PURPOSE:To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS:This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. RESULTS:A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). CONCLUSION:Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

8508 Background: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) effective in treating advanced EGFR-mutated non-small cell lung cancer (NSCLC). Adjuvant osimertinib significantly decreases disease recurrence in stage IB-IIIA EGFR-mutated NSCLC. However, the benefit of neoadjuvant osimertinib prior to surgical resection remains unknown. Methods: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (NCT03433469). Patients received osimertinib 80 mg orally daily for up to two 28-day cycles prior to surgical resection. The primary endpoint was major pathological response (mPR) rate (≤10% residual viable tumor). 27 evaluable patients provide 87% power to detect a mPR rate of 50% with α = 0.05. Secondary endpoints included pathological response (PR) rate (≤50% residual viable tumor), pathological complete response (pCR) rate, unconfirmed objective response rate (ORR), rate of lymph node downstaging, unanticipated delays to surgery, surgical complication rate, disease-free survival (DFS), overall survival (OS), safety, and tumor mutational profile. Results: A total of 27 patients with early-stage (8 stage IA/B, 10 stage IIA/B, 9 stage IIIA) EGFR-mutated (11 exon 19 del, 16 L858R) NSCLC were treated with neoadjuvant osimertinib for a median 56 days prior to surgical resection. 24 (89%) patients underwent subsequent surgery; 3 (11%) patients were converted to definitive chemoradiotherapy. The mPR rate was 15% (4/27 patients) by intention-to-treat analysis. The PR rate was 48% (13/27). No pCR’s were observed. Partial responses by radiography were observed in 52% (14/27) of patients and stable disease in 44% (12/27) of patients. Lymph node downstaging was achieved in 44% (4/9) of patients with positive lymph nodes. Median DFS after surgical resection was 32 months (95% CI 26-not reached) with a median follow-up of 11 months. OS data are immature. Significant adverse events occurred in 3 patients with grade 2 (G2) dyspnea, grade 3 (G3) pulmonary embolism, and G3 atrial fibrillation. One patient developed G2 treatment-related pneumonitis that resolved without steroids. Perioperative complications occurred in 38% (9/24) of patients; most involved rapidly reversible postoperative G2 atrial fibrillation (6/9) unrelated to study drug. Tumors were evaluable for genetic alterations from 16 patients. 4/6 patients who did not achieve a PR had tumors that harbored loss of function mutations in RBM10 as compared to 0/10 patients who achieved a PR (p < 0.01). Conclusions: Neoadjuvant osimertinib in surgically resectable EGFR-mutated NSCLC achieved a 15% mPR, which did not meet the primary endpoint. Treatment was safe and may induce pathological responses and lymph node-downstaging of disease. Co-mutations in RBM10 may limit response. Clinical trial information: NCT03433469 .

XLSX file - 31K, PCR primers and genes. Sequences of the primers for the differential diagnosis of MPM. Selected genes for each diagnostic test.

XLSX file - 240K, List of the differentially expressed probes for the analysis MPM vs. other tumor types.

XLSX file - 196K, List of the enriched functional terms for the analysis Epithelioid MPM vs. Sarcomatoid MPM.

8508 Background: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) effective in treating advanced EGFR-mutated non-small cell lung cancer (NSCLC). Adjuvant osimertinib significantly decreases disease recurrence in stage IB-IIIA EGFR-mutated NSCLC. However, the benefit of neoadjuvant osimertinib prior to surgical resection remains unknown. Methods: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (NCT03433469). Patients received osimertinib 80 mg orally daily for up to two 28-day cycles prior to surgical resection. The primary endpoint was major pathological response (mPR) rate (≤10% residual viable tumor). 27 evaluable patients provide 87% power to detect a mPR rate of 50% with α = 0.05. Secondary endpoints included pathological response (PR) rate (≤50% residual viable tumor), pathological complete response (pCR) rate, unconfirmed objective response rate (ORR), rate of lymph node downstaging, unanticipated delays to surgery, surgical complication rate, disease-free survival (DFS), overall survival (OS), safety, and tumor mutational profile. Results: A total of 27 patients with early-stage (8 stage IA/B, 10 stage IIA/B, 9 stage IIIA) EGFR-mutated (11 exon 19 del, 16 L858R) NSCLC were treated with neoadjuvant osimertinib for a median 56 days prior to surgical resection. 24 (89%) patients underwent subsequent surgery; 3 (11%) patients were converted to definitive chemoradiotherapy. The mPR rate was 15% (4/27 patients) by intention-to-treat analysis. The PR rate was 48% (13/27). No pCR’s were observed. Partial responses by radiography were observed in 52% (14/27) of patients and stable disease in 44% (12/27) of patients. Lymph node downstaging was achieved in 44% (4/9) of patients with positive lymph nodes. Median DFS after surgical resection was 32 months (95% CI 26-not reached) with a median follow-up of 11 months. OS data are immature. Significant adverse events occurred in 3 patients with grade 2 (G2) dyspnea, grade 3 (G3) pulmonary embolism, and G3 atrial fibrillation. One patient developed G2 treatment-related pneumonitis that resolved without steroids. Perioperative complications occurred in 38% (9/24) of patients; most involved rapidly reversible postoperative G2 atrial fibrillation (6/9) unrelated to study drug. Tumors were evaluable for genetic alterations from 16 patients. 4/6 patients who did not achieve a PR had tumors that harbored loss of function mutations in RBM10 as compared to 0/10 patients who achieved a PR (p < 0.01). Conclusions: Neoadjuvant osimertinib in surgically resectable EGFR-mutated NSCLC achieved a 15% mPR, which did not meet the primary endpoint. Treatment was safe and may induce pathological responses and lymph node-downstaging of disease. Co-mutations in RBM10 may limit response. Clinical trial information: NCT03433469 .

PDF file - 53K, Identification of Diagnostic Molecular Markers and Data Analysis, Real-Time Quantitative PCR Results, Hierarchical clustering analysis.

PDF file - 188K, Heat-map of the 26-gene signature used in the sequential combination of gene expression ratio tests in the 112 thoracic samples. Probes are annotated with gene symbol on the right. Relative gene expression levels are given by the scale at the top. The red asterisk indicates the mesothelioma samples.

XLSX file - 66K, List of the differentially expressed probes for the analysis Epithelioid MPM vs. Sarcomatoid MPM.

XLSX file - 34K, List of the enriched functional terms for for the analysis MPM vs. other tumor types.

XLSX file - 191K, Results of the binary diagnostic tests using microarray data and RT-PCR data in the original set of samples.

XLSX file - 42K, Results of the binary diagnostic tests in a test set analyzed by RT-PCR.

Importance Informed consent is a critical component of patient care before invasive procedures, yet it is frequently inadequate. Electronic consent forms have the potential to facilitate patient comprehension if they provide information that is readable, accurate, and complete; it is not known if large language model (LLM)-based chatbots may improve informed consent documentation by generating accurate and complete information that is easily understood by patients.Objective To compare the readability, accuracy, and completeness of LLM-based chatbot- vs surgeon-generated information on the risks, benefits, and alternatives (RBAs) of common surgical procedures.Design, Setting, and Participants This cross-sectional study compared randomly selected surgeon-generated RBAs used in signed electronic consent forms at an academic referral center in San Francisco with LLM-based chatbot-generated (ChatGPT-3.5, OpenAI) RBAs for 6 surgical procedures (colectomy, coronary artery bypass graft, laparoscopic cholecystectomy, inguinal hernia repair, knee arthroplasty, and spinal fusion).Main Outcomes and Measures Readability was measured using previously validated scales (Flesh-Kincaid grade level, Gunning Fog index, the Simple Measure of Gobbledygook, and the Coleman-Liau index). Scores range from 0 to greater than 20 to indicate the years of education required to understand a text. Accuracy and completeness were assessed using a rubric developed with recommendations from LeapFrog, the Joint Commission, and the American College of Surgeons. Both composite and RBA subgroup scores were compared.Results The total sample consisted of 36 RBAs, with 1 RBA generated by the LLM-based chatbot and 5 RBAs generated by a surgeon for each of the 6 surgical procedures. The mean (SD) readability score for the LLM-based chatbot RBAs was 12.9 (2.0) vs 15.7 (4.0) for surgeon-generated RBAs (P = .10). The mean (SD) composite completeness and accuracy score was lower for surgeons' RBAs at 1.6 (0.5) than for LLM-based chatbot RBAs at 2.2 (0.4) (P < .001). The LLM-based chatbot scores were higher than the surgeon-generated scores for descriptions of the benefits of surgery (2.3 [0.7] vs 1.4 [0.7]; P < .001) and alternatives to surgery (2.7 [0.5] vs 1.4 [0.7]; P < .001). There was no significant difference in chatbot vs surgeon RBA scores for risks of surgery (1.7 [0.5] vs 1.7 [0.4]; P = .38).Conclusions and Relevance The findings of this cross-sectional study suggest that despite not being perfect, LLM-based chatbots have the potential to enhance informed consent documentation. If an LLM were embedded in electronic health records in a manner compliant with the Health Insurance Portability and Accountability Act, it could be used to provide personalized risk information while easing documentation burden for physicians.

INTRODUCTION:The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021. METHODS AND ANALYSIS:The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing. ETHICS AND DISSEMINATION:ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER:NCT04488081.

Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor (RERG) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity.

This review describes the management of mechanical ventilation in patients with acute respiratory distress syndrome, including in those with coronavirus disease 2019. Low tidal volume ventilation with a moderate to high positive end-expiratory pressure remains the foundation of an evidence-based approach. We consider strategies for setting positive end-expiratory pressure levels, the use of recruitment maneuvers, and the potential role of driving pressure. Rescue therapies including prone positioning and extracorporeal membrane oxygenation are also discussed.

Castillo-Angeles, Manuel MD, MPH; Coleman, Melissa MD; Coleman, Natasha MD; Armand, Philippe MD, PhD; Bendix, Peter G. MD, MPH; Salim, Ali MD, FACS; Askari, Reza MD, FACS Author Information