Nobuyuki Kondo

Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase–positive (ALK ⁺ ) and ROS proto-oncogene 1–positive (ROS1 ⁺ ) non–small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR/Cas9 knockout screening was performed using an ALK ⁺ NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor suppressor genes, such as NF2 or MED12, and multiple candidate genes. Among them, this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly, MIG6 loss induced resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration, through the upregulation of MAPK and PI3K/AKT/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this verified that MIG6 loss induces resistance to ROS1-TKIs in ROS1 ⁺ cell lines. This study found a potentially novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.

A 78‐year‐old man with exposure to asbestos was admitted to our hospital for back pain. A chest computed tomography showed right pleural effusion and a significant increase in the size of masses in the right chest wall over an interval of six months. He did not undergo further examinations and expired one month later. Autopsy revealed the presence of diffuse large B‐cell lymphoma (DLBCL) and complicated by benign asbestos pleural effusion. We considered that this tumour had originated from the soft tissue in the chest wall based on the radiological and autopsy findings. The present report highlights that primary DLBCL of chest wall might be associated with chronic inflammation due to asbestos‐related pleural diseases.

21074 Background: Mutations in the epidermal growth factor receptor (EGFR) gene and k-ras gene are found in 10–30% of non-small cell lung cancer, and are useful to predict the efficacy of EGFR-tyrosine kinase inhibitors. Such mutations are also onco- developmentally important especially in lung adenocarcinoma, but the exact incidences of such mutations in adenocarcinoma/AAH and surrounding normal lung. Methods: A total of 45 consecutive patients with lung adenocarcinoma and/or AAH (18 females; mean age, 65 years) who received thoracotomy from August 2005 through December 2006. In each case, EGFR/k-ras mutations were examined in specimens cut from adenocarcinoma/AAH and normal lung; in the present study, pure bronchioalveolar carcinoma (BAC) was reviewed separately from adenocarcinoma. Results: As 12 (27%) of all 45 patients had multiple adenocarcinoma/BAC/AAH lesions, mutations were examined in 59 lesions (41 adenocarcinomas, 7 BACs, 11 AAHs) and 45 normal lung tissues. EGFR and k-ras mutations were documented in 37% (15/41) and 2% (1/41) of adenocarcinomas, and no EGFR/k-ras mutation was documented in any BAC, AAH, or normal lung tissue. Next, clinical characteristics of patients were compared between patients with solitary adenocarcionma/BAC/AAH lesion and those with multiple lesions; non-smoker were more frequently documented in multiple-lesions group (42%) than in solitary-lesion group (15%), and there was no significant difference in other characteristics such as sex and age. Conclusions: EGFR mutation was not documented in non-invasive (BAC) or pre-neoplastic (AAH) lesion in this series, which may suggest that EGFR mutation play a critical role in the development of invasive adenocarcinoma. No significant financial relationships to disclose.