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Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non–small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089–97. ©2018 AACR.

Figure S1. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by 25(OH)D equal to or greater than 30 ng/mL. Figure S2. Kaplan-Meier curves of patients restricted only to adenocarcinoma, or both early stages (IA - IIB) and adenocarcinoma. Figure S3. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of FokI. Mean (SD) of 25(OH)D in each genotype are as follows; FokI CC, 19.9 (6.2) ng/ml; CT, 21.8 (6.6) ng/ml; TT 21.4 (7.9) ng/ml. Figure S4. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of BsmI. Mean (SD) of 25(OH)D in each genotype are as follows: BsmI AA, 15 (-) ng/ml; AG, 20.2 (6.4) ng/ml; GG 21.7 (6.8) ng/ml. Figure S6. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of ApaI. Mean (SD) of 25(OH)D in each genotype are as follows: ApaI GG, 21.2 (7.2) ng/ml; GT, 21.4 (6.3) ng/ml; TT, 21.5 (7.7) ng/ml. Figure S7. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of TaqI. Mean (SD) of 25(OH)D in each genotype are as follows: TaqI TT, 21.7 (6.7) ng/ml; TG, 20.4 (6.9) ng/ml; GG, - (-) ng/ml. Figure S8. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of DBP1. Mean (SD) of 25(OH)D in each genotype are as follows: DBP1 TT, 21.3 (7.0) ng/ml; TG, 20.8 (6.0) ng/ml; GG, 23.6 (7.9) ng/ml. Figure S9. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of DBP2. Mean (SD) of 25(OH)D in each genotype are as follows: DBP2 CC, 22.7 (6.6) ng/ml; CA, 20.0 (6.3) ng/ml; AA, 12.8 (1.5) ng/ml.

This study evaluated the feasibility of performing non-intubated video-assisted thoracoscopic surgery (VATS) with local anesthesia for parapneumonic effusion and empyema resistant to conservative treatment.We retrospectively reviewed 80 patients who underwent surgery for parapneumonic effusions and empyema between 2015 and 2021. Patients were divided into those who received non-intubated local anesthesia and general anesthesia during surgery. Patient demographics, characteristics, laboratory findings, treatment progress, and treatment outcomes were compared. The primary outcomes were duration of postoperative drainage, postoperative complication rate, and postoperative mortality rate within 30 days.Among patients who received local (n = 21) and general anesthesia (n = 59), there was a significant difference in age (median 79.0 years [interquartile range (IQR) 77.0-80.0] vs. 68.0 years [IQR 54.5-77.5]; p 0.001), preoperative performance status (3.0 [IQR 2.0-4.0] vs. 2.0 [IQR 1.0-3.0]; p 0.001), and operative time (69 min [IQR 50-128] vs. 150 min [IQR 107-198]; p 0.001) but not in preoperative white blood cell count (12,100/μL [IQR 8,400-18000] vs. 12,220/μL [IQR 8,950-16,724]; p = 0.840), C-reactive protein (15.2 mg/dL [8.8-21.3] vs. 17.9 mg/dL [IQR 9.5-23.6]; p = 0.623), postoperative drainage period (11 days [IQR 7-14] vs. 9 days [7-13]; p = 0.216), postoperative hospital stay (22 days [IQR 16-53] vs. 18 days [IQR 12-26]; p = 0.094), reoperation rate (9.5% vs. 15.3%; p = 0.775), postoperative complication rate (19.0% vs. 18.6%; p = 0.132), or postoperative 30-day mortality rate (4.8% vs. 0%; p = 0.587).VATS using local anesthesia is feasible for patients with treatment-resistant parapneumonic effusion and empyema with poor general condition.

Background Whole-layer laparoscopic cholecystectomy (W-LC) has recently been advocated as a total biopsy for potentially malignant neoplasms of the gallbladder; however, it is not an injury-proof procedure. This study reports W-LC using the segment IV approach (technique for securing the whole-layer gallbladder at the medial origin of the cystic plate).MethodsTwenty among twenty-five patients diagnosed with potentially malignant gallbladder polyps underwent this technique.ResultsMostly, W-LC was performed successfully (median operative time 135 min) without intraoperative and postoperative complications. Pathological findings indicated that cholesteric polyps was the most common type (n=13), followed by adenomatous polyps (25%) and carcinoma in situ (5%).ConclusionsWe conclude that the segment IV approach is appropriate for performing total biopsy in patients diagnosed with potentially malignant gallbladder polyps.

Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD., Altered iron homeostasis resulting in excessive oxidative stress has been implicated in smoke-induced lung diseases. Here the authors show that ferroptosis of lung epithelial cells, potentially resulting from excessive ferritinophagy, is involved in the pathogenesis of COPD.

OBJECTIVES Difficult thoracoscopic surgery sometimes requires a long operative time. It is unclear whether patients benefit from such thoracoscopic surgeries. We investigated whether thoracoscopic surgery for difficult cases contributed to improvements in perioperative outcomes. METHODS We retrospectively reviewed cases of anatomical lung resection with thoracoscopic surgery, including conversion to thoracotomy, between January 2006 and December 2016 and compared patient demographics and perioperative outcomes of the long (≥360 min) and the normal operative time groups (

Background: The present study evaluated the impact of the introduction of thoracoscopic lung lobectomy (TL) for non-small cell lung cancer at our institution. Methods: This study retrospectively compared surgical and oncological outcomes in the period before and after the introduction of TL for non-small cell lung cancer. Propensity score-matched analysis was performed with respect to baseline patient variables and tumor characteristics. Results: Patients were divided into two groups: those who underwent lung lobectomy in the period before (BI group, n=261) and after (AI group, n=261) the introduction of TL. The proportion of TLs at our institution increased from 1.3% in the BI group to 93% in the AI group. The AI group experienced a longer duration of surgery, lesser intraoperative blood loss, and a significantly shorter postoperative hospital stay (POHS). There were no significant differences in postoperative complications between the two groups. The median follow-up period was 50 months in both groups. No significant differences were observed between the BI and AI groups with respect to 5-year overall survival (OS) (76.1% and 71.7%, respectively; P=0.1973) and disease-free survival (DFS) (67.6% and 66.1%, respectively; P=0.4071). On multivariate analysis, pathological N1–2 status was an independent predictor of survival. AI group and TL showed no independent association with survival. Conclusions: The introduction of TL represented a positive change at our institution owing to decreased invasiveness and oncological equivalence of the surgical treatment for non-small cell lung cancer.

Background: We assessed how the severity of chronic obstructive pulmonary disease (COPD) and other comorbidities affect long-term survival after thoracoscopic lung resection for c-stage I non-small cell lung cancer (NSCLC). Methods: Patients with c-stage I NSCLC who underwent thoracoscopic lung resection at our hospital between 2006 to 2014 were retrospectively analyzed. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grades were used to classify the severity of COPD, and comorbidity was classified according to the Charlson comorbidity index (CCI). Various outcomes were assessed and compared. Results: The cohort comprised 404 patients with NSCLC, of whom 133 were diagnosed with COPD (51 as GOLD 1, 79 as GOLD 2, and 3 as GOLD 3) and 271 were diagnosed without COPD. The 5-year overall survival (OS) rates were 86.0%, 80.2%, and 71.1% for the non-COPD, GOLD 1, and GOLD 2/3 groups, respectively (P=0.0221); the corresponding 5-year disease-specific survival (DSS) rates were 91.7%, 86.9%, and 85.1% (P=0.2136). Univariate analysis indicated that sex, smoking status, pathology, COPD severity, CCI, and pathological stage were associated with OS, and multivariate analysis confirmed the association with CCI and pathological stage. Postoperative complications were significantly more frequent in the GOLD 1 (21.5%) and GOLD 2/3 (26.8%) groups than in the non-COPD group (12.1%) (P=0.0040). Conclusions: Following thoracoscopic surgery (TS) for NSCLC, patients with COPD had a poorer OS than patients without COPD. However, the CCI and not the COPD severity was the independent prognostic factor for OS. Comorbidities adversely affected long-term survival of patients with stage I NSCLC and COPD after TS, and the same effect can be oncologically expected regardless of the COPD severity.

Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.

Objectives For the purpose of simulating thoracoscopic surgery, we have conducted stepwise development of a life-like chest model including thorax and intrathoracic organs. Methods First, CT data of the human chest were obtained. First-generation model: based on the CT data, each component of the chest was made from a 3D printer. A hard resin was used for the bony thorax and a rubber-like resin for the vessels and bronchi. Lung parenchyma, muscles and skin were not created. Second-generation model: in addition to the 3D printer, a cast moulding method was used. Each part was casted using a 3D printed master and then assembled. The vasculature and bronchi were casted using silicon resin. The lung parenchyma and mediastinum organs were casted using urethane foam. Chest wall and bony thorax were also casted using a silicon resin. Third-generation model: foamed polyvinyl alcohol (PVA) was newly developed and casted onto the lung parenchyma. The vasculature and bronchi were developed using a soft resin. A PVA plate was made as the mediastinum, and all were combined. Results The first-generation model showed real distribution of the vasculature and bronchi; it enabled an understanding of the anatomy within the lung. The second-generation model is a total chest dry model, which enabled observation of the total anatomy of the organs and thorax. The third-generation model is a wet organ model. It allowed for realistic simulation of surgical procedures, such as cutting, suturing, stapling and energy device use. This single-use model achieved realistic simulation of thoracoscopic surgery. Conclusions As the generation advances, the model provides a more realistic simulation of thoracoscopic surgery. Further improvement of the model is needed.

OBJECTIVES Thoracoscopic surgery is widely used for the surgical treatment of thymoma. However, large-sized thymomas are typically treated using open surgery. This study evaluated the feasibility of performing thoracoscopic thymectomy (TT) for thymoma ≥50 mm. METHODS A retrospective review was conducted on 135 patients who underwent TT or open thymectomy (OT) for Masaoka stage I-IVa thymoma between 1996 and 2014. RESULTS Patients were first divided into two groups based on thymoma size: thymoma ≥50 mm and thymoma

Background Minimally invasive thoracoscopic lobectomy is the recommended surgery for clinical stage I non-small cell lung cancer (NSCLC). The purpose of this study was to identify the risk factors, including sarcopenia, for postoperative complications in patients undergoing a complete single-lobe thoracoscopic lobectomy for clinical stage I NSCLC, as well as the impact of complications on disease-free survival. Methods We retrospectively investigated 173 patients with pathologically-diagnosed NSCLC who underwent curative thoracoscopic lobectomies between April 2013 and March 2018. Sarcopenia was assessed using the psoas muscle index calculated from preoperative computed tomography images at the third lumbar vertebral level. Results Complications developed in 38 (22%) patients, including 21 with prolonged air leak. In univariate analysis, the significant risk factors for complications were advanced age, male sex, higher Charlson Comorbidity Index (CCI) score, lower cholinesterase, lower albumin, higher creatinine level, pleural adhesion, operative time ≥ five hours, nonadenocarcinoma cancer, and larger tumor size. Multivariate analysis showed that age ≥ 75 years (P = 0.002) and pleural adhesion (P = 0.026) were significant independent risk factors for complications. Compared with the patient group without complications, postoperative complications were independently associated with shorter disease-free survival (P = 0.01). Conclusions Advanced age and pleural adhesion were independent risk factors for complications after complete single-lobe thoracoscopic lobectomies for clinical stage I NSCLC, and postoperative complications were statistically associated with poor prognosis. Surgical teams should ensure an experienced surgeon leads the operation for patients at higher risk to avoid prolonged postoperative hospitalization and a possible poor prognosis.

Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition–mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.

Downregulation of lamin B1 has been recognized as a crucial step for development of full senescence. Accelerated cellular senescence linked to mechanistic target of rapamycin kinase (MTOR) signaling and accumulation of mitochondrial damage has been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. We hypothesized that lamin B1 protein levels are reduced in COPD lungs, contributing to the process of cigarette smoke (CS)–induced cellular senescence via dysregulation of MTOR and mitochondrial integrity. To illuminate the role of lamin B1 in COPD pathogenesis, lamin B1 protein levels, MTOR activation, mitochondrial mass, and cellular senescence were evaluated in CS extract (CSE)–treated human bronchial epithelial cells (HBEC), CS-exposed mice, and COPD lungs. We showed that lamin B1 was reduced by exposure to CSE and that autophagy was responsible for lamin B1 degradation in HBEC. Lamin B1 reduction was linked to MTOR activation through DEP domain–containing MTOR-interacting protein (DEPTOR) downregulation, resulting in accelerated cellular senescence. Aberrant MTOR activation was associated with increased mitochondrial mass, which can be attributed to peroxisome proliferator-activated receptor γ coactivator-1β–mediated mitochondrial biogenesis. CS-exposed mouse lungs and COPD lungs also showed reduced lamin B1 and DEPTOR protein levels, along with MTOR activation accompanied by increased mitochondrial mass and cellular senescence. Antidiabetic metformin prevented CSE-induced HBEC senescence and mitochondrial accumulation via increased DEPTOR expression. These findings suggest that lamin B1 reduction is not only a hallmark of lung aging but is also involved in the progression of cellular senescence during COPD pathogenesis through aberrant MTOR signaling.

Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non–small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869). Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment. Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089–97. ©2018 AACR.

Introduction The objective of this study was to evaluate the feasibility of thoracoscopic thymectomy (TT) for treatment of early-stage thymoma and to compare the outcomes with those after open thymectomy (OT). Methods A retrospective review of 98 patients who underwent TT or OT of Masaoka stage I-II thymoma without thymic cancer between 1996 and 2013 was performed. Results Thoracoscopic thymectomy was performed in 67 patients, and OT was performed in 31 patients. The intraoperative blood loss amounts differed significantly between the TT group and OT group (100 vs 185 mL, P = 0.0070). The postoperative hospital stay was significantly shorter in the TT group than in the OT group (4 vs 12 days, P

Background Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy. Methods Transforming growth factor-β (TGF-β)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice. Results We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-β. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD. Conclusions These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.

Thymoma remains the most common primary anterior mediastinal neoplasm. Surgical resection remains central to the treatment of thymoma, with thoracoscopic thymectomy (TT) being increasingly performed. This present review article aimed to summarize current studies comparing TT and open thymectomy (OT). Recently, most patients with Masaoka stage I-II thymoma have been receiving TT. This procedure is associated with a significantly shorter post-operative hospital stay, decreased intraoperative blood loss, and fewer complications compared with OT. Recurrence rates of thymoma after TT range from 0% to 6.7%, and the 5-year disease-free survival (DFS) ranges from 83.3% to 96%. The oncological outcomes of TT are comparable to that of OT. Masaoka stage and the World Health Organization (WHO) type classification are valuable predictors of the prognosis of thymoma; hence, the optimal treatment for thymoma should be performed according to these two. TT is less invasive, with equivalent oncological outcomes, when compared with the OT. Minimally invasive surgery including TT for stage I-II thymomas is becoming the mainstay of therapy.

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Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

OBJECTIVES: Thoracoscopic thymectomy has gradually replaced conventional sternotomy for resection of thymoma; however, a thoracoscopic approach for thymoma remains controversial. We evaluated the oncological outcomes of thoracoscopic thymectomy for the treatment of stages I–III thymomas. METHODS: Sixty-two patients who underwent thoracoscopic thymectomy for the treatment of thymoma were retrospectively reviewed between July 2005 and September 2011 at Jikei University Hospital. Surgical outcomes and pathological results between stages I + II and stage III were compared. RESULTS: Twenty-nine patients had Masaoka stage I, 28 had stage II and 5 had stage III. Three stage III patients needed conversions to open surgery. Masaoka stage III comprised pathological type B3 in 3 patients and thymic carcinoma in 2. For all patients, the 5-year overall survival rate was 100%. Three recurrences, diagnosed as thymic carcinoma, were observed in the Masaoka stage II or III patients. The 5year disease-free survival rate was 94.2% for all patients, 100% for Masaoka stage I, 96.1% for stage II and 37.5% (55 months) for stage III (P= 0.002). The 5-year disease-free survival rate was 100% for the World Health Organization classification types A, AB and B1–3 and 0% for thymic carcinoma (P< 0.0001). Significant differences were found in the 5-year disease-free survival stratified by the Masaoka stage or WHO classification, but not by surgical procedures. CONCLUSIONS: Thoracoscopic thymectomy for Masaoka stages I and II thymomas presented acceptable oncological outcomes. Further investigation in a large series with longer follow-up is required. Masaoka stage III thymoma requires careful consideration of the approaches, including median sternotomy.

Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF.

Introduction Secondary spontaneous pneumothorax (SSP) can be life threatening because patients often have severe lung disease with other coexisting diseases such as heart disease. In this study, we evaluate the feasibility of thoracoscopic surgery to treat SSP and discuss thoracoscopic techniques for managing complicated cases. Methods We retrospectively evaluated the outcome of thoracoscopic surgeries in 21 SSP patients. Results Fifteen patients had chronic emphysema, four had interstitial pneumonia, and two had inflammatory lung disease. All patients presented with persistent air leaks, and their median preoperative hospital stay was 11 days. All patients underwent thoracoscopic surgery. In 12 patients, the leaking bullae were excised by endoscopic stapling. Fibrin glue was used in 16 cases and polyglycolic acid sheets in 17. Polyglycolic acid sheets and fibrin glue without bullectomy were used in three cases. Air leaks were treated by simple stapling in four cases and by gelatin-resorcin formaldehyde glue in five. Median postoperative hospital stay was 8 days. No patients required conversion to open surgery. Postoperative complications such as persistent air leaks, pneumonia, and acute respiratory failure were observed in six patients. Four recurrences of pneumothorax were observed during the median postoperative follow-up period of 19.3 months. Conclusion Our results suggest that thoracoscopic surgery is feasible and less invasive than open surgery for high-risk patients, and it improves patient quality of life. Various techniques to stop air leaks enabled us to treat patients with refractory SSP.

Cigarette smoke induces damage to proteins and organelles by oxidative stress, resulting in accelerated epithelial cell senescence in the lung, which is implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Although the detailed molecular mechanisms are not fully understood, cellular energy status is one of the most crucial determinants for cell senescence. Creatine kinase (CK) is a constitutive enzyme, playing regulatory roles in energy homeostasis of cells. Among two isozymes, brain-type CK (CKB) is the predominant CK in lung tissue. In this study, we investigated the role of CKB in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBECs). Primary HBECs and Beas2B cells were used. Protein carbonylation was evaluated as a marker of oxidative protein damage. Cellular senescence was evaluated by senescence-associated β-galactosidase staining. CKB inhibition was examined by small interfering RNA and cyclocreatine. Secretion of IL-8, a hallmark of senescence-associated secretary phenotype, was measured by ELISA. CKB expression levels were reduced in HBECs from patients with COPD compared with that of HBECs from nonsmokers. CSE induced carbonylation of CKB and subsequently decreased CKB protein levels, which was reversed by a proteasome inhibitor. CKB inhibition alone induced cell senescence, and further enhanced CSE-induced cell senescence and IL-8 secretion. CSE-induced oxidation of CKB is a trigger for proteasomal degradation. Concomitant loss of enzymatic activity regulating energy homeostasis may lead to the acceleration of bronchial epithelial cell senescence, which is implicated in the pathogenesis of COPD.

TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8–dependent mechanisms. However, insulin efficiently inhibited TLR3/ polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.

Details with regard to the standard criteria for a therapeutic metastasectomy and the use of video-assisted thoracic surgery (VATS) remain elusive. To evaluate the feasibility of VATS using a tailor-made virtual lung for patients with pulmonary metastases after chemotherapy, we reviewed the following cases.Clinical data from October 2006 to April 2010 were obtained from patients who received chemotherapy before a pulmonary metastasectomy (lobectomy or segmentectomy). VATS was the primarily selected surgical approach except for treating hilar lesions. A lobectomy was performed when the metastasis was greater than 3.0 cm in diameter or located deeply in the lobe. Tailor-made virtual lungs were created using three-dimensional multidetector computed tomography before lobectomy on a routine basis. The virtual lung consisted of three-dimensional pulmonary vessels, a tracheobronchial tree, pulmonary parenchyma, and tumors.Twelve operations, consisting of 1 segmentectomy, 10 lobectomies, and 1 wedge bronchoplasty upper lobectomy, were performed on 11 patients during the study period. VATS was completed in 10 of these 12 operations. The mean operative time for the lobectomies was 257 min, and the mean operative bleeding volume was 215 ml. Two cases experienced postoperative transient atrial fibrillation, and no mortalities associated with these operations were reported.VATS was performed safely in instances of metastasectomy after chemotherapy, and the tailor-made virtual lung assisted in lung orientation during the operation.

Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated β-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-β-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1β expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-β induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-β also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-β-induced senescence via proteasomal degradation of p21. TGF-β-induced senescent HBEC secreted increased amounts of IL-1β, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.

症例は23歳女性．2009年5月頃より左胸痛を自覚し，6月下旬より発熱を認めた．胸部X線上左下肺野に異常陰影および左胸水貯留を呈し，胸部CTでは左胸腔内に7cm大の境界明瞭な嚢胞性腫瘤影が確認された．採血では腫瘍マーカーCA19-9が異常高値を示した．画像上縦隔腫瘍を疑い，手術目的で当科受診した．完全胸腔鏡下手術により病変の完全切除が行われ，切除した検体の内腔には毛髪や皮脂を含み，組織学的には膵組織などを伴う成熟型嚢胞性奇形腫と考えられた．術前高値を示した血中CA19-9は術後正常値に戻った．

Precise imaging modalities are necessary during pulmonary resection to assess nodules that are otherwise difficult to diagnose. Studies have demonstrated that partial lung resection can completely cure adenocarcinoma in situ and minimally invasive adenocarcinoma. The important considerations for partial lung resection are: (I) to accurately identify the location of a small tumor intraoperatively and (II) to ensure a sufficient resection margin and preserve the remaining lung function. Hence, precise detection of hardly palpable or invisible tumors is essential. Although some reports describe methods for marking tumor locations, these processes are both invasive and complicated. Here, we describe a novel intraoperative navigation system that easily feeds image information to the operator on-site and evaluated its feasibility in three cases of partial lung resection. Implementing the software developed by Amin Inc. allowed three-dimensional scaling, rotation, transparency display, and calculation of tumor volumes in real time using a tablet computer (TC) interfaced with a hand tracking and voice control device. The surgeon, assistant, and digital imaging assistant can preoperatively verify the image using a TC by simulating the virtual resection line and insertion angle of the endoscopic stapler. During surgery, the tumor was assessed with a thoracoscope in comparison with the constructed three-dimensional image. Partial resection was successfully performed and pathological excision margins were negative in all cases. Other than prolonged air leakage in one case, no other complications were encountered. This novel navigation system appears to be safe and effective for less invasive partial lung resection.

Introduction: The thoracoscopic approach is becoming the standard for intrathoracic neurogenic tumors, though certain technical issues still need to be resolved. The purpose of this study is to evaluate the feasibility of thoracoscopic surgery for intrathoracic neurogenic tumors. Methods: We evaluated short-term outcomes of 14 consecutive patients who underwent resection of intrathoracic neurogenic tumors between July 2005 and June 2009. Among them, three patients had tumors located at the thoracic apex, and one had a tumor with an intraspinal extension (dumbbell-type tumor). Results: A complete thoracoscopic resection was achieved in all patients with no postoperative mortality. The dumbbell-type tumor was resected with a combined neurosurgical–thoracoscopic approach. The postoperative course was uneventful in all patients. Conclusion: Our thoracoscopic approach was able to obtain satisfactory visualization of the field and enabled safe surgery for intrathoracic neurogenic tumors. This approach is minimally invasive and is indicated even for tumors located at the thoracic apex or those with intraspinal extensions.

胸腔頂部に発生する神経原性腫瘍に対する外科的治療は手術アプローチの選択が難しい．手術操作が可能な術創と視野を確保するため大きな術創を必要とし侵襲が大きい．そこで近年，胸腔鏡手術が選択されるようになってきた．縦隔腫瘍に対し胸腔鏡手術が広く行われているとはいえ，胸腔頂部の腫瘍に対する胸腔鏡手術は技術的に容易ではなく適切な手術操作を要する．症例は25歳男性．健康診断で右肺尖部に異常影を指摘され当院を受診した．胸部CTで右胸腔頂部に腫瘍を認め，胸腔頂部に発生した神経原性腫瘍と診断し胸腔鏡手術を施行した．腫瘍は交感神経幹から発生し胸腔頂部から半球状に突出しており，周囲を剥離し腫瘍を切除した．経過は良好であり，術後4日目に退院した．胸腔頂部の神経原性腫瘍に対して胸腔鏡手術は良好な視野を得ることができ，安全な手術操作が可能であった．

症例は47歳の男性．主訴は易疲労感，労作時の息切れであった．精査にて赤芽球癆および低ガンマグロブリン血症と診断し，胸部CT上，前縦隔に胸腺と一致して長径87mmの境界明瞭な腫瘤性病変を認めた．本症例に対し，われわれはintension to treatによる胸腔鏡下胸腺胸腺腫切除を施行した．手術時間は255分で出血量は100mlであった．切除検体は88×53×30mm，93g．病理組織検査にてWHO分類type AB，正岡分類II期の胸腺腫と診断した．本症は術後42病日に貧血を認め輸血を行い，現在，内科的治療にて経過観察中である．赤芽球癆および低ガンマグロブリン血症を合併した胸腺腫は非常に稀である．赤芽球癆は難治性自己免疫疾患で，胸腺腫合併例に対する胸腺全摘術は，赤芽球癆に対する内科的治療の抵抗性を改善させる．さらに，胸腔鏡下手術は従来の胸骨正中切開手術と比較し，低侵襲手術であり，自己免疫疾患と関連する胸腺疾患への適応拡大が期待される．本例と同様の症例に対する，胸腔鏡手術の術後成績の蓄積が必要と考える．

This study evaluated the feasibility of thoracoscopic thymectomy (TT) for the treatment of early- and advanced-stage thymoma and compared patient outcomes with those following open thymectomy (OT). A retrospective review was conducted for 140 patients who underwent TT or OT for Masaoka stage I–IV thymoma between 1996 and 2014. TT was performed in 88 patients and OT in 52 patients. The postoperative hospital stay was significantly shorter in the TT group than in the OT group (4 and 13 days, respectively; P