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Recently approved RET tyrosine kinase inhibitors (TKIs) have shown promising therapeutic effects against RET-rearranged non-small cell lung cancer (NSCLC) or RET-mutated thyroid cancer. However, resistance develops, limiting long-term efficacy. Although many RET-TKI resistance mechanisms, such as secondary mutations in RET or activation of bypass pathways, are known, some primary or acquired resistance mechanisms are unclear. Here, human genome-wide CRISPR/Cas9 screening was performed to identify genes related to drug-tolerant persister cells. Patient-derived cells with RET-fusion were introduced genome-wide sgRNA library and treated with RET-TKI for 9 days, resulting in the discovery of several candidate genes. Knockout of MED12 or MIG6 significantly increased residual drug-tolerant persister cells under RET-TKI treatment. MIG6 loss induced significant EGFR activation even with low concentrations of EGFR ligands and led to resistance to RET-TKIs. EGFR inhibition with afatinib or cetuximab in combination with RET TKIs was effective in addressing drug persistence. By contrast, a KIF5B-RET positive cells established from a RET-rearranged NSCLC patient, showed significant resistance to RET-TKIs and high dependence on EGFR bypass signaling. Consistently, knocking out EGFR or RET led to high sensitivity to RET or EGFR inhibitor respectively. Here, we have provided a comprehensive analysis of adaptive and acquired resistance against RET-rearranged NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.R. Katayama received research grants from Chugai, and TOPPAN. The other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The surgical treatment of malignant pleural mesothelioma (MPM) involves procedures to achieve macroscopic complete resection, depending on the patient's condition. We reviewed the evolution of surgical approaches for resectable MPM. Since surgery is no more than a single step in the set of processes in multimodality treatment (MMT), we concluded that these procedures should give precedence to lung preservation and minimize resection whenever possible. Postoperative quality of life must be prioritized when the patient can receive appropriate adjuvant therapy., (© 2023. The Author(s).)

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.

Objectives: We previously established a novel method of lung repair called the ventilation and anchoring (V/A) method. We evaluated the usefulness of the V/A method for controlling air leakage during pleurectomy/decortication (P/D)., Methods: For this study, we enrolled patients with malignant pleural mesothelioma (MPM) who planned to receive P/D. Our lung repair method involves (1) suturing lung parenchyma for an apparent injured lesion and (2) coating the lung parenchyma with fibrin glue (FG) using the V/A method. The tidal volume (TV) was measured under pressure-controlled ventilation in the ipsilateral-affected lung 10 times at the following four points: after thoracotomy, at completion of visceral pleurectomy, after suturing lung parenchyma, and 5 min after coating with FG. The primary endpoint was the mean TV (mTV) change, and the secondary endpoints were the duration of air leakage and incidence of pleurodesis., Results: Between April 2014 and April 2016, 25 patients of the 29 consecutive patients enrolled were eligible. The mTV significantly decreased after completion of visceral pleurectomy but significantly increased after repair of the lung parenchyma, especially after coating with FG. The median duration of postoperative air leakage was 4 days (range: 2-19 days). Postoperative air leakage > 7 days was observed in 11 (44%) patients. Of these 11 patients, 6 received pleurodesis; however, no further revision was needed., Conclusions: Significant increases in TV were observed after coating with FG via the V/A method during P/D. Coating with FG using the V/A method can contribute to a reduction in air leakage during P/D., (© 2022. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Background/aim: To evaluate the incidence and grade of radiation pneumonitis after volumetric modulated arc therapy (VMAT) performed for the treatment of non-small cell cancer (NSCLC)., Patients and Methods: Fifty consecutive non-surgical candidates with NSCLC underwent VMAT. Thirty-five patients had stage-III tumors and 15 had recurrent tumors. The prescribed radiation dose for the gross tumor and the elective nodal area was 69 Gy in 30 fractions and 51 Gy in 30 fractions, respectively., Results: Radiation pneumonitis developed in 38 patients (76%, 38/50), and grade ≥2 radiation pneumonitis developed in 11 patients (22%, 11/50). The percentage of lung volume that received a dose in excess of 5 Gy (V5), V10, V20, V30, and the mean lung dose (MLD) in the bilateral and ipsilateral lung were significantly associated with the development of grade ≥2 radiation pneumonitis., Conclusion: The incidence and degree of radiation pneumonitis are acceptable following treatment of NSCLC with VMAT., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: Impact of pleurectomy/decortication (P/D) on quality of life (QOL) is not widely reported. We investigated QOL and lung function after P/D., Methods: A single-centre, retrospective cohort study was performed among patients who underwent P/D for malignant mesothelioma between June 2014 and June 2018 at Hyogo College of Medicine. Data at 4 points before and 3, 6 and 12 months on QOL and lung function were evaluated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and pulmonary function tests., Results: Forty-five out of 65 patients completed SF-36. Physical function and role physical decreased from 78 to 65 and 69 to 41 and did not recover. Body pain decreased from 74 to 52. It increased to 62 at 12 months but was lower than before. General health perceptions, vitality and social function decreased from 56 to 49, 50 to 47 and 63 to 50, respectively, but returned to baseline. Role emotional decreased from 75 to 54, then once increased to 63, but decreased again to 58. Mental health tended to improve from 58 to 70. Thirty-eight patients out of 45 completed pulmonary function tests. Forced vital capacity and forced expiratory volume in 1 s decreased from 98% to 61% and 93% to 67% and did not increase. Right-sided surgery or complications was the risk factors of poor lung function but no significant risk factors in QOL., Conclusions: This study suggests that P/D had an impact on QOL. Despite the lack of recovery in lung function QOL in mental aspects tended to improve, suggesting that pulmonary function tests alone are limited in assessing QOL., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: To compare three fluorine-18-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) (EORTC criteria and PERCIST) and computed tomography (CT) (RECIST1.1) for response evaluation and prognosis prediction in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitor (ICI) monotherapy., Subjects and Methods: Forty NSCLC patients underwent 18 F-FDG PET/CT scans at baseline and after 4 to 8 cycles of nivolumab or pembrolizumab. Therapeutic response was evaluated according to EORTC criteria, PERCIST, and RECIST1.1,then concordance among those was assessed using Cohen's κ coefficient. Progression-free survival (PFS) and overall survival (OS) was examined using log-rank and Cox methods., Results: The number of complete metabolic response (CMR)/partial metabolic response (PMR)/stable metabolic disease (SMD)/progressive metabolic disease (PMD) were 8/10/4/18 for EORTC criteria and 9/9/4/18 for PERCIST. Using RECIST1.1, those of CR/PR/SD/PD were 4/10/12/14. Although there was high concordance between PERCIST and EORTC (92.5% of patients; κ=0.924), that between PERCIST and RECIST1.1 was substantial (65.0%; κ=0.560) and that between EORTC and RECIST1.1 (65.0%; κ=0.574). After a median 23.2 months (range 7.2 to 51.8 months), 32 patients had documented progression and 24 patients died from NSCLC. According to both PET and CT, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and OS than PMD or PD patients (EORTC: P<0.0001 and P<0.0001, respectively, PERCIST: P<0.0001 and P=0.0001, respectively, RECIST1.1: P<0.0001 and P<0.0001, respectively). In a univariate analysis total MTV (P=0.042) on pre-ICI treatment 18 F-FDGPET/CT scans was significantly associated with progression. Highest SUVmax (P<0.0001), total MTV (P=0.0062), total TLG (P<0.0001), highest SULpeak (P<0.0001), and total TLGL (P<0.0001) on post-ICI treatment 18 F-FDG PET/CT scans were also were significantly associated with progression. Moreover, the change rate of highest SUVmax (P<0.0001), total metabolic tumor volume (MTV) (P<0.0001), total lesion glycolysis(TLG) (P<0.0001), highest SULpeak (P<0.0001), total TLGL (P<0.0001), size (P=0.0012), EORTC (P<0.0001), PERCIST (P<0.0001), and RECIST 1.1 (P<0.0001) on two PET/CT scans were significantly associated with progression. A multivariate analysis confirmed the change rate of total MTV (P=0.034), and total TLGL (P=0.0027), EORTC (P=0.018), PERCIST (P=0.045), and RECIST1.1 (P=0.0037) as independent negative PFS predictors., Conclusion: Both 18 F-FDG PET (EORTC criteria and PERCIST) and CT (RECIST1.1) after 4 to 8ICI monotherapy cycles are accurate for evaluation of tumor response and predicting prognosis in NSCLC patients.

Background: We occasionally encounter malignant pleural mesothelioma (MPM) of no apparent tumor or pleural thickening that is radiological early MPM. This study aimed to examine the clinicopathological outcomes of radiological early MPM., Methods: Patients with MPM treated with neoadjuvant chemotherapy and planned surgery at the time of diagnosis between July 2004 and December 2019 were retrospectively examined. Pretreatment maximal pleural thickness of all patients was measured on chest computed tomography. We extracted and investigated the patients who exhibited a lack of pleural thickening or visible tumor, which was defined as radiological early MPM. Survival was analyzed by the Kaplan-Meier method., Results: Of 296treated patients, 16 (5.4%) exhibited radiological early MPM. Fourteen (87.5%) of these patients underwent pleurectomy/decortication and 2 (12.5%) underwent extrapleural pneumonectomy. Pathological stage T1 disease was diagnosed in 14 (87.5%) patients; 2 (12.5%) exhibited pulmonary parenchymal invasion (pathological stage T2). Lymphatic invasion was detected in only 1 patient. Lymph node metastases and vascular invasion were not detected. Median follow-up was 42 months. Median progression-free survival and median overall survival were 40.7 and 56.1 months, respectively. The 3-year progression-free survival and overall survival rates were 84.8% and 83.6%, respectively., Conclusions: Radiological early MPM occurs in approximately 1 of every 20 patients treated with neoadjuvant chemotherapy and surgery planned at the time of diagnosis in an experienced center. Radiological early MPM was associated with early pathological stage and long-term survival.

Background: Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM in a real-world setting., Methods: This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan-Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0., Results: Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1-14 months), and median of 8 cycles (range: 2-32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed., Conclusion: Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: Pleural biopsy through video-assisted thoracic surgery (VATS pleural biopsy) is the most reliable diagnostic procedure for malignant pleural mesothelioma (MPM). However, definitive diagnosis of MPM is occasionally difficult to establish. This study aims to investigate clinicopathological features of MPM patients who failed diagnosis by the first VATS pleural biopsy., Methods: Four hundred consecutive patients with suspected MPM who received VATS pleural biopsy between March 2004 and July 2017 were enrolled in this retrospective study. Patients, whose histological diagnoses were not definitive in the first VATS pleural biopsy, were followed up as atypical mesothelial proliferation (AMP) or non-specific pleuritis (NSP). Re-examination was performed in cases strongly suspected of having MPM., Results: Of the 400 patients, 267 (66.8%) were pathologically diagnosed with MPM, 25 with metastatic carcinoma and 6 with benign pleural disease by the first VATS pleural biopsy. Of the remaining 102 patients diagnosed with AMP or NSP, 10 patients (9.8%) were subsequently diagnosed with MPM. Analysis of the clinical course revealed that only insufficient tissue for diagnosis was obtained via VATS pleural biopsy in all cases and that it was caused by very early stage without visible tumour in 4 patients, intrathoracic inflammation in 4 and desmoplastic MPM in 2., Conclusions: In our review, 9.8% of patients diagnosed with AMP or NSP in first VATS pleural biopsy were subsequently diagnosed with MPM due to insufficient tissue for diagnosis. Definitive diagnosis via VATS pleural biopsy is sometimes challenging in following situation; very early stage, intrathoracic inflammation and desmoplastic MPM.

A 64-year-old female presented to our hospital with a chronic cough. She was diagnosed with cStage ⅢA small cell lung cancer(cT2aN2M0, limited disease). On admission for chemoradiation therapy, laboratory data incidentally revealed liver dysfunction. Further examination resulted in the patient being diagnosed with autoimmune hepatitis. Oral prednisolone therapy was started, and after the improvement of liver function tests, consecutive chemoradiation therapy with cisplatin and etoposide was administered. To the best of our knowledge, this is the first report of a patient with autoimmune hepatitis and small cell lung cancer. Autoimmune hepatitis might arise as a paraneoplastic syndrome.

Background: Most patients with malignant pleural mesothelioma experience recurrence after treatment. However no clinical studies have evaluated postrecurrence survival after pleurectomy/decortication for malignant pleural mesothelioma. This study aimed to clarify postrecurrence survival, treatment, prognostic factors, and recurrence pattern after pleurectomy/decortication., Methods: We conducted a retrospective cohort study of 90 patients who underwent neoadjuvant chemotherapy followed by pleurectomy/decortication at our hospital between September 2012 and December 2017. Survival and recurrence were calculated using the Kaplan-Meier method with the log-rank test. Clinical factors related to postrecurrence survival were assessed using multivariate analysis with the Cox proportional hazards model., Results: Of 90 patients, 57 (63.3%) developed recurrence. The 1- and 3-year recurrence-free survival rates were 69.7% and 34.0%, respectively (median recurrence-free survival time, 19.0 months). With regard to initial recurrence, 39 patients (68.4%) developed local recurrence, 6 (10.5%) developed distant recurrence, and 12 (21.1%) developed both local and distant recurrences. The 1-year postrecurrence survival rate was 59.5% (median post-recurrence survival time, 14.4 months). Forty-three patients (75.4%) underwent a postrecurrence treatment. Multivariate analysis revealed that postrecurrence treatment (hazard ratio, 0.2; 95% confidence interval, 0.07-0.55; P = .002), performance status 0 to 1 (hazard ratio, 0.24; 95% confidence interval, 0.08-0.76; P = .01), and disease-free interval more than 12 months (hazard ratio, 0.4; 95% confidence interval, 0.16-0.99; P = .04) were the independent, favorable, and significant prognostic factors of postrecurrence survival., Conclusions: Postrecurrence survival after pleurectomy/decortication is acceptable, and postrecurrence treatment, performance status, and disease-free interval are important prognostic factors of postrecurrence survival., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background/aim: We performed multimodality therapy comprising preoperative chemotherapy, extrapleural pneumonectomy (EPP), and radiation therapy for patients with malignant pleural mesothelioma (MPM). Although multimodality therapy resulted in good prognosis, further improvement is required. Therefore, herein, we analysed the prognostic factors using surgical specimens and searched for suitable molecular targets to improve the prognosis after multidisciplinary treatment., Patients and Methods: Forty-six patients with MPM underwent multimodality therapy. Paraffin-embedded surgical samples were used for immunohistochemistry to evaluate the expression of phosphorylated (p-) AKT, extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and S6 ribosomal protein (S6RP)., Results: On univariate and multivariate analyses, significant differences were observed according to the histological type, pathological stage, and p-mTOR expression rate., Conclusion: The prognosis of MPM is affected by p-mTOR expression, suggesting that molecular-targeted treatment might be used during multimodal therapy for MPM., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We compared less invasive surgery with conventional surgery for malignant pleural mesothelioma (MPM). We retrospectively reviewed consecutive patients with MPM who received surgery at Hyogo College of Medicine between July 2004 and April 2016. Patients underwent multimodal treatment comprising chemotherapy (neoadjuvant and/or adjuvant) and surgery with or without 54 Gy hemithoracic radiotherapy. Patients were grouped into 3 groups according to the surgery intended: Conventional extrapleural pneumonectomy was intended in Group 1 (until August 2009); less invasive extrapleural pneumonectomy was intended in Group 2 (after September 2009); pleurectomy/decortication was intended in Group 3 (after September 2012). We included 152 patients (median age 64 [37-71] years; 131 men, 21 women), mostly with epithelioid subtypes (91.4%). Of them, 149 (98.0%) underwent neoadjuvant chemotherapy and 117 (77.0%) underwent surgery (60 had extrapleural pneumonectomy and 57 had pleurectomy/decortication). Macroscopic complete resection was achieved in 94.9% (111/117), and the mortality rates at 30 and 90 days were 1.7% (2/117) and 3.4% (4/117), respectively. The overall median survival time and progression-free survival for all 152 patients were 34.9 and 17.4 months. The overall median survival time for Groups 1, 2, and 3 were 18.5, 41.9, and 43.4 months, respectively. The progression-free survival for Groups 1, 2, and 3 were 12.0, 24.5, and 21.8 months, respectively. Compared with conventional surgical techniques, less invasive surgery for MPM yielded lower surgical risks and comparable or improved survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A 55-year-old man with malignant pleural mesothelioma underwent multimodality treatment comprising induction chemotherapy followed by extrapleural pneumonectomy and radiation therapy. After 2.5 years, focal recurrence occurred, with computed tomography revealing a tumor in the left cardiophrenic angle. Surgery was considered a problem for the patient because of the previous extrapleural pneumonectomy and difficult tumor location. Radiofrequency ablation was therefore performed; the course was uneventful, and there was no recurrence. Radiofrequency ablation should be considered an option to treat recurrence of malignant pleural mesothelioma., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Additional chemotherapy is often not feasible in patients with recurrent malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), due to deteriorated cardiopulmonary reserve. We thus examined the feasibility and efficacy of additional chemotherapy in patients with recurrent MPM after EPP., Methods: A retrospective review was conducted of 59 consecutive patients who underwent bi-/tri-modal treatment with induction chemotherapy, EPP, and radiation therapy from July 2004 to August 2013 at Hyogo College of Medicine (Nishinomiya, Japan)., Results: Of 59 patients, 39 (male/female = 31/8, right/left = 15/24, pathological stage I/II/III/IV = 1/7/23/3, bi-/tri-modality = 27/12) relapsed at a median age of 62 (range 37-71) years. The median time to recurrence after EPP was 11.6 months. Of the 39 relapsed patients, 12 received best supportive care alone, six started but discontinued chemotherapy, and the remaining 21 (53%) completed more than three cycles of intravenous chemotherapy. The median survival time after EPP was significantly longer in 21 patients who received additional chemotherapy than in 18 patients who did not (39.2 vs. 12.2 months, P = 0.009)., Conclusions: Additional systemic chemotherapy was successfully administered in more than 50% of relapsed patients after bi-/tri-modal treatment, which included EPP, and resulted in a longer survival in comparison with best supportive care alone.

Introduction: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM., Methods: We evaluated the effects of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells by using cell viability assays, Western blot analysis, and a mouse xenograft model., Results: Trametinib and 4-MU exhibited antiproliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1 (the activator protein 1 [AP1] component), inhibited ERK phosphorylation, and decreased CD44 expression. 4-MU inhibited ERK phosphorylation but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone., Conclusions: Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a standard procedure for the pathological evaluation of the mediastinal nodal (N2) status of lung cancer; however, its feasibility in potentially operable patients with suspicion of minimal N2 disease remains unestablished., Patients and Methods: A prospective multicenter study was conducted to assess the feasibility of EBUS-TBNA in this setting. Patients with clinical stage IIIA-N2 non-small cell lung cancer (NSCLC) and mediastinal nodal enlargement on computed tomography (CT) were eligible; patients were ineligible when CT revealed bulky (> 3 cm in the long-axis diameter) N2 or multiple (≥ 3) station N2. If EBUS-TBNA revealed negative results, surgical staging procedures were mandatory., Results: Among 20 eligible patients, EBUS-TBNA provided pathological confirmation of N2 disease (true-positive) in 12 patients. Among 8 patients with negative results with EBUS-TBNA, 4 patients were pathologically diagnosed as having N2 disease with surgical staging procedures (false-negative), and 4 were finally diagnosed as having non-N2 disease with nodal dissection by thoracotomy (true-negative). As a result, the sensitivity of EBUS-TBNA for N2 evaluation (primary endpoint) was 75.0% (95% confidence interval 47.6-92.7%). No grade 3-5 adverse event were documented., Conclusion: EBUS-TBNA is potentially safe and useful in the pathological evaluation of N2 status even in potentially operable NSCLC patients with suspicion of minimal N2 disease on preoperative CT., (© 2016 S. Karger GmbH, Freiburg.)

A patient was found to have a new pleural lesion 14 years after undergoing complete resection of primary lung cancer. Histologic and genetic analysis of the previously resected specimen and the samples obtained of a newly performed biopsy confirmed that the tumors were identical, and the recurrence of lung cancer was determined. This case is instructive because of the rather long interval between the resection of the initial tumor and the recurrence and because of the presence of validated proof of recurrence by both clinical features and genetic analysis., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Circulating tumour cells (CTCs) are tumour cells shed from a primary tumour and circulate in the peripheral blood after passing through the drainage vein. In previous studies, we showed that high numbers of CTCs were detected in the drainage pulmonary venous blood of most patients with resectable primary lung cancer, whereas only low numbers of CTCs were detected in the peripheral blood of some patients. Accordingly, this prospective study was conducted to assess changes in CTCs in the drainage pulmonary vein (PV) during lung cancer surgery., Methods: A total of 30 consecutive peripheral-type primary lung cancer patients who underwent lobectomy (or right upper and middle bilobectomy) through open thoracotomy were included. For each patient, 2.5 ml of blood was sampled from the lobar PV of the primary tumour site before and after surgical manipulation for lobectomy. The CTCs were evaluated quantitatively with the CellSearch® system., Results: Before surgical manipulation, CTCs were detected in PV blood in the majority of patients (22 of 30, 73.3%), although CTCs were detected in peripheral blood in only two patients (6.7%). The median number of CTCs in the PV (pvCTC-count) before surgical manipulation was 4.0 cells/2.5 ml, and there was no significant correlation between pvPV-count and any clinicopathological characteristic, including tumour size, progression and histological type. After surgical manipulation, at the time of completion of the lobectomy, the pvCTC-count significantly increased (median, 60.0 cells/2.5 ml; P = 0.001). The increase in pvCTC-count was significantly associated with microscopic lymphatic tumour invasion (ly); pvCTC-count significantly increased in ly-positive patients (pvCTC-count before and after surgical manipulation, 4.0 and 90.5 cells/2.5 ml, respectively; P = 0.006), but not in ly-negative patients (3.5 and 7.0 cells/2.5 ml, respectively; P = 0.153). The increase in pvCTC-count was not significantly associated with any other clinicopathological factor or with any surgical procedure, including the sequence of vessel interruption., Conclusions: We documented a significant increase in CTC count in drainage PV blood after surgical manipulation, especially in tumours with lymphatic invasion. We are awaiting survival data at 5 year follow-up examination, which may provide clinical significance of the pvCTC-count., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Worldwide studies on lung adenocarcinoma have demonstrated a genetic divergence of the epidermal growth factor receptor (EGFR) pathway according to ethnicity, such as higher frequency of activated EGFR mutations among East Asian patients. However, such information is still lacking in some developing countries., Methods: We investigated the frequency of EGFR mutations among Bangladeshi patients with adenocarcinoma of the lung. Fine-needle aspiration tissue samples were collected from 61 Bangladeshi patients. Polymerase chain reaction-single-strand conformation polymorphism was performed on extracted DNA for mutational analysis of EGFR exons 19 and 21., Results: EGFR mutations were found in 14 of 61 (23.0 %) Bangladeshi patients. There was no significant difference in EGFR mutation rate with regard to patient's age, sex, smoking history, clinical stage of lung cancer, subtypes of adenocarcinoma, and tumor differentiation., Conclusion: The present study revealed that the EGFR mutation rate in Bangladeshi patients with adenocarcinoma of the lung was higher than in African-American, Arabian, and white Caucasian patients, and was lower than in East Asia.

Background: Most patients with lung cancer experience relapse, although epidermal growth factor receptor (EGFR) of tyrosine kinase inhibitor (TKI) has an astounding effect on tumors with EGFR-activating mutations. It is therefore critical to determine the mechanisms of resistance against agents and the prognostic value of acquired resistance-related molecules to EGFR-TKI., Materials and Methods: Tumor specimens were obtained from 19 matched specimens before and after treatment with gefitinib. A retrospective multi-institutional study analyzed the correlation between patients' survival and acquired resistance-related molecules in non-small cell lung cancer (NSCLC) samples, that possessed sensitive EGFR mutations (7 cases: exon 19 deletion, and 12 cases: exon 21 point mutation). The status of the epidermal growth factor receptor (EGFR) and KRAS genes were investigated by polymerase chain reaction (PCR)-based analyses. Real-time PCR assays were also used to evaluate MET gene amplification. The expression of hepatocyte growth factor (HGF) and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and γ-catenin as epithelial markers, and those of vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry., Results: Eight of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type KRAS gene expression. No MET amplification was detected in any of the samples. A strong expression of HGF was detected in eight of the specimens at post-treatment. A change in the EMT status between pre-and post-treatment was found in five cases. The 5-year survival rate of patients with and without T790M was 86.7% and 13.3%, respectively (p=0.020). The 5-year overall survival (OS) rate for patients with overexpresion and for those with weak expression of HGF was 75.0% and 22.2%, respectively (p=0.259). In addition, the 5-year OS rate for patients with unchanged and changed EMT status was 83.3% and 40.0%, respectively (p=0.123)., Conclusion: The current results showed that the presence of T790M is associated with favorable survival. On the other hand, the patients with weak HGF expression and EMT change tend to have a poor survival. The current patients' selection might be changed by discrimination of acquired resistance-related molecules in patients with NSCLC treated with an EGFR-TKI.

Alveolar adenoma is a rare pulmonary neoplasm. This report describes a case of alveolar adenoma of the lung in a 61-year-old woman. A chest X-ray demonstrated a solitary round pulmonary nodule. After six years of observation, this lesion had increased in size. Thoracoscopic left upper segmentectomy was performed on account of a possible low-grade malignant tumor. Histologically, the neoplastic epithelial cells, which had the appearance of proliferative type II pneumocytes, revealed no evidence of malignancy. These findings indicated that the tumor is alveolar adenoma of the lung. The course of disease remains uneventful, one year after the resection.

The diagnosis of multiple primary lung cancer is sometimes difficult when multiple lung tumors with the same histologic type are identified. We now present a case of synchronous double primary lung adenocarcinomas (one in the right upper lobe and another in the right middle lobe) diagnosed based on mutational analysis of the epidermal growth factor receptor (EGFR) gene, although clinico-pathological findings suggested the diagnosis of intrapulmonary metastasis. After complete resection, pathological sections revealed the similar pathological features of two adenocarcinomas and unexpected subcarinal nodal metastasis. As the L858R mutation within exon 21 of the EGFR gene was identified in the middle-lobe tumor and the subcarinal node but not in the upper-lobe tumor, we diagnosed as double primary cancers. Local mediastinal recurrence after operation has been well-controlled with administration of gefitinib, a EGFR-tyrosine kinase inhibitor, and mutational analysis of the EGFR gene provided important information not only in the diagnosis of double primary cancers but also in decision-making of selection of chemotherapeutic agent., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To investigate the diagnostic performance of circulating tumor cells (CTC) in discrimination between primary lung cancer and nonmalignant diseases as well as in prediction of distant metastasis., Patients and Methods: We prospectively evaluated CTCs in 7.5-mL samples of peripheral blood sampled from patients with a suspicion or a diagnosis of primary lung cancer. A semiautomated system was used to capture CTCs with an antibody against epithelial cell adhesion molecule., Results: Of 150 eligible patients, 25 were finally diagnosed as having nonmalignant disease, and 125 were diagnosed as having primary lung cancer with (n = 31) or without (n = 94) distant metastasis. CTCs were detected in 30.6% of lung cancer patients and in 12.0% of nonmalignant patients. CTC count was significantly higher in lung cancer patients than in nonmalignant patients, but a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between lung cancer and nonmalignant diseases with an area under ROC curve of 0.598 (95% confidence interval, 0.488-0.708; P = 0.122). Among lung cancer patients, CTC count significantly increased along with tumor progression, especially with development of distant metastasis. The area under ROC curve for CTC count in prediction of distant metastasis was 0.783 (95% confidence interval, 0.679-0.886; P < 0.001). When patients with one or more CTCs were judged as having metastatic disease, sensitivity and specificity of the CTC test were 71.0% and 83.0%, respectively., Conclusions: CTC is a useful surrogate marker of distant metastasis in primary lung cancer.

Background: Circulating tumor cells in peripheral blood (CTC) is a potential surrogate of distant metastasis, which is the critical factor influencing decision making regarding therapy and prognosis of primary lung cancer patients. After our preliminary study showing that CTCs were detected in peripheral blood in 29.4% of resectable lung cancer patients, we conducted a prospective study on CTC in pulmonary vein (PV) blood because tumor cells apart from the primary tumor may circulate after passing through the drainage PV., Methods: A total of 30 consecutive lung cancer patients who underwent thoracotomy were included. The CTCs in peripheral blood and in PV blood from the primary tumor site were quantitatively examined with the CellSearch system, and the numbers of CTCs per 7.5 mL peripheral and PV blood in each patient were represented as periCTC count and pvCTC count, respectively., Results: Circulating tumor cell was detected in peripheral blood in 5 patients (16.7%; the periCTC count was 1 in 2 patients; and 2, 3, and 16 in 1 patient each), and the incidence of positive periCTC was higher in squamous carcinoma patients than in adenocarcinoma patients (p = 0.028). Circulating tumor cell was detected in PV blood in most patients (29 of 30, 96.7%), and the mean and median pvCTC counts were 1,195 and 81, respectively (range, 0 to 10,034). There was no significant correlation between pvCTC count and any other patient characteristic, including periCTC count., Conclusions: In resectable lung cancer, CTC was positive in peripheral blood of some patients and in PV blood of most patients. A long-term follow-up study to clarify the clinical significance of pvCTC status is warranted.

Pulmonary lymphangioleiomyomatosis is a rare disease that generally progresses to respiratory failure. We experienced a patient who had recurring lymphangioleiomyomatosis in the transplanted lungs. A chest computed tomographic scan showed a progressing emphysematous change. The patient had a subclinical extent of pan-circumferential stricture at the distal site of the left bronchial anastomosis. We treated the patient with sirolimus for three years. Chest computed tomography showed no sign of exacerbation during the late 3 years, whereas pulmonary function test revealed a slight increase after the use of sirolimus. Bronchial stricture also disappeared almost completely. This is the first reported case with sirolimus treatment for post-transplant recurrent lymphangioleiomyomatosis.