Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity.

BACKGROUND: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. RESULTS: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. CONCLUSIONS: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.

An educational course including medical simulation for early goal-directed therapy and the severe sepsis resuscitation bundle: an evaluation for medical student training.

OBJECTIVE: Widespread application of early goal-directed therapy (EGDT) and the severe sepsis resuscitation bundle is limited by clinician knowledge, skills and experience. This study evaluated use of simulation-based teaching during medical training to increase future clinician knowledge in the above therapies for severe sepsis and septic shock. METHODS: A prospective cohort study was performed with medical students at all levels of training. A 5-h course including didactic lectures, skill workshops, and a simulated case scenario of septic shock were administered to the participants. A checklist including 21 tasks was completed during the patient simulation. An 18-question pre-test, post-test and 2-week post-test were given. The participants completed a survey at the end of the course. RESULTS: Sixty-three students were enrolled. There was statistical difference between the pre-test and each of the post-test scores: 57.5+/-13.0, 85.6+/-8.8, and 80.9+/-10.9%, respectively. 20.6% of participants thought the pre-test was too difficult, whereas all participants thought the post-test was either appropriate or too easy. The task performance during the simulated septic shock patient was 94.1+/-6.0%. The participants noted improvements in their confidence levels at managing severe sepsis and septic shock, and agreed that the course should be a requirement during medical school training. CONCLUSIONS: Medical simulation is an effective method of educating EGDT and the severe sepsis resuscitation bundle to medical students with limited experience in patient care. The results suggest that our course may be of further benefit at increasing clinical experience with this intensive protocol for the management of severe sepsis and septic shock.