We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

Background/Aim: Lung squamous cell carcinoma often arises from precancerous lesions where alterations in tumor suppressor genes and subsequent chromosomal instability are often observed due to carcinogen exposure. These tumors are often immunogenic; as such, immune checkpoint inhibitors are a promising therapeutic option. We hypothesized that the DNA damage response in tumor cells induces an immune response, thereby up-regulating programmed death-ligand 1 (PD-L1) expression on tumor cells, which in turn sensitizes them to anti-PD-1 therapy. Patients and Methods: An immunohistochemical analysis was performed in 41 consecutive lung squamous cell carcinoma patients who underwent surgery at our institution between April 2013 and March 2014. Results: The analysis revealed a high PD-L1 expression in 15 patients (37%) (p=0.028). The PD-L1 expression was positively associated with the nuclear γH2AX expression (p=0.02), that was confirmed by immunofluorescent staining. Conclusion: Our findings demonstrate that nuclear γH2AX expression is positively associated with the PD-L1 expression in lung squamous cell carcinoma.

Salivary gland-type tumor (SGT) of the lung, which arises from the bronchial glands of the tracheobronchial tree, was first recognized in the 1950s. SGT represents less than 1% of all lung tumors and is generally reported to have a good prognosis. Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) are the two most common subtypes, comprising more than 90% of all SGTs. The reported 5-year survival rate of patients with SGT is 63.4%. Because this type of tumor develops in major bronchi, patients with SGT commonly present with symptoms of bronchial obstruction, including dyspnea, shortness of breath, wheezing, and coughing; thus, the tumor is usually identified at an early stage. Most patients are treated by lobectomy and pneumonectomy, but bronchoplasty or tracheoplasty is often needed to preserve respiratory function. Lymphadenectomy in the surgical resection of SGT is recommended, given that clinical benefit from lymphadenectomy has been reported in patients with MEC. For advanced tumors, appropriate therapy should be considered according to the subtype because of the varying clinicopathologic features. MEC, but not ACC, is less likely to be treated with radiation therapy because of its low response rate. Although previous researchers have learned much from studying SGT over the years, the diagnosis and treatment of SGT remains a complex and challenging problem for thoracic surgeons. In this article, we review the diagnosis, prognosis, and treatment (surgery, chemotherapy, and radiotherapy) of SGT, mainly focusing on MEC and ACC. We also summarize reports of adjuvant and definitive radiation therapy for ACC in the literature.

Background: Based on the results of JCOG0802 and CALGB studies, segmentectomy has considered to be a standard procedure for early-stage non-small cell lung cancer (NSCLC). After lobectomy, the residual cavity is filled with mediastinal and diaphragmatic deviations, and compensatory volume changes are present in the residual lungs. In this study, we examined the efficacy of segmentectomy, a surgical procedure, by focusing on its impact on postoperative lung volume and function. Methods: We enrolled 77 patients who underwent segmentectomy as their initial surgical procedure, excluding those with additional lung resections and those who lacked postoperative computed tomography imaging. The predicted residual volume (mL) was defined as the total lung volume before surgery minus the volume of the resected area. Using the predicted residual volume (mL) and postoperative total lung volume (mL), we calculated the rate of postoperative lung volume increase [(postoperative total lung volume/predicted residual volume) × 100] (%). We also classified 52 cases with a rate of postoperative lung volume increase of ≥100% into a compensatory group, while those with a rate of <100% were classified into a non-compensatory group. Results: The average postoperative lung volume increase was 104.6% among 77 cases. Age ≥65 years, pack year index ≥27.5, ≥3 resected segments, and use of electrocautery for intersegmental plane division were significantly associated with compensatory group classification. In 20 compensatory cases with preoperative and postoperative pulmonary function tests, postoperative vital capacity and forced expiratory volume in one second values exceeded the preoperative predictions. This study further examined the areas responsible for postoperative compensatory lung volume increase. In the compensatory group, significant expansion was observed in the ipsilateral lobes, excluding the resected segment and contralateral lung, while no significant changes were noted in the volume of the lobe, including the resected segment. Conversely, the non-compensatory group showed a significant volume decrease in the resected lobe, but no significant increase in other areas. Conclusions: This study emphasizes the importance of preserving lung segments in segmentectomy. The study demonstrates extensive compensatory volume changes in the ipsilateral lung and contralateral lung. There was no significant volume decrease in any residual segment. This underlines the potential of segmentectomy to maintain lung function and expand treatment options post-surgery. In addition, the compensated group included patients with a lower pack-year index and younger patients. These results suggest that postoperative compensatory lung expansion includes not only hyperinflation of the remaining lung, but also an increase in the functional lung parenchyma.