Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes

PURPOSE: Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. EXPERIMENTAL DESIGN: A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS). RESULTS: Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R-NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P \u3c 0.0001). CONCLUSIONS: This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset

Structured Communication: Teaching Delivery of Difficult News with Simulated Resuscitations in an Emergency Medicine Clerkship

Introduction: The objective is to describe the implementation and outcomes of a structured communication module used to supplement case-based simulated resuscitation training in an emergency medicine (EM) clerkship. Methods: We supplemented two case-based simulated resuscitation scenarios (cardiac arrest and blunt trauma) with role-play in order to teach medical students how to deliver news of death and poor prognosis to family of the critically ill or injured simulated patient. Quantitative outcomes were assessed with pre and post-clerkship surveys. Secondarily, students completed a written self-reflection (things that went well and why; things that did not go well and why) to further explore learner experiences with communication around resuscitation. Qualitative analysis identified themes from written self-reflections. Results: A total of 120 medical students completed the pre and post-clerkship surveys. Majority of respondents reported that they had witnessed or role-played the delivery of difficult news, but only few had real-life experience of delivering news of death (20/120, 17%) and poor prognosis (34/120, 29%). This communication module led to statistically significant increased scores for comfort, confidence, and knowledge with communicating difficult news of death and poor prognosis. Pre-post scores increased for those agreeing with statements (somewhat/very much) for delivery of news of poor prognosis: comfort 69% to 81%, confidence 66% to 81% and knowledge 76% to 90% as well as for statements regarding delivery of news of death: comfort 52% to 68%, confidence 57% to 76% and knowledge 76% to 90%. Respondents report that patient resuscitations (simulated and/or real) generated a variety of strong emotional responses such as anxiety, stress, grief and feelings of loss and failure. Conclusion: A structured communication module supplements simulated resuscitation training in an EM clerkship and leads to a self-reported increase in knowledge, comfort, and competence in communicating difficult news of death and poor prognosis to family. Educators may need to seek ways to address the strong emotions generated in learners with real and simulated patient resuscitations. [West J Emerg Med. 2015;16(2):344–352.

Structured Communication: Teaching Delivery of Difficult News with Simulated Resuscitations in an Emergency Medicine Clerkship

Introduction: The objective is to describe the implementation and outcomes of a structured communication module used to supplement case-based simulated resuscitation training in an emergency medicine (EM) clerkship. Methods: We supplemented two case-based simulated resuscitation scenarios (cardiac arrest and blunt trauma) with role-play in order to teach medical students how to deliver news of death and poor prognosis to family of the critically ill or injured simulated patient. Quantitative outcomes were assessed with pre and post-clerkship surveys. Secondarily, students completed a written self-reflection (things that went well and why; things that did not go well and why) to further explore learner experiences with communication around resuscitation. Qualitative analysis identified themes from written self-reflections. Results: A total of 120 medical students completed the pre and post-clerkship surveys. Majority of respondents reported that they had witnessed or role-played the delivery of difficult news, but only few had real-life experience of delivering news of death (20/120, 17%) and poor prognosis (34/120, 29%). This communication module led to statistically significant increased scores for comfort, confidence, and knowledge with communicating difficult news of death and poor prognosis. Pre-post scores increased for those agreeing with statements (somewhat/very much) for delivery of news of poor prognosis: comfort 69% to 81%, confidence 66% to 81% and knowledge 76% to 90% as well as for statements regarding delivery of news of death: comfort 52% to 68%, confidence 57% to 76% and knowledge 76% to 90%. Respondents report that patient resuscitations (simulated and/or real) generated a variety of strong emotional responses such as anxiety, stress, grief and feelings of loss and failure. Conclusion: A structured communication module supplements simulated resuscitation training in an EM clerkship and leads to a self-reported increase in knowledge, comfort, and competence in communicating difficult news of death and poor prognosis to family. Educators may need to seek ways to address the strong emotions generated in learners with real and simulated patient resuscitations. [West J Emerg Med. 2015;16(2):344–352.

Capturing Genomic Evolution of Lung Cancers through Liquid Biopsy for Circulating Tumor DNA

Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumor’s dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA) analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors

β-blockade protection of bone marrow following trauma: the role of G-CSF.

BACKGROUND: Following severe trauma, there is a profound elevation of catecholamine that is associated with a persistent anemic state. We have previously shown that β-blockade (βB) prevents erythroid growth suppression and decreases hematopoietic progenitor cell (HPC) mobilization following injury. Under normal conditions, granulocyte colony stimulating factor (G-CSF) triggers the activation of matrix metalloprotease-9 (MMP-9), leading to the egress of progenitor cells from the bone marrow (BM). When sustained, this depletion of BM cellularity may contribute to BM failure. This study seeks to determine if G-CSF plays a role in the βB protection of BM following trauma. METHODS: Male Sprague-Dawley rats were subjected to either unilateral lung contusion (LC) ± βB, hemorrhagic shock (HS) ± βB, or both LC/HS ± βB. Propranolol (βB) was given immediately following resuscitation. Animals were sacrificed at 3 and 24 h and HPC mobilization was assessed by evaluating BM cellularity and flow cytometric analysis of peripheral blood for HPCs. The concentration of G-CSF and MMP-9 was measured in plasma by ELISA. RESULTS: BM cellularity is decreased at 3 h following LC, HS, and LC/HS. HS and LC/HS resulted in significant HPC mobilization in the peripheral blood. The addition of βB restored BM cellularity and reduced HPC mobilization. Three h following HS and LC/HS, plasma G-CSF levels more than double, however LC alone showed no change in G-CSF. βB significantly decreased G-CSF in both HS and LC/HS. Similarly, MMP-9 is elevated following LC/HS, and βB prevents this elevation (390 ± 100 pg/mL versus 275 ± 80 pg/mL). CONCLUSION: βB protection of the BM following shock and injury may be due to reduced HPC mobilization and maintenance of BM cellularity. Following shock, there is an increase in plasma G-CSF and MMP-9, which is abrogated by βB and suggests a possible mechanism how βB decreases HPC mobilization thus preserving BM cellularity. In contrast, βB protection of BM following LC is not mediated by G-CSF. Therefore, the mechanism of progenitor cell mobilization from the BM is dependent on the type of injury