Kathryn E. Coan

PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target

BACKGROUND Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets. METHODS We profiled 44 ACC and 4 normal adrenals on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by Western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation. RESULTS Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Overexpression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average β-actin <-3.04) was 1.8 years compared with 9.0 years if tumors expressed lower levels of PTTG1 (P < .0001). Analysis of a previously published dataset confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of 2 ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (median inhibition concentrations of 1.69 μmol/L and 0.891 μmol/L, for SW-13 and H295R, respectively). CONCLUSION Overexpression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.

Overcoming clinical inertia in the management of postoperative patients with diabetes

OBJECTIVE To assess the impact of an intervention designed to increase basal-bolus insulin therapy administration in postoperative patients with diabetes mellitus. METHODS Educational sessions and direct support for surgical services were provided by a nurse practitioner (NP). Outcome data from the intervention were compared to data from a historical (control) period. Changes in basal-bolus insulin use were assessed according to hyperglycemia severity as defined by the percentage of glucose measurements >180 mg/dL. RESULTS Patient characteristics were comparable for the control and intervention periods (all P≥.15). Overall, administration of basal-bolus insulin occurred in 9% (8/93) of control and in 32% (94/293) of intervention cases (P<.01). During the control period, administration of basal-bolus insulin did not increase with more frequent hyperglycemia (P = .22). During the intervention period, administration increased from 8% (8/96) in patients with the fewest number of hyperglycemic measurements to 60% (57/95) in those with the highest frequency of hyperglycemia (P<.01). The mean glucose level was lower during the intervention period compared to the control period (149 mg/dL vs. 163 mg/dL, P<.01). The proportion of glucose values >180 mg/dL was lower during the intervention period than in the control period (21% vs. 31% of measurements, respectively, P<.01), whereas the hypoglycemia (glucose >70 mg/dL) frequencies were comparable (P = .21). CONCLUSION An intervention to overcome clinical inertia in the management of postoperative patients with diabetes led to greater utilization of basal-bolus insulin therapy and improved glucose control without increasing hypoglycemia. These efforts are ongoing to ensure the delivery of effective inpatient diabetes care by all surgical services.

Clinical inertia during postoperative management of diabetes mellitus: relationship between hyperglycemia and insulin therapy intensification.

Objective: Our objective was to assess the application of insulin regimens in surgical postoperative patients with diabetes. Methods: A chart review was conducted of patients with diabetes who were hospitalized postoperatively between January 1 and April 30, 2011. Analysis was restricted to patients hospitalized for ≥3 days and excluded cases with an endocrinology consult. Insulin regimens were categorized as “basal plus short acting,” “short acting only,” or “none,” and the pattern of use was evaluated by hyperglycemia severity according to tertiles of both mean glucose and the number of glucose measurements >180 mg/dl. Results: Among cases selected for analysis (n = 119), examination of changes in insulin use based on tertiles of mean glucose showed that use of basal plus short-acting insulin increased from 10% in the lowest tertile (mean glucose, 120 mg/dl) to 18% in the highest tertile (mean glucose, 198 mg/dl; p < .01); however, 70% of patients in the highest tertile continued to receive short-acting insulin only, with 12% receiving no insulin. Intensification of insulin to a basal plus short-acting regimen was also seen when changes were evaluated by the number of measurements >180 mg/dl (p < .01), but 70% and 12% of patients in the highest tertile still remained only on short-acting insulin or received no insulin, respectively. Conclusions: Use of basal plus short-acting insulin therapy increased with worsening hyperglycemia, but many cases did not have therapy intensified to the recommended insulin regimen—evidence of clinical inertia. Strategies should be devised to overcome inpatient clinical inertia in the treatment of postoperative patients with diabetes.

Bilateral Pulmonary Emboli Secondary to Indwelling Hemodialysis Reliable Outflow Catheter

We present a 33-year-old dialysis-dependent female who presented with new onset split second heart sound. Following a failed left upper extremity dialysis fistula, a right upper extremity hemodialysis reliable outflow (HeRO) graft was performed in 2011. Her subsequent cadaveric renal transplant had delayed function necessitating concurrent use of hemodialysis. However, as renal function improved, hemodialysis was discontinued. Two weeks following transplantation, the HeRO graft occluded. Subsequent clinical and radiological assessment confirmed widespread pulmonary emboli. Following cessation of hemodialysis and subsequent HeRO graft occlusion, removal was deemed appropriate to reduce further thromboembolic phenomenon. Right atrial thrombi are complications associated with central venous catheters. However, their actual incidence varies significantly. Right heart thromboemboli are associated with a 4% to 6% pulmonary embolism rate. Katzman et al assessed 38 patients who underwent HeRO graft and reported 1 (2.6%) patient with right atrial emboli and likely pulmonary embolism. Although thrombotic complications remain rare, consideration of graft removal should always be evaluated particularly in the absence of an alternative thrombotic source.

Abstract 978: Inhibition of Polo-like kinase 1 as a strategy in the treatment of adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5-year survival rate of 20-30%. Mitotane is the only approved drug for the treatment of patients with ACC. It often carries significant toxicities which result in the discontinuation of treatment. There are no approved second line therapies. The increased incidence of ACC in the cancer predisposition syndrome, Li-Fraumeni, suggests the involvement of the p53 pathway in ACC pathogenesis. Our analysis of the gene expression profiles of 19 ACC samples identified dysregulation of the G2/M transition and the activity of the p53 modulator, MDM2 as important in ACC pathogenesis. Polo-like kinase-1 (PLK1) is involved in the G2/M transition and acts to promote MDM2 activity through its phosphorylation. We observed that PLK1 inhibition by siRNA results in up to a 70% reduction in viability in the ACC cell lines SW-13 and H295R. Therefore, we studied PLK1 inhibition as a potential therapeutic strategy. We used the small molecule inhibitor, BI-2536, to inhibit PLK1 function in SW-13 and H295R. Drug-dose response curves demonstrated that both cell lines are sensitive to pharmacological inhibition of PLK1 (IC50 doses of 0.0094815 μM and 0.062805 μM for SW-13 and H295R, respectively.) Murine xenograft studies demonstrated that BI-2536 resulted in a statistically significant reduction in tumor growth in SW-13 but not H295R. Examination of p53 protein levels in the presence of the drug showed a dose-dependent reduction in p53 levels in SW-13, which carries a homozygous p53 mutation. The same was not true in H295R, which is p53 wild-type. To test the hypothesis that BI-2536 was decreasing mutant p53 levels by promoting its proteasomal degradation, both cell lines were treated with previously determined inhibitory concentrations of BI-2536, either alone or in combination with the proteasome inhibitor, MG132. Western blot analysis showed recovery of p53 protein when cells were concomitantly treated with MG132, supporting a role for BI-2536 as a regulator of proteasomal degradation. Both ACC cell lines are relatively insensitive to MDM2 inhibition by nutlin-3 (NCI60 GI50 values range from ∼4 uM to ∼2 uM versus ACC cell lines @13-15uM), possibly because PLK1 stimulates MDM2 and renders nutlin-3 ineffective. We therefore assessed the ability of BI-2536 to sensitize ACC cell lines to the effects of the MDM2 inhibitor. BI-2636 did show synergy with nutlin-3, shifting the IC50 in SW-13 from 19.78 μM to 6.45 μM and from 12.75 μM to 2.84 μM in H295R. These results demonstrate that inhibition of PLK1 alone or in combination with an MDM2 inhibitor warrants further investigation as a treatment for patients with ACC. Cells with mutant p53 are more sensitive to the growth inhibitory effects of BI-2536. In the context of wild-type p53, the combined inhibition of both PLK1 and MDM2 results in loss of viability. Further clinical development of PLK1 as a target should take p53 mutation status into account. 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 978. doi:1538-7445.AM2012-978

Percutaneous Thrombolysis of Acute-On-Chronic Inferior Vena Cava Thrombosis After Previous Insertion of an Adams-DeWeese Clip

We describe the successful percutaneous treatment of acute-on-chronic IVC thrombosis 30 years following previous placement of Adams-DeWeese clip.

Successful Percutaneous Management of Ruptured Middle Colic Aneurysm Following Endovascular Aneurysm Repair

A 56-year-old male with end-stage renal failure secondary to hypertension was admitted for endovascular repair of an asymptomatic right common iliac aneurysm that had been identified intraoperatively during his renal transplant via a right retroperitoneal incision. Computed tomography (CT) angiography confirmed a 6.2-cm right common iliac aneurysm. Following bilateral vertical groin incisions to access the common femoral arteries, the patient proceeded to embolization of the right internal iliac artery using a 22-mm Amplatzer II plug. A bifurcated Zenith Flex abdominal aortic aneurysm endovascular stent was successfully deployed followed by the contralateral limb and then bilateral iliac extensions. Completion angiogram demonstrated successful exclusion of the right internal iliac artery and a late type II endoleak from the inferior mesenteric artery (IMA). The patient was discharged home the following day but represented later that day to our emergency department following a syncopal episode with increased abdominal pain. The CT angiography revealed a left upper quadrant intraperitoneal hematoma with evidence of active contrast extravasation (Figure 1). The endograft was stable. Mesenteric angiography identified a 3-mm pseudoaneurysm arising from a branch of the splenic artery that was embolized. However, subsequent superior mesenteric angiography identified a larger pseudoaneurysm with active contrast extravasation at the junction of the middle colic artery and ascending branch of the IMA (Figure 2). Microcatheter access, because of tortuosity, facilitated coil embolization (Figure 3). Completion angiography confirmed arterial occlusion. He was discharged home on day 4. Six weeks later, he was treated for Klebsiella urinary sepsis where CT angiogram demonstrated a hematoma in the left upper quadrant, with no evidence of contrast extravasation. A percutaneous drain was inserted and bacteriological cultures identified Klebsiella. He completed a 2-week course of intravenous cetriaxone followed by oral ciprofloxacin. He showed continued improvement clinically. Endovascular aneurysm repair (EVAR) is an established treatment modality with a lower perioperative blood loss Division of Vascular and Endovascular Surgery, Mayo Clinic, Phoenix, AZ, USA DivisionofVascular and Interventional Radiology,MayoClinic, Phoenix,AZ, USA

Brachiocephalic Vein Bypass with Sternal Reconstruction for Symptomatic Occlusion

Complications attributed to central venous stenosis and subsequent thrombosis are increasing in frequency and are most commonly associated with neointimal fibroplasia as well as neoplastic, fibrotic, and traumatic pathologies. We present the successful venous bypass and thoracic wall reconstruction of a 58-year-old female with chronic atypical symptoms secondary to brachiocephalic vein occlusion from congenital thoracic dystrophy.