Stacy Ugras

Small RNA sequencing and functional characterization reveals microRNA-143 tumor suppressor activity in liposarcoma

Liposarcoma remains the most common mesenchymal cancer, with a mortality rate of 60% among patients with this disease. To address the present lack of therapeutic options, we embarked upon a study of microRNA (miRNA) expression alterations associated with liposarcomagenesis with the goal of exploiting differentially expressed miRNAs and the gene products they regulate as potential therapeutic targets. MicroRNA expression was profiled in samples of normal adipose tissue, well-differentiated liposarcoma, and dedifferentiated liposarcoma by both deep sequencing of small RNA libraries and hybridization-based Agilent microarrays. The expression profiles discriminated liposarcoma from normal adipose tissue and well differentiated from dedifferentiated disease. We defined over 40 miRNAs that were dysregulated in dedifferentiated liposarcomas in both the sequencing and the microarray analysis. The upregulated miRNAs included two cancer-associated species (miR-21 and miR-26a), and the downregulated miRNAs included two species that were highly abundant in adipose tissue (miR-143 and miR-145). Restoring miR-143 expression in dedifferentiated liposarcoma cells inhibited proliferation, induced apoptosis, and decreased expression of BCL2, topoisomerase 2A, protein regulator of cytokinesis 1 (PRC1), and polo-like kinase 1 (PLK1). The downregulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells. In support of this idea, treatment with a PLK1 inhibitor potently induced G(2)-M growth arrest and apoptosis in liposarcoma cells. Taken together, our findings suggest that miR-143 re-expression vectors or selective agents directed at miR-143 or its targets may have therapeutic value in dedifferentiated liposarcoma.

Expression Profiling of Liposarcoma Yields a Multigene Predictor of Patient Outcome and Identifies Genes That Contribute to Liposarcomagenesis

Liposarcomas are the most common type of soft tissue sarcoma but their genetics are poorly defined. To identify genes that contribute to liposarcomagenesis and serve as prognostic candidates, we undertook expression profiling of 140 primary liposarcoma samples, which were randomly split into training set (n = 95) and test set (n = 45). A multigene predictor for distant recurrence-free survival (DRFS) was developed by the supervised principal component method. Expression levels of the 588 genes in the predictor were used to calculate a risk score for each patient. In validation of the predictor in the test set, patients with low risk score had a 3-year DRFS of 83% versus 45% for high risk score patients (P = 0.001). The HR for high versus low score, adjusted for histologic subtype, was 4.42 (95% CI, 1.26-15.55; P = 0.021). The concordance probability for risk score was 0.732. In contrast, the concordance probability for histologic subtype, which had been considered the best predictor of outcome in liposarcoma, was 0.669. Genes related to adipogenesis, DNA replication, mitosis, and spindle assembly checkpoint control were all highly represented in the multigene predictor. Three genes from the predictor, TOP2A, PTK7, and CHEK1, were found to be overexpressed in liposarcoma samples of all five subtypes and in liposarcoma cell lines. RNAi-mediated knockdown of these genes in liposarcoma cell lines reduced proliferation and invasiveness and increased apoptosis. Taken together, our findings identify genes that seem to be involved in liposarcomagenesis and have promise as therapeutic targets, and support the use of this multigene predictor to improve risk stratification for individual patients with liposarcoma.

Ascaris lumbricoides Infection Causing Respiratory Distress after Coronary Artery Bypass Grafting

BACKGROUND Ascaris lumbricoides infects an estimated 1.2 billion people worldwide, but is usually asymptomatic. Herein we report a case of acute respiratory distress caused by upper airway obstruction due to an adult A. lumbricoides nematodes after cardiac surgery. METHODS Case report and review of pertinent literature. CASE REPORT A 70-year old female, until recently a resident of the rural Philippines, underwent coronary bypass grafting in New York City. Nine hours after surgery (one hour after endotracheal extubation), cough and arterial oxygen desaturation prompted airway suctioning, which retrieved an adult nematode from the posterior oroharynx. symptomes abated immediately, after which the patient receive a curative course of mebendazole. CONCLUSION Although infection with A. lumbricoides is rare in the United States, it may become manifest with severe consequences in the postoperative period.

Abstract P2-13-08: Initial experience with an ambulatory extended recovery program for patients undergoing mastectomy

Introduction: An ambulatory surgical program has been introduced at Memorial Sloan Kettering Cancer Center for patients undergoing select procedures that require a single overnight stay. The aim of this study was to review the initial experience with this program for patients undergoing mastectomy and to determine the rate and cause of unanticipated hospital admission. Methods: All patients undergoing mastectomy with or without implant based reconstruction from March 2013 to February 2014 inclusive were entered into the Ambulatory Extended Recovery (AXR) program and data were recorded in a prospectively maintained AXR database. Data on patient demographics, type of procedure performed, and whether the patient remained on the AXR program were extracted. Electronic Medical Records were reviewed for all patients who required hospital admission in order to determine the reasons for this. Results: 926 consecutive patients (905 female, 21 male) requiring mastectomy with or without implant based reconstruction were entered into the AXR program during this one-year period (mean age was 51 years, range 21-90). The procedures performed were as follows: bilateral mastectomy with reconstruction (n=433, 46.8%); bilateral mastectomy without reconstruction (n=48, 5.2%); unilateral mastectomy with reconstruction (n=255, 27.5%); and unilateral mastectomy without reconstruction (n=190,20.5%), with or without axillary procedures. Reconstructive procedures deemed suitable for the AXR program included tissue expander or permanent implant insertion only. 861 of 926 patients (93%) remained on the AXR program and were discharged following overnight stay. 62 patients (6.7%) (61 female, 1 male) did not complete the AXR program and required hospital admission (mean age, 52 years; range, 22-81). 3 additional patients (0.3%) required hospital admission on occasions that the AXR unit was at maximum capacity. Reasons for admission are shown in Table 1. Of the 26 patients with postoperative hematoma, 17 were brought back to the Operating Room for definitive management and 9 patients were treated conservatively. Following admission, most patients (52 of 62, 83.9%) were fit for discharge after 1 day. Of the remaining 10 patients, 9 were discharged after 2 days and 1 after 5 days. Conclusion: Unilateral and bilateral mastectomy, with or without implant based reconstruction, is safely performed in the setting of an AXR program. Only a small minority of patients will subsequently require hospital admission, most commonly for management of postoperative hematoma or inadequate pain control. Citation Format: Aidan T Manning, Danielle Cassella, Stacy Ugras, Beverly Tseng-Reyes, Lisa Sclafani. Initial experience with an ambulatory extended recovery program for patients undergoing mastectomy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-08.

Endovascular approach to acute hemorrhage in locally advanced breast cancer.

We report a case of a woman with recurrent axillary fungating breast cancer who developed catastrophic hemorrhage from tumor erosion of her axillary artery. This was treated successfully with endovascular placement of a covered arterial stent. We discuss the suitability of endovascular therapy for patients with advanced malignancy given its lower morbidity in this population with decreased life expectancy.