The major driver mutations of lung cancer, EGFR mutations and EML4‐ALK fusion, are mainly detected in terminal respiratory unit (TRU)‐type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non‐TRU‐type lung cancer, we carried out whole‐exome sequencing on 43 non‐TRU‐type lung adenocarcinomas based on morphology (17 acinar, nine solid, and two enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX2‐1/TTF‐1 (7/43; 16.3%) as the top three significantly mutated genes, while the EGFR mutation was rare (1/43, 2.3%) in this cohort. Eight NKX2‐1/TTF‐1 mutations (five frameshift, two nonsense, and one missense) were identified, with one case harboring two distinct NKX2‐1/TTF‐1 mutations (one missense and one frameshift). Functional assays with the NK2 homeobox 1 (NKX2‐1)/thyroid transcription factor 1 (TTF‐1) mutants revealed that none of them retain the activity as a transcriptional factor. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2‐1/TTF‐1 mutations (five cases), as well as one enteric and one acinar adenocarcinoma. Immunohistochemistry showed that the cohort was largely divided into TTF‐1‐postive/hepatocyte nuclear factor 4‐α (HNF4‐α)‐negative and TTF‐1‐negative/HNF4‐α‐positive groups. NKX2‐1/TTF‐1 mutations were exclusively found in the latter, in which the gastrointestinal markers, mucin 5AC and cytokeratin 20, were frequently expressed. Bisulfite sequencing revealed that the NKX2‐1/TTF‐1 gene body was highly methylated in NKX2‐1/TTF‐1‐negative cases, including those without the NKX2‐1/TTF‐1 mutations. The genetic or epigenetic inactivation of NKX2‐1/TTF‐1 may play an essential role in the development and aberrant differentiation of non‐TRU‐type lung adenocarcinomas.

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell‐cell and cell‐matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O‐glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.

Bronchoscopic occlusion with polyglycolic acid mesh with or without fibrin glue is easy and feasible as the first step in postoperative management of bronchopleural fistula.

Decreased cell-substratum adhesion is crucially involved in metastasis. Previous studies demonstrated that lung cancer with floating cell clusters in histology is more likely to develop metastasis. In the present study, we investigated whether cancer cells in long-term, three-dimensional low attachment cultures acquire high metastatic potential; these cells were then used to examine the mechanisms underlying metastasis. Two KRAS-mutated adenocarcinoma cell lines (A549 and H441) were cultured and selected on ultra-low attachment culture dishes, and the resulting cells were defined as FL (for floating) sublines. Cancer cells were inoculated into NOD/SCID mice via an intracardiac injection, and metastasis was evaluated using luciferase-based imaging and histopathology. In vitro cell growth (in attachment or suspension cultures), migration, and invasion were assayed. A whole genomic analysis was performed to identify key molecular alterations in FL sublines. Upon detachment on low-binding dishes, parental cells initially formed rounded spheroids with limited growth activity. However, over time in cultures, cells gradually formed smaller spheroids that grew slowly, and, after 3–4 months, we obtained FL sublines that regained prominent growth potential in suspension cultures. On ordinary dishes, FL cells reattached and exhibited a more spindle-shaped morphology than parental cells. No marked differences were observed in cell growth with attachment, migration, or invasion between FL sublines and parental cell lines; however, FL cells exhibited markedly increased growth potential under suspended conditions in vitro and stronger metastatic abilities in vivo. A genomic analysis identified epithelial-mesenchymal transition (EMT) and c-Myc amplification in A549-FL and H441-FL cells, respectively, as candidate mechanisms for metastasis. The growth potential of FL cells was markedly inhibited by lentiviral ZEB1 knockdown in A549-FL cells and by the inhibition of c-Myc through lentiviral knockdown or the pharmacological inhibitor JQ1 in H441-FL cells. Long-term three-dimensional low attachment cultures may become a useful method for investigating the mechanisms underlying metastasis mediated by decreased cell-substratum adhesion.

Anatomical variations in the pulmonary vessels present a potential risk for intraoperative bleeding and damage to the pulmonary circulation during pulmonary resection. Here, we present a patient who underwent left upper lobectomy for lung cancer. The patient had a dangerous mediastinal basal pulmonary artery variation that could be mistaken for the mediastinal lingular pulmonary artery and be divided during left upper lobectomy.

Molecular targeted therapies against EGFR and ALK have improved the quality of life of lung adenocarcinoma patients. However, targetable driver mutations are mainly found in thyroid transcription factor‐1 (TTF‐1)/NK2 homeobox 1 (NKX2‐1)‐positive terminal respiratory unit (TRU) types and rarely in non‐TRU types. To elucidate the molecular characteristics of the major subtypes of non‐TRU‐type adenocarcinomas, we analyzed 19 lung adenocarcinoma cell lines (11 TRU types and 8 non‐TRU types). A characteristic of non‐TRU‐type cell lines was the strong expression of TFF‐1 (trefoil factor‐1), a gastric mucosal protective factor. An immunohistochemical analysis of 238 primary lung adenocarcinomas resected at Jichi Medical University Hospital revealed that TFF‐1 was positive in 31 cases (13%). Expression of TFF‐1 was frequently detected in invasive mucinous (14/15, 93%), enteric (2/2, 100%), and colloid (1/1, 100%) adenocarcinomas, less frequent in acinar (5/24, 21%), papillary (7/120, 6%), and solid (2/43, 5%) adenocarcinomas, and negative in micropapillary (0/1, 0%), lepidic (0/23, 0%), and microinvasive adenocarcinomas or adenocarcinoma in situ (0/9, 0%). Expression of TFF‐1 correlated with the expression of HNF4‐α and MUC5AC (P < .0001, P < .0001, respectively) and inversely correlated with that of TTF‐1/NKX2‐1 (P < .0001). These results indicate that TFF‐1 is characteristically expressed in non‐TRU‐type adenocarcinomas with gastrointestinal features. The TFF‐1‐positive cases harbored KRAS mutations at a high frequency, but no EGFR or ALK mutations. Expression of TFF‐1 correlated with tumor spread through air spaces, and a poor prognosis in advanced stages. Moreover, the knockdown of TFF‐1 inhibited cell proliferation and soft‐agar colony formation and induced apoptosis in a TFF‐1‐high and KRAS‐mutated lung adenocarcinoma cell line. These results indicate that TFF‐1 is not only a biomarker, but also a potential molecular target for non‐TRU‐type lung adenocarcinomas.

Post‐operative peripheral bronchopleural fistulas (BPF) are sometimes caused by post‐operative pneumonia and empyema. Conservative treatment options such as administration of antibiotics and chest tube drainage can have limited outcomes in certain cases. Bronchial occlusion is an effective treatment option if the target bronchi for BPF are identified. This case study describes a successful bronchial occlusion for peripheral BPF with endobronchial Watanabe spigots (EWSs) and a digital drainage system. This case involved a 70‐year‐old man who developed a post‐operative peripheral BPF after a left upper lobectomy. Bronchial occlusion with EWS was performed because the target bronchi responsible for BPF were clearly detected by a chest computerized tomography scan. The effectiveness of the occlusion was confirmed with the use of a digital drainage system immediately after the procedure was completed. The chest tube was removed one week following the bronchial occlusion procedure.

ObjectivesTo improve surgical outcomes, clinicians must provide optimal perioperative care for comorbidities identified as significant factors in risk models for patients undergoing lung cancer surgery.MethodsWe reviewed trends in perioperative care for idiopathic pulmonary fibrosis, cardiovascular diseases, and end-stage renal diseases in patients undergoing lung cancer surgery, as large clinical databases indicate that these comorbidities are significant risk factors for lung cancer surgery. Articles identified by keyword searches were included in the analysis.ResultsSignificant predictive factors for acute exacerbation of idiopathic pulmonary fibrosis were identified. However, no effective perioperative care was identified for prevention of acute exacerbation of interstitial pneumonia. The timing of coronary revascularization and antithrombotic management for cardiovascular diseases are subjects of ongoing research, and acid–base balance is essential in the management of hemodialysis patients with end-stage renal diseases.ConclusionsTo improve surgical outcomes for lung cancer patients, future studies should continue to study optimal perioperative management of comorbidities.