Karnes, R. Jeffrey

Purpose: Pelvic lymph node dissection is an important step during robotic radical prostatectomy. The collection of lymphatic fluid (lymphocele) is the most common complication with potentially severe impact; therefore, different strategies have been proposed to reduce its incidence. Materials and Methods: In this systematic review, EMBASE, MEDLINE, Cochrane Library, and NIH Registry of Clinical Trials were searched for articles including the following interventions: transperitoneal vs extraperitoneal approach, any reconfiguration of the peritoneum, the use of pelvic drains, and the use of different sealing techniques and sealing agents. The outcome evaluated was the incidence of symptomatic lymphocele. Randomized, nonrandomized, and/or retrospective studies were included. Results: Twelve studies were included (including one ongoing randomized clinical trial). Because of heterogeneity of included studies, no meta-analysis was performed. No significant impact was reported by different sealing techniques and agents or by surgical approach. Three retrospective, nonrandomized studies showed a potential benefit of peritoneal reconfiguration to maximize the peritoneal surface of reabsorption. Conclusion: Lymphocele formation is a multistep and multifactorial event; high-quality literature analyzing risk factors and preventive measures is rather scarce. Peritoneal reconfiguration could represent a reasonable option that deserves further evaluation; no other preventive measure is supported by current evidence.

AbstractBackgroundMetabolic syndrome (MetS) has a negative impact on functional recovery and complications after many surgical procedures.AimTo assess the role of Mets on functional outcomes and complications after radical prostatectomy (RP) for prostate cancer.Patients and MethodsComplete data were collected from 5758 patients, undergoing RP at a single referral centers in a 10‐year period and the presence of MetS before surgery was ascertained in 17.7% of them using a modified version of the IDF‐AHA/NHLBI criteria. Outcomes included 1‐year continence and potency rates, early (≤90 days) and late (>90 days) complications.ResultsPostoperative continence (no pads) was significantly less likely in MetS patients (75.4% vs 82.6%, P < .01), despite no difference in preoperative continence. Erections with or without therapy were reached in 55.8% of non‐MetS and 41.8% of MetS patients (P < .01), in this case a significant difference in preoperative function was seen. No differences in early and late complications, except for wound infections (5.8% vs 3.9%, P < .01) were observed.ConclusionsIn the present study RP was safe from the complications standpoint in MetS patients, but the presence of the syndrome was a significant risk factor for post‐RP incontinence and impotence.

AbstractBackgroundTo assess whether a prespecified statistical model based on the four kallikrein markers measured in blood—total, free, and intact prostate‐specific antigen (PSA), together with human kallikrein‐related peptidase 2 (hK2)—or any individual marker measured in pretreatment serum were associated with biochemical recurrence‐free (BCR) or metastasis‐free survival after radical prostatectomy (RP) in a subgroup of men with very high‐risk disease.MethodsWe identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes.ResultsBCR and metastasis occurred in 67 and 30 patients, respectively. The median follow‐up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2‐11.8). In this high‐risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis‐free survival.ConclusionsConventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high‐risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high‐risk setting.

Abstract Purpose: The heterogeneity of androgen receptor (AR)-activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications. Experimental Design: Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n = 5,239) and validation (n = 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n = 1,170), and The Cancer Genome Atlas (n = 333). Results: A low AR-active subclass was identified, which comprised 9%–11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22–5.60; P = 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21–0.80; P = 0.008). Conclusions: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.

AbstractBackgroundMolecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed.MethodsBased on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic‐lethal events from those who remained recurrence‐free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan‐Meier curves and receiver operating characteristic analyses to evaluate the model's performance.ResultsThirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four‐gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic‐lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10−11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69‐0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56‐0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment‐Surgery).ConclusionOur validated 4GT score has prognostic value for metastatic‐lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.

Abstract Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

PURPOSE Multiparametric magnetic resonance imaging (mpMRI) is used widely for prostate cancer (PCa) evaluation. Approximately 35% of aggressive tumors, however, are not visible on mpMRI. We sought to identify the molecular alterations associated with mpMRI-invisible tumors and determine whether mpMRI visibility is associated with PCa prognosis. METHODS Discovery and validation cohorts included patients who underwent mpMRI before radical prostatectomy and were found to harbor both mpMRI-visible (Prostate Imaging and Reporting Data System 3 to 5) and -invisible (Prostate Imaging and Reporting Data System 1 or 2) foci on surgical pathology. Next-generation sequencing was performed to determine differential gene expression between mpMRI-visible and -invisible foci. A genetic signature for tumor mpMRI visibility was derived in the discovery cohort and assessed in an independent validation cohort. Its association with long-term oncologic outcomes was evaluated in a separate testing cohort. RESULTS The discovery cohort included 10 patients with 26 distinct PCa foci on surgical pathology, of which 12 (46%) were visible and 14 (54%) were invisible on preoperative mpMRI. Next-generation sequencing detected prioritized genetic mutations in 14 (54%) tumor foci (n = 8 mpMRI visible, n = 6 mpMRI invisible). A nine-gene signature (composed largely of cell organization/structure genes) associated with mpMRI visibility was derived (area under the curve = 0.89), and the signature predicted MRI visibility with 75% sensitivity and 100% specificity (area under the curve = 0.88) in the validation cohort. In the testing cohort (n = 375, median follow-up 8 years) there was no significant difference in biochemical recurrence, distant metastasis, or cancer-specific mortality in patients with predicted mpMRI-visible versus -invisible tumors (all P > .05). CONCLUSION Compared with mpMRI-invisible disease, mpMRI-visible tumors are associated with underexpression of cellular organization genes. mpMRI visibility does not seem to be predictive of long-term cancer outcomes, highlighting the need for biopsy strategies that detect mpMRI-invisible tumors.