YAP1 status defines two intrinsic subtypes of LCNEC with distinct molecular features and therapeutic vulnerabilities.

PURPOSE: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with an absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies which are often adapted from SCLC and non-small cell lung cancer (NSCLC) approaches. EXPERIMENTAL DESIGN: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed immunohistochemistry and single-cell (sc)RNAseq of core needle biopsies from LCNEC patients and preclinical models. RESULTS: Here, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK and AXL targeting strategies, including a novel preclinical AXL CAR-T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by expression of SCLC subtype-defining transcription factors - especially ASCL1 and NEUROD1 - and, as expected given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including Delta-like ligand 3 (DLL3) and CD56 targeting, as with novel preclinical DLL3 and CD56 CAR T-cells, and DNA damage repair (DDR) inhibition. CONCLUSION: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.

Making an Impact: Evaluation of an Enduring Online Training Empowering Clinicians to Respond to Hate Speech.

Mental health clinicians frequently experience hate speech during patient care, resulting in an ethical dilemma. This study evaluated a 1-hour webinar discussing the ethics of working with Veterans who use hate speech, motivations and intentions of hate speech, and guidance on how to respond. The webinar was offered through the virtual Community-Based Outpatient Clinic Mental Health Grand Rounds session at the Veterans Health Administration (VHA). Rural mental health clinicians were the target audience; however, all VHA clinicians could attend. Participants were VHA clinicians who completed the evaluation for the training and received one continuing education unit for this training (n = 668). They were highly satisfied with the training and would recommend it to others. They also reported the intention to talk with coworkers and trainees about responding to hate speech and requested additional training. The recorded training can be viewed for free at https://www.mirecc.va.gov/visn16/working-with-patients-who-use-hate-speech.asp.

Wellness for Warriors: Developing and Disseminating a Veteran-centric Wellness Guide.

BACKGROUND: Evidence-based self-help wellness interventions have several benefits, including low cost, brevity, and lack of need for a health care professional. Veterans, in particular, may benefit from a self-guided resource, given a culture of self-reliance, mental health help-seeking stigma, and a high need for mental health care. Despite the high need, few self-help resources are designed for veterans. OBJECTIVES: The goal of this project was to create the Veteran Wellness Guide, a self-guided resource comprising SMART goal setting and evidence-based interventions for veterans (e.g., self-kindness, gratitude, diaphragmatic breathing, mindfulness). METHODS: First, a Veteran Engagement Group reviewed the guide and provided feedback on veteran-centric content and design. After the authors revised the guide, a subset of the group approved changes. Additional veterans used it for 2 weeks and provided feedback. RESULTS: Veterans reported the guide as being highly useful, were willing to recommend it to other veterans, and identified a need for it in the veteran community. Veterans and Veterans Health Administration clinicians and leadership helped to craft a dissemination plan to reach veterans whether they receive care through the Veterans Health Administration or the community. CONCLUSIONS: Partnering with veterans in the creation of the wellness guide led to a veteran-centric product tailored to meet the unique wellness needs of veterans. The guide has been nationally disseminated and downloaded over 3000 times and can be downloaded for free from our website.