Lohse, Christine M.

AbstractRecently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa.

AbstractBackgroundIndications and survival benefit for adrenalectomy (ADX) in the setting of metastasis are not clearly defined. We aimed to determine which patients with primary malignancies may benefit from ADX performed for metastasis. Mayo Clinic institutional outcomes in patients with metastatic disease to the adrenal(s) treated by adrenalectomy were compared to stage‐matched historical controls from the Surveillance Epidemiology and End Results (SEER) database.MethodsA retrospective review (1992–2010) was conducted to identify patients treated with ADX for metastatic cancer at Mayo Clinic, Rochester. Associations of clinical, surgical, and pathologic features with overall survival (OS) were evaluated using Cox proportional regression models. OS for those treated with ADX was compared with that for SEER database stage‐matched patients who underwent primary resection without resection of distant disease using log‐rank tests.ResultsA total of 166 patients underwent ADX for metastatic primaries involving the kidney 60, lung 24, sarcoma 19, colon 15, pancreas 13, and other‐35. Patients with sarcoma and kidney, lung, and pancreatic tumors who underwent ADX had better OS at 1, 2, and 3 years than did the SEER‐matched controls. Respectively, the rates were for sarcoma (100, 93, 86% vs. 57, 36, 30%), kidney (86, 80, 72% vs. 55, 37, 27%), lung (91, 69, 52% vs. 52, 34, 25%), and pancreas (79, 56, 45% vs. 33, 20, 12%). Univariate analysis identified primary diagnosis <2 years before ADX, other distant site, pancreatic primary, palliative operation, and persistent disease as risk factors for death.ConclusionsAn aggressive surgical approach results in improved OS in patients with metastatic disease arising from soft tissues, kidney, lung, and pancreas. Other tumors may benefit, but larger study cohorts are needed for a meaningful comparison.

Abstract Purpose: Release of inhibitory coregulatory proteins into the circulation may represent one mechanism by which tumors thwart immune responses. Our objective was to determine whether soluble B7-H1 (sB7-H1) levels in patients with clear cell renal cell carcinoma (ccRCC) are associated with pathologic features and patient outcome. Experimental Design: We developed an ELISA for quantification of sB7-H1 in biological fluids. Biochemical confirmation of the measured analyte as sB7-H1 was done by protein microsequencing using supernates from tumor cell lines. Biological activity of sB7-H1 was assessed in vitro utilizing T-cell apoptosis assays. We tested sB7-H1 levels in the sera from 172 ccRCC patients and correlated sB7-H1 levels with pathologic features and patient outcome. Results: sB7-H1 was detected in the cell supernatants of some B7-H1–positive tumor cell lines. Protein sequencing established that the measured sB7-H1 retained its receptor-binding domain and could deliver proapoptotic signals to T cells. Higher preoperative sB7-H1 levels were associated with larger tumors (P &lt; 0.001), tumors of advanced stage (P = 0.017) and grade (P = 0.044), and tumors with necrosis (P = 0.003). A doubling of sB7-H1 levels was associated with a 41% increased risk of death (P = 0.010). Conclusion: Our observations suggest that sB7-H1 may be detected in the sera of ccRCC patients and that sB7-H1 may systemically impair host immunity, thereby fostering cancer progression and subsequent poor clinical outcome. Clin Cancer Res; 17(7); 1915–23. ©2011 AACR.

AbstractBackgroundProper management of small bowel obstruction (SBO) requires a methodology to prevent nontherapeutic laparotomy while minimizing the chance of overlooking strangulation obstruction causing intestinal ischemia. Our aim was to identify preoperative risk factors associated with strangulating SBO and to develop a model to predict the need for operative intervention in the presence of an SBO. Our hypothesis was that free intraperitoneal fluid on computed tomography (CT) is associated with the presence of bowel ischemia and need for exploration.MethodsWe reviewed 100 consecutive patients with SBO, all of whom had undergone CT that was reviewed by a radiologist blinded to outcome. The need for operative management was confirmed retrospectively by four surgeons based on operative findings and the patient’s clinical course.ResultsPatients were divided into two groups: group 1, who required operative management on retrospective review, and group 2 who did not. Four patients who were treated nonoperatively had ischemia or died of malignant SBO and were then included in group 1; two patients who had a nontherapeutic exploration were included in group 2. On univariate analysis, the need for exploration (n = 48) was associated (p < 0.05) with a history of malignancy (29% vs. 12%), vomiting (85% vs. 63%), and CT findings of either free intraperitoneal fluid (67% vs. 31%), mesenteric edema (67% vs. 37%), mesenteric vascular engorgement (85% vs. 67%), small bowel wall thickening (44% vs. 25%) or absence of the “small bowel feces sign” (so‐called fecalization) (10% vs. 29%). Ischemia (n = 11) was associated (p < 0.05 each) with peritonitis (36% vs. 1%), free intraperitoneal fluid (82% vs. 44%), serum lactate concentration (2.7 ± 1.6 vs. 1.3 ± 0.6 mmol/l), mesenteric edema (91% vs. 46%), closed loop obstruction (27% vs. 2%), pneumatosis intestinalis (18% vs. 0%), and portal venous gas (18% vs. 0%). On multivariate analysis, free intraperitoneal fluid [odds ratio (OR) 3.80, 95% confidence interval (CI) 1.5–9.9], mesenteric edema (OR 3.59, 95% CI 1.3–9.6), lack of the “small bowel feces sign” (OR 0.19, 95% CI 0.05–0.68), and a history of vomiting (OR 4.67, 95% CI 1.5–14.4) were independent predictors of the need for operative exploration (p < 0.05 each). The combination of vomiting, no “small bowel feces sign,” free intraperitoneal fluid, and mesenteric edema had a sensitivity of 96%, and a positive predictive value of 90% (OR 16.4, 95% CI 3.6–75.4) for requiring exploration.ConclusionClinical, laboratory, and radiographic factors should all be considered when making a decision about treatment of SBO. The four clinical features—intraperitoneal free fluid, mesenteric edema, lack of the “small bowel feces sign,” history of vomiting—are predictive of requiring operative intervention during the patient’s hospital stay and should be factored strongly into the decision‐making algorithm for operative versus nonoperative treatment.