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Objectives: The surgical Apgar score (SAS) is a simple score that predicts postoperative complications based on 3 intraoperative valuables. The present study evaluated the association between the SAS and postoperative outcomes in non-small-cell lung cancer patients who underwent surgery., Methods: A total of 585 patients who underwent lung resection were enrolled in the present study. We calculated the SAS of each patient and investigated its influence on the short- and long-term outcomes., Results: Postoperative complications of any grade were detected in 164 cases (28%). The morbidity rate increased with decreasing SAS. When all the patients were divided into 2 groups (SAS <7 vs ≥7), postoperative complications were observed more frequently in the SAS <7 group than in the SAS ≥7 group (41% vs 25%, P < 0.001). In the multivariate analysis, the SAS was an independent risk factor for postoperative complications (odds ratio: 1.64 [1.03-2.61], P = 0.036). In terms of long-term outcomes, the 5-year disease-free survival (54.1% vs 73.2%, P < 0.001) and overall survival (73.8% vs 83.0%, P = 0.031) were significantly worse in the SAS <7 group than in the SAS ≥7 group. In a multivariate analysis, however, the SAS was not found to be an independent prognostic factor for either disease-free survival (hazard ratio: 1.39 [0.97-2.00], P = 0.075) or overall survival (hazard ratio: 0.90 [0.57-1.42], P = 0.642)., Conclusions: The SAS reflected preoperative and intraoperative characteristics and was able to stratify the morbidity rate, suggesting it to be a useful predictor of short-term outcomes in non-small-cell lung cancer patients who undergo surgery., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Non-small cell lung cancer (NSCLC) patients with idiopathic pulmonary fibrosis (IPF) show poor prognosis. Periostin is an extracellular matrix protein highly expressed in the lung tissues of IPF. This study aimed to investigate the possibility that periostin secreted by fibroblasts derived from IPF lung might affect proliferation of NSCLC cells. Periostin was more highly expressed and secreted by fibroblasts from diseased human lung with IPF (DIPF) than by normal human lung fibroblasts (NHLF). Cocultivation of NSCLC cells with conditioned media (CM) from DIPF increased proliferation of NSCLC cells through pErk signaling, with this proliferation attenuated by periostin-neutralizing antibodies. Knockdown of integrin β3, a subunit of the periostin receptor, in NSCLC cells suppressed proliferation of NSCLC cells promoted by recombinant human periostin and CM of DIPF. On in vivo examination, DIPF promoted tumor progression more than NHLF, and knockdown of integrin β3 in NSCLC cells suppressed tumor progression promoted by DIPF. Fibroblasts derived from surgical specimens from IPF patients also increased secretion of periostin compared to those from non-IPF patients. Periostin secreted from IPF-activated fibroblasts plays critical roles in the proliferation of NSCLC cells. The present study provides a solid basis for considering periostin-targeted therapy for NSCLC patients with IPF., (© 2021. The Author(s).)

Objectives: With improvements in the outcome of treatment for non-small-cell lung cancer (NSCLC), other diseases may account for a high death rate after surgery in patients with stage I NSCLC. In the present study, we analysed the associations between the clinical factors and non-cancer death after surgery in these patients., Methods: The records of 514 patients with stage I NSCLC who underwent surgery were retrospectively reviewed; a proportional hazards model for the subdistribution of a competing risk was conducted to define the risk factors for non-cancer death., Results: The mean patient age was 67 years. A total of 367 patients (71%) underwent bilobectomy or lobectomy while 147 (29%) underwent sublobar resection. The pathological stage was IA in 386 (75%) and IB in 128 (25%) patients. Three patients (0.6%) died within 90 days after surgery, and 108 (21%) experienced postoperative complications. Until the time of writing this report, 83 patients had died during the follow-up. The cause of death was primary lung cancer in 38 (46%) patients and other diseases in 45 (54%) patients, including non-cancer causes in 29 patients, such as pneumonia, cardiac death and cerebral stroke. According to a multivariable competing risk analysis for non-cancer death age (≥70 years), sex (male), body mass index (BMI <18.5), postoperative complications and % forced expiratory volume in 1 s (<80) were identified as risk factors for postoperative non-cancer death., Conclusions: Advanced age (≥70 years), male sex, low BMI (<18.5), postoperative complications and low preoperative % forced expiratory volume in 1 s (<80) were found to be the risk factors for postoperative non-cancer death after surgery in patients with stage I NSCLC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Targeting cancer-associated fibroblasts (CAFs), as well as the crosstalk between stroma and cancer cells, could be of value in managing cancers. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of fibroblast activation and the tumor-stroma interaction in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. PFD significantly inhibited myofibroblast differentiation and activation of both primary cultured normal human lung fibroblasts and CAFs. Cocultivation of NSCLC cells with conditioned media (CM) of fibroblasts changed the morphology or epithelial to mesenchymal transition (EMT) status, and PFD suppressed these changes. Cocultivation of CAFs with CM of NSCLC cells also induced activation of CAFs, and these changes were suppressed by PFD. On in vivo examination, CAFs promoted tumor progression, and PFD suppressed tumor progression with an inhibitory effect on tumor-stroma crosstalk. PFD might inhibit not only fibroblast activity, but also the crosstalk between cancer cells and fibroblasts. PFD may have great potential as a novel treatment for NSCLC from multiple perspectives.

Background: The survival outcome in lung cancer patients with chronic kidney disease (CKD) has not been well evaluated. The aim of this study was to evaluate the survival outcomes following non-small cell lung cancer (NSCLC) surgery in patients with CKD as a preoperative comorbidity., Methods: Among 671 patients who underwent surgery for NSCLC between 2007 and 2014 at our hospital, 55 (8%) had CKD and we retrospectively analyzed the survival outcomes of these patients., Results: Most patients with CKD were elderly and male. Patients with CKD had a higher frequency of smoking habit, cardiovascular disease, and pulmonary diseases, and a notably lower pulmonary function, resulting in receiving limited pulmonary resection. There were no marked differences in the frequency of surgical complications between patients with and without CKD (p = 0.16). Squamous cell carcinoma was more frequently diagnosed in patients with CKD than in those without it. The 5-year disease-free survival rates in patients with and without CKD were 60.0% and 69.7% (p = 0.06), respectively, and the 5-year overall survival rates were 68.9% and 80.0%, respectively, showing significant differences (p = 0.01). The rate of receiving supportive care was higher in patients with CKD when recurrence observed., Conclusion: CKD is associated with a poorer overall survival in patients who undergo lung cancer resection for recurrent disease. As patients with CKD tend to have a poor respiratory function, thoracic surgeons should carefully select the resection type to balance the therapeutic benefit and invasiveness.

Purpose: Information on the short- and long-term outcomes of induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer is limited. We analyzed the short- and long-term outcomes of induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer., Methods: Patients with non-small cell lung cancer who underwent induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer were retrospectively reviewed (initial treatment group, n = 31). Their results were compared to those patients who underwent surgery as an initial treatment during the same period (initial surgery group, n = 35)., Results: Downstaging was achieved in 14 (45%) patients in the initial treatment group. R0 resection was achieved in 28 (90%) patients in the initial treatment group and 31 (88%) patients in the initial surgery group. The 90-day mortality rate was 3% in each group. Postoperative complications occurred in 16 (52%) patients in the initial treatment group and 13 (37%) patients in the initial surgery group. The 5-year overall survival rate of the initial treatment group was significantly higher than that of the initial surgery group (62.6% vs 43.5%, P = .04). The 5-year overall survival rates of the initial treatment N0-1 group and the initial surgery N0-1 group were 88.9% and 49.3%, respectively; the difference was statistically significant ( P = .02). Multivariate analysis using 4 factors (age [≤65 vs >65], cN [cN0-1 vs cN2], general condition [chemoradiotherapy fit vs chemoradiotherapy unfit], and treatment mode [induction chemoradiotherapy followed by surgery vs surgery as an initial treatment]) revealed that treatment mode (induction chemoradiotherapy followed by surgery) and cN status (cN0-1) were significantly associated with good overall survival and disease-free survival., Conclusions: Induction chemoradiotherapy followed by surgery for cT3-4 non-small cell lung cancer could be performed with an acceptable degree of surgical risk. At present, it is thought to be one of the reasonable treatment approaches for selected patients with cT3-4 disease, even those with a cN0-1 status.

Background: PDGFR-β is used as a stromal biomarker and is functional in mesenchymal cells of the tumor microenvironment. The significance of stromal PDGFR-β expression in non-small cell lung cancer (NSCLC) in patients undergoing preoperative chemo- or chemoradiotherapy had not been determined., Methods: Patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy between 1996 and 2014 were assessed for expression of stromal PDGFR-β by immunohistochemistry using resected specimens. Relationships between stromal PDGFR-β expression and survival after operation were analyzed. Forty-three patients who underwent surgery without preoperative treatment in 2005 were also analyzed as a chemo-naïve control group., Results: The mean age of the 92 patients was 60.2 years. Seventy-eight (85%) were male, and 14 (15%) were female. Fifty-four patients (59%) underwent preoperative chemoradiotherapy, and 38 patients (41%) underwent preoperative chemotherapy. Regimens for preoperative chemotherapy were cisplatin (CDDP) based in 48 patients (52%) and carboplatin (CBDCA) based in 43 (42%). While stromal cells expressed PDGFR-β in 21 chemo-naïve patients (49%), stromal cells expressed PDGFR-β in 65 patients who underwent preoperative therapy (p = 0.02). The 5-year disease-free survival rate (DFS) of the PDGFR-β-positive group was significantly worse than that of the negative group (27 vs. 48%, p = 0.04). The 5-year disease-specific survival rate (DSS) in the stromal PDGFR-β-positive group was also significantly worse than in the negative group (43 vs. 70%, p = 0.01). On the other hand, stromal PDGFR-β expression did not influence survival in chemo-naïve patients., Conclusions: Stromal PDGFR-β expression is negatively associated with DFS and DSS in patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy.

In cancer immunology, the programmed cell death 1-programmed cell death 1/ligand 1 (PD-1/PD-L1) pathway plays a major role. Anti-PD-1 and anti-PD-L1 antibodies provide reliable immunotherapy when given as treatment for various types of malignancy including lung cancer. PD-L1 expression in cancer cells has been reported to be a predictive factor for the therapeutic effects of immunotherapy. However, the mechanism of PD-L1 expression remains unclear. Another key process in cancer progression is epithelial-mesenchymal transition (EMT). In the present study, we investigated the mechanism of PD-L1 expression as well as changes in its expression during the EMT process in non-small cell lung cancer (NSCLC). In this study, A549 cells underwent EMT by treatment with TGF-β or chemotherapeutic agents and then PD-L1 expression was evaluated. The alterations of PD-L1 expression was also examined during the reverse EMT process; mesenchymal-epithelial transition (MET). The relationship between for PD-L1 expression and EMT status in clinical specimens with NSCLC after induction chemotherapy were analyzed by immunohistochemical staining. We found that PD-L1 expression was upregulated following TGF-β induction; in contrast, it was downregulated by TGF-β receptor-kinase inhibitors and the MET process. Furthermore, chemo-treatment increased TGF-β expression and enhances PD-L1 expression via autocrine TGF-β induced EMT. Analysis of clinical samples revealed a significant relationship between PD-L1 expression and EMT status (P<0.05). In conclusion, our results suggest that PD-L1 expression is regulated by TGF-β induced EMT and enhanced by chemo-treatment via the chemo-induced TGF-β signaling. The anti-PD-1/PD-L1 blockade may provide more effective anticancer activities in combination with chemotherapy in NSCLC.

Purpose: To investigate the surgical outcomes of surgery for non-small cell lung cancer (NSCLC) in patients with atrial fibrillation (AF) as a preoperative comorbidity., Methods: Among 805 patients who underwent surgery for NSCLC, 27 (3.4%) had a history of AF. We analyzed the perioperative and long-term outcomes of these 27 patients., Results: Fourteen patients (52%) had chronic AF and 13 (48%) had paroxysmal AF; being high rates of a comorbid illness. Nineteen patients (70%) underwent lobectomy, and 8 (30%) underwent sublobar resection. Ten patients (37%) received perioperative heparinization. There was no mortality. Other non-AF postoperative complications developed in 8 patients (30%), this incidence being higher than among the patients without AF (16%, 127 out of 778, p = 0.09). A thromboembolic event occurred in one patient (4%). With respect to the long-term outcomes, the 5-year overall survival and disease-free survival rates among the patients with AF were 70.3 and 60.8%, respectively, which were similar to those in the patients without AF (79.8 and 72.6%, p = 0.30 and 0.31)., Conclusions: Lung cancer surgery in patients with AF is safe and provides favorable long-term outcomes; however, thoracic surgeons should monitor these patients carefully for postoperative thromboembolic events.

Purpose: To propose a treatment strategy for simultaneously discovered non-small cell lung cancer (NSCLC) and cardiovascular disease (CVD)., Methods: Of 1302 patients who underwent surgery for NSCLC, CVD requiring invasive treatment was simultaneously discovered in 33 (3 %). The details of the treatments as well as the short- and long-term outcomes of pulmonary resection were analyzed., Results: CVD included coronary artery disease in 20 patients, valvular disease in 6, abdominal aortic aneurysm in 5, and congenital heart disease in 2. Twenty-six patients underwent two-stage treatment, while seven received simultaneous surgery. In 23 patients whose treatment for CVD preceded that for lung cancer, the median interval between those treatments was 78 days (range 18-197 days). Postoperative complications occurred in 8 (31 %) of 26 patients who underwent 2-stage treatment and in 3 (43 %) of 7 who underwent simultaneous surgery. Notably, of 3 patients who underwent lobectomy or bilobectomy, 2 (67 %) experienced respiratory dysfunction that required intubation. The 5-year overall survival rate of all 33 patients was 84.5 %., Conclusion: The outcomes of two-stage treatment in the present cohort were favorable. Given our experience, simultaneous surgery for lung cancer and CVD should, therefore, be selected only for patients who may benefit from that strategy.

Introduction: Epithelial to mesenchymal transition (EMT) relates to both organ fibrosis and malignant behavior of cancer. Pirfenidone (PFD) is an anti-fibrotic agent for idiopathic pulmonary fibrosis and one of its functions may be to inhibit fibrotic EMT. This study aimed to investigate the possibility that PFD might exert an anti-tumor effect through inhibition of EMT in non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo., Methods: NSCLC cells (A549, NCI-H358) were used to evaluate PFD effects on TGF-β1 induced phenotypic changes. Possible TGF-β1 signaling pathways modulated by PFD were evaluated. The effects of PFD on EMT induced by an anti-cancer drug was also analyzed. The impact of PFD on tumor growth in nude mice as well as on EMT change in vivo was also determined., Results: PFD significantly inhibited TGF-β1-induced EMT. Smad2 phosphorylation and TGF-β1 receptor I expression were also inhibited as was translocation of Smad2 from the cytoplasm into the nucleus. Carboplatin induced elevation of TGF-β1 production from cancer cells together with induction of EMT, which were suppressed by co-treatment with PFD. In in vivo examination, PFD alone did not inhibit tumor progression whereas its combination with carboplatin significantly decreased tumor growth. Immunohistological analysis showed that PFD suppressed EMT change induced by carboplatin., Conclusions: PFD could attenuate the EMT process induced not only by exogenous TGF-β1 but also by paracrine TGF-β produced from NSCLC cells. PFD may be a promising new therapeutic agent for the treatment of NSCLC through the regulation of EMT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The aim of this study is to investigate the surgical outcomes of surgery for non-small cell lung cancer (NSCLC) in patients with coronary artery disease (CAD)., Methods: Among 805 patients who underwent surgery for NSCLC at our hospital within a recent 10-year period, 43 (5.3 %) had a history of CAD. We analyzed the surgical outcomes and risk factors for postoperative complications in these 43 patients., Results: The postoperative mortality and morbidity rates were 2 and 42 %, respectively. The morbidity rate was significantly higher in the patients with CAD than in those without CAD (P < 0.01). Postoperative cerebrovascular or cardiovascular events occurred in four patients (9 %). Having two of the following was significantly associated with the development of postoperative complications: decreased cardiac function, respiratory dysfunction, or deteriorated renal function (p = 0.04). The 5-year overall and disease-free survival rates of the patients with CAD were 75.6 and 64.5 %, respectively; comparable with those of the patients without CAD; at 77.9 % and 72.5 %, respectively (p = 0.46 and 0.69)., Conclusions: Patients with NSCLC and a history of CAD are at higher risk of complications after pulmonary resection. Combined decreased organ function is a risk factor for postoperative complications. CAD did not influence the long-term outcomes of patients after pulmonary resection for NSCLC.

Background: PSF1 (Partner of SLD Five 1) is an evolutionarily conserved DNA replication factor that is part of the GINS (Go, Ichi, Nii, and San) complex . The objective of this study was to evaluate the relationship between PSF1 expression and prognosis in patients with non-small cell lung cancer (NSCLC) treated with surgery following preoperative chemotherapy or chemoradiotherapy., Methods: Sixty-nine patients with NSCLC treated with surgery following preoperative chemotherapy or chemoradiotherapy who did not achieve pathologic complete response were enrolled. The status of PSF1 expression was evaluated by immunohistochemistry, and the relationship between expression of PSF1 and Ki-67 was determined, as well as correlations between PSF1 expression and prognosis., Results: We found that 27 of 69 patients' tumors (39 %) were positive for PSF1 expression. The Ki-67 index was significantly higher in the PSF1-positive versus the PSF1-negative group (p = 0.0026). Five-year, disease-free survival of the PSF1-positive group was significantly worse (17.7 vs. 44.3 %, p = 0.0088), and the 5-year overall survival also was worse (16.6 vs. 47.2 %, p = 0.0059). Moreover, PSF1 expression was found to be a significant independent prognostic factor for shorter survival by Cox multivariate analysis (hazard ratio 2.43, 95 % confidence interval 1.27-4.60, p = 0.0076)., Conclusions: PSF1 is a useful prognostic biomarker to stratify NSCLC patients treated with surgery following preoperative chemotherapy or chemoradiotherapy.

Introduction: The tumor microenvironment is composed of different types of stromal cells that represent a key component of tumor progression. Cancer-associated fibroblasts (CAFs) secrete several factors that promote tumorigenesis. The purpose of this study was to clarify the role of the interleukin-6 (IL-6) secreted from CAFs in the communication between CAFs and NSCLC cells that modulates chemoresistance., Methods: We used standard NSCLC cell lines as well as NSCLC cells, lung normal fibroblasts, and CAFs obtained from specimens from patients with NSCLC to evaluate phenotypic changes. Immunohistochemical analysis was also utilized to examine the stromal changes in tumor specimens obtained from patients with NSCLC who had undergone chemotherapy., Results: IL-6 significantly increased transforming growth factor-β1-induced epithelial-to-mesenchymal transition (EMT) changes in cancer cells. Cisplatin treatment increased expression of transforming growth factor-β in cancer cells, and the conditioned media from cancer cells activated fibroblasts and increased their IL-6 production. Expression of IL-6 was increased in CAFs compared with in lung normal fibroblasts. The conditioned media from CAFs induced EMT and resistance to cisplatin in NSCLC cells through IL-6 signaling. Immunohistochemical analysis showed that stromal IL-6 expression was correlated with EMT changes in cancer cells as well as with a diffuse distribution of smooth muscle actin-stained fibroblasts. Univariate and multivariate analyses indicated that stromal IL-6 expression was an independent prognostic factor in patients with NSCLC., Conclusions: IL-6 from CAFs enhanced EMT in NSCLC cells. IL-6 may contribute to maintenance of a paracrine loop that functions as part of the communication between CAFs and NSCLC cells, resulting in chemoresistance., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Intraoperative alveolar air leaks remain a significant problem in thoracoscopic surgery (TS) cases. We examined the usefulness of covering damaged lung tissue with a subcutaneous fat pad for preventing postoperative air leakage in patients with non-small cell lung cancer (NSCLC)., Methods: Patients with NSCLC underwent a thoracoscopic lobectomy or segmentectomy. When alveolar air leakage from the superficial pulmonary parenchyma was found, fibrin glue in combination with an absorbable mesh sheet was applied (S group; n = 100). When leakage originated from deep within the pulmonary parenchyma, a subcutaneous fat pad about 2 × 2 cm in size was harvested from the utility incision and placed on the damaged lung tissue with fibrin glue and sutures (F group; n = 66). Patient characteristics, air leak duration, and chest-tube removal time were analyzed., Results: The homogeneity of each group was consistent, with no statistical differences for age, respiratory function, surgical procedures, pathologic stage, and histological type. The air leak duration was significantly shorter (p = 0.015), and the chest tube was removed significantly earlier (p = 0.002) in patients in the F group., Conclusion: Use of a free subcutaneous fat pad during pulmonary resection for TS patients with NSCLC reduced the duration of air leakage and chest tube drainage. The present method is easy, safe, and effective for repairing an air leak from remaining lung tissues in such cases.

Objectives: A new pathological classification for pre- and minimally invasive adenocarcinoma has been established, with distinction prior to surgery crucial because of the extremely good prognosis., Methods: Of 412 patients who underwent surgery for lung cancer from 2008 to 2011, 110 classified as c-stage I had each of the following four parameters assessed for predictive power for pre- or minimally invasive adenocarcinoma and relapse-free survival (RFS): (i) whole tumour size (WS) shown by computed tomography (CT) , (ii) size of the solid (SS) component in CT findings, (iii) maximum standard uptake value in fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan images (SUVmax) and (iv) serum level of carcinoembryonic antigen., Results: For prediction of pre- or minimally invasive adenocarcinoma, the area under the receiver-operating curve was >0.7 for all the four parameters, while only SS was found to be an independent factor in multivariate logistic regression analysis. In Cox proportional hazard model analysis, SS and SUVmax were statistically significant, and SS was exclusively independent in multivariate analysis. Differences in RFS between T1a and T1b were more pronounced when using SS compared with WS. In the sub-classification of T1a, we used a breakpoint of 1.0 cm in SS (T1a-α and T1a-β), which resulted in a 2-year RFS rate of 1.00 for T1a-α (n=21), 0.89 for T1a-β (n=27) and 0.68 for T1b (n=26) (P=0.002 between T1a-β and T1b)., Conclusions: The SS parameter was useful to distinguish pre- and minimally invasive adenocarcinoma from other types of lung cancer, and set a T1a sub-classification.

Introduction: Fibroblasts are key components of the tumor microenvironment. We clarified the role of transforming growth factor (TGF)-β and interleukin (IL)-6 in the interaction between fibroblasts and non-small-cell lung cancer (NSCLC) cells., Methods: We used NSCLC cells (A549, NCI-H358) and normal human lung fibroblast (NHLF) cells to evaluate phenotypic changes in the presence of human IL-6, TGF-β1, and conditioned media (CM) from these cells. Possible pathways were evaluated with SB431542, a TGF-β receptor inhibitor, or an anti-human IL-6 receptor neutralizing antibody (IL-6R-Ab)., Results: A549 and NCI-H358 cells incubated with IL-6 (50 ng/mL) and TGF-β1 (2 ng/mL) showed significantly increased epithelial-mesenchymal transition (EMT) signaling compared to those treated with TGF-β1 alone. Furthermore, NHLF cells were synergistically activated by IL-6 and TGF-β1. IL-6 increased the expression of TGF-β type I receptors on the surface of A549, NCI-H358 and NHLF cells and enhanced TGF-β signaling. TGF-β1 induced phenotypic changes were attenuated by IL-6R-Ab. NHLF cells were activated and A549 cells showed induction of EMT in response to CM from the other cell type. These activities were attenuated by SB431542 or IL-6R-Ab, suggesting that interplay between NSCLC cells and NHLF may lead to increased EMT signaling in NSCLC cells and activation of NHLF cells through TGF-β and IL-6 signaling. Subcutaneous co-injection of A549 and NHLF cells into mice resulted in a high rate of tumor formation compared with injection of A549 cells without NHLF cells. SB431542 or IL-6R-Ab also attenuated the tumor formation enhanced by co-injection of the two cell types., Conclusion: IL-6 enhanced epithelial cell EMT and stimulated tumor progression by enhancing TGF-β signaling. IL-6 and TGF-β may play a contributing role in maintenance of the paracrine loop between these two cytokines in the communication between fibroblasts and NSCLC cells for tumor progression., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Fibroblasts are key components of the tumor microenvironment. The purpose of this study was to clarify the role of fibroblasts in tumor progression in non-small cell lung cancer (NSCLC)., Methods: Fibroblasts isolated from surgical exploration were co-cultured with human lung adenocarcinoma cell lines. We defined fibroblasts obtained from tumors as cancer associated fibroblasts (CAFs) and those from normal lung tissue as lung normal fibroblasts (LNFs)., Results: Expression levels of myofibroblast markers were higher in CAFs than LNFs within 5 passages in the absence of continuing interaction with carcinoma cells. Thus, we used at least 2 pairs of these CAFs and LNFs in the following experiments; conditioned medium (CM) from fibroblast-induced epithelial mesenchymal transition and acquisition of cancer stem cell-like qualities in lung cancer cells (A549 and NCI-H358), indicating that CM from fibroblasts was biologically active. Furthermore, the concentration of the transforming growth factor (TGF)-β1 was higher in CM from CAFs as compared with that from LNFs, and phenotypic changes of cancer cells by CM from CAFs were greater than those induced by CM from LNFs. These CAF-induced changes were inhibited by addition of the TGF-β inhibitor SB431542. Subcutaneous co-injection of lung cancer cells and CAFs in mice enhanced tumor growth when compared with cancer cells alone, which was attenuated by administration of SB431542., Conclusions: Fibroblasts were associated with increased malignant potential and the acquisition of stem cell-like properties in NSCLC tumors. Targeting CAFs as a therapeutic strategy against cancer is an intriguing concept that would benefit from further study., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The existence of clustered isolated tumour cells (ITCs) in the pulmonary vein (PV) of the lungs of patients with lung cancer has been reported to be a prognostic factor. However, the clinical-pathological characteristics related to their presence in the PV remain unclear., Methods: We analysed the surgical results and clinical-pathological findings of 130 patients who underwent surgery for non-small-cell lung cancer in regard to blood vessel invasion (BVI), serum carcinoembryonic antigen (CEA) level, maximum standardized uptake value (SUV-max), size of the solid region in computed tomography findings and pathological stage according to an ITC type, i.e. no tumour (N), singular tumour cells (S) and clustered tumour cells (C)., Results: ITCs were detected in 96 (74%) of the patients, with C observed in 43, S in 53 and N in 34. Recurrence was seen in 33 (26%) cases, 21 of which were classified as C, 9 as S and 3 as N. The disease-free survival rate was significantly worse in C cases when compared with the others (P < 0.01). The rate of C was high in cases with high serum CEA, advanced p-staging and positive BVI ratio. Furthermore, BVI positive and ITC morphology were strongly related (BVI positive; 79 in C, 40 in S, 9% in N; P < 0.01)., Conclusions: Clustered ITCs were shown to be a prognostic indicator and strongly related to BVI. Our results suggest that determination of BVI has prognostic value, as clustered ITCs with metastatic potential are disseminated from the invaded vein.

A sublobar resection is currently recognized as an option for early small-sized non-small cell lung cancer (NSCLC), and intraoperative rapid and accurate lymph node assessment is required for a complete resection. To solve this issue, we investigated the clinical utility of one-step nucleic acid amplification (OSNA) assay, an automated rapid molecular diagnostic method and its optimal mRNA marker for detection of lymph node metastasis in lung cancer. We extracted 16 target candidate mRNA markers with high expression in lung cancer from a genetic database, and then quantified their expression levels by quantitative RT-PCR using surgically dissected lymph nodes with or without metastasis. Cytokeratin 19 (CK19), cytokeratin 7 (CK7), stratifin (SFN), and anterior gradient homolog 2 (AGR2) showed significant differences for mRNA expression between metastasis-negative and -positive lymph nodes in quantitative-RT-PCR screening. CK19 and CK7 were finally selected as potential target markers and were quantified using OSNA assay findings of 165 dissected lymph nodes obtained from 49 lung cancer patients. The OSNA assay with CK19 and CK7 were completed within 40 min and their positive predictive value, negative predictive value, and accuracy comparing to pathological diagnosis with hematoxylin-eosin staining and immunohistochemistry were shown to be 95.0%, 99.3%, and 98.8%, and 85.0%, 97.9%, and 96.4%, respectively, using a cut-off value of 250 copies/μL. Among the 165 lymph nodes tested, 1 false negative result was due to massive necrosis of cancer cells and 1 false positive was caused by the allocation bias of cancer cells in the sampling in patient with pleural dissemination. The best performance was observed when CK19 was used as a marker, while the addition of CK7 mRNA as a marker did not increase sensitivity or specificity. In conclusion, an OSNA assay using CK19 could be effective for molecular diagnosis of lymph node metastasis in lung cancer. This is the first report suggesting the potential clinical utility of OSNA assay for intraoperative rapid diagnosis of nodal status in lung cancer., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose as a tracer and computed tomography (FDG-PET/CT) are utilized for the diagnosis of lymph node (LN) metastasis from lung cancer. In this study, we analyzed the diagnostic ability of FDG-PET for N staging by focusing on the clinical features of false-positive (FP) and false-negative (FN) cases., Methods: From March 2006 to February 2010, 112 patients underwent preoperative examinations using FDG-PET/CT followed by radical resection with hilar and mediastinal dissection. We analyzed their clinicopathological characteristics based on preoperative FDG-PET/CT findings and post-operative histopathological diagnosis of resected LNs., Results: Based on the PET/CT results, 17 patients were misdiagnosed (9 FN and 8 FP). The sensitivity, specificity, accuracy and negative and positive predictive values for N1/N2 were 50.0, 94.5, 84.0, 93.0 and 58.3%, respectively, whereas those for N2 were 57.8, 90.3, 84.8, 90.3 and 61.1%, respectively. FP findings more frequently occurred in cases with elevated white blood cell (WBC) count (P=0.015) and smokers (P=0.04). In the FN group, the maximum standardized uptake value for the primary tumour was lower than that in the true-positive (TP) group (P=0.01). The short-axis sizes of 71 LNs differently diagnosed by PET/CT and histopathology findings were significantly smaller in the FN group than the TP group (P<0.001), whereas there was no difference between TP and FP. As for FN LNs in the TP group, there was no significant difference., Conclusions: PET/CT showed a good ability to detect metastatic LNs, especially for N2 diagnosis. However, there were some limitations, especially in cases with elevated peripheral WBC count and/or smoking history.

A 64-year-old man, who had received chemoradiation therapy for stage IIIB non-small-cell lung cancer, underwent stent insertion with a covered expandable metallic stent for post-radiation bronchial stenosis. Stenosis due to formation of granulation tissue at the distal stent site resulted in critical respiratory failure. The stent was removed after 43 months, using rigid bronchoscopy.

Background: The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype; it has a profound impact on cancer progression. The purpose of this study was to clarify the role of EMT in the sensitivity of non-small cell lung cancer (NSCLC) to chemoradiotherapy (CRT)., Methods: We evaluated the correlation between EMT and sensitivity to chemotherapy or radiotherapy using NSCLC cells induced to undergo EMT with epidermal growth factor or transforming growth factor-β1. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin, cytokeratin, N-cadherin, and vimentin in 50 tumor specimens obtained from patients with NSCLC both before and after CRT., Results: The EMT resulted in increased malignant potential and reduced sensitivity to cisplatin and paclitaxel in NSCLC cells. Furthermore, chronic exposure to cisplatin, paclitaxel, or radiation altered the cells into therapy-resistant sub-lines that showed phenotypic changes such as a spindle-cell shape and increased EMT marker expression. Also, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after CRT compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors., Conclusions: The EMT marker expression was detected in NSCLC tumors after CRT, indicating that EMT changes are associated with insensitivity to CRT. New therapeutic combinations using EMT-signaling inhibitors may be needed to circumvent the resistance of some types of cancer to CRT., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: The presence of isolated tumor cells (ITCs) in the pulmonary vein (PV) of a lung resected for lung cancer has been reported to be a prognostic factor. Previous investigations noted correlations between prognosis and the presence or amount of ITCs, although few studies have investigated the clinical implications of the morphological characteristics of those cells. We assessed the clinical implications of ITCs in the PV using a novel enrichment approach that maintained their morphological characteristics., Methods: Ninety-four consecutive patients with primary non-small-cell lung cancer (NSCLC) without preoperative chemo- and/or radiation therapy (p-stage I in 75, II in 13, III or IV in six) were studied. Blood samples were drawn from the PV draining the lung just after pulmonary resection, and ITCs were enriched using a CD45-negative selection method and density-gradient centrifugation, followed by Papanicolaou staining using 1ml of PV blood and immunohistochemical staining for cytokeratin in cases with an additional available blood sample. The ITCs were classified into four types based on patterns of cluster formation: no tumor cells (N), singular tumor cells (S), clustered cells (≤ 0.2mm) (CSs), and bulky clustered cells (> 0.2mm) (BCSs). We evaluated the correlations between ITC morphology and clinical results., Results: ITCs were detected in 68 of 94 patients (72%), of which the BCS type was observed in two, CS in 33, S in 33, and N in 26. Over a median follow-up period of 13 months (range 6-22 months), cancer recurrence occurred in 16 cases (17%): 14 in the combined CS/BCS group, one in S, and one in N. Log-rank analysis revealed that the disease-free survival rate was exclusively worse in patients with clustered ITCs as compared with the other two groups (p < 0.01)., Conclusions: The present method was useful to detect and enrich ITCs from the PV, and showed the clinical relevance of their morphology in lung cancer cases. The presence of ITC clusters may be a prognostic biomarker for patients with resected NSCLC., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: The chances of pulmonary resection for small-sized lung cancer have increased because of the development of thin-slice computed tomography (CT). Though sublobar resection could be indicated for ground glass opacity (GGO)-dominant adenocarcinoma with low-grade behaviour, the malignant potential of solid-type, small-sized lung cancer has not been sufficiently assessed. We aimed to address the clinical outcomes of resected solid-type c-stage IA non-small cell lung cancer (NSCLC) smaller than 2 cm., Methods: A retrospective observational study involving 118 patients who had undergone a complete resection for lung cancer smaller than 2 cm with solid component more than 50% on CT was conducted, and their postoperative survival and recurrence pattern were analysed., Results: Thirty-five patients with solid component-dominant lesion (SCDL) and 83 patients with pure solid lesion (PSL) without GGO were enrolled. Lymph node involvement was found in 15 patients with PSL (18%). The 5-year disease-free survival (DFS) was 100% in SDCL patients and 83% in PSL patients. Multivariate analysis of PSL patients showed that lymph node metastasis and pleural invasion were independent negative prognostic predictors. The 5-year DFS was 88%, 80% and 46% in p-N0, p-N1 and p-N2 patients, respectively. The 5-year DFS was 33% for patients with pleural invasion, which was significantly worse than that for patients without pleural involvement. Postoperative recurrence was mainly observed as intrathoracic lesions within 3 years., Conclusions: A proportion of solid-type NSCLC has malignant potential, even for tumours smaller than 2 cm. Periodic intrathoracic evaluation is required following complete resection., (Copyright 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Although video-assisted thoracic surgery (VATS) has been in use for more than a decade, its application to major lung resection for lung cancer is still not widely practiced. The success of a cancer operation is judged by the long-term survival of the treated patients. Therefore, the goal of the present study was to evaluate long-term outcomes associated with various video-assisted lobectomy techniques and conventional surgery in patients with peripheral non-small cell lung cancer less than or equal to 2 cm in diameter (stage IA)., Methods: A multi-institutional, retrospective review was performed in 145 consecutive patients. Patients with clinical stage IA disease, with tumor size less than or equal to 2 cm in diameter, from three institutions underwent a complete VATS (c-VATS, n = 56), an assisted VATS (a-VATS, n = 34), or a conventional open (open, n = 55) approach for pulmonary lobectomy and lymph node dissection., Results: Patients undergoing lobectomy and lymph node dissection with c-VATS had less blood loss, faster recovery, shorter hospitalization, and longer operating times than did patients undergoing the lobectomy with the a-VATS and open approaches. At a mean follow-up of 38.8 months, Kaplan-Meier probabilities of survival at 5 years were as follows: c-VATS, 96.7%; a-VATS, 95.2%; open, 97.2%. There was no significant difference in the rate of recurrence among the 3 different procedures., Conclusion: VATS lobectomy, a safe procedure with earlier return to normal activities, can be regarded as an acceptable cancer operation for the patients with peripheral non-small cell lung cancer less than or equal to 2 cm in diameter (clinical stage IA) with the same long-term survivals as open surgery.

We evaluated the usefulness of a real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) method for detecting occult tumor cells in histologically malignant-negative lymph nodes resected from patients with non-small cell lung cancer. First, we examined the relationship between tumor cell number and carcinoembryonic antigen (CEA) mRNA copy number using a PCR method with a cancer cell line (A549) in a serial dilution study. Next, we evaluated the relationship between nodal metastatic area size and CEA mRNA copy number using lymph nodes with histologically proven metastasis in a serial slice study. On the basis of those results, we performed RT-PCR analyses with 28 primary tumors and 211 lymph nodes from 28 patients who underwent a lobectomy with systematic node dissection. Our results in the serial dilution study showed that the detectable limitation by quantitative RT-PCR was 25-100 neoplastic cells and 20-100 CEA mRNA copy numbers. In the serial slice study, we found a correlation between CEA mRNA copy number and nodal metastatic area. In the clinical samples, amplification of CEA mRNA was obtained with all 28 primary tumors and 13 of the lymph nodes with metastasis shown by hematoxylin-eosin staining. Furthermore, 52 (25%) of 211 histologically negative lymph nodes and the specimens from 14 (64%) of the 22 pN0 patients revealed a significant level of CEA mRNA. These results indicate that micrometastases, which are not detectable with conventional examinations, can be detected by the present method of RT-PCR for CEA mRNA in a proportion of patients with resected pN0 non-small cell lung cancer.

Objective: The number of surgical interventions for small-sized lung cancer has increased with the development of computed tomography. We attempted to identify clinicopathologic characteristics of peripheral, small-sized, non-small cell lung cancer to show the limitation of partial resection or segmentectomy., Methods: A retrospective analysis of 143 patients who underwent a complete resection for a peripheral non-small cell lung cancer of 2 cm or less in diameter was performed. The relationships between nodal involvement and other clinical factors were also assessed in patients who underwent a lobectomy plus node dissection., Results: The overall 5-year survival rate was 88.1%. The 5-year survival rate was 100% for patients with a tumor of 1.5 cm or less. Survival for patients with adenocarcinoma histology was significantly better than for those with nonadenocarcinoma histology (P = .03). The 5-year survival rate for patients without lymph node metastases was 91.6%, whereas it was 62.5% for those with nodal involvement (P < .01). Increase of prethoracotomy serum carcinoembryonic antigen level was an independent predictor of a poor prognosis. Lymph node metastasis was significantly increased in those with pleural invasion by the primary lesion and increased serum carcinoembryonic antigen level. Fourteen (16.9%) of 83 patients with a tumor diameter of larger than 1.5 cm had nodal metastasis., Conclusions: Nodal involvement should be considered in patients with non-small cell lung cancer of 2 cm or less in diameter who show pleural invasion or an increased carcinoembryonic antigen level. A lobectomy with node dissection is recommended for patients with a tumor larger than 1.5 cm, suspected pleural invasion, or prethoracotomy carcinoembryonic antigen level increase.