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Purpose: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI–resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs.Experimental Design: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed.Results: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells.Conclusions: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs. Clin Cancer Res; 18(6); 1663–71. ©2012 AACR.

This study seeks to clarify the current situation and associated factors regarding Work Engagement (WE) among midwives working in advanced care facilities, which bear the brunt of care for high-risk pregnancies, as well as the contribution of WE to quality of care. A self-administered questionnaire survey was conducted in 2016 with the participation of 503 midwives working in 36 general perinatal maternal and child medical centers and with 125 nurses working at a university hospital selected for analysis as a comparison group. The survey used the Utrecht Work Engagement Scale and the Brief Job Stress Questionnaire, subjecting all results to multiple regression analysis to adjust the sample size. Results revealed that WE among midwives was not found to be significantly different from that among nurses. WE among midwives was found to be positively associated with the “presence of a role model” and “doctor support”. In addition, WE as well as “career opportunities” and the “presence of a role model” were associated with quality of care (adjusted R2 =0.137, P < 0.05). From the study, WE among midwives working at advanced perinatal care facilities was not found to be different from that among nurses working at university hospitals. Among factors contributing to higher WE, the presence of a role model and relationships of trust with physicians were found to be those that represented the occupational characteristics of midwifery. Key words: Midwife, work engagement, job stress, role model, quality of care.

Introduction: The three major clinically relevant mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant lung cancer are a second mutation in the EGFR gene (T790M), Met amplification, and increased expression of hepatocyte growth factor (HGF). Heat shock protein90 (Hsp90) is a 90 kDa molecular chaperone for proteins that include EGFR, Met, and echinoderm microtubule-associated proetin-like-4-the anaplastic lymphoma kinase. Here, we determined whether inhibition of Hsp90 could overcome HGF-triggered EGFRTKI resistance in EGFR mutant lung cancer cells. Methods: The effects of the Hsp90 inhibitor 17-demethoxygeldanamycin (17-DMAG) on the growth of lung cancer cells resistant to the EGFR-TKI were examined in the presence and absence of HGF, and in cells transfected with the HGF gene in vitro and in vivo. Results: EGFR-TKI erlotinib did not inhibit the growth of HGFgene transfected Ma-1 (Ma-1/HGF) cells and H1975 cells, containing the EGFR L858R and T790M mutations, respectively. Erlotinib also did not inhibit the growth of PC-9 and Ma-1 cells, with deletions in EGFR exon19, in the presence of HGF. However, 17-DMAG induced apoptosis and markedly inhibited the growth of these cell lines, even in the presence of HGF. This inhibition by 17-DMAG was associated with decreased expression of EGFR and Met in tumor cells. An in vivo model of HGF-triggered erlotinib-resistance, which used Ma-1/HGF cells, showed that 17-DMAG markedly suppressed tumor growth by decreasing angiogenesis and increasing apoptosis. Conclusions: Hsp90 inhibitors may overcome HGF-triggered resistance to EGFR-TKIs and may result in more successful treatment of patients with EGFR-mutant lung cancers.

Purpose: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI–resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. Experimental Design: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed. Results: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. Conclusions: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs. Clin Cancer Res; 18(6); 1663–71. ©2012 AACR.

Recently, actinomycosis has become a relatively rare bacterial infection, which is difficult to diagnose when clinical symptoms are not typical. We report a rare case of actinomycosis arising in the maxilla that showed atypical symptoms and was suspected to be a benign tumor or osteomyelitis.The patient was a 53-year-old man referred for examination of a lesion in the left side of the maxilla. Intraoral examination showed a diffuse swelling and a purulent fistula in the left side of the maxillary premolar region. Computed tomography revealed an irregular radiolucent mass with small nodular components similar in density to bone. An odontogenic tumor or osteomyelitis was suspected. The clinical diagnosis was a benign tumor, and the lesion was enucleated by an intraoral approach with the patient under general anesthesia. The histopathological diagnosis was actinomycosis.

The three major, clinically relevant mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant lung cancer are a second mutation in the EGFR gene (T790M), Met amplification, and increased expression of hepatocyte growth factor (HGF). Heat shock protein90 (Hsp90) is a 90kDa molecular chaperone for proteins that include EGFR, Met and EML4-ALK. Hsp90 inhibitors have been reported to reverse resistance to EGFR-TKIs caused by EGFR T790M mutation and Met amplification. Here, we determined whether inhibition of Hsp90 could overcome HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer cells. EGFR-TKI erlotinib inhibited the growth of PC-9, HCC827, and Ma-1 cells, with deletions in exon19 of EGFR, but not HGF-gene transfected Ma-1 (Ma-1/HGF) cells and H1975 cells, which contain the EGFR L858R and T790M mutations, respectively. Erlotinib also did not inhibit the growth of PC-9 and Ma-1 cells in the presence of HGF. However, an Hsp90 inhibitor, 17-DMAG, induced apoptosis and markedly inhibited the growth of these cell lines, even in the presence of HGF. This inhibition by 17-DMAG was associated with decreased expression of EGFR and Met, thereby decreasing Akt phosphorylation in tumor cells. In an in vivo model of HGF-triggered erlotinib-resistance, using Ma-1/HGF cells, 17-DMAG markedly suppressed tumor growth by decreasing angiogenesis and increasing apoptosis. These results indicate that Hsp90 inhibitors may overcome HGF-triggered resistance to EGFR-TKIs and that the use of Hsp90 inhibitors may result in more successful treatment of EGFR mutant lung cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1907. doi:1538-7445.AM2012-1907