Surgical treatment for pulmonary metastasis from ovarian cancer: a retrospective case series.

BACKGROUND: Distant metastases of ovarian cancer are rarely detected alone. The effectiveness of surgical intervention for pulmonary metastases from ovarian cancer remains uncertain. This study aimed to investigate the clinicopathologic characteristics and outcomes of patients undergoing resection for pulmonary metastasis from ovarian cancer. CASE PRESENTATION: The clinicopathologic characteristics and outcomes of radical surgery for pulmonary metastasis from ovarian cancer were investigated. Out of 537 patients who underwent pulmonary metastasis resection at two affiliated hospitals between 2010 and 2021, four (0.74%) patients who underwent radical surgery for pulmonary metastasis from ovarian cancer were included. The patients were aged 67, 47, 21, and 59 years; the intervals from primary surgery to detection of pulmonary metastasis from ovarian cancer were 94, 21, 36, and 50 months; and the overall survival times after pulmonary metastasectomy were 53, 50, 94, and 34 months, respectively. Three of the four patients experienced recurrence after pulmonary metastasectomy. Further, preoperative carbohydrate antigen (CA) 125 levels were normal in two surviving patients and elevated in the two deceased patients. CONCLUSION: In this study, three of the four patients experienced recurrence after pulmonary metastasectomy, but all patients survived for > 30 months after surgery. Patients with ovarian cancer and elevated CA125 levels may not be optimal candidates for pulmonary metastasectomy. To establish appropriate criteria for pulmonary metastasectomy in patients with ovarian cancer, further research on a larger patient cohort is warranted.

Prognostic factors in pulmonary metastases resection from colorectal cancer: impact of right-sided colon cancer and early recurrence.

OBJECTIVE: This retrospective cohort study aimed to explore the surgical outcomes and prognostic factors of resection of pulmonary metastases (PM) from colorectal cancer (CRC). METHODS: Overall, 60 patients who underwent resection of PM from CRC between 2015 and 2021 at two institutions were reviewed. The primary outcome were overall survival (OS) and early recurrence after PM resection. The association between OS and right-sided colon cancer (RCC) was investigated. Early recurrence after PM resection was defined as recurrence within one year. RESULTS: The 5-year OS after CRC resection was 83.8% (95% confidence interval [CI] 67.5-92.4) and after PM resection was 69.4% (95% CI 47.5-83.6). In total, 25 patients had recurrence after PM resection (16 within 1 year and 9 after 1 year). In multivariable analysis for OS, RCC (hazard ratio [HR] 4.370, 95% CI 1.020-18.73; p = 0.047) and early recurrence after resection of PM (HR 17.23, 95% CI 2.685-110.6; p = 0.003) were risk factors for poor OS. In multivariable analysis for early recurrence after PM resection, higher value of carcinoembryonic antigen (CEA) (> 5.0 mg/dL) before PM resection was a risk factor for early recurrence (HR 3.275, 95% CI 1.092-9.821; p = 0.034). CONCLUSION: The RCC and early recurrence after PM resection were poor prognosis factors of OS. Higher value of CEA before PM resection was an independent risk factor for early recurrence after resection of PM. Comparitive study between surgery and nonsurgery is necessary in patients with higher CEA values.

Reduction in drain-related adverse events using the barbed suture method for chest tube wound closure.

OBJECTIVE: A chest tube is usually placed in patients undergoing general thoracic surgery. Although the barbed suture method has been introduced for chest tube wound closure, its superiority to the conventional suture methods for drain management remains unclear. The study aimed to determine whether the barbed suture method could reduce drain-related adverse events compared to the conventional method. METHODS: We retrospectively reviewed the medical records of patients who underwent general thoracic surgery between January 2021 and December 2022, 1 year before and after the introduction of the barbed suture method at our institution. Patients who underwent the barbed suture or conventional method were included. Univariate and multivariate analyses of drain-related adverse events were performed. RESULTS: Of the 250 participants, 110 and 140 underwent the barbed suture method and conventional suture method, respectively. The univariate analysis showed that a higher body mass index, preoperative malignant diagnosis, lobectomy, longer operative time, larger tube size, longer chest drainage duration, surgical complications, and conventional method were risk factors for drain-related adverse events. The multivariate analysis showed that the barbed suture method was a protective factor against drain-related adverse events (odds ratio 0.267; 95% confidence interval 0.103-0.691; P = 0.007). CONCLUSIONS: The barbed suture method could reduce drain-related adverse events compared to the conventional method. Therefore, it might be a potential standard method for chest tube wound closure in patients undergoing general thoracic surgery.

Pulmonary metastases of a borderline ovarian tumor with multiple cystic formations: a case report.

BACKGROUND: Metastatic lung tumors rarely present with cystic formations. This is the first report of multiple cystic formations in pulmonary metastases from mucinous borderline ovarian tumors written in English. CASE PRESENTATION: A 41-year-old woman underwent left adnexectomy + partial omentectomy + para-aortic lymphadenectomy for a left ovarian tumor 4 years ago. The pathological finding was mucinous borderline ovarian tumor with a microinvasion. A chest computed tomography performed 3 years after surgery revealed multiple cystic lesions in both lungs. After 1-year follow-up, the cysts increased in size and wall thickness. Subsequently, she was referred to our department with multiple cystic lesions in both lungs. No laboratory findings indicated infectious diseases or autoimmune disorders that could cause cystic lesions in both lungs. Positron emission tomography showed slight accumulation in the cyst wall. Partial resection of the left lower lobe was performed to confirm the pathological diagnosis. The diagnosis was consistent with pulmonary metastases from a previous mucinous borderline ovarian tumor. CONCLUSIONS: This is a rare case of lung metastases from a mucinous borderline ovarian tumor presenting with multiple lesions with cystic formation. Pulmonary cystic formations in patients with a borderline ovarian tumor should be considered as possible pulmonary metastases.

Comparative study of local versus general anesthesia in video-assisted thoracoscopic surgery for empyema.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: VATS using local anesthesia is feasible for patients with treatment-resistant parapneumonic effusion and empyema with poor general condition.

Risk factors and cancer recurrence associated with postoperative complications after thoracoscopic lobectomy for clinical stage I non-small cell lung cancer.

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.

Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis.

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.

Involvement of Lamin B1 Reduction in Accelerated Cellular Senescence during Chronic Obstructive Pulmonary Disease 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-1ß-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.

PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis.

Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: CS extract; CXCL1: C-X-C motif chemokine ligand 1; CXCL8: C-X-C motif chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL: interleukin; KO: knockout; LF: lung fibroblasts; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PCD: programmed cell death; PFD: pirfenidone; PIK3C: phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1: PTEN induced putative kinase 1; PTEN: phosphatase and tensin homolog; RA: rheumatoid arthritis; ROS: reactive oxygen species; SA-GLB1/ß-Gal: senescence-associated-galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF: tumor necrosis factor.

Perioperative outcomes of thoracoscopic lung resection requiring a long operative time.

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 (<360 min). RESULTS: One hundred and seventy-six patients were in the long operative time group and 655 patients were in the normal operative time group. The long operative time group had more male patients, more progressive clinical stages, bilobectomy or pneumonectomy, conversion to thoracotomy and more blood loss than the normal operative time group. The long operative time group had higher rates of postoperative complications and longer hospital stay (30% vs 16%, P < 0.001 and 9 ± 9 days vs 7 ± 8 days, P < 0.001; respectively). Multivariate analysis showed that in the first half of the operative period, chronic obstructive pulmonary disease and bilobectomy or pneumonectomy were independent predictive factors for postoperative complications. The long operative time as a factor was close to statistical significance (odds ratio 1.689, P = 0.079) unlike the elective conversion to thoracotomy (odds ratio 0.784, P = 0.667) and emergency conversion to thoracotomy (odds ratio 0.938, P = 0.924). CONCLUSIONS: In conclusion, when difficult cases are encountered, conversion to thoracotomy should be considered by surgeons if continuation of thoracoscopic surgery increases the operative time.

Impact of the introduction of thoracoscopic lobectomy for non-small cell lung cancer: a propensity score-matched analysis.

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.

Vitamin D Supplementation and Survival of Patients with Non-small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.

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, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D-binding protein (DBP) and survival were also examined.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.

Effect of comorbidities on long-term outcomes after thoracoscopic surgery for stage I non-small cell lung cancer patients with chronic obstructive pulmonary disease.

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.

Surgical and oncological outcomes of thoracoscopic thymectomy for thymoma.

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.

Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4.

Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor ß) 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.

Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy.

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-ß (TGF-ß)-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-ß. 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.

A step-by-step development of real-size chest model for simulation of thoracoscopic surgery.

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.

Thoracoscopic thymectomy is a feasible and less invasive alternative for the surgical treatment of large thymomas.

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 <50 mm groups. There was no significant difference in the 5-year disease-free survival (DFS) between the groups ( P = 0.5352). Patients in the thymoma ≥50 mm group were further subdivided into TT and OT groups. The length of postoperative hospital stay was significantly shorter in the TT group than in the OT group (5 vs 14 days, P < 0.0001), with significantly fewer postoperative complications (6 patients vs 14 patients, P = 0.0008). There was no significant difference in the 5-year DFS between patients with thymoma ≥50 mm in the TT and OT groups ( P = 0.3501). Finally, patients undergoing TT were further subdivided into thymoma ≥50 mm and thymoma <50 mm groups and, no significant difference in the 5-year DFS was found between these groups ( P = 0.6661). Masaoka stages III-IV, but not thymoma size, were an independent prognostic factor for DFS. CONCLUSIONS: These results demonstrate the decreased invasiveness and feasibility of TT for large-sized thymomas.

Comparison of oncological results for early- and advanced-stage thymomas: thoracoscopic thymectomy versus open thymectomy.

BACKGROUND: 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). METHODS: A retrospective review was conducted for 140 patients who underwent TT or OT for Masaoka stage I-IV thymoma between 1996 and 2014. RESULTS: 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 < 0.0001). WHO types B3-C were identified in Masaoka stage III-IV disease with high frequency. There was a significant relationship between Masaoka stage and WHO type (P < 0.05); the numbers of advanced-stage thymoma progressively increased in WHO type B3-C. Eight patients in each group had recurrent disease, with greater recurrence for WHO types B3-C and stage III-IV tumors. Five-year disease-free survival (DFS) was not different between groups (P = 0.3906); however, survival for patients with stage III-IV thymomas (47 %) was significantly worse than that for patients with stage I and II tumors (97.5 and 94.1 %, respectively; P < 0.0001). Based on multivariate analysis, both Masaoka stage and WHO type were significant predictors of thymoma patient survival. CONCLUSIONS: These results demonstrate the safety and substantially decreased invasiveness of TT for thymoma. The oncological results were comparable between the TT and OT groups. Furthermore, Masaoka stage III-IV and WHO B3-C were revealed as independent prognostic factors for DFS.

Metformin attenuates lung fibrosis development via NOX4 suppression.

BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci (FF) is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis (IPF) pathogenesis, and transforming growth factor (TGF)-ß plays a key regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS) has been proposed to be involved in the mechanism for TGF-ß-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMP-activated protein kinase (AMPK), which regulates not only energy homeostasis but also stress responses, including ROS. Therefore, we sought to investigate the inhibitory role of metformin in lung fibrosis development via modulating TGF-ß signaling. METHODS: TGF-ß-induced myofibroblast differentiation in lung fibroblasts (LF) was used for in vitro models. The anti-fibrotic role of metfromin was examined in a bleomycin (BLM)-induced lung fibrosis model. RESULTS: We found that TGF-ß-induced myofibroblast differentiation was clearly inhibited by metformin treatment in LF. Metformin-mediated activation of AMPK was responsible for inhibiting TGF-ß-induced NOX4 expression. NOX4 knockdown and N-acetylcysteine (NAC) treatment illustrated that NOX4-derived ROS generation was critical for TGF-ß-induced SMAD phosphorylation and myofibroblast differentiation. BLM treatment induced development of lung fibrosis with concomitantly enhanced NOX4 expression and SMAD phosphorylation, which was efficiently inhibited by metformin. Increased NOX4 expression levels were also observed in FF of IPF lungs and LF isolated from IPF patients. CONCLUSIONS: These findings suggest that metformin can be a promising anti-fibrotic modality of treatment for IPF affected by TGF-ß.