The utility of the Stapler with PGA sheet for pulmonary wedge resection: a propensity score-matched analysis.

BACKGROUND: Air leakage is a common complication after pulmonary wedge resection. The aim of this study was to evaluate the effect of staple line reinforcement in reducing air leakage after pulmonary wedge resection. METHODS: A retrospective analysis was performed on patients who underwent pulmonary wedge resection. The patients were classified into 2 groups; the Stapler with polyglycolic acid sheet was used for the reinforced and the Stapler without polyglycolic acid sheet was used for the non-reinforced group. The patients were matched one-to-one based on a propensity score that comprised several patient characteristics. A propensity score-matched analysis was performed to compare patient outcomes. RESULTS: A total of 291 patients who met the inclusion criteria were investigated. There were 165 in the reinforced group and 126 patients in the non-reinforced group. Propensity score analysis generated 104 matched pairs of patients in both the reinforced and the non-reinforced groups. The rate of non-placement of chest tube was significantly higher in the reinforced group than in the non-reinforced group (61.5% vs. 36.5%; P<0.001). The rate of postoperative air leakage was higher in the non-reinforced group than in the reinforced group (13.5% vs. 1.9%, P<0.001). On logistic regression analysis, not using the reinforcement device was one of the independent factors related to pulmonary air leakage after pulmonary wedge resection (OR: 8.58, P<0.001). CONCLUSIONS: The use of the Stapler with polyglycolic acid sheet during pulmonary wedge resection increased the rate of intraoperative chest tube removal and reduced the rate of postoperative air leakage.

Impact of the genetic variants of GLCCI1 on clinical features of asthmatic patients.

BACKGROUND: Several gene variants are associated with a response to an inhaled corticosteroids (ICSs) treatment in patients with bronchial asthma. A variant of the glucocorticoid-induced transcript 1 (GLCCI1) genes has previously been associated with decreased lung function improvement upon treatment with ICSs in patients with bronchial asthma. Another report has also demonstrated that this genetic biomarker did not influence the change in flow volume in 1 second. However, no studies have considered the treatment content and the GLCCI1 variants. We were able to determine the relationship between the pulmonary function and clinical features and the variant of the GLCCI1 in Japanese asthmatic patients receiving long-term ICS treatment. MATERIALS AND METHODS: In this study, 405 patients with bronchial asthma, who were receiving ICS and living in Japan, were recruited, genotyped and underwent pulmonary function tests. To identify the GLCCI1 protein expression cells, endobronchial biopsy specimens were examined. RESULTS: We found that the pulmonary function was not significantly different in the homozygotes compared to the wild types. Also, the homozygotes increased the risk of a sustained step-up of the asthma treatment when compared to the wild type and heterozygotes. GLCCI1-positive cells were localized to the bronchial epithelial cells. The amount of GLCCI1 protein that cultured epithelial cells harboring GLCCI1 variants produced was less than the GLCCI1 wild type in the presence of a corticosteroid. CONCLUSIONS: A worsening of pulmonary function caused by GLCCI1 variants could be prevented due to recently used medications based on new action mechanisms.

Hyaluronic acid enhances cell migration and invasion via the YAP1/TAZ-RHAMM axis in malignant pleural mesothelioma.

Most malignant mesotheliomas (MPMs) frequently show activated forms of Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ), which transcriptionally regulates the receptor for hyaluronic acid-mediated motility (RHAMM). As RHAMM is involved in cell migration and invasion in various tumors, we speculated that hyaluronic acid (HA) in pleural fluid might affect the progression of mesothelioma by stimulating cell migration and invasion through RHAMM. The level of RHAMM expression was decreased by YAP1/TAZ knockdown, and conversely increased by forced expression of the active form of YAP1, suggesting that RHAMM was regulated by YAP1/TAZ in MPM cells. Cell migration and invasion were also decreased by YAP1/TAZ or RHAMM knockdown. Notably, HA treatment increased cell motility and invasion, and this was abolished by RHAMM knockdown, suggesting that HA may augment local progression of MPM cells via RHAMM. Furthermore, treatment with fluvastatin, which regulates RHAMM transcription by modulating YAP1/TAZ activity, decreased the motility and invasion of MPM cells. Collectively, these data suggest that HA is an "unfavorable" factor because it promotes malignancy in mesothelioma and that the YAP1/TAZ-RHAMM axis may have potential value as a therapeutic target for inhibition of disease progression in MPM.

Mitigation of tight junction protein dysfunction in lung microvascular endothelial cells with pitavastatin.

BACKGROUND: Statin use in individuals with chronic obstructive pulmonary disease (COPD) with coexisting cardiovascular disease is associated with a reduced risk of exacerbations. The mechanisms by which statin plays a role in the pathophysiology of COPD have not been defined. To explore the mechanisms involved, we investigated the effect of statin on endothelial cell function, especially endothelial cell tight junctions. METHOD: We primarily assessed whether pitavastatin could help mitigate the development of emphysema induced by continuous cigarette smoking (CS) exposure. We also investigated the activation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, which plays a role in maintaining endothelial functions, important tight junction proteins, zonula occludens (ZO)-1 and claudin-5 expression, and lung microvascular endothelial cell permeability. RESULTS: We found that pitavastatin prevented the CS-induced decrease in angiomotin-like protein 1 (AmotL1)-positive vessels via the activation of LKB1/AMPK signaling and IFN-γ-induced hyperpermeability of cultured human lung microvascular endothelial cells by maintaining the levels of AmotL1, ZO-1, and claudin-5 expression at the tight junctions. CONCLUSION: Our results indicate that the maintenance of lung microvascular endothelial cells by pitavastatin prevents tight junction protein dysfunctions induced by CS. These findings may ultimately lead to new and novel therapeutic targets for patients with COPD.

Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor.

PURPOSE: Epidermal growth factor receptor (EGFR) gene mutations are the most established genomic biomarkers for the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). The most frequent deletion in exon 19 is delE746_750, followed by del747_753insS and del747_750insP. Since investigations of delE746 have not been reported previously, it is unclear if delE746 conveys sensitivity to TKI effect of TKI on EGFR delE746. The objective was to characterize delE746 of the EGFR gene and to explore the effects of TKIs on the delE746. METHODS: We assessed the ability of gefitinib to inhibit phosphorylation of clonal L929 cell lines expressing EGFR with delE746. 3-D structures of the EGFR proteins were also used to investigate the interaction with gefitinib. RESULTS: The delE746 mutant EGFR-expressing cells exhibited gefitinib-sensitive autophosphorylation, which altered the structure of the EGFR and increased the instances of docking during docking simulations of gefitinib with the EGFR-TK. This mutant revealed that it exhibited molecular conformation alterations, and more frequent binding with gefitinib compared to wild-type EGFR. We administered EGFR-TKI, gefitinib to a Japanese woman with lung cancer that contained delE746. The patient achieved partial response after a 5 month of treatment with gefitinib. CONCLUSION: Our study revealed biological, structural, and probably clinical features of the delE746 form of EGFR.

Chaperone protein L-isoaspartate (D-aspartyl) O-methyltransferase as a novel predictor of poor prognosis in lung adenocarcinoma.

Endoplasmic reticulum stress and chaperone dysfunction have recently been associated with poor prognoses in various cancers. The newly discovered chaperone protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PIMT) regulates the viability of cancer cells in various cancers, although no clinical information regarding the relationship between lung cancer and PIMT expression has been reported. In this study, we aimed to elucidate the relationship between PIMT expression and the prognosis of lung adenocarcinoma. Paraffin-embedded lung tissues obtained from 208 patients with surgically resected lung adenocarcinoma were subjected to immunohistochemical analyses using primary antibodies against PIMT. Kaplan-Meier curves, log-rank tests, and the Cox proportional hazards model were used to analyze the association between PIMT expression and patient survival. Strong PIMT expression was detected in 106 (50.9%) patients, being particularly observed in patients with advanced stages of lung adenocarcinoma. Strong PIMT expression was associated with that of 78-kDa glucose-regulated protein, a marker of endoplasmic reticulum stress. Patients with strong PIMT expression had a shorter survival time (Kaplan-Meier analysis, P<.001). Multivariate Cox hazard regression analysis demonstrated that strong PIMT expression was an independent predictor of poor prognosis of lung adenocarcinoma, including those with stage I disease (hazard ratios, 6.45 and 6.81, respectively; 95% confidence intervals, 2.46-16.9 and 1.79-25.8, respectively; P<.001 and P=.005, respectively). Collectively, strong PIMT expression was a predictive marker of poor prognosis for surgically resected lung adenocarcinoma, and this finding might help clinicians determine the need for postoperative adjuvant chemotherapy in patients with stage I lung adenocarcinoma.

The role of tumor necrosis factor-α and interferon-γ in regulating angiomotin-like protein 1 expression in lung microvascular endothelial cells.

BACKGROUND: Angiogenesis in the alveolar septa is thought be a critical factor in pulmonary emphysema. Angiomotin-like protein 1 (AmotL1) is involved in angiogenesis via regulating endothelial cell function. However, the role of AmotL1 in the pathogenesis of pulmonary emphysema has not been elucidated. The objective of this study is to evaluate the expression of AmotL1 in lung tissues from a murine model with emphysema, as well as from patients with chronic obstructive pulmonary disease (COPD). Furthermore, we analyzed the regulation of AmotL1 expression by TNF-α and IFN-γ in endothelial cells in vitro. METHODS: Nrf2 knockout mice were exposed to cigarette smoke (CS) for 4 weeks, and the down-regulated genes affecting vascularity in the whole lung were identified by microarray analysis. This analysis revealed that the mRNA expression of AmotL1 decreased in response to CS when compared with air exposure. To confirm the protein levels that were indicated in the microarray data, we determined the expression of AmotL1 in lung tissues obtained from patients with COPD and also determined the expression of AmotL1, NFκB and IκBα in cultured normal human lung microvascular endothelial cells (HLMVECs) that were stimulated by TNF-α and IFN-γ. RESULTS: We found that the number of AmotL1-positive vessels decreased in the emphysema lungs compared with the normal and bronchial asthmatic lungs. IFN-γ pretreatment diminished the TNF-α-induced AmotL1 in the cultured HLMVECs by blocking the degradation of IκBα. CONCLUSIONS: These results suggested that IFN-γ exhibits anti-angiogenesis effects by regulating the expression of TNF-α-induced AmotL1 via NFκB in emphysema lungs.

[Stapler].

The use of endostaplers during thoracoscopic pulmonary resections has been a common procedure for respiratory surgeons. In Japan, we can choose 2 different types of staplers from 2 companies, namely, Tyco Healthcare Japan and Johnson & Johnson company. The staplers from each company show different characteristics. Therefore, we should choose which stapler to use by each character equipped. Each stapler has differences in compatibilities of cartridges, in sizes and in weights. Some adverse events or incidents were attributable to surgical or technical errors; many of them might be linked to the device. This manuscript aims to explain the differences and advantages in each stapler and to help to choose which stapler is suitable. However, we have to do surgery taking malfunctions of devices into consideration at all times.

Successful repair using innominate vein flap, pericardial flap and thymus pedicle flap for tracheo-innominate artery fistula.

Tracheo-innominate artery fistula (TIF) is a rare but frequently fatal complication after tracheostomy. Without operation, the mortality is nearly 100% because of acute massive tracheal hemorrhage. Although the survival rate is extremely low, survival is possible only when an immediate operation is performed. Many surgeons have chosen ligation or resection of the innominate artery because repair with blood flow maintained in the innominate artery carries a high risk of postoperative fatal recurrent bleeding. We report on a successful surgical management of one case by patch closure with an innominate vein flap, wrapping of the innominate artery with a pericardial flap, and interposition of a thymus pedicle flap between the innominate artery and the trachea. Our surgical procedure is effective in maintaining the patency of the innominate artery preventing neurological deficits, and in preventing postoperative recurrent bleeding.

[Lung cancer in elderly patients: lung cancer and lung function].

The incidence of bronchogenic carcinoma is increasing as life expectancy rises. With increase in the aged population in Japan, the number of patients suffering from lung cancer and candidates for lung resections are increasing. In this paper, the author lists up indispensable procedures for diagnosis, namely, lung function tests, unilateral pulmonary arterial occlusion test and exercise tolerance test. The cut-offs for identifying candidates for elderly patients for lung resections can be applied the same cut-offs for younger patients. Also the author indicates the importance of postoperative management for lung lobe resections. In order to prevent postoperative problems such as congestive heart failure that might be a fetal complication, the most useful check values after the lung surgery for elderly patients are rate of transfusion and urine volume. In conclusion, when elderly patients assert their rights to undergo lung surgery, we, the thoracic surgeons, should reply their requests under the equal quality of safe surgery as that for younger patients. Besides, it is desirable that even elderly patients, over 80 years old, who undergo lung surgery should guarantee their quality of daily life after surgery.

[Preoperative evaluation for lung resection using right ventricular hemodynamic functions by unilateral pulmonary arterial occlusion test].

We performed a unilateral pulmonary arterial occlusion (UPAO) test for the preoperative evaluation of right ventricular functions as a loading test in patients undergoing a lung resection without cardiac complications preoperatively. We investigated the relationship between changes in right ventricular hemodynamic functions and postoperative cardiac complications, namely right heart failure or arrhythmia. To evaluate the right ventricular hemodynamic function test, we measured the mean pulmonary arterial pressure, cardiac index, right ventricular ejection fraction end-diastolic volume, and stroke volume before and during the UPAO test using the thermodilution method, and calculated the total pulmonary vascular resistance and right ventricular stroke work indexes. The incidence of postoperative cardiac complications was not related to the changes in the total pulmonary vascular resistance index. However, the postoperative cardiac complications were common in patients whose right ventricular end-diastolic volume index was increased by more than 20% during the UPAO test. These results suggest that the changes in the right ventricular end-diastolic volume index during the UPAO test can predict postoperative cardiac complications in patients undergoing a pulmonary resection.

Review of preoperative functional evaluation for lung resection using the right ventricular hemodynamic functions.

Surgery for patients with lung cancer diminishes their lung functions, due to removal of their lung lobes. Therefore, thoracic surgeons have to consider postoperative lung function of patients. In this review, we explained recent approaches of estimation of postoperative lung function by spirometrical and also pulmonary circulatory measurement values. The most common and simple way to estimate postoperative conditions for patients who undergo lung resections is calculated by numbers of segments that are removed by surgery. However, these methods are not so accurate when the patients have chronic obstructive pulmonary disease. Another method for estimating postoperative conditions using right heart catheterization is a unilateral pulmonary arterial occlusion (UPAO) test. Applying this method, surgery related deaths have been decreased. Since, UPAO test mimics the postoperative state by occluding the pulmonary artery prior to lung surgery, it is supposed to be very accurate. Recently, a novel method to estimate postoperative right heart reserve functions was developed. Using this method, postoperative right heart failures can be anticipated prior to lung resections. In this review, we explain these kinds of methods to prevent impairment of postoperative quality of life.

Endothelial barrier strengthening by activation of focal adhesion kinase.

Endothelial cell barrier (EC) properties regulate blood tissue fluid flux. To determine the role of endothelial-matrix interactions in barrier regulation, we induced cell shrinkage by exposing confluent endothelial monolayers to hyperosmolarity. The dominant effect of a 15-min hyperosmolar exposure was an increase in the trans-endothelial electrical resistance, indicating the induction of barrier strengthening. Hyperosmolar exposure also increased activity of focal adhesion kinase and E-cadherin accumulation at the cell periphery. Concomitantly, the density of actin filaments increased markedly. In EC monolayers stably expressing constitutively active or dominant negative isoforms of Rac1, the actin response to hyperosmolar exposure was enhanced or blocked, respectively, although the response in trans-endothelial resistance was unaffected, indicating that the endothelial barrier enhancement occurred independently of actin. However, in monolayers expressing a kinase-deficient mutant of focal adhesion kinase, the hyperosmolarity-induced increases in activity of focal adhesion and peripheral E-cadherin enhancement were blocked and the induced increase of electrical resistance was markedly blunted. These findings indicate that in EC exposed to hyperosmolar challenge, the involvement of focal adhesion kinase was critical in establishing barrier strengthening.