Introduction: BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA doublestrand break repair, is frequently mutated in mesothelioma. Because poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) would be beneficial.Methods: A total of 10 patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization, and sensitivity to the PARPIs, olaparib, and talazoparib, alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin with 7-amido-4methylcoumarin assay. BAP1 knockout mesothelioma cell lines were generated by CRISPR-Cas9. Because Schlafen 11 (SLFN11) and O 6 -methylguanine-DNA methyltransferase also drive response to TMZ and PARPIs, we tested their expression and relationship with drug response.Results: BAP1 mutations or copy-number alterations, or both were present in all 10 cell lines. Nonetheless, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half maximal-inhibitory concentrations of olaparib and talazoparib ranged from 4.8 mM to greater than 50 mM and 0.039 mM to greater than 5 mM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1 knockout resulted in the loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression.

LMB-100 is an immunotoxin targeting the cell surface protein mesothelin, which is highly expressed in many cancers including mesothelioma. Having observed that patients receiving pembrolizumab off protocol after LMB-100 treatment had increased tumor responses; we characterized these responses and developed animal models to study whether LMB-100 made tumors more responsive to antibodies blocking programmed cell death protein 1 (PD-1). The overall objective tumor response in the 10 patients who received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. Of the seven evaluable patients, four had objective tumor responses, including one complete response and three partial responses, and the overall survival for these patients was 39.0+, 27.7, 32.6+, and 13.8 months. When stratified with regard to programmed death ligand 1 (PD-L1) expression, four of five patients with tumor PD-L1 expression had objective tumor response. Patients with positive tumor PD-L1 expression also had increased progression-free survival (11.3 versus 2.1 months, P = 0.0018) compared with those lacking PD-L1 expression. There was no statistically significant difference in overall survival (27.7 versus 6.8 months, P = 0.1). LMB-100 caused a systemic inflammatory response and recruitment of CD8+ T cells in patients’ tumors. The enhanced antitumor effects with LMB-100 plus anti–PD-1 antibody were also observed in a human peripheral blood mononuclear cell–engrafted mesothelioma mouse model and a human mesothelin–expressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma.

IssueMedical educators and educational researchers continue to improve their processes for managing medical student and program evaluation data using sound ethical principles. This is becoming even more important as curricular innovations are occurring across undergraduate and graduate medical education. Dissemination of findings from this work is critical, and peer-reviewed journals often require an institutional review board (IRB) determination.ApproachIRB data repositories, originally designed for the longitudinal study of biological specimens, can be applied to medical education research. The benefits of such an approach include obtaining expedited review for multiple related studies within a single IRB application and allowing for more flexibility when conducting complex longitudinal studies involving large datasets from multiple data sources and/or institutions. In this paper, we inform educators and educational researchers on our analysis of the use of the IRB data repository approach to manage ethical considerations as part of best practices for amassing, pooling, and sharing data for educational research, evaluation, and improvement purposes.ImplicationsFostering multi-institutional studies while following sound ethical principles in the study of medical education is needed, and the IRB data repository approach has many benefits, especially for longitudinal assessment of complex multi-site data.

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patterns. The composite scoring system further improved stratification of overall survival based on 2-tier nuclear grade (19.8 vs. 13.4 vs. 8.1 months, p<0.001). Conclusion:Epithelioid MPM growth patterns predicted survival in our cohort. Composite architecture-nuclear grade scoring system further improved prognostic stratification.