Boorjian, Stephen A.

Abstract Recent studies suggest that progression to castrate-resistant prostate cancer (CRPC) is due to generation of androgen receptor (AR) splice variants, lacking the ligand binding domain. These AR variants originally identified in cell-based models of CRPC, have also been detected in benign and malignant human prostate tissue, with the highest levels observed in late state CRPC. The diversity and complexity of AR variants is well appreciated but not fully understood. Using RT-PCR we assessed the expression of a number of AR variants in cell-based models of both castrate-resistant and androgen-dependent prostate cancer. Several AR variants were expressed in both 22Rv1 and VCaP cells, but not in LNCaP cells. Coding sequences for AR variants were cloned into expression vectors and constitutive transcriptional activity was observed using a luciferase reporter assay. Augmented transcriptional activity of AR variants was observed in cells that express full-length AR, when full-length AR was silenced using shRNA targeting exons 7/8. This observation suggests the constitutive activity of AR variants may be independent of full-length AR. We profiled the AR variant transcriptome in 22Rv1 cells, using the Illumina HumanHT12 v4 whole-genome expression array platform. shRNA targeting exon 1 was used to silence all AR isoforms and shRNA targeting exons 7/8 was used to silence full-length AR. 5,256 genes were modulated by knocking down all AR isoforms and 5,086 genes were modulated by knocking down full-length AR. A total of 3,714 genes were common to both groups, leaving 1542 genes modulated by AR variants and 1372 modulated by full-length AR (p<0.05). The represents a subset of genes differentially regulated by AR variants independently of full length AR. Aggregate function of multiple AR variants may confer a CRPC phenotype independent of full-length AR. Pathway analysis of these genes differentially regulated by AR variants may reveal potential targets for therapeutic intervention in patients who progress despite androgen deprivation or anti-androgen therapy. (Supported by NIH grants CA125747, CA091956 and CA121277, T.J. Martell Foundation and the Mayo Clinic Prostate Cancer SPORE). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2924. doi:1538-7445.AM2012-2924

What's known on the subject? and What does the study add? Postoperative complications for open radical nephrectomy ( ORN ), laparoscopic radical nephrectomy ( LRN ), and open partial nephrectomy ( OPN ) and its relationship with hospitalisation costs and mortality remain poorly described. The present population‐based study suggests modest differences in postoperative complications estimated at 27%, 23%, and 24% among patients with kidney cancer undergoing ORN , LRN , and OPN , respectively. Moreover, postoperative complications were associated with higher mortality, length of stay and total costs of hospitalisation. Objectives The association of complications after renal surgery for renal cell carcinoma ( RCC ) with in‐hospital mortality and costs remains to be defined. To describe the incidence of complications after open radical nephrectomy ( ORN ), laparoscopic RN ( LRN ), and open partial nephrectomy ( OPN ); and to evaluate its relationship with in‐hospital mortality and total costs. Patients and Methods We identified 49 983 individuals who underwent ORN (35 712), LRN (5327), or OPN (8944) for RCC at 2037 hospitals from the Nationwide Inpatient Sample 2001–2008. The outcomes assessed were in‐hospital mortality and total hospitalisation costs. Multivariable logistic regression and generalised estimating equations were used to test the associations between complications and in‐hospital mortality and total costs. Results With 26.0% of patients experiencing postoperative complications, there were modest differences in the proportion of patients with complications after ORN , LRN , and OPN at 27.0%, 22.6%, and 24.0%, respectively ( P < 0.001). After adjusting for patient and hospital variables, postoperative complications resulted in higher odds of in‐hospital death for ORN (odds ratio [ OR ] 7.20; P < 0.001), LRN ( OR 12.04; P < 0.001), and OPN ( OR 7.82; P < 0.001). Adjusted total costs also rose significantly with the presence of any postoperative complications compared with those without any complications for ORN ($21 242 vs $13 183; P < 0.001), LRN ($19 548 vs $12 555; P < 0.001), and OPN ($18 883 vs $12 098; P < 0.001). Conclusions With about a quarter of patients experiencing postoperative complications, adverse events for ORN , LRN , and OPN carry a significant risk of in‐hospital death and higher total costs. Efforts to reduce postoperative complications may correlate with substantial reductions in hospital mortality and total costs.

What's known on the subject? and What does the study add? There is great variability in the utilization of partial nephrectomy, but the causes of these variations are not well understood. The present study underscores the already observed phenomenon of surgical volume influencing surgical planning and outcomes, but it gets at why this might be so. We observe that high‐volume renal surgeons have different thresholds of ‘technical feasibility’. Objective To investigate why there continues to be wide variability in the application of partial nephrectomy ( PN ) for treating small renal masses despite guidelines in the US and E urope stating that a PN is a standard of care for a patient with a T 1 renal mass. Patients and Methods In June 2009, 764 surgeon‐members of the A merican U rologic A ssociation ( AUA ) participated in a survey evaluating the management of renal masses. Renal mass complexity was graded by nephrometry score ( NS ). Multivariable logistic regression models with generalized estimating equations were constructed to evaluate how tumour, surgeon and practice‐setting characteristics influence the use of PN . Results The survey response rate was 19%. Each urological surgeon responded to eight scenarios, providing 6112 evaluable cases. Tumour NS ranged from 4 to 10, and each unit increase in NS was associated with 59% increased likelihood of a surgeon offering RN on multivariable analysis (odds ratio [ OR ] = 1.59; 95% CI : 1.52–1.64). When holding patient and tumour characteristics constant, the following surgeon and practice‐setting characteristics significantly increased the odds of offering a PN: increasing renal case volume ( OR = 1.57; 95% CI : 1.27–1.95), academic practice ( OR = 1.80; 95% CI : 1.42–2.29), increasing PN % volume ( OR = 3.7; 95% CI : 2.46–5.55) and younger surgeon age (≤40 vs >50 years) ( OR = 1.64; 95% CI : 1.35–1.96). Conclusion The characteristics of a surgeon and the setting in which he or she practices influence the utilization of PN , the adherence to professional guidelines, and the threshold of tumour complexity at which a surgeon stops offering PN .