Tomaszek, Sandra

Abstract ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine cell development, but its value as a biomarker of neuroendocrine differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1expression in lung cancer samples of varied histologic subtype, clinical outcome, and smoking status and compared to expression of traditional neuroendocrine markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers. ASCL1 protein expression by immunohistochemistry (IHC) correlated best with synaptophysin compared to chromogranin and CD56/NCAM. Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1 positive tumors (ASCL1+) compared to ASCL1- tumors (q-value < 10 - 9). High levels of RET expression in ASCL1+ but not in ASCL1- tumors was associated with significantly shorter overall survival in stage 1 (p = 0.007) and in all AD (p = 0.037). RET protein expression by IHC had an association with overall survival in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene. Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression define a clinically relevant subgroup of approximately 10% of AD characterized by neuroendocrine differentiation. Citation Format: Farhad Kosari, Cristiane M. Ida, Marie Christine Aubry, Lin Yang, Irina V. Kovtun, Janet L. Schaefer Klein, Sandra C. Tomaszek, Stephen J. Murphy, Ping Yang, Dennis Wigle, George Vasmatzis. ASCL1 and RET expression define a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5251. doi:10.1158/1538-7445.AM2014-5251

Introduction. We investigated the expression of microRNAs and mRNAs in pleural tissues from patients with either malignant pleural mesothelioma or benign asbestos-related pleural effusion.Methods. Fresh frozen tissues from a total of 18 malignant pleural mesothelioma and 6 benign asbestos-related pleural effusion patients were studied. Expression profiling of mRNA and microRNA was performed using standard protocols.Results. We discovered significant upregulation of multiple microRNAs in malignant pleural mesothelioma compared to benign asbestos-related pleural effusion. Hsa-miR-484, hsa-miR-320, hsa-let-7a, and hsa-miR-125a-5p were able to discriminate malignant from benign disease. Dynamically regulated mRNAs were also identified. MET was the most highly overexpressed gene in malignant pleural mesothelioma compared to benign asbestos-related pleural effusion. Integrated analyses examining microRNA-mRNA interactions suggested multiple altered targets within the Notch signaling pathway.Conclusions. Specific microRNAs and mRNAs may have diagnostic utility in differentiating patients with malignant pleural mesothelioma from benign asbestos-related pleural effusion. These studies may be particularly helpful in patients who reside in a region with a high incidence of mesothelioma.

Objective Robotic-assisted surgery is not widely accepted for general thoracic surgical procedures, and the technical advantages, cost effectiveness, and patient benefit are in question. Few reports have been published to date regarding clinical experience with this technology. We describe our first consecutive case experience with robotic-assisted lung resection. Methods A total of 23 robotic-assisted lung resections were performed from December 1, 2008, to September 30, 2010. Patients were selected on the basis of being candidates for a minimally invasive approach to their lung resection, including criteria such as known or suspected early-stage nonsmall-cell lung cancer, no prior thoracotomy, no neoadjuvant therapy, and a body mass index (BMI) less than 40 kg/cm 2 . Data on patient characteristics and perioperative results were collected retrospectively. Results Overall 90-day mortality was 0%. The total postoperative complication rate was 39%. Conversion of the robotic-assisted procedure to a video-assisted procedure was necessary in four patients (17%), and to a thoracotomy in one patient (4%). We assessed operative time, chest tube duration, and length of hospital stay. Comparison to published outcomes from the Society of Thoracic Surgeons database demonstrated comparable outcomes to standard approaches. Conclusions Robotic-assisted lung resection is safe and feasible, with comparable short-term outcomes to published results from video-assisted or open approaches.