Hidemi Suzuki

Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling.

BackgroundThe aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC).Materials and MethodsThe methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD.ResultsIL-12Rβ2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16INK4A and WNT antagonist genes was a negative prognostic factor in the non-COPD group.ConclusionsNovel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

Risk of acute exacerbation of interstitial pneumonia after pulmonary resection for lung cancer in patients with idiopathic pulmonary fibrosis based on preoperative high-resolution computed tomography

PurposeIn patients with lung cancer accompanied by idiopathic pulmonary fibrosis (IPF), acute exacerbation of the IPF often occurs after pulmonary resection; however, few studies have been done to identify its preexisting risk factors.MethodsWe analyzed the high-resolution computed tomography (HRCT) findings of IPF to identify the radiological characteristics of IPF susceptible to acute exacerbation after lung cancer surgery. We reviewed retrospectively 28 lung cancer patients with IPF who underwent pulmonary resection. Clinical data, respiratory function, HRCT findings, and historical features were compared between the acute exacerbation (n = 9) and nonexacerbation (n = 19) groups. The classification of radiological findings of IPF on HRCT was done using a scoring system of seven factors related to the interstitial shadow, including fibrosis, ground-glass opacity, and low-attenuation area.ResultsThere were no significant differences in clinical background, respiratory function, composite physiologic index, or pathological features between the groups; however, the degree of fibrosis on preoperative HRCT was significantly higher in the exacerbation group (P < 0.003). The fibrosis score was higher on the opposite side to the lung cancer in the exacerbation group (P < 0.05).ConclusionAlthough it is difficult to predict postoperative acute IPF exacerbation, the degree and laterality of co-existing fibrosis seem to be predictors.

Role of Complement Activation in Obliterative Bronchiolitis Post–Lung Transplantation

Obliterative bronchiolitis (OB) post-lung transplantation involves IL-17–regulated autoimmunity to type V collagen and alloimmunity, which could be enhanced by complement activation. However, the specific role of complement activation in lung allograft pathology, IL-17 production, and OB is unknown. The current study examines the role of complement activation in OB. Complement-regulatory protein (CRP) (CD55, CD46, complement receptor 1–related protein y/CD46) expression was downregulated in human and murine OB; and C3a, a marker of complement activation, was upregulated locally. IL-17 differentially suppressed complement receptor 1–related protein y expression in airway epithelial cells in vitro. Neutralizing IL-17 recovered CRP expression in murine lung allografts and decreased local C3a production. Exogenous C3a enhanced IL-17 production from alloantigen- or autoantigen (type V collagen)-reactive lymphocytes. Systemically neutralizing C5 abrogated the development of OB, reduced acute rejection severity, lowered systemic and local levels of C3a and C5a, recovered CRP expression, and diminished systemic IL-17 and IL-6 levels. These data indicated that OB induction is in part complement dependent due to IL-17–mediated downregulation of CRPs on airway epithelium. C3a and IL-17 are part of a feed-forward loop that may enhance CRP downregulation, suggesting that complement blockade could be a therapeutic strategy for OB.

Prosthetic Reconstruction of the Superior Vena Cava for Malignant Disease: Surgical Techniques and Outcomes

BACKGROUND This retrospective study investigated long-term graft patency and outcomes for malignant diseases with invasion of the superior vena cava (SVC). METHODS From October 1995 to November 2008, 20 patients underwent combined surgical resection of malignant tumors and the SVC with vascular reconstruction using a ringed polytetrafluoroethylene graft (8 to 12 mm) Sigmoid-curved spatulation of the graft end at the right auricle was performed to obtain a wide orifice left graft. Anticoagulation therapy was routinely administered for 3 to 6 months. Postoperative graft patency was verified at 2 to 4 weeks, 3 months, and after 12 months. Indications were lung cancer in 9 patients, thymic tumors in 8, germ cell tumors in 2, and thyroid cancer in 1. RESULTS Procedures were single graft replacement in 9 patients, bilateral grafts in 10, and bilateral SVC grafts and 1 pulmonary artery graft in 1. All grafts were patent over a short-term period, but 1 limb of the bilateral grafts became occluded in 2 patients who received bilateral grafts during long-term follow-up. Bronchial dehiscence after lung cancer resection caused 1 in-hospital death. Mean follow-up was 44.7 months. Median survival was 22.1 months. Overall survival was 66.4% and 41.5% at 1 and 5 years, respectively. Survival for lung cancer was significantly worse at 5 years (62.5%) than thymic tumor (18.8%, p = 0.04). CONCLUSIONS Prosthetic reconstruction of the SVC for anterior mediastinal tumors and lung cancer is feasible. Reconstruction of the SVC using a single left graft to avoid total cross-clamping of the SVC is effective.

Severity of chronic obstructive pulmonary disease and its relationship to lung cancer prognosis after surgical resection.

OBJECTIVE The purpose was to determine the rates of postoperative pulmonary complications, and to clarify the impact of COPD on long-term survival in lung cancer patients after surgical resection. METHODS A retrospective chart review was performed on 1,461 patients who had undergone pulmonary resection for lung cancer from 1990 to 2005. Classification of COPD severity was based on spirometric guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Postoperative complication rates among the four COPD groups were compared and long-term overall and disease-specific survivals were analyzed. RESULTS The frequencies of all pulmonary complications in three COPD groups were higher than in the non-COPD group (all p < 0.05). Overall and disease-specific survivals were significantly worse in relation to higher COPD grades (all p ≤ 0.05). Significant prognostic factors were age, body mass index, positive smoking history, tumor size, pneumonectomy, pathologic stage, and COPD grade (p < 0.05). CONCLUSION Higher COPD grades had higher rates of postoperative pulmonary complications and poorer long-term survivals because of higher rates of cancer-related deaths.

Endobronchial neurogenic tumors treated by transbronchial electrical snaring and Nd-YAG laser abrasion : Report of three cases

Neurogenic benign tumors arising from the trachea and bronchus are relatively rare. We experienced three cases of neurofibroma of the bronchus which were successfully treated by transbronchial electrical snaring and Nd-YAG laser abrasion. The first was a 67-year-old man with right lung cancer, who was pointed out to have a neurofibroma in the left main bronchus. The second was a 34-year-old man with an obstruction in the right main bronchus due to neurofibroma. The third was a 66-year-old woman with a complete obstruction in the left main bronchus due to schwannoma. All patients were successfully treated to remove the tumors and obtain a patency of the bronchus by transbronchial electrical snaring and Nd-YAG laser abrasion. We also review 23 reported cases of endobronchial neurogenic tumors and discuss the efficacy of endoscopic treatments for endobronchial neurogenic tumors.

Trends of bacterial colonisation and the risk of postoperative pneumonia in lung cancer patients with chronic obstructive pulmonary disease

BACKGROUND Lung cancer patients with chronic obstructive pulmonary disease (COPD) have a high risk of developing postoperative pneumonia (POP). This study aims to investigate the impact of COPD on POP and the trends for perioperative bronchial colonisation by micro-organisms. METHODS A retrospective chart review was made for 626 patients who underwent lung cancer surgeries at the Chiba University Hospital between 1996 and 2005. The patients were categorised as non-COPD (n=475) and COPD (forced expiratory volume in 1s/forced vital capacity (FEV1/FVC) <70%; n=151). All the patients had sputum and bronchial bacterial cultures examined for potentially pathogenic micro-organisms (PPMs). Risk factors for POP and mortality were analysed. RESULTS Patients with COPD had a significantly higher incidence of POP (23/151, 15.2%) than those without COPD (17/475, 3.6%) (p<0.0001). Preoperative bronchial bacterial examinations showed that 50 of 475 patients without COPD (10.5%) had positive cultures, while the results for 30 of 151 patients with COPD (19.9%) were positive (p=0.0111). Only 31 of 548 patients (5.7%) who did not show any preoperative PPMs had POP, while nine of 78 patients (11.5%) who presented preoperative PPMs had POP (p=0.0469). The PPMs that emerged postoperatively were primarily Staphylococcus aureus (and Gram-negative bacilli (94.4% of PPMs), while they were seen less frequently preoperatively (46.5% of PPMs). Multivariate analysis demonstrated that advanced age and FEV1/FVC were independent risk factors for POP. Patients with POP had significantly worse long-term survivals than those without POP (p=0.0004). CONCLUSION COPD was a risk factor for POP. Staphylococcus aureus and Gram-negative bacilli should be targets for postoperative prophylactic antibiotic selection. Patients with POP had poor long-term survivals.

CD4 T cells but not Th17 cells are Required for Mouse Lung Transplant Obliterative Bronchiolitis

Lung transplant survival is limited by obliterative bronchiolitis (OB), but the mechanisms of OB development are unknown. Previous studies in a mouse model of orthotopic lung transplantation suggested a requirement for IL‐17. We have used this orthotopic mouse model to investigate the source of IL‐17A and the requirement for T cells producing IL‐17A. The major sources of IL‐17A were CD4+ T cells and γδ T cells. Depletion of CD4+ T cells led to a significantly decreased frequency and number of IL‐17A+ lymphocytes and was sufficient to prevent acute rejection and OB. However, mice with STAT3‐deficient T cells, which are unable to differentiate into Th17 cells, rejected lung allografts and developed OB similar to control mice. The frequency of IL‐17A+ cells was not decreased in mice with STAT3‐deficient T cells due mainly to the presence of IL‐17A+ γδ T cells. Deficiency of γδ T cells also did not affect the development of airway fibrosis. Our data suggest that CD4+ T cells are required for OB development and expansion of IL‐17A responses in the lung, while Th17 and γδ T cells are not absolutely required and may compensate for each other.

Efficacy of perioperative administration of long-acting bronchodilator on postoperative pulmonary function and quality of life in lung cancer patients with chronic obstructive pulmonary disease. Preliminary results of a randomized control study

PurposeLong-acting bronchodilators are recommended as a first-line treatment for chronic obstructive pulmonary disease (COPD), although their effects for postoperative lung cancer patients with COPD are still not well known. A prospective randomized trial was used to examine the efficacy of bronchodilators on postoperative pulmonary function and quality of life (QOL).MethodsTwenty lung cancer patients with COPD who had lobectomies were randomized. A control group (n = 10) did not receive bronchodilators. An experimental group (n = 10) received tiotropium and salmeterol. Patients were divided into two COPD grades: stage I COPD and stage II–III COPD. Results for pulmonary function, 6-minute walking test, and the St. George’s Respiratory Questionnaire (SGRQ) were compared. Diaphragmatic motion on dynamic magnetic resonance imaging was also analyzed.ResultsThe patient demographics were similar in the two groups. Except for pulmonary function results at 2 weeks, no other parameters were significantly different. However, in stage II–III COPD, forced expiratory volume in 1 second, forced vital capacity, inspiratory capacity, the total score of the SGRQ, and diaphragmatic motion in the experimental group (n = 5) were significantly better than those in the control group (n = 4) at various time points (all P < 0.05).ConclusionThe daily inhalation of bronchodilators was effective for maintaining the respiratory function and QOL in lung cancer patients with moderate to severe COPD.

Risk factors predictive of atrial fibrillation after lung cancer surgery

Postoperative atrial fibrillation (POAF), the most frequent arrhythmia after pulmonary resection, is a cause of both morbidity and mortality. Being able to predict the risk of POAF before surgery would help us evaluate the surgical risk and plan prophylaxis. We investigated the reported preoperative risk factors associated with the incidence of POAF and found that the recommended predictive factors were quite variable. Therefore, we evaluated the previously reported preoperative risk factors for POAF using our institutional data. We discuss our findings in this short review. Male gender, resected lung volume, brain natriuretic peptide (BNP), and left ventricular early transmitral velocity/mitral annular early diastolic velocity (E/e′) calculated by echocardiography were suggested as independent predictors for POAF, but the predictive values of each individual parameter were not high. The lack of definitive predictors for POAF warrants further investigations by gathering the reported knowledge, to establish an effective preoperative examination strategy.