Personalizing Localized Prostate Cancer: Validation of a Combined Clinical Cell-cycle Risk (CCR) Score Threshold for Prognosticating Benefit From Multimodality Therapy.

INTRODUCTION: The combined clinical cell-cycle risk (CCR) score is a validated model that combines the cell-cycle progression (CCP) score with the University of California San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score. This score determines the risk of progressive disease for men with prostate cancer. Here, we further validate the prognostic ability of the CCR score and evaluate its ability to help determine which patients may safely forgo multimodality therapy. PATIENTS AND METHODS: We evaluated the CCR and a CCR-based multimodality threshold (2.112) in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Network intermediate- or high-risk localized disease (N = 718). These men received single or multimodality therapy (androgen deprivation with radiation [RT], or surgery with adjuvant RT or hormones). RESULTS: CCR score prognosticated metastasis for single-modality therapy, as a continuous variable (hazard ratio, 3.97; 95% confidence interval [CI], 2.61-6.06) and when dichotomized at the threshold (hazard ratio, 15.90; 95% CI, 5.43-46.52). The 10-year Kaplan-Meier risk for those receiving single-modality (RT or surgical) therapy with CCR scores below and above the threshold for single-modality treatment was 4.3% (95% CI, 1.0%-17.1%) and 20.4% (95% CI, 13.2%-30.7%), respectively. Using the threshold, 27% of men with newly diagnosed high-risk and 73% with unfavorable intermediate-risk disease could avoid multimodality therapy. CONCLUSIONS: Patients with CCR scores below the multimodality threshold (2.112) may safely forgo multimodality therapy. The CCR score can be used as a decision aid to counsel men whether or not single-modality therapy would be sufficient for their intermediate- or high-risk prostate cancer.

Novel Opiate-Free Anesthetic Technique for Major Urologic Procedures.

OBJECTIVES: We postulated that an opiate-free (OF) general anesthesia (GA) technique could adequately control a patient's pain without adversely affecting recovery. We compared patients undergoing major urologic procedures with and without opiate-based GA. METHODS: A propensity-matched analysis was performed comparing hospital length of stay, postoperative nausea and vomiting, ileus occurrence, postanesthesia care unit, and total opiate consumption, as well as sedation and hemodynamic variables. The data are expressed as medians and were analyzed with the Wilcoxon rank-sum test. P < 0.05 indicate statistical significance. RESULTS: In total, 166 patients were evaluated in both the OF group and the opiate-based treatment group. American Society of Anesthesiologists classification and age were comparable, with most surgeries being laparoscopic and confined to the bladder, kidney, and prostate gland. The median opiate consumption in morphine equivalents in the postanesthesia care unit was 7.7 mg (range 5-11.7 mg) for the OF cohort versus 11.7 mg (range 5-17.3 mg) for the control group (P < 0.001). Similarly, the median total postoperative opiate consumption in morphine equivalents was 23.9 mg (range 13.8-42.4 mg) for the OF group compared with 32.1 mg (range 17.38-57.51 mg) for the control group (P = 0.0081). The median hospital length of stay for the OF group was 1.4 days (range 1.2-2.3 days) versus 1.3 days (range 1.2-2.4 days) for the control group (P = 0.8466). CONCLUSIONS: There was a statistically significant difference in opiate consumption postoperatively for patients who underwent an OF technique compared with a conventional opiate-based technique. This technique appears to be a possible alternative approach, without any apparent untoward consequences during admission.

Analysis of the prognostic utility of the cell cycle progression (CCP) score generated from needle biopsy in men treated with definitive therapy.

BACKGROUND: Accurate risk stratification can help guide appropriate treatment decisions in men with localized prostate cancer. Here, we evaluated the independent ability of the molecular cell cycle progression (CCP) score and the combined cell-cycle clinical risk (CCR) score to predict 10-year risk of progression to metastatic disease in a large, pooled analysis of men with definitively treated prostate cancer. METHODS: The pooled analysis included 1,062 patients from four institutions (Martini Clinic, Durham VA Medical Center, Intermountain Healthcare, Ochsner Clinic) treated definitively for localized prostate cancer by either radical prostatectomy or radiotherapy (brachytherapy or external beam radiotherapy ± hormone therapy). The CCP score was determined using the RNA expression of 46 genes from archival formalin-fixed paraffin-embedded biopsy tissue. The CCR score was calculated using a predefined linear combination of the CCP score and the Cancer of the Prostate Risk Assessment (CAPRA) score. The scores were evaluated for association with 10-year risk of metastatic disease following definitive therapy after adjusting for other clinical variables. RESULTS: The CCP score was strongly associated with 10-year risk of metastatic disease in multivariable analysis [Hazard Ratio per unit score = 2.21; 95% confidence interval (CI) 1.64, 2.98; p = 1.9 × 10-6] after adjusting for CAPRA, treatment type, and cohort. CCR was also highly prognostic (Hazard Ratio per unit score = 4.00; 95% CI 2.95, 5.42; p = 6.3 × 10-21). There was no evidence of interaction between CCP or CCR and cohort (p = 0.79 and p = 0.86, respectively) or treatment type (p = 0.55 and p = 0.78, respectively). Observed patient CCR-based predicted risks for metastatic disease by 10 years ranged from 0.1 to 99.4%, (IQR 0.7%, 4.6%). CONCLUSIONS: Both CCP and CCR scores provided independent prognostic information for predicting progression to metastatic disease after both surgery and radiation. These results further demonstrate their potential use as a risk stratification tool in patients with newly-diagnosed prostate cancer.

Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis.

Cancer patients have poor prognoses when lymph node (LN) involvement is present in both high-grade urothelial cell carcinoma (HG-UCC) of the bladder and colorectal cancer (CRC). More than 50% of patients with muscle-invasive UCC, despite curative therapy for clinically-localized disease, will develop metastases and die within 5 years, and metastatic CRC is a leading cause of cancer-related deaths in the US. Xenograft models that consistently mimic UCC and CRC metastasis seen in patients are needed. This study aims to generate patient-derived orthotopic xenograft (PDOX) models of UCC and CRC for primary tumor growth and spontaneous metastases under the influence of LN stromal cells mimicking the progression of human metastatic diseases for drug screening. Fresh UCC and CRC tumors were obtained from consented patients undergoing resection for HG-UCC and colorectal adenocarcinoma, respectively. Co-inoculated with LN stromal cell (LNSC) analog HK cells, luciferase-tagged UCC cells were intra-vesically (IB) instilled into female non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and CRC cells were intra-rectally (IR) injected into male NOD/SCID mice. Tumor growth and metastasis were monitored weekly using bioluminescence imaging (BLI). Upon sacrifice, primary tumors and mouse organs were harvested, weighed, and formalin-fixed for Hematoxylin and Eosin and immunohistochemistry staining. In our unique PDOX models, xenograft tumors resemble patient pre-implantation tumors. In the presence of HK cells, both models have high tumor implantation rates measured by BLI and tumor weights, 83.3% for UCC and 96.9% for CRC, and high distant organ metastasis rates (33.3% detected liver or lung metastasis for UCC and 53.1% for CRC). In addition, both models have zero mortality from the procedure. We have established unique, reproducible PDOX models for human HG-UCC and CRC, which allow for tumor formation, growth, and metastasis studies. With these models, testing of novel therapeutic drugs can be performed efficiently and in a clinically-mimetic manner.

Comparison of the Prognostic Utility of the Cell Cycle Progression Score for Predicting Clinical Outcomes in African American and Non-African American Men with Localized Prostate Cancer.

BACKGROUND: Better prostate cancer risk stratification is necessary to inform medical management, especially for African American (AA) men, for whom outcomes are particularly uncertain. OBJECTIVE: To evaluate the utility of both a cell cycle progression (CCP) score and a clinical cell-cycle risk (CCR) score to predict clinical outcomes in a large cohort of men with prostate cancer highly enriched in an AA patient population. DESIGN, SETTING, AND PARTICIPANTS: Patients were diagnosed with clinically localized adenocarcinoma of the prostate and treated at The Ochsner Clinic (New Orleans, LA, USA) from January 2006 to December 2011. CCP scores were derived from archival formalin-fixed, paraffin-embedded biopsy tissue. CCR scores were calculated as the combination of molecular (CCP score) and clinical (Cancer of the Prostate Risk Assessment [CAPRA] score) components. INTERVENTION: Active treatment (radical prostatectomy, radiation therapy alone, or radiation and hormone therapy) or watchful waiting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was progression to metastatic disease. Association with outcomes was evaluated via Cox proportional hazards survival analysis and likelihood ratio tests. RESULTS AND LIMITATIONS: The final cohort included 767 men, of whom 281 (36.6%) were AA. After accounting for ancestry, treatment, and CAPRA in multivariable analysis, the CCP score remained a significant predictor of metastatic disease (hazard ratio [HR] 2.04; p<0.001), and there was no interaction with ancestry (p=0.20) or treatment (p=0.09). The CCR score was highly prognostic (HR 3.86; p<0.001), and as with the CCP score, there was no interaction with ancestry (p=0.24) or treatment (p=0.32). Limitations include the retrospective study design and the use of self-reported ancestry information. CONCLUSIONS: A CCR score provided significant prognostic information regardless of ancestry. The findings demonstrate that AA men in this study cohort appear to have similar prostate cancer outcomes to non-AA patients after accounting for all available molecular and clinicopathologic variables. PATIENT SUMMARY: In this study we evaluated the ability of a combined molecular and clinical score to predict the progression of localized prostate cancer. We found that the combined molecular and clinical score predicted progression to metastasis regardless of patient ancestry or treatment. This suggests that the combined molecular and clinical score may be a valuable tool for determining the risk of metastasis in men with newly diagnosed prostate cancer in order to make appropriate treatment decisions.

Effect of the Need for Preoperative Dialysis on Perioperative Outcomes on Patients Undergoing Laparoscopic Nephrectomy: An Analysis of the National Surgical Quality Improvement Program Database.

OBJECTIVE: To investigate whether patients requiring dialysis are a higher risk surgical population and would experience more perioperative adverse events even when undergoing a perceived less invasive operation as a laparoscopic radical nephrectomy (LRN). LRN is generally a well-tolerated surgical procedure with minimal morbidity and mortality. Prior to transplantation, dialysis patients will often have to undergo a LRN to remove a native kidney with a suspicious mass. MATERIALS AND METHODS: Patients in the American College of Surgeons National Surgical Quality Improvement Program who underwent a LRN between 2011 and 2016 were included. Patients were stratified by the need for preoperative dialysis 2 weeks prior to surgery, and perioperative outcomes were compared. A multivariable logistic regression analysis was performed to test the association between the need for preoperative dialysis and perioperative risk. RESULTS: There were 8315 patients included in this analysis of which 445 (5.4%) patients required preoperative dialysis. Patients who required preoperative dialysis had more minor (P <.0001) and major (P = .0025) complications, a higher rate of return to the operating room (P = .002), and a longer length of stay (P <.0001) than those patients not requiring preoperative dialysis. In a multivariate analysis, the need for preoperative dialysis was independently associated with adverse perioperative outcomes (OR= 1.45, CI = 1.08-1.95, P = .015). CONCLUSION: Patients requiring preoperative dialysis were more likely to experience a perioperative complication and have a longer length of stay. For LRNs performed prior to transplantation, further risk stratification is needed, and treatment sequencing may need to be reconsidered.

A patient-derived orthotopic xenograft model enabling human high-grade urothelial cell carcinoma of the bladder tumor implantation, growth, angiogenesis, and metastasis.

High-grade urothelial cell carcinoma of the bladder has a poor prognosis when lymph nodes are involved. Despite curative therapy for clinically-localized disease, over half of the muscle-invasive urothelial cell carcinoma patients will develop metastases and die within 5 years. There are currently no described xenograft models that consistently mimic urothelial cell carcinoma metastasis. To develop a patient-derived orthotopic xenograft model to mimic clinical urothelial cell carcinoma progression to metastatic disease, the urothelial cell carcinoma cell line UM-UC-3 and two urothelial cell carcinoma patient specimens were doubly tagged with Luciferase/RFP and were intra-vesically (IB) instilled into NOD/SCID mice with or without lymph node stromal cells (HK cells). Mice were monitored weekly with bioluminescence imaging to assess tumor growth and metastasis. Primary tumors and organs were harvested for bioluminescence imaging, weight, and formalin-fixed for hematoxylin and eosin and immunohistochemistry staining. In this patient-derived orthotopic xenograft model, xenograft tumors showed better implantation rates than currently reported using other models. Xenograft tumors histologically resembled pre-implanted primary specimens from patients, presenting muscle-invasive growth patterns. In the presence of HK cells, tumor formation, tumor angiogenesis, and distant organ metastasis were significantly enhanced in both UM-UC-3 cells and patient-derived specimens. Thus, we established a unique, reproducible patient-derived orthotopic xenograft model using human high-grade urothelial cell carcinoma cells and lymph node stromal cells. It allows for investigating the mechanism involved in tumor formation and metastasis, and therefore it is useful for future testing the optimal sequence of conventional drugs or the efficacy of novel therapeutic drugs.

Pathogenesis of prostate cancer: lessons from basic research.

In the United States, prostate cancer is the second most common cause of cancer-related deaths in men. While the importance of androgens and androgen receptors (ARs) in primary prostate cancer is well established, the role of ARs in prostate cancers that emerge despite androgen ablation therapies remains poorly understood. The aim of this article is to illustrate the fundamental biology of prostate cancer. We focus mainly on the AR because of its critical role in the progression and metastatic spread of prostate cancer. We also summarize the alternate pathways that may potentially contribute to the progression of prostate cancer. Identifying the underlying mechanisms of androgen independence is crucial in the design of appropriate therapies for hormone-refractory neoplasms.