Group Of Interstitial Pneumonias Research Articles

Clinical characteristics, proteins, and genes related to interstitial pneumonia-associated squamous cell carcinoma of the lungs

Squamous cell carcinoma (SCC) is a common histological type of lung carcinoma that is associated with interstitial pneumonia (IP). We hypothesized that identifying specific genetic alterations or molecular markers of SCC with IP may aid the development of novel therapeutic strategies for the same. Therefore, in the present study, we aimed to identify tumorigenic genetic alterations and molecular markers in cases of SCC with IP. We included 28 lung SCC cases (14 cases with IP and 14 cases without IP). We performed immunohistochemistry for STAT3, STAT5, and TLE1, and next-generation sequencing was performed using an iSeq 100 system. The panel used in this study targeted 50 cancer-associated genes. Immunohistochemically, the rate of TLE1 positivity was higher in the SCC without IP group (93 %) than in the SCC with IP group (29 %), while that of STAT5 was higher in the SCC with IP group (79 %) than in the SCC without IP group (14 %). STAT3 expression was high in both the groups (SCC with IP, 64 %; SCC without IP, 71 %). Eighteen genes were mutated in more than six samples, and FBXW7 mutation was mainly observed in the SCC with IP group (p < 0.01). Mechanisms underlying tumorigenesis in SCC with IP included STAT5 activation via inflammation, while that in SCC without IP included squamous TLE1-mediated metaplasia. These findings are based on smoking-induced STAT3 activation; therefore, patients with IP who smoke are more likely to have progressive SCC. We also found that FBXW7 mutations may be associated with SCC with IP and keratinization. ERBB4 and KDR mutations were observed in both with or without IP, and these genes may be tumor-related genes in SCC. These molecular markers may help determine the prognoses of patients with SCC with IP and direct the development of treatment approaches.

Surgery for Secondary Spontaneous Pneumothorax with Chronic Lung Diseases.

Secondary spontaneous pneumothorax (SSP) is occasionally observed in elderly patients suffering from diffuse lung diseases. The purpose of this study was to analyze the outcomes of surgical treatment of SSP patients with chronic lung diseases. In total, 242 patients who underwent surgery for spontaneous pneumothorax at Chiba University Hospital from January 2006 to October 2016 were included in this study. The patients' records were reviewed retrospectively for data on their background, surgical treatment, morbidity, mortality, and recurrence. Of the spontaneous pneumothorax cohort, primary spontaneous pneumothorax (PSP) accounted for 144 patients. Among the 98 patients with SSP, 57 cases were caused by chronic obstructive pulmonary disease (COPD) and 21 were caused by interstitial pneumonia (IP). The postoperative complication rate was 19.3% in the COPD group, 42.9% in the IP group, and 11.1% in the PSP group. The recurrence rate was 5.3% in the COPD group, 28.6% in the IP group, and 21.5% in the PSP group. The morbidity and recurrence were comparable between PSP and SSP cases with COPD, whereas these values were unfavorable in SSP cases with IP compared with PSP ones. Surgical intervention should be carefully considered in SSP patients with IP.

A distinctive cytomorphological feature of interstitial pneumonia–related lung adenocarcinoma: The potential issues and solutions in practical diagnosis

The cytological features of interstitial pneumonia (IP)-related lung adenocarcinoma (LADC) have not been clearly described. This study aimed to describe its cytomorphological features, uncover potential problems in practical cytological diagnosis, and provide possible solutions. Bronchial brushing cytology samples from 40 IP-related LADC cases (the IP group) and 110 control cases (LADC unrelated to IP; the non-IP group) were analyzed. All patients underwent surgery after brushing cytology, and their histopathological subtypes were determined. The authors reviewed the cytological features and focused particularly on cytoplasmic mucin production. In the IP group, neoplastic cells with cytoplasmic mucin were detected at a significantly higher frequency (44.4% [8 of 18] vs. 6.3% [4 of 64]), and most of them were invasive mucinous adenocarcinomas (IMAs). Twenty-two of the 40 LADC cases in the IP group failed to be judged as "malignant/positive" (thus, they were judged to be "equivocal and/or negative"). The frequency of equivocal and/or negative judgments was 55.0% (22 of 40) in the IP group and 41.8% (46 of 110) in the non-IP group. The cytological diagnosis of IMA was difficult because it showed only slight nuclear atypia. Therefore, the authors examined the immunocytochemical expression of hepatocyte nuclear factor 4α (HNF4α), a diagnostic marker for IMA. As a result, four of the six cases that were judged to be equivocal in the IP group showed positive signals and could be retrospectively judged as malignant/positive. The cytological diagnosis of IP-related LADC may be more difficult because of the larger proportion of IMA. Immunocytochemistry for HNF4α can be used to improve diagnostic confidence in IP-related LADC.

Patients with Terminal Interstitial Pneumonia Require Comparable or More Palliative Pharmacotherapy for Refractory Dyspnea than Patients with Terminal Lung Cancer.

Background: Dyspnea is a severe symptom of terminal-stage interstitial pneumonia (IP). We commonly use continuous morphine or midazolam for terminal refractory dyspnea.Objective: We aimed to determine whether there is a difference in the use of continuous morphine and midazolam for terminal dyspnea between IP patients and lung cancer (LC) patients.Design: This is a single-center retrospective study.Setting/Subjects/Measurements: We retrospectively examined the clinical records of IP and LC patients who had died in our hospital. These patients were divided into the IP and LC groups to compare the use of morphine and midazolam.Results: Continuous morphine was administered to 50.0% of those in the IP group and 38.0% of those in the LC group for terminal dyspnea. There was no difference in the effect at six hours after morphine initiation between the two groups, but the concomitant use of continuous midazolam and morphine was more common in the IP group than in the LC group. The dose of continuous midazolam was significantly higher in the IP group than in the LC group, and the survival time after morphine initiation was significantly shorter in the IP group.Conclusions: The efficacy of continuous morphine administration for terminal dyspnea in IP patients was similar to that in LC patients for a short time after initiation, but just before death, more patients in the IP group required concomitant use of midazolam and morphine. Thus, IP patients require comparable or more palliative treatment than LC patients.

P2.05-09 FDG-PET for Predicting Acute Exacerbation of Interstitial Pneumonia After Lung Cancer Surgery

Acute exacerbation of interstitial pneumonia (IP) is a critical complication after lung cancer resection. Although FDG-PET is commonly used for preoperative assessment of lung cancer, its role for predicting acute exacerbation of IP after lung cancer resection is unclear. We retrospectively analyzed data of lung cancer patients that underwent surgical resection at Gunma University Hospital between 2008 and 2016. We analyzed data from patients with IP based on computed tomography findings (IP group). As control, we also analyzed data in patients with no underlying lung disease (normal group) and with emphysema (emphysema group). Patients with sufficient FDG-PET data were selected and a final of 92 patients in the IP group, 21 patients in the normal group, and 20 patients in the emphysema group were enrolled in analysis. The FDG-PET values were measured at the aorta and the basal lung. Aorta values were used for reference and we calculated the basal/aorta ratio and analyzed correlation with preoperative factors, including acute exacerbation of IP and mortality. The basal/aorta ratio was significantly higher in the IP group when compared to normal and emphysema group (both p<0.01). The incidence of acute exacerbation of IP was 10.9%, and the sensitivity and specificity of basal/aorta value for predicting acute exacerbation of IP were 70.0% and 77.2%, respectively (cutoff of basal/aorta ratio at 0.833). Patients were further classified into high basal/aorta ratio group (n=35) and low basal/aorta ratio group (n=57). The incidence of acute exacerbation of IP was significantly higher in the high basal/aorta ratio group (p=0.035). We also compared the value of basal/aorta ratio in comparison to the existing IP acute exacerbation score. Patients were divided into low score (less than 10, n=64) and high score (higher or equal to 11, n=28). The sensitivity and specificity for predicting acute exacerbation of IP was 60.0% and 82.3%, respectively, and there was no significant difference between the high and low score groups (p=0.062). The basal/aorta ratio of FDG-PET values showed a significant correlation with the incidence of postoperative acute exacerbation of IP. Since FDG-PET is commonly used for preoperative assessment of lung cancer in Japan, it may be used not only for lung cancer staging but also for surgical indication in IP patients with lung cancer by preoperatively detecting patients at high risk for acute exacerbation.

Impact of combined pulmonary fibrosis and emphysema on surgical complications and long-term survival in patients undergoing surgery for non-small-cell lung cancer.

PurposeThe outcome of radical surgery for lung cancer was investigated in patients with combined pulmonary fibrosis and emphysema (CPFE).MethodsA retrospective chart review involved 250 patients with lung cancer who underwent pulmonary resection at Tokyo Women’s Medical University Yachiyo Medical Center between 2008 and 2012. Based on the status of nontumor-bearing lung evaluated by preoperative computed tomography (CT), the patients were divided into normal, emphysema, interstitial pneumonia (IP), and CPFE groups, and their clinical characteristics and surgical outcome were analyzed.ResultsThe normal, emphysema, IP, and CPFE groups comprised 124 (49.6%), 108 (43.2%), seven (2.8%), and eleven (4.4%) patients, respectively. The 5-year survival rate of the CPFE group (18.7%) was significantly lower than that of the normal (77.5%) and emphysema groups (67.1%) (P<0.0001 and P=0.0027, respectively) but equivalent to that of the IP group (44.4%) (P=0.2928). In a subset analysis of cancer stage, the 5-year overall survival rate of the CPFE group in stage I (n=8, 21.4%) was also lower than that of the normal group and emphysema group in stage I (n=91, 84.9% and n=70, 81.1%; P<0.0001 and P<0.0001, respectively). During entire observation period, the CPFE group was more likely to die of respiratory failure (27.2%) compared with the normal and emphysema groups (P<0.0001). Multivariate analysis of prognostic factors using Cox proportional hazard model identified CPFE as an independent risk factor (P=0.009).ConclusionCPFE patients have a poorer prognosis than those with emphysema alone or with normal lung on CT finding. The intensive evaluation of preoperative CT images is important, and radical surgery for lung cancer should be decided carefully when patients concomitantly harbor CPFE, because of unfavorable prognosis.

Respiratory mechanics measured by forced oscillation technique in rheumatoid arthritis-related pulmonary abnormalities: frequency-dependence, heterogeneity and effects of smoking.

Rheumatoid arthritis (RA)-related pulmonary disorders specifically airway abnormalities and interstitial pneumonia (IP) are important extra-articular manifestations. The forced oscillation technique (FOT) is a useful method to assess respiratory impedance, respiratory resistance (Rrs) and reactance (Xrs), at different oscillatory frequencies during tidal breathing. The aim of this study was to characterize the respiratory mechanics of patients with RA and to relate them to parameters of the pulmonary function test and findings of chest CT images. Respiratory impedance of RA patients (n = 69) was measured as a function of frequency from 4 to 36 Hz using the FOT device and compared with that of healthy subjects (n = 10). Data were retrospectively reviewed. Patients were female-dominant (60.9 %) and 95.7 % had abnormal CT findings including airway and parenchymal abnormalities. Thirty-seven of 69 patients (53.6 %) were smokers. Rrs was significantly frequency-dependent in RA patients but not in the healthy subjects. Xrs were significantly frequency-dependent in both RA and healthy groups. Rrs was significantly higher during an expiratory phase in both RA and healthy groups. Xrs was significantly lower (more negative) during an expiratory phase than that during an inspiratory phase in RA patients but not in healthy subjects. Xrs of the RA group was significantly more negative than that of the normal control. There was no difference in impedance parameters between the airway lesion dominant (n = 27) and IP dominant groups (n = 23) in the RA group. The impedance parameters of the RA group significantly correlated with most parameters of the pulmonary function test. In pulmonary function test results, % of the predicted value for forced expiratory flow from 25 to 75 % of forced vital capacity was significantly lower and % of the predicted value for diffusing capacity of the lung for carbon monoxide was higher in the airway lesion dominant group than those in the IP dominant group. Krebs von den Lungen-6, a serum indicator of IP, was significantly higher in the IP group than that in the airway lesion dominant group. Taken together, the impedance results reflect abnormalities in pulmonary functions and structures in patients with RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-1952-8) contains supplementary material, which is available to authorized users.

Quantitative diagnosis of connective tissue disease-associated interstitial pneumonia using thoracic computed tomography images.

Patients with polymyositis (PM) or dermatomyositis (DM) frequently show interstitial pneumonia (IP), which is sometimes rapidly progressive or resistant to treatment, thereby significantly affecting the prognosis. The diagnosis and response evaluation of IP are commonly performed qualitatively based on imaging findings, which may cause disagreement among rheumatologists in the evaluation of early lesions and atypical interstitial changes. To determine whether IP could be diagnosed in a quantitative manner during the early stage of PM/DM using a workstation that allows quantitative image processing. Thoracic computed tomography (CT) images of 20 PM/DM patients were reconstructed into a three-dimensional (3D) image using an image processing workstation. The CT values of the constituent voxels were arranged in a histogram of -1000 to +1000 Hounsfield units (HU). The most frequent lung field density was -900 to -801 HU, and relative size was as follows: IP (+) group 0.45 and IP (-) group 0.53. Between -1000 and -701 HU, relative size was not significantly different between the IP (+) group and IP (-) group. Between -700 and -1 HU, the relative size of the lung field was significantly larger in the IP (+) than in the IP (-) group, demonstrating its IP-diagnosing ability. Particularly, within the range from -700 to -301 HU, the macroscopically-assessed ground glass opacity was consistent with the CT value, which, in turn, was closely correlated with KL-6, the pre-existing marker for IP diagnosis. The results of this study may lead to the establishment of quantitative methods of evaluating IP and possible elucidation of the pathogenesis of IP.

Multi-institutional retrospective cohort study of patients with severe pulmonary hypertension associated with respiratory diseases.

Pulmonary hypertension (PH) is often associated with respiratory diseases, but only a small number of patients present with severe PH defined as mean pulmonary arterial pressure ≥ 35 mm Hg. We here conducted a multicenter, retrospective study of patients with severe PH associated with respiratory diseases (R-PH) to reveal their demographics, treatment, prognosis and determinants of prognosis. From 101 patients with severe R-PH collected by postal survey at the first stage, 70 patients with four major diseases (chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis with emphysema (CPFE), interstitial pneumonia associated with connective tissue disease (CTD-IP), interstitial pneumonia (IP)) and normal pulmonary arterial wedge pressure were studied for clinical characteristics, treatment and prognosis. Three-year survival rates were 50% for COPD (n = 18), 35.7% for IP (n = 19) and 68.1% for CTD-IP (n = 20), and the 2-year survival rate for CPFE (n = 13) was only 22.6%. Eighty-one per cent of patients had been treated with pharmacotherapy specific for pulmonary arterial hypertension. Those patients who had received phosphodiesterase-5 inhibitors (PDE-5I) displayed significantly better survival from the date of diagnosis than those who had not (3-year survival: 61.8% vs 20.0% P < 0.0001), especially in the IP, CTD-IP and CPFE groups. Multivariate analysis also revealed that treatment with PDE-5I was a positive prognostic factor. We here demonstrated the dismal prognosis of patients with severe R-PH. The remarkably better survival in those patients who had received PDE-5I warrants and facilitates future prospective randomized studies in this particular population.

The expressions and meanings of BMP-7 and TGF-β in idiopathic pulmonary fibrosis and idiopathic nonspecific interstitial pneumonia

To investigate the expressions of cytokines in idiopathic pulmonary fibrosis (IPF) and in idiopathic nonspecific interstitial pneumonia (INSIP); To discuss expressions and meanings of bone morphogenetic protein 7 (BMP-7) and transforming growth factor beta (TGF-β) in IPF and IPF. Selected 47 cases of idiopathic interstitial pneumonia (IIP), which were diagnosed by clinical-radiologic-pathologic (CRP), and classified into two groups which were group IPF (25 IPF) and group INSIP (22 INSIP, including 6 cellular pattern and 16 fibrosing pattern). The normal lung tissues were collected as the control group: The fresh tissues were made to detect more than 114 kinds of cytokines' expressions via Oligo GEArray gene microarray technology. Made a tissue microarray which applied EnVision immunohistochemistry technology to detect the expressions of BMP-7 and TGF-β in both kinds of IIPs. The two groups of patients were followed-up visited around 5 to 8 years and the survival curves were evaluated by Kaplan-Meier method. According to gene microarray results, these two groups were up-expression in TGF family,IL family and TNF family. Most of BMP members were down-expression, in comparison with the control group, except BMP-5,BMP-8B and BMP-15. As the tissue microarray results demonstrated, compared with normal lung tissues,BMP-7 expressed decreasingly in IPF and INSIP groups (t1 = 27.618, P < 0.001; t2 = -12.404, P < 0.001). The expression of IPF were lower than INSIP (t = 5.387, P < 0.05); In INSIP group, patients of cellular pattern expressed BMP-7 more than fibrosing pattern's (t = -5.341, P < 0.001). There were dramatically increasing expressions of TGF-β in IPF and INSIP, when compared with the control group (t1 = 23.393, P < 0.001; t2 = -13.445, P < 0.001) and it presented negative correlation with BMP-7(group IPF: r = -0.771, P < 0.001; group INSIP: r = -0.729, P < 0.001). (3) Clinical follow-up data showed, the stability(improvement), deterioration and death rates of the group IPF and the group INSIP were, respectively, 0(0%), 2 (8%), 23 (92%) and 15 (68.1%), 3 (13.6%), 4 (18.2%). The results were statistically significant (all P < 0.05). The median survival time of the part with higher BMP-7 expression and the part with relatively lower BMP-7 expression, in the group IPF, were 110.8 and 66.4 months (t = -2.686, P < 0.05); In the group INSIP, were 146.4 and 74.9 months (t = -3.037, P < 0.05). Cellular cytokines presented different expression profiles in IPF and INSIP patients. Differently with highly activated TGF-β, BMP-7 was inhibited in IIP patients, which would remind the degree of fibrosis and prognosis of IIP. BMP-7 would be expected to be a novel target for IIP pathogenesis and prognostic research.

Evaluation of the Usefulness of Spectral Analysis of Inspiratory Lung Sounds Recorded with Phonopneumography in Patients with Interstitial Pneumonia

We investigated whether spectral analysis with fast Fourier transform (FFT) of inspiratory lung sounds is useful in the diagnosis and evaluation of the severity of interstitial pneumonia (IP). The study population included 10 healthy volunteers (healthy group) and 21 patients with IP (IP group). We generated inspiratory averaged linear intensities using FFT and determined frequency at maximum sound intensity (Fmax), and quartile frequencies (f25, f50, and f75), compared these values between the groups, generated receiver operating characteristic curves to compare the detectability of IP between the indices and auscultation in all cases, and tested for the correlation of these indices with pulmonary function tests and the fibrosis scores from high-resolution computed tomography images assessed by 3 observers. Both f50 and f75 were significantly higher in the IP group, but their ability to detect IP was inferior to that of auscultation. They had negative correlations with percent vital capacity and had positive correlations with the fibrosis scores calculated by the 3 different observers. These results were considered to reflect the presence of fine crackles and alterations in pulmonary sound-conduction characteristics caused by IP and indicate that spectral analysis of lung sounds is useful in the diagnosis and evaluation of the severity of IP, although future study is necessary to improve its utility.

Clinical Impact of Interstitial Pneumonia Following Surgery for Lung Cancer

Operative morbidity in patients with lung cancer associated with perioperative interstitial pneumonia (IP) has emerged as a serious problem. We studied the clinical impact of perioperative related IP in 11 patients (IP group: 7 preoperative known, 4 acute onset) of 473 lung cancer patients who received a pulmonary resection. The IP group was compared to the remaining 462 patients (non-IP group). Demographic data, clinical presentation, and serum KL-6 levels were compared. There were no differences in age, gender, type of surgery, and pulmonary function except for % DLco between the non-IP and IP groups. The IP group showed a higher in-hospital mortality (n=2: 18.3%) than that of the non-IP group (n=3: 0.6%) (P<0.005). Seven patients with underlying IP with high KL-6 levels showed an uneventful recovery. Two patients with postoperative onset of acute IP had a fatal course associated with elevation of serum KL-6 levels. Postoperative development IP is a serious complication with high mortality, and serial measurement of KL-6 levels is useful to assess the activity of IP.