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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.

Background: Surgical margin recurrence following segmentectomy is a critical issue because it may have been avoided by lobectomy., Methods: Between January 2000 and December 2018, we retrospectively investigated 199 patients who underwent segmentectomy for c-StageⅠ non-small cell lung cancer at our hospital., Results: Recurrence occurred in 20 cases, of which 3 cases had surgical margin recurrence. In our previous study, the recurrence risk factor after segmentectomy was radiologic solid tumor size( cut-off value 1.5 cm). Of the 130 patients in the low-risk group with radiologic solid tumor size of less than 1.5 cm, five had any recurrence, three of which had surgical margin recurrence. In the high-risk group with radiologic solid tumor size of 1.5 cm or more, no surgical margin recurrence was observed. Three cases of surgical margin recurrence were accompanied by lepidic components, and the tumors were difficult to identify intraoperatively and were located close to adjacent areas., Conclusion: Surgical margin recurrence may be avoided by carefully considering the segments to be resected and improving the method for identifying the intersegmental plane.

Objectives: The optimal surgical approach for metachronous second primary lung cancer (MSPLC), especially ipsilateral MSPLC, remains unclear. This study aimed to review postoperative complications and examine surgical outcomes based on the extent of resection after surgery for ipsilateral MSPLC., Methods: Clinical data from 61 consecutive patients who underwent pulmonary resection for ipsilateral MSPLC according to the Martini-Melamed criteria between January 2005 and December 2017 in 3 institutes were retrospectively reviewed., Results: Postoperative complications were identified in 12 patients (19.7%). Regarding the combination of initial and second surgery, intraoperative bleeding was significantly greater in patients with anatomic-anatomic resection than in others (P < 0.001). Operation time was significantly longer in patients with anatomic-anatomic resection than in others (P < 0.001). However, postoperative complications showed no significant differences based on the combination of surgeries. Five-year overall survival rates in patients with anatomic resection and wedge resection after second surgery were 75.8% and 75.8%, respectively (P = 0.738), and 5-year recurrence-free survival rates were 54.2% and 67.6%, respectively (P = 0.368). Cox multivariate analysis identified ever-smoker status (P = 0.029), poor performance status (P = 0.011) and tumour size >20 mm (P = 0.001) as independent predictors of poor overall survival, while ever-smoker status (P = 0.040) and tumour size >20 mm (P = 0.007) were considered independent predictors of poor recurrence-free survival., Conclusions: Regarding postoperative and long-term outcomes for patients with ipsilateral MSPLC, surgical intervention is safe and offers good long-term survival. Wedge resection is an acceptable provided tumours ≤2 cm and ground-glass opacity-predominant as a second surgery for early-stage ipsilateral MSPLC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: The best surgical approach for second primary lung cancer remains a subject of debate. The purpose of this study was to review the postoperative complications after second surgery for second primary lung cancer and to investigate the outcomes based on these complications., Methods: The clinical data of 105 consecutive patients who underwent pulmonary resection for multiple primary lung cancers between January, 1996 and December, 2017, were reviewed according to the Martini-Melamed criteria., Results: After the second surgery, low body mass index (BMI) (< 18.5 kg/m 2 ) (P = 0.004) and high Charlson comorbidity index (CCI) (P = 0.002) were independent predictors of postoperative complications. Survival analysis revealed the 5-year overall survival rates of 74.5% and 61.4% for patients without postoperative complications and those with postoperative complications (P = 0.044), respectively, but the 5-year cancer-specific survival rates of 82.5% and 80.0% (P = 0.926), respectively. During this period, there were significantly more respiratory-related deaths of patients with complications than of those without complications (P = 0.011)., Conclusion: Surgical intervention is feasible and potentially effective for second primary lung cancer but may not achieve positive perioperative and long-term outcomes for patients with a low BMI or a high CCI. Treatment options should be considered carefully for these patients.

Objective: Although lobectomy is the standard surgical procedure for small-sized non-small cell lung cancer (NSCLC), segmentectomy has been performed for various reasons. The aim of this study was to investigate the characteristics of and risk factors for recurrence in early-stage NSCLC patients undergoing segmentectomy., Methods: We retrospectively reviewed 179 patients with clinical stage I NSCLC who underwent segmentectomy. Preoperative factors were analyzed using the log-rank test for univariate analyses. Multivariate analyses were performed using a Cox proportional hazards regression model to identify independent risk factors for recurrence. For the significant factors, optimal cutoff points were determined by receiver operating characteristic (ROC) analysis., Results: During the follow-up period of 51 months, 18 patients developed recurrence; 5 had locoregional (including 2 with margin recurrences only), 9 had distant, and 4 had both locoregional and distant recurrence. Multivariate and ROC analysis identified radiologic solid tumor size with a cutoff point of 1.5 cm as an independent risk factor for recurrence. Three patients in the solid size < 1.5 cm group (n = 119) developed recurrence, 2 of whom had surgical margin recurrence, compared to 15 patients in the solid size ≥ 1.5 cm group (n = 60)., Conclusions: The indication for segmentectomy should be decided upon with caution, and the segments to be resected should be carefully considered to secure an appropriate surgical margin in this low-risk subgroup of patients because they may have a relatively higher risk of surgical margin recurrence, despite being at decreased risk.

Associated with an increase of small-sized lung cancer or metachronous second primary lung cancer, we have more opportunities to perform sublobar resection. Difficulties of identifying tumor location and appropriate surgical margin for small-sized ground-glass opacity (GGO) dominant lesions in thoracoscopic surgery is the big issue of sublobar resection. Virtual-assisted lung mapping (VAL-MAP) that makes markings on the lung surface through some peripheral bronchi by bronchoscopically projects intrapulmonary anatomy on the lung surface and literally draw a map. We report a case of thoracoscopic left upper division segmentectomy for multiple ground-glass nodules (GGNs) using preoperative VAL-MAP. A 65-year-old women who had undergone right upper lobectomy for primary lung cancer, and had multiple GGNs in the bilateral lungs was followed up as an outpatient. Eleven years after initial pulmonary resection, 2 lesions in the left upper division became bigger, and we decided to perform surgery for 4 GGNs in the left upper division including these 2 lesions. We preoperatively made bronchoscopic dye markings through B1+2c, B3a and B4a for in the left upper lobe. The 3 markings were intraoperatively identified. We decided the resection line based on the markings and performed thoracoscopic left upper division segmentectomy. The pathological diagnosis was minimally invasive adenocarcinoma, adenocarcinoma in situ and pneumonitis. Surgical margins were negative. VAL-MAP will assume an important role as an intraoperative navigation system for sublobar resection.

Background: The presence of emphysema on computed tomography (CT) is associated with an increased frequency of lung cancer, but the postoperative outcomes of patients with pulmonary emphysema are not well known. The objective of this study was to investigate the association between the extent of emphysema and long-term outcomes, as well as mortality and postoperative complications, in early-stage lung cancer patients after pulmonary resection., Methods: The clinical records of 566 consecutive lung cancer patients who underwent pulmonary resection in our department were retrospectively reviewed. Among these, the data sets of 364 pathological stage I patients were available. The associations between the extent of lung emphysema and long-term outcomes and postoperative complications were investigated. Emphysema was assessed on the basis of semiquantitative CT. Surgery-related complications of Grade ≥ II according to the Clavien-Dindo classification were included in this study., Results: Emphysema was present in 63 patients. The overall survival and relapse-free survival of the non-emphysema and emphysema groups at 5 years were 89.0 and 61.3% (P < 0.001), respectively, and 81.0 and 51.7%, respectively (P < 0.001). On multivariate analysis, significant prognostic factors were emphysema, higher smoking index, and higher histologic grade (p < 0.05). Significant risk factors for poor recurrence-free survival were emphysema, higher smoking index, higher histologic grade, and presence of pleural invasion (P < 0.05). Regarding Grade ≥ II postoperative complications, pneumonia and supraventricular tachycardia were more frequent in the emphysema group than in the non-emphysema group (P = 0.003 and P = 0.021, respectively)., Conclusion: The presence of emphysema affects the long-term outcomes and the development of postoperative complications in early-stage lung cancer patients.

Objectives: To aim of this study was to clarify the safety of simultaneous thoracic aortic endografting and combined resection of the aortic wall and thoracic malignancy in a one-stage procedure over the early and mid-term periods., Methods: From March 2013 to December 2017, 6 patients underwent aortic endografting followed by one-stage en bloc resection of the tumor and aortic wall. Thoracic surgeons and cardiovascular surgeons discussed predicted tumor invasion range and resection site, stent placement position, stent length and size, and the surgical procedure, taking into account the safe margin., Results: The proximal site of aortic endografting was the: aortic arch in 2 cases (subclavian artery (SCA) occlusion in one, and SCA fenestration in one); distal arch just beneath the SCA in 2; descending aorta in 2. Pulmonary resection involved lobectomy in 2 patients, pneumonectomy in 2, and completion pneumonectomy in 1. Aortic resection was limited to the adventitia in 2 cases, extended to the media in 3, and extended to the intima in 1. An endograft-related complication, external iliac artery intimal damage requiring vessel repair, was observed in one case. No complications associated with aortic resection were observed. Two postoperative complications of atrial fibrillation and chylothorax developed. There were no surgery-related deaths. During follow-up, no late endograft-related complications such as migration or endoleaks occurred., Conclusions: Early and mid-term outcomes of stent graft-related complications are acceptable. Simultaneous thoracic aortic endografting and combined resection of the aortic wall and thoracic malignancies are feasible in one stage on the same day.

We herein describe a case of pulmonary tumor thrombotic microangiopathy (PTTM) with rapidly progressing colon cancer. A 61-year-old man who had been receiving treatment for type 2 diabetes mellitus for 3 years was hospitalized due to critical hypoxemia. Computed tomography, which had not shown any abnormalities 3 months previously, revealed a tumor in the ascending colon, multiple nodules in the liver, and the absence of any lung abnormalities. On day 3 of hospitalization, a sudden onset of severe dyspnea and tachycardia occurred, followed by death. Autopsy revealed microscopic metastatic tumor emboli in multiple pulmonary vessels with fibrin thrombus and intimal proliferation, which led to a diagnosis of PTTM.

Background: Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer, but few studies have investigated the long-term outcomes of repeated surgery in such patients. The purpose of this study was to evaluate the surgical outcomes of repeated lung cancer surgery in patients with IPF., Methods: From January 2001 to December 2015, 108 lung cancer patients with IPF underwent pulmonary resection at two institutions; 13 of these patients underwent repeated surgery for lung cancer, and their data were reviewed., Results: The initial procedures of the 13 patients were lobectomy in 8, segmentectomy in 2, and wedge resection in 3. The subsequent procedures were wedge resection in 10 and segmentectomy in 3. The clinical stage of the second tumor was stage IA in 12 and stage IB in 1. Postoperatively, 3 patients (23.1%) developed acute exacerbation (AE) of IPF and died. The rate of decrease in percent vital capacity was significantly higher in patients with AE than in those without AE (p = 0.011). The 3-year overall survival rate was 34.6%. The causes of death were cancer-related in 7, AE of IPF in 3, and metachronous lung cancer in 1., Conclusions: Despite limited resection, a high incidence of AE was identified. The early and long-term outcomes of repeated surgery in lung cancer patients with IPF were poor because of the high risk of AE of IPF and lung cancer recurrence. Long-term intensive surveillance will be required to determine whether surgical intervention is justified in patients with multiple primary lung cancers and IPF.