Monomorphic Epitheliotropic Intestinal T-cell Lymphoma Involving the Lung and Brain: A Rare Case Study.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma and other organ involvement is very rare. A rare case of MEITL involving the lung and brain is herein reported. The patient developed panperitonitis with a small intestinal perforation, and emergency surgery was performed. The pathological findings from the surgical specimens demonstrated atypical lymphoid cells which were positive for CD3, CD8, and CD56. Moreover, the pathological findings of lung specimens taken by bronchoscopy were consistent with those of the small intestine. It is therefore important to include the possibility of MEITL in the differential diagnosis of cancer patients.

Clinical significance of thyroid hormone and antibodies in patients with idiopathic interstitial pneumonia.

BACKGROUND: Hypothyroidism was recently reported to be common and to predict mortality in patients with idiopathic pulmonary fibrosis (IPF). In addition, a high prevalence of hypothyroidism was shown in patients with idiopathic pleuroparenchymal fibroelastosis. However, in idiopathic interstitial pneumonia (IIP), a clinical significance of thyroid function has not been clarified in detail. The goal of this study was to investigate the clinical significance of thyroid function and the presence of thyroid antibodies in IIP. METHODS: We have reviewed IIP patients, and analyzed the positivity of thyroid antibodies at first. Next, the relationship of clinical characteristics with thyroid function and the positivity of thyroid antibodies was analyzed. Lastly, the positivity of thyroid antibodies and other autoantibodies was evaluated. RESULTS: In IIP patients, thyroglobulin and thyroid peroxidase antibodies were positive in 17 and 16%, respectively, and 22% of patients had either or both antibodies. Subclinical and/or overt hypothyroidism was confirmed in 7% of IIP patients. The free thyrotropin level had a significant positive correlation with vital capacity and a significant negative correlation with the C-reactive protein and surfactant protein-A levels, and erythrocyte sedimentation ratio (ESR). In addition, autoantibodies suggestive of connective tissue diseases (CTDs) were positive in more than two thirds of IIP patients with the thyroid antibody, and the positive rate of antinuclear and proteinase-3 anti-neutrophil cytoplasmic antibodies was significantly higher in IIP patients with thyroid antibodies than those without the antibodies. CONCLUSIONS: Although thyroid dysfunction is not frequent, thyroid hormones and thyroid antibodies are possibly involved in the pathogenesis of IIP and their evaluation may be clinically useful to identify the clinical phenotype of IIP with autoimmune features.

Comparison of fractional exhaled nitric oxide levels measured by different analyzers produced by different manufacturers.

Objective: Fractional exhaled nitric oxide (FeNO) is widely used as a biomarker of allergic airway inflammation. At present, both stationary chemiluminescence and portable electrochemical analyzers produced by different manufacturers are available. However, it remains debatable whether those analyzers are comparable to each other. We compare FeNO levels obtained by different analyzers.Methods: For the first study, 153 subjects were enrolled to compare differences in FeNO levels measured using three analyzers (NA623NP®, NObreath®, and NIOX MINO®) which were produced by different manufacturers. For the second study, 30 subjects were recruited to compare FeNO levels obtained by the two analyzers (NIOX MINO® and NIOX VERO®) produced by the same manufacturer. FeNO was measured twice using each analyzer in random order.Results: FeNO levels obtained using the NIOX MINO® and NObreath® were more variable than those measured using the NA623NP®. There were strong positive correlations in FeNO levels measured by the NA623NP®, NIOX MINO®, and NObreath® (p < 0.001). The NA623NP® and NIOX MINO® provided the highest and lowest FeNO levels, respectively; whereas, those obtained by NObreath® were intermediate. No significant differences were observed in FeNO levels obtained using the NIOX MINO® and NIOX VERO®.Conclusions: FeNO levels measured by the NIOX MINO® and NIOX VERO®, both of which were produced by the same manufacturer, have comparability. However, significant differences in FeNO levels exist when measured by analyzers manufactured by different manufacturers. This should be taken into account for FeNO measurement.

Serum decorin is a potential prognostic biomarker in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Decorin is a small leucine-rich repeat proteoglycan that plays a critical role in collagen fibrillogenesis, and regulates inflammation, wound healing and angiogenesis. In idiopathic pulmonary fibrosis (IPF), decorin is expressed in fibrotic lesions; furthermore, intratracheal gene transfer of decorin has been demonstrated to inhibit bleomycin-induced pulmonary fibrosis. Although these results suggest the critical role of decorin in pulmonary fibrosis, the role of decorin in the acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) has not been clarified in detail. Thus, the goal of this study was to determine the role of decorin in AE-IIP. METHODS: We retrospectively analyzed AE-IIP patients who had been admitted to our hospital. First, serum decorin levels were compared among patients with AE-IIP, patients with stable idiopathic interstitial pneumonia (SD-IIP), and healthy subjects. Next, the relationship between serum decorin levels and clinical parameters was analyzed in AE-IIP patients. Finally, the association between serum decorin levels and prognosis was evaluated in AE-IIP patients. IIP was divided into IPF and non-IPF, according to the published guidelines. RESULTS: The serum decorin levels of AE-IIP patients were significantly lower than those of both healthy subjects and SD-IIP patients. Serum decorin levels were not related with the clinical parameters and prognosis, when all IIP patients were analyzed. In IPF patients, serum decorin levels had a significant correlation with oxygenation, and IPF patients with low serum decorin levels had a significantly higher survival rate than those with high serum decorin levels. CONCLUSIONS: Serum decorin levels are a potential prognostic biomarker in AE-IPF.

The association between risk of airflow limitation and serum uric acid measured at medical health check-ups.

The prevalence of COPD and asthma is increasing all over the world; however, their morbidities are thought to be greatly underestimated because of unawareness of patients' conditions and respiratory symptoms. Spirometry is useful for the early detection of COPD and asthma with airflow limitation (AL), although it is not yet widely used for screening in epidemiological and primary care settings. A simple predictive marker used in combination with spirometry for AL is expected to be established. In medical health check-ups, serum uric acid (s-UA) is measured when screening for gout and has recently been suggested to have an association with several respiratory disorders, including asthma and COPD. However, whether s-UA influences the development of AL remains unclear. Therefore, the aims of this study were to examine the relationship between AL and s-UA and to investigate s-UA as a potential auxiliary marker for predicting AL risk in medical health check-ups. A total of 8,662 subjects aged >40 years were included. They were administered a simple questionnaire and assessed using pulmonary function tests, blood pressure (BP) measurements, and blood samplings. One hundred and fifty-six subjects (1.8%) had AL, just 29% of whom had experienced respiratory symptoms. The subjects with AL had significantly higher s-UA levels compared with never-smoking subjects without AL. Forced expiratory volume in 1 second (FEV1) %predicted showed significant correlations with age, smoking index, body mass index (BMI), mean BP, white blood cells, hemoglobin A1c, s-UA, and high-density lipoprotein cholesterol. In multiple logistic regression analysis, s-UA, in addition to age, smoking index, respiratory symptoms, and BMI, was independently associated with AL. In conclusion, elevated s-UA levels, together with respiratory symptoms, high smoking index, and weight loss, may epidemiologically predict the development of AL risk.

Identification of Clinical Phenotypes in Idiopathic Interstitial Pneumonia with Pulmonary Emphysema.

Objective Since the term "combined pulmonary fibrosis and emphysema" (CPFE) was first proposed, the co-existence of pulmonary fibrosis and pulmonary emphysema (PE) has drawn considerable attention. However, conflicting results on the clinical characteristics of patients with both pulmonary fibrosis and PE have been published because of the lack of an exact definition of CPFE. The goal of this study was thus to clarify the clinical characteristics and phenotypes of idiopathic interstitial pneumonia (IIP) with PE. Methods We retrospectively analyzed IIP patients who had been admitted to our hospital. Their chest high-resolution computed tomography images were classified into two groups according to the presence of PE. We then performed a cluster analysis to identify the phenotypes of IIP patients with PE. Results Forty-four (53.7%) out of 82 patients had at least mild emphysema in their bilateral lungs. The cluster analysis separated the IIP patients with PE into three clusters. The overall survival rate of one cluster that consisted of mainly idiopathic pulmonary fibrosis (IPF) patients was significantly worse than those of the other clusters. Conclusion Three different phenotypes can be identified in IIP patients with PE, and IPF with PE is a distinct clinical phenotype with a poor prognosis.

Exhaled nitric oxide and inducible nitric oxide synthase gene polymorphism in Japanese asthmatics.

BACKGROUND: Inducible nitric oxide synthase (iNOS) induced by inflammatory cytokines and iNOS activity in bronchial epithelial cells is a major determinant of fractional exhaled nitric oxide (FeNO) levels. The aim of this study was to investigate the association of iNOS promoter gene polymorphisms and FeNO levels in Japanese asthmatics before the introduction of asthma treatment. METHODS: Asthmatics were recruited from Fukushima Medical University Hospital. Genotyping of the pentanucleotide repeat (CCTTT)n and seven previously detected single nucleotide polymorphisms (SNPs) in the iNOS promoter lesion was performed. The relationships between the genotypes and FeNO levels before the introduction of asthma treatment were compared. RESULTS: In 91 asthmatics, the number of microsatellite repeats ranged from 9 to 20 and showed a bimodal distribution. According to this distribution, asthmatics were divided into two groups: genotypes with at least one long allele with more than 14 repeats (L/s or L/L) and genotypes with both short alleles with 14 or fewer repeats (s/s). No significant differences were observed in each parameter between the two groups. The mean FeNO level before treatment was significantly higher in the L/s or L/L subjects than in the s/s subjects. After treatment, the lowest FeNO level did not differ between the two groups. Three SNPs detected in the Japanese subjects were not associated with FeNO levels. CONCLUSIONS: The number of CCTTT repeats in the iNOS promoter region was associated with FeNO levels in asthmatics before treatment, suggesting the importance of iNOS genotype in the clinical application of FeNO for asthmatics.

Cholesteryl palmitate crystals in bronchoalveolar lavage fluid smears as a possible prognostic biomarker for chronic interstitial pneumonia: A preliminary study.

BACKGROUND: We observed cholesterol-like crystals (Crystal X) in the bronchoalveolar lavage fluid (BALF) smears of patients with diffuse pulmonary disease. We analyzed the clinical data of patients with and without crystals, and elucidated the structure of Crystal X and its concentration in the BALF. METHODS: Two hundred eighty-nine patients with diffuse pulmonary disease who underwent bronchoalveolar lavage (BAL) were analyzed. The relationships between the presence and number of Crystal X in BALF smears and clinical parameters were investigated. Furthermore, structure determination and quantitative analyses of the crystals were performed. RESULTS: Seventy-five (26.0%) patients had Crystal X in their BALF. The crystals were frequently observed in patients with chronic interstitial pneumonia (CIP, 60/160=35.3%). Patients with Crystal X exhibited significantly higher serum Kerbs von Lungren 6 antigen and surfactant protein-D levels (P<0.01) and lower percentage vital capacity (P<0.05) than patients without Crystal X. The number of crystals was significantly correlated with these parameters. The presence of crystals was also associated with a lower survival rate at 1 year after the BAL. The interfacial angles of the crystals were 126±2° and 144±2°, different from those of cholesterol monohydrate crystals. Infrared absorption spectrometry showed Crystal X was cholesteryl palmitate. Its concentration was significantly higher in BALF with crystals than in BALF without crystals (P<0.01). CONCLUSIONS: Crystal X in the BALF of patients with diffuse pulmonary disease was identified as cholesteryl palmitate, which may be a useful prognostic biomarker for CIP.

Early detection of colon cancer by increased serum level of Krebs von den Lungen-6 in a patient with dermatomyositis-associated interstitial pneumonia.

Krebs von den Lungen-6 (KL-6) is a high-molecular-weight glycoprotein which is elevated in serum of patients with interstitial pneumonia (IP). Serum KL-6 level is clinically used for the diagnosis of IP as well as the evaluation of its disease activity. KL-6 is originally identified when exploring novel soluble antigens in patients with lung cancer, and is known to be elevated in patients with several malignant tumors. The risk of malignant tumors is high in IP patients with polymyositis and dermatomyositis (PM/DM), and follow-up of KL-6 levels may allow earlier detection of such tumors. However, to date, there are only a few reports showing the usefulness of following-up serum KL-6 levels for finding malignant tumors in IP patients with PM/DM. Here, we described the first patient in whom increased serum KL-6 led to the diagnosis of colon cancer during follow-up of DM-associated IP.

Serum Syndecan-4 as a Possible Biomarker in Patients With Acute Pneumonia.

BACKGROUND: Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and glycosaminoglycan side chains of syndecan-4 bind to several proteins, suggesting several biological functions. However, the role of syndecan-4 in acute bacterial pneumonia has not yet been elucidated. METHODS: Serum syndecan-4 levels were measured in patients with acute pneumonia, and the relationships between serum syndecan-4 levels and clinical parameters were analyzed. Next, we treated wild-type and syndecan-4-deficient mice with Streptococcus pneumoniae intranasally and analyzed the phenotype of syndecan-4-deficient mice. RESULTS: In the patients with acute pneumonia, serum syndecan-4 levels were significantly higher than in the healthy volunteers and correlated negatively with the pneumonia severity score. In addition, in patients who improved with short-term antibiotic therapy, serum syndecan-4 levels were higher on admission and gradually increased during antibiotic therapy. Furthermore, in syndecan-4-deficient mice, the survival rate was significantly worse, and total neutrophil counts in bronchoalveolar lavage fluid, bacterial counts in blood, and plasma levels of inflammatory cytokines were significantly higher than in wild-type mice. CONCLUSIONS: These results suggest that syndecan-4 has an anti-inflammatory function in acute pneumonia and could serve as a useful biomarker in these patients.

Secretoglobin 3A2 attenuates lipopolysaccharide-induced inflammation through inhibition of ERK and JNK pathways in bronchial epithelial cells.

Secretoglobin (SCGB) 3A2, previously known as uteroglobin-related protein 1, is a secreted protein highly expressed in the epithelial cells of the airways. It has been demonstrated that SCGB3A2 is involved in allergic airway inflammation such as bronchial asthma. However, the role of SCGB3A2 in lipopolysaccharide (LPS)-induced airway inflammation has yet to be reported. The goal of this study was therefore to clarify the role of SCGB3A2 in LPS-induced airway inflammation. We stimulated BEAS-2B, human bronchial epithelial cells, with LPS and analyzed messenger RNA (mRNA) expression of tumor necrosis factor (TNF)-α and CXCL8 with or without pre-incubation of SCGB3A2. The mRNA expression of TNF-α and CXCL8 was clearly upregulated 3 h after LPS stimulation, and pre-incubation of SCGB3A2 significantly inhibited the upregulation of the mRNA expression. The pre-incubation of SCGB3A2 also inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase in BEAS-2B cells. Furthermore, PD98059, a specific inhibitor for ERK, as well as SP600125, a specific inhibitor for JNK, inhibited LPS-induced mRNA upregulation of inflammatory mediators. These results demonstrate the novel biological activity of SCGB3A2, which is that it attenuates LPS-induced inflammation in bronchial epithelial cells through inhibition of ERK and JNK activation.

Clinical significance of serum hyaluronan in chronic fibrotic interstitial pneumonia.

BACKGROUND AND OBJECTIVE: Hyaluronan is an important constituent of the extracellular matrix in lungs, and growing evidence demonstrates its important biological properties in the lung. However, its role in interstitial pneumonia remains to be fully clarified. The goal of this study was to clarify the role of hyaluronan in interstitial pneumonia. METHODS: Hyaluronan in serum and bronchoalveolar lavage (BAL) fluid of chronic interstitial pneumonia (CIP) patients was measured, and the correlation with clinical parameters was determined. In addition, the correlation between hyaluronan in serum and clinical parameters was analysed in patients with acute exacerbation of interstitial pneumonia (IP-AE). RESULTS: When compared with healthy controls, serum hyaluronan was significantly greater in patients with CIP and was positively correlated with serum biomarkers of inflammation and fibrosis, such as C-reactive protein and surfactant protein-D. In BAL fluid, the amount of hyaluronan was positively correlated with the percentage of inflammatory cells and the amount of CXCL8. When compared with CIP patients, patients with IP-AE had significantly greater amounts of serum hyaluronan, and patients with the highest serum hyaluronan had the worst 60-day outcomes. CONCLUSIONS: This work suggests that serum hyaluronan may be a clinically useful biomarker of interstitial pneumonia and suggests the possibility that hyaluronan is involved in the pathogenesis of interstitial pneumonia by recruiting inflammatory cells into the lungs.

Association of asthma education with asthma control evaluated by asthma control test, FEV1, and fractional exhaled nitric oxide.

BACKGROUND: Asthma education is an important adjunct for asthma control although the way asthma education affects asthma outcomes is poorly understood. The asthma control test (ACT), forced expiratory volume in 1 s (FEV(1)), and fractional exhaled nitric oxide (FeNO) have all been used as markers of asthma control. However, the use of FeNO as a surrogate marker remains controversial. OBJECTIVES: (i) To examine whether asthma education is associated with asthma control; (ii) to compare absolute levels and changes of ACT, FEV(1), and FeNO over a year; and (iii) to evaluate whether FeNO can be used as an additional marker of asthma control. METHODS: Fifty asthmatics with poor adherence (12 mild, 21 moderate, and 17 severe) received asthma education at study entry. Medications were unchanged for the first 3 months, and ACT, FEV(1), and FeNO measurements were recorded at entry, 3, 6, and 12 months. Asthma control was assessed at each visit and patients were categorized as either "stable" or "unstable" asthmatics according to the global initiative for asthma (GINA) guidelines. RESULTS: A significant decrease in FeNO and increase in ACT score were noted in the stable asthmatic group at 3 months (p < .001), and this persisted over 12 months. Significant correlations were seen between changes (Δ) in FeNO, ACT, and FEV(1) over time. However, significant correlations between the absolute levels were not maintained over 12 months. A decrease of ≥18.6% in FeNO and a ≥3-point increase in ACT score (sensitivity: 80% and 73.3% and specificity: 83.3% and 87.5%, respectively) were associated with stable asthma control although the absolute levels were not. CONCLUSIONS: Asthma education may be useful to achieve stable control. In addition, changes rather than absolute levels of FeNO and ACT may be better markers of asthma control.