallasivam Palanisamy. Racial differences in clinical outcome in patients treated for clinically localized prostate cancer by radical prostatectomy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 747.

To compare perioperative outcomes following robot-assisted partial nephrectomy (RAPN) in patients with age ≥ 70 years to age 70 years.Using Vattikuti Collective quality initiative (VCQI) database for RAPN we compared perioperative outcomes following RAPN between the two age groups. Primary outcome of the study was to compare trifecta outcomes between the two groups. Propensity matching using nearest neighbourhood method was performed with trifecta as primary outcome for sex, body mass index (BMI), solitary kidney, tumor size and Renal nephrometery score (RNS).Group A (age ≥ 70 years) included 461 patients whereas group B included 1932 patients. Before matching the two groups were statistically different for RNS and solitary kidney rates. After propensity matching, the two groups were comparable for baselines characteristics such as BMI, tumor size, clinical symptoms, tumor side, face of tumor, solitary kidney and tumor complexity. Among the perioperative outcome parameters there was no difference between two groups for operative time, blood loss, intraoperative transfusion, intraoperative complications, need for radical nephrectomy, positive margins and trifecta rates. Warm ischemia time was significantly longer in the younger age group (18.1 min vs. 16.3 min, p = 0.003). Perioperative complications were significantly higher in the older age group (11.8% vs. 7.7%, p = 0.041). However, there was no difference between the two groups for major complications.RAPN in well-selected elderly patients is associated with comparable trifecta outcomes with acceptable perioperative morbidity.

To compare perioperative outcomes following retroperitoneal robot-assisted partial nephrectomy (RPRAPN) and transperitoneal robot-assisted partial nephrectomy (TPRAPN).With this Vattikuti Collective Quality Initiative (VCQI) database, study propensity scores were calculated according to the surgical access (TPRAPN and RPRAPN) for the following independent variables, i.e., age, sex, side of the surgery, RENAL nephrometry scores (RNS), estimated glomerular filtration rate (eGFR) and serum creatinine. The study's primary outcome was the comparison of trifecta between the two groups.In this study, 309 patients who underwent RPRAPN were matched with 309 patients who underwent TPRAPN. The two groups matched well for age, sex, tumor side, polar location of the tumor, RNS, preoperative creatinine and eGFR. Operative time and warm ischemia time were significantly shorter with RPRAPN. Intraoperative blood loss and need for blood transfusion were lower with RPRAPN. There was a significantly higher number of intraoperative complications with RPRAPN. However, there was no difference in the two groups for postoperative complications. Trifecta outcomes were better with RPRAPN (70.2% vs. 53%, p 0.0001) compared to TPRAPN. We noted no significant change in overall results when controlled for tumor location (anteriorly or posteriorly). The surgical approach, tumor size and RNS were identified as independent predictors of trifecta on multivariate analysis.RPRAPN is associated with superior perioperative outcomes in well-selected patients compared to TPRAPN. However, the data for the retroperitoneal approach were contributed by a few centers with greater experience with this technique, thus limiting the generalizability of the results of this study.

Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching.

Background: About 33,000 men will die due to prostate cancer in the US in the year 2021. Prostate cancer initially responds to androgen receptor (AR) targeted therapies (e.g., enzalutamide, darolutamide). However, therapy-resistant, aggressive, lethal malignancy invariably develops for which no effective, targeted treatment options are available. Though failures of AR-targeted therapies remain as major cause for mortality among prostate cancer patients, molecular mechanisms underlying the emergence of resistance are still to be fully characterized. Methods: To understand the molecular basis of enzalutamide resistance, we developed a prostate cancer cell model to mimic the clinical conditions in enzalutamide-resistant disease. These cells were transcriptionally profiled for gene expression analysis by Illumina Hi-Seq whole genome gene-expression array. Hits were validated by RT-qPCR and Western blot. For clinical correlation, samples from enzalutamide treated prostate PDX models as well as surgical prostate tumors from patients were comprehensively analyzed. Role of new hits were determined by lentiviral shRNAs and analysis of cell viability, apoptosis, and downstream targets. Pro-cancer effects were analyzed by cell proliferation, invasion, and soft-agar colony formation. Results: We identified that the Tribbles 2 (TRIB2) pseudokinase is overexpressed in enzalutamide resistant prostate cancer (ERPC) cells. Elevated level of TRIB2 was also observed in enzalutamide treated PDX tumors in mice, and in prostate tumors from patients who were treated with enzalutamide. We found that TRIB2 protein level is especially higher in prostate cancer cells where the AR activity is low, or absent due to genetic changes. Forced overexpression of TRIB2 results in aggressive prostate cancer cell growth and makes the cells resistant to enzalutamide. Conversely, inhibition of TRIB2 by shRNA or chemical inhibitor decreases viability and re-sensitizes ERPC cells back to enzalutamide, suggesting that TRIB2 plays an important role as a driver in the resistance mechanism. Interestingly, TRIB2 downregulates luminal markers, but upregulates neuroendocrine markers via the master neuronal transcription factor, BRN2, and the reprogramming factor, SOX2. Inhibition of either BRN2 or SOX2 also re-sensitizes ERPC cells to enzalutamide. Conclusion: These findings suggest that TRIB2 confers resistance to enzalutamide therapy through lineage switching from luminal to neuroendocrine type, involving BRN2 and SOX2. Citation Format: Jitender Monga, Indra Adrianto, Craig Rogers, Shirish Gadgeel, Dhananjay Chitale, Jagadananda Ghosh. Tribbles 2 confers resistance to anti-androgenic therapy in prostate cancer via lineage switching [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 398.