microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to improve patient outcomes. In contrast, established treatment regimens of adrenolytics and chemotherapy have demonstrated treatment benefit, although admittedly in a minority of patients. Identification of microRNAs (miRNAs) in patients responsive to adjuvant therapy may offer a means to sensitize patients with progressive disease to existing adjuvant regimens. MATERIALS AND METHODS: Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a "sensitive" and "resistant" cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed. RESULTS: microRNA-431 (miR-431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR-431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial-mesenchymal transition underlies the action of miR-431 with doxorubicin treatment, with Zinc Finger E-Box Binding Homeobox 1 implicated as the molecular target of miR-431 in ACC. CONCLUSION: This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well-studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings. IMPLICATIONS FOR PRACTICE: Adrenocortical carcinoma (ACC) is a rare endocrine cancer with outcomes not improving despite extensive research and new targeted therapies. Mitotane and etoposide/doxorubicin/cisplatin chemotherapy is trial validated for improved recurrence-free survival. However, a minority of patients experience sustained benefit. Significant side effects exist for this regimen, with patients often unable to attain target drug doses shown to give survival benefit. This preclinical study examines the role of microRNAs in sensitizing ACC to doxorubicin or mitotane. This study offers an important bridge between new and existing cancer treatments, offering an imminently translatable approach to the treatment of adrenocortical carcinoma.

Improving Venous Thromboembolism Prophylaxis Administration in an Acute Surgical Unit.

OBJECTIVES: Venous thromboembolism (VTE) prophylaxis regimes frequently have a wide variation in application. Nepean acute surgical unit was established in 2006 as a novel model for emergency surgical care. As part of the model's rollout, there were several areas of clinical management targeted for improvement, one being VTE prophylaxis compliance. It was decided all patients older than 18 years treated for a variety of acute surgical conditions within the acute surgical unit should be administered routine VTE prophylaxis with heparin and compression stockings. A novel multifaceted intervention was implemented at the time to achieve this goal. The primary aim of this study was to determine VTE prophylaxis administration rates before and after this intervention. METHODS: A before-after study conducted as a retrospective review of medical records of all patients 18 years or older, having an appendicectomy in 3 periods: Before acute surgical unit (ASU) (November 2004 to October 2006), Early ASU (November 2006 to October 2008), and Established ASU (January 2012 to December 2013). Outcomes were mechanical and pharmacological VTE prophylaxis administration rates for each group. RESULTS: There were 1149 patients included in the study: Before ASU, 167; Early ASU, 375; and Established ASU, 607. There was a significant stepwise increase in parmacological VTE prophylaxis administration: Before ASU, 54.5%; Early ASU, 74.7%; and Established ASU, 96.9% (Before versus Early: odds ratio [OR], 2.46; 95% confidence interval [CI], 1.68-3.61; P < 0.001; Early versus Established: OR, 10.500; 95% CI, 6.29-17.53; P < 0.001). Mechanical VTE prophylaxis was significantly increased in the established group (Before versus Established: OR, 47.18; 95% CI, 25.61-86.91; P < 0.001). CONCLUSIONS: There was a significant increase in VTE prophylaxis administration after the implementation of our multifaceted intervention. Allocating a responsible provider dedicated to VTE prophylaxis prescription and compliance checking was a key component to this intervention.

Treatment and management of adrenal cancer in a specialized Australian endocrine surgical unit: approaches, outcomes and lessons learnt.

BACKGROUND: Adrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21-year experience in managing adrenocortical carcinoma with a view towards outcomes and lessons learnt. METHODS: A retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken. RESULTS: Thirty-five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immunohistochemical marker Ki-67 index were strong prognostic indicators for survival. CONCLUSIONS: Early stage, complete resection and Ki-67 <10% are the best prognosticators for survival. Aggressive surgical resection at index operation and of recurrent oligometastatic disease along with multimodal adjuvant treatment has led to long-term survivors of patients with Stage 4 disease in our aggregate cohort.

The Established Acute Surgical Unit: A reduction in nighttime appendicectomy without increased morbidity.

INTRODUCTION: Nighttime surgery for non-life threatening disease has been associated with poorer outcomes, but delaying surgery for acute appendicitis may also be detrimental. The aim was to assess the effect of the Acute Surgical Unit [ASU] model on nighttime surgery rates and outcomes for patients undergoing appendicectomy. METHOD: A retrospective review of medical records of patients having an appendicectomy. Primary outcomes were nighttime surgery rate, time from presentation to surgery, perforation rate, complication rate and length of stay. RESULTS: There was a large increase in workload: Pre ASU 278, Early ASU 553 and Est. ASU 923. There was a significant decrease in nighttime surgery rates: Pre ASU 46.9%, Early ASU 30.2% and Established ASU 28.3% (Pre vs. Early p < 0.001; Pre vs. Est. p < 0.001; Early vs. Est p = 0.004). When comparing the Pre ASU and Established ASU groups there was an increase in mean time from presentation to surgery (Pre 14.43 Hrs, Est. 18.65 Hrs; p = 0.001), an increase in perforation rate that was not significant (Pre 9.8%, Est. 14.2%; p = 0.05) and similar complication rates (Pre 8.66%, Est. 7.04%; p = 0.37). There was a significant decrease in length of stay between the Early and Established ASU groups (Pre 3.1 D, Est. 2.8D, p = 0.01). At our institution there was no statistically significant increase in complications for patients undergoing nighttime appendicectomy (Night 10.0%, Day 8.2%; p = 0.16). CONCLUSION: There was a significant decrease in nighttime surgery, without any difference in morbidity or length of stay for patients treated within the Established ASU (compared to Pre ASU group). LEVEL OF EVIDENCE: IIb.