Associations between Comorbidities and Acute Exacerbation of Interstitial Lung Disease after Primary Lung Cancer Surgery.

Acute exacerbation (AE) of interstitial lung disease (ILD) is a severe complication of lung resection in lung cancer patients with ILD (LC-ILD). This study aimed to assess the predictive value of comorbidities other than ILD for postoperative AE in patients with LC-ILD. We retrospectively evaluated 68 patients with LC-ILD who had undergone lung resection. We classified them into two groups: those who had developed postoperative AE within 30 days after resection and those who had not. We analyzed patient characteristics, high-resolution computed tomography findings, clinical data, pulmonary function, and intraoperative data. The incidence of postoperative AEs was 11.8%. In univariate analysis, performance status (PS), honeycombing, forced vital capacity (FVC), and high hemoglobin A1c (HbA1c) levels without comorbidities were significantly associated with postoperative AE. Patients were divided into two groups according to cutoff levels of those four variables as determined by receiver operating characteristic curves, revealing that the rates of patients without postoperative AE differed significantly between groups. The present results suggested that preoperative comorbidities other than ILD were not risk factors for postoperative AE in patients with LC-ILD. However, a high preoperative HbA1c level, poor PS, low FVC, and honeycombing may be associated with postoperative AE of LC-ILD.

Phase II trial of S-1 as third-line or further chemotherapy in patients with advanced non-small-cell lung cancer.

OBJECTIVES: This study was conducted to evaluate the efficacy and safety of S-1 in patients with advanced non-small-cell lung cancer (NSCLC), receiving two or more prior chemotherapy regimens. METHODS: S-1 was administered orally for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity occurred. RESULTS: From 2010 to 2012, 45 patients were enrolled in this study. Of the 45 patients, 4 patients [8.9 %, 95 % confidence interval (CI) 0.6-17.2 %] exhibited a partial response and 24 patients (53.3 %) exhibited stable disease. The disease control rate was 62.2 % (95 % CI 48.1-76.4 %). Median progression-free survival was 71 days, and median survival time was 205 days. Four patients had grade 3 hematological toxicities, but toxicities of grade 4 were not observed in this study. CONCLUSION: Although S-1 monotherapy as third-line treatment or beyond was well tolerated, the response rate for this regimen did not demonstrate sufficient activity for patients with advanced NSCLC.

Exophiala dermatitidis coinfection with nontuberculous mycobacteria: A case report and literature review.

Six years ago, a 60-year-old man presented to our hospital with a cough and sputum. Upon suspicion of nontuberculous mycobacterial (NTM) infection, he was followed up at our hospital. Because the abnormal shadows in the bilateral lung fields deteriorated slightly over 6 years, bronchoscopy was performed. Exophiala dermatitidis and Mycobacterium intracellulare were detected in the bronchial lavage fluid. The patient underwent follow-up examinations without drug administration. Currently, the patient's condition remains stable. E. dermatitidis is regulatory found in the lungs of patients with cystic fibrosis, but only rarely is it found in respiratory samples from patients without cystic fibrosis. However, NTM complications have been reported more frequently in recent years. Due to the increasing number of NTM patients, E. dermatitidis pulmonary infections may also increase. Additional research is required to develop strategies for treating this infection.

Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease.

BACKGROUND: A high incidence of interstitial lung disease (ILD) has been reported in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), particularly in Japanese populations. A previous report from our laboratory demonstrated that KL-6 was a useful serum biomarker to assess the severity of drug-induced pneumonitis. Based on these observations, this study was conducted to evaluate the risk factors of EGFR-TKIs induced ILD and the usefulness of monitoring serum KL-6 levels in patients who developed EGFR-TKIs induced ILD in a large multi-institutional setting. METHODS: We retrospectively reviewed clinical records and radiographies of 341 patients with advanced NSCLCs who were treated with EGFR-TKIs, and analyzed risk factors for the development of EGFR-TKIs induced ILD. Changes of circulating levels of KL-6 were also evaluated in the patients who developed EGFR-TKIs induced ILD. RESULTS: Among the 341 patients included in this study, 20 (5.9%) developed EGFR-TKIs induced ILD, and 9 (2.6%) died from ILD. Univariate analyses revealed that only preexisting pulmonary fibrosis was a significant risk factor for the development of EGFR-TKIs induced ILD (p = 0.003). Absolute levels of circulating KL-6 at neither baseline nor the onset of ILD could discriminate between life-threatening and non-life threatening EGFR-TKIs induced ILDs. However, we found that the ratios of serum KL-6 levels just after the onset of EGFR-TKIs induced ILD to those at baseline could quite precisely distinguish survivors from non-survivors (p = 0.006) as well as acute interstitial pneumonia (AIP) pattern from non-AIP pattern (p = 0.005). CONCLUSIONS: The results of this study strongly support the potential of KL-6 as a diagnostic biomarker for life-threatening EGFR-TKIs induced ILD. Monitoring of KL-6 is also useful to evaluate the progression and severity of EGFR-TKIs induced ILD.

In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth.

Malignant pleural mesothelioma (MPM), an aggressive and refractory tumor type, is increasing in frequency throughout the world. Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists have anticancer activity against several cancer cell lines in vitro and in vivo. However, there have been no reports that PPAR-γ agonists induce growth inhibition of MPM cell lines. In this study, we investigated the inhibitory effect of a PPAR-γ agonist in combination with an anticancer agent on MPM cell growth in vitro and in vivo. We examined the therapeutic efficacy of the PPAR-γ agonist troglitazone (TGZ) in combination with cisplatin against a human MPM cell line, both in vitro and orthotopically inoculated into severe combined immunodeficient (SCID) mice. Troglitazone (TGZ) alone inhibited MPM cell growth in vitro in a dose-dependent manner via induction of G1 cell cycle arrest and apoptosis. The combination of TGZ and cisplatin showed an additive inhibitory effect on MPM cell growth compared to treatment with either individual drug. Treatment with 500 mg/kg or 1000 mg/kg TGZ effectively inhibited the production of thoracic tumors and pleural effusion in EHMES-10 cell-bearing SCID mice. Moreover, treatment with 500 mg/kg TGZ in combination with 3 mg/kg cisplatin more effectively prolonged survival compared to treatment with either individual drug. These results suggest that TGZ in combination with cisplatin may become a novel therapy for MPM.

Prediction of Spirometric Indices Using Forced Oscillometric Indices in Patients with Asthma, COPD, and Interstitial Lung Disease.

Background and Objective: Spirometry is sometimes difficult to perform in elderly patients and patients with cognitive impairment. Forced oscillometry (FOT) is a simple, noninvasive technique used for measuring respiratory impedance. The aim of this study was to develop regression equations to estimate vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in 1 s (FEV1.0) on the basis of FOT indices and to evaluate the accuracy of these equations in patients with asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Materials and Methods: We retrospectively included data on 683 consecutive patients with asthma (388), COPD (128), or ILD (167) in this study. We generated regression equations for VC, FVC, and FEV1.0 by multivariate linear regression analysis and used them to estimate the corresponding values. We determined whether the estimated data reflected spirometric indices. Results: Actual and estimated VC, FVC, and FEV1.0 values showed significant correlations (all r > 0.8 and P < 0.001) in all groups. Biases between the actual data and estimated data for VC, FVC, and FEV1.0 in the asthma group were -0.073 L, -0.069 L, and 0.017 L, respectively. The corresponding values were -0.064 L, 0.027 L, and 0.069 L, respectively, in the COPD group and -0.040 L, -0.071 L, and -0.002 L, respectively, in the ILD group. The estimated data in the present study did not completely correspond to the actual data. In addition, sensitivity for an FEV1.0/FVC ratio of <0.7 and the diagnostic accuracy for the classification of COPD grade using estimated data were low. Conclusion: These results suggest that our method is not highly accurate. Further studies are needed to generate more accurate regression equations for estimating spirometric indices based on FOT measurements.

Endobronchial hamartoma coexisting with lung cancer.

Clinicians should be careful when examining a case with endobronchial hamartoma with concurrent malignant disease because radiographic imaging and symptoms cannot clearly differentiate between both diseases.

Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis.

OBJECTIVES: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations. MATERIALS AND METHODS: Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups. RESULTS: The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients' demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076-2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510-20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899-2.298) (pinteraction = 0.015). CONCLUSION: In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent.

Bacterial tracheobronchitis. A rare cause of adult airway stenosis.

Bacterial tracheobronchitis is a rare cause of airway stenosis in adults. This report describes a 73-year-old woman with a recent history of polysialadenitis, who presented with severe airway obstruction due to infection and stenosis of tracheal and bronchial tissue. Tissue culture of the bronchial mucosa showed growth of methicillin resistant Staphylococcus epidermidis (MRSE). Sputum culture showed growth of MRSE, Pseudomonas aeruginosa, Enterobacter cloacae and Enterococcus faecalis; the same organisms were cultured from the salivary glands. Tracheostomy and antibiotic therapy were effective in controlling the disease.

Phase 2 Study of Afatinib Alone or Combined With Bevacizumab in Chemonaive Patients With Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations: AfaBev-CS Study Protocol.

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non-small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients.

[A case of sarcoidosis with multiple nodules showing cavitary formation].

A 24-year-old woman was admitted to our hospital for examinations of multiple nodules in bilateral lung fields. Mediastinal lymph node specimen by surgical resection revealed non-caseating epithelioid cell granuloma which was compatible with sarcoidosis. Some nodules showed cavitary formation without any treatment. Bacteriological and cytological studies yielded negative results. This is a rare case of sarcoidosis with multiple nodules showing cavitary formation.

[Successful treatment of non-small cell lung cancer by gefitinib in an elderly patient with poor performance status].

A 91-year-old woman was admitted to our hospital with dyspnea. A chest radiograph and chest CT films revealed a large amount of pleural effusion in the right side pleural cavity. After serial thoracentesis, chest CT films showed a mass shadow in the right S(6). Adenocarcinoma cells were found in the pleural effusion, leading to a diagnosis of non-small cell lung cancer (stage IIIB). After administration of gefitinib, the mass shadow and pleural effusion reduced and her performance status improved. Gefitinib may be a well-tolerated therapeutic strategy in elderly and poor performance status patients with advanced non-small cell lung cancer.

Pulmonary Hemorrhaging as a Fatal Complication of IgA Vasculitis.

A 64-year-old man was admitted to our hospital for purpuric rash, joint pain, and a fever. He had earlier undergone a follow-up examination for interstitial lung disease. At the current visit, the diagnosis was immunoglobulin A (IgA) vasculitis, based on skin and renal biopsy findings. He developed sudden breathlessness and hemoptysis. Chest computed tomography revealed ground glass opacity in the right lower lung fields, suggesting pulmonary hemorrhaging associated with IgA vasculitis. Despite steroid and cyclophosphamide therapy, and plasma exchange, he died 52 days after admission. Early aggressive therapies may be recommended for old patients with IgA vasculitis who have an additional comorbidities.

Use of the forced-oscillation technique to estimate spirometry values.

PURPOSE: Spirometry is sometimes difficult to perform in elderly patients and in those with severe respiratory distress. The forced-oscillation technique (FOT) is a simple and noninvasive method of measuring respiratory impedance. The aim of this study was to determine if FOT data reflect spirometric indices. PATIENTS AND METHODS: Patients underwent both FOT and spirometry procedures prior to inclusion in development (n=1,089) and validation (n=552) studies. Multivariate linear regression analysis was performed to identify FOT parameters predictive of vital capacity (VC), forced VC (FVC), and forced expiratory volume in 1 second (FEV1). A regression equation was used to calculate estimated VC, FVC, and FEV1. We then determined whether the estimated data reflected spirometric indices. Agreement between actual and estimated spirometry data was assessed by Bland-Altman analysis. RESULTS: Significant correlations were observed between actual and estimated VC, FVC, and FEV1 values (all r>0.8 and P<0.001). These results were deemed robust by a separate validation study (all r>0.8 and P<0.001). Bias between the actual data and estimated data for VC, FVC, and FEV1 in the development study was 0.007 L (95% limits of agreement [LOA] 0.907 and -0.893 L), -0.064 L (95% LOA 0.843 and -0.971 L), and -0.039 L (95% LOA 0.735 and -0.814 L), respectively. On the other hand, bias between the actual data and estimated data for VC, FVC, and FEV1 in the validation study was -0.201 L (95% LOA 0.62 and -1.022 L), -0.262 L (95% LOA 0.582 and -1.106 L), and -0.174 L (95% LOA 0.576 and -0.923 L), respectively, suggesting that the estimated data in the validation study did not have high accuracy. CONCLUSION: Further studies are needed to generate more accurate regression equations for spirometric indices based on FOT measurements.

Separate origins of three coronary arteries arising from the right sinus of Valsalva.

A 58-year-old woman underwent coronary angiography because of chest pain on exertion. Her three coronary arteries arose from separate ostia in the right sinus of Valsalva. The left anterior descending coronary artery coursed between the great vessels, and the circumflex coronary artery coursed anterior to the pulmonary artery. Angiographic and clinical data of this rare anomaly are described.

[Repeated changes of electrocardiogram caused by Takotsubo-type cardiomyopathy: a case with hypertrophic nonobstructive cardiomyopathy].

A 67-year-old woman had been examined due to abnormalities on electrocardiography (ECG) at a medical checkup three years previously. When a negative T-wave was seen in leads I, aVL, and V1 to V4, but the abnormal findings were improved at consultation. Echocardiography revealed apical hypertrophy and hypertrophic nonobstructive cardiomyopathy was diagnosed. She felt chest discomfort in September, 2003 and an ECG showed a negative T-wave in leads I, II, III aVL, aVF and V2 to V6 and an elongation of QT interval Left ventriculography revealed myocardial hypertrophy at the left ventricular apex and left ventriclar wall motion was normal. Coronary angiography did not show any significant luminal narrowing. I-123 metaiodobenzyl-guanitidine scintigraphy showed marked perfusion defects at the left ventricular apex. After five months, ECG showed an improvement of the QT interval and a decrease in the negative T-wave. We considered that the repeated changes of ECG were caused by Takotsubo-type cardiomyopathy.

A case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-tyrosine kinase inhibitors with MET amplification and epithelial-to-mesenchymal transition.

EGFR mutant lung cancer responds to EGFR tyrosine kinase inhibitors (TKIs), but all patients eventually develop resistance to EGFR-TKIs. Herein we report a case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-TKI with MET amplification and epithelial-to-mesenchymal transition (EMT). A 73-year-old woman was diagnosed with adenocarcinoma harboring an EGFR exon 19 deletion. She received gefitinib as second-line therapy. Tumors were reduced 1 month after gefitinib therapy. However, only a few months later, chest computed tomography results indicated cancer progression. Gefitinib therapy was stopped and docetaxel therapy started. However, she died 13 days after admission. Microscopic examination of postmortem specimens revealed a diffuse proliferation of atypical giant cells in primary and metastatic lesions, but no adenocarcinomatous components as in the antemortem specimens. Immunohistochemical analyses showed that antemortem tumor specimens were positive for CDH1 but negative for VIM. In contrast, postmortem tumor specimens were positive for VIM but negative for CDH1. Genetic analyses revealed MET amplification. We concluded that resistance to EGFR-TKI might be caused by MET amplification and EMT. To our knowledge, no clinical studies have reported that MET amplification and EMT together may be associated with acquired resistance to EGFR-TKI. Second biopsy after the development of EGFR-TKI resistance may be recommended to determine the best therapeutic strategy.

Cell stress induces upregulation of osteopontin via the ERK pathway in type II alveolar epithelial cells.

Osteopontin (OPN) is a multifunctional protein that plays important roles in cell growth, differentiation, migration and tissue fibrosis. In human idiopathic pulmonary fibrosis and murine bleomycin-induced lung fibrosis, OPN is upregulated in type II alveolar epithelial cells (AEC II). However, the mechanism of OPN induction in AEC II is not fully understood. In this study, we demonstrate the molecular mechanism of OPN induction in AEC II and elucidate the functions of OPN in AEC II and lung fibroblasts. Human lung adenocarcinoma cells (A549) and mouse alveolar epithelial cells (MLE12), used as type II alveolar epithelial cell lines for in vitro assays, and human pulmonary alveolar epithelial cells (HPAEpiC) were treated with either bleomycin, doxorubicin or tunicamycin. The mechanism of OPN induction in these cells and its function as a pro-fibrotic cytokine on A549 and lung fibroblasts were analyzed. The DNA damaging reagents bleomycin and doxorubicin were found to induce OPN expression in A549, MLE12 and HPAEpiC. OPN expression was induced via activation of the extracellular signal-regulated protein kinase (ERK)-dependent signaling pathway in A549 and MLE12. The endoplasmic reticulum (ER) stress-inducing reagent tunicamycin induced OPN mRNA expression in A549, MLE12 and HPAEpiC, and OPN mRNA expression was induced via activation of the ERK-dependent signaling pathway in A549 and MLE12. Another ER stress-inducing reagent thapsigargin induced the expression of OPN mRNA as well as the subsequent production of OPN in A549 and MLE12. Furthermore, OPN promoted the proliferation of A549 and the migration of normal human lung fibroblasts. Inhibition of OPN by small interference RNA or neutralizing antibody suppressed both of these responses. The results of this study suggest that cell stress induces the upregulation of OPN in AEC II by signaling through the ERK pathway, and that upregulated OPN may play a role in fibrogenesis of the lung.