Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease.

Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality.

Overexpression of microRNA-155 suppresses chemokine expression induced by Interleukin-13 in BEAS-2B human bronchial epithelial cells.

BACKGROUND: MicroRNAs are non-coding small RNAs that regulate expression of target genes by binding to 3' untranslated regions. In this study, we used bronchial epithelial cells to investigate in vitro the role of the microRNA miR-155 in the expression of chemokines associated with airway inflammation. miR-155 has previously been reported to regulate allergic inflammation. METHODS: BEAS-2B bronchial epithelial cells were cultured and transfected with mimic or inhibitor oligonucleotides to overexpress or downregulate miR-155, as confirmed by real-time PCR. Cells were then stimulated with tumor necrosis factor-alpha, interleukin-13 (IL-13), and a double stranded RNA that binds Toll-like receptor 3. Expression and secretion of the chemokines CCL5, CCL11, CCL26, CXCL8, and CXCL10 were then quantified by real-time PCR and ELISA, respectively. Phosphorylation of signal transducer and activator of transcription 6 (STAT6), a target of the IL-13 receptor, was analyzed by ELISA. RESULTS: miR-155 overexpression significantly suppressed IL-13-induced secretion of CCL11 and CCL26. These effects were specific, and were not observed for other chemokines, nor in cells with downregulated miR-155. miR-155 overexpression also suppressed CCL11 and CCL26 mRNA, but did not affect expression of the IL-13 receptor or phosphorylation of STAT6. CONCLUSIONS: miR-155 specifically inhibits IL-13-induced expression of eosinophilic chemokines CCL11 and CCL26 in bronchial epithelial cells, even though the 3'-untranslated region of these genes do not contain a consensus binding site for miR-155.

Clinical features and outcomes of aspiration pneumonia compared with non-aspiration pneumonia: a retrospective cohort study.

Pneumonia is a leading cause of death among elderly patients. Although aspiration pneumonia (AP) commonly occurs with aging, its clinical features and outcomes are still uncertain. The aims of this study were to describe the clinical features and outcomes of AP and to assess whether presence of AP affects clinical outcomes in patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). We retrospectively analyzed patients with CAP and HCAP hospitalized in our institution in Japan from October 2010 to March 2012. We compared clinical features and outcomes between AP and non-AP, and investigated risk factors for recurrence of pneumonia and death. Of 214 consecutive patients, 100 (46.7%) were diagnosed as having aspiration pneumonia. These patients were older and had lower body mass index, more comorbidities, and poorer Eastern Cooperative Oncology Group performance status (ECOG PS) than the patients with non-AP. Patients with AP had more severe disease, required longer hospital stays, and had a frequent recurrence rate of pneumonia and higher mortality. In multivariate analyses, AP, age, and ECOG PS were related to recurrence of pneumonia, and the prognostic factors were CURB-65 score and ECOG PS. AP was not a significant indicator for prognosis but was the strongest risk factor for recurrence of pneumonia. Clinical background and outcomes including recurrence and mortality of AP were obviously different from those of non-AP; therefore AP should be considered as a distinct subtype of pneumonia, and it is important to prevent the recurrence of pneumonia in the patients with AP.

[A case of lung adenocarcinoma of pancoast type successfully treated with concurrent chemoradiotherapy].

We reported a case of lung adenocarcinoma of Pancoast type that was successfully treated with chemoradiotherapy. A 66-year-old man was admitted to our hospital because of back pain. Chest computed tomography (CT) showed a Pancoast tumor on the left side. Using transbronchial needle aspiration, we diagnosed lung adenocarcinoma (cT3N0M0). The patient received chemoradiotherapy simultaneously(carboplatin AUC5 and irinotecan 60 mg/m2). There are no findings of tumor recurrence 8 years after chemoradiotherapy. This patient was successfully treated with concurrent chemoradiotherapy, which is suggested to be a useful therapy for Pancoast tumor.

[A case of MALT lymphoma simultaneously associated with gastric and pulmonary involvement].

A 52-year-old man had been treated by hemodialysis because of IgA nephropathy since 1994. Gastric MALT lymphoma was diagnosed in January 2007. Radiation therapy was performed for 4 weeks (40Gy) and the response was complete remission (CR) by September 2007. He was admitted to our hospital in February 2008 because of an abnormal chest shadow. Chest CT showed multiple cystic lesions with calcification and consolidation. Transbronchial lung biopsy from the area of consolidation (left S5) showed pulmonary invasion of small lymphoid cells. PCR analysis showed clonal rearrangement of the heavy chain of the immunoglobulin gene. Accordingly, MALT lymphoma was diagnosed. Rituximab infusion was performed, because CD20 immunostaining was positive and he had been treated by hemodialysis. The abnormal chest shadow was presented since gastric MALT lymphoma was diagnosed. We considered that MALT lymphoma occurred simultaneously in the stomach and lung.

[Hypersensitivity pneumonitis induced by Hypsizigus marumoreus].

We present the case of a 53-year-old woman who was employed at a mushroom (Pleurotus eryngii and Hypsizigus marumoreus) cultivation factory for 15 years. She was admitted to our hospital because of fever and dry cough. Chest radiography and CT scanning revealed diffuse ground glass opacity and centrilobular nodules in both lung fields. Serum KL-6 was elevated. In the bronchoalveolar lavage fluid, the CD4/CD8 ratio was reduced, and the lymphocyte fraction was very high. Transbronchial lung biopsy specimens showed lymphocyte alveolitis. After admission, the patient's symptoms improved rapidly without medication. Although these findings are compatible with hypersensitivity pneumonitis, it was difficult to identify a causative antigen. Serum antibody against Trichosporon was positive. A lymphocyte stimulation test of the peripheral blood was positive against extracts of P. eryngii and H. marumoreus. Furthermore, precipitins against the extracts of H. marumoreus were detected by a double immunodiffusion test. Therefore, we decided to conduct a challenge test using H. marumoreus. As an inhalation provocation test with H. marumoreus conducted in a sickroom caused the same clinical symptoms and signs as experienced in the workplace, we diagnosed hypersensitivity pneumonitis caused by H. marumoreus. A provocation test, in which antigen exposure is limited using a closed space, such as a sickroom, was simple, safe and effective for determining the antigen causing hypersensitivity pneumonitis.

Analysis of systemic lupus erythematosus-related interstitial pneumonia: a retrospective multicentre study.

Thoracic diseases in patients with systemic lupus erythematosus (SLE), especially interstitial pneumonia (SLE-IP), are rare and have been poorly studied. The aims of this multicentre study were to evaluate SLE-IP and elucidate its clinical characteristics and prognosis. Fifty-five patients with SLE-IP who had attended the respiratory departments of participating hospitals were retrospectively evaluated in this multicentre study. Clinical information, high-resolution computed tomography (HRCT), and surgical lung biopsy/autopsy specimens were analysed by respiratory physicians, pulmonary radiologists, and pulmonary pathologists. IP patterns on HRCT and lung specimens were classified based on the international classification statement/guideline for idiopathic interstitial pneumonias. The most frequent form of SLE-IP at diagnosis was chronic IP (63.6%), followed by subacute (20.0%), and acute IP (12.7%). Radiologically, the most common HRCT pattern was "Unclassifiable" (54%). Histologically, "Unclassifiable" was the most frequently found (41.7%) among 12 patients with histologically proven IP. Interestingly, accompanying airway diseases were present in nine of these patients (75%). In multivariate analysis, current smoking (hazard ratio [HR] 6.105, p = 0.027), thrombocytopenia (HR 7.676, p = 0.010), anti-double-strand DNA titre (HR 0.956, p = 0.027), and nonspecific interstitial pneumonia (NSIP) + organizing pneumonia (OP) pattern on HRCT (vs. NSIP, HR 0.089, p = 0.023) were significant prognostic factors. In conclusion, chronic IP was the most frequent form of IP in patients with SLE-IP, and "Unclassifiable" was the commonest pattern radiologically and histologically.

[Lung cancer associated with rheumatoid arthritis and usual interstitial pneumonia].

UNLABELLED: To assess the effects of usual interstitial pneumonia (UIP) and smoking in rheumatoid arthritis (RA) patients regarding lung cancer risk, we studied 86 RA patients (14 patients with lung cancer, 58 patients with UIP (RA/ UIP), and 14 patients with both). Among the 28 RA patients with lung cancer, 14 patients (50%) had UIP. Compared to the lung cancer patients without UIP, the proportion of smokers (92.6 vs 50%, p = 0.0328) and total pack-years of smoking (57.1 +/- 37.1 vs 19.5 +/- 21.9, p = 0.003) were significantly higher in lung cancer patients with UIP. There was no significant difference in age, sex, and histological type and location of lung cancer between these two groups. Among the 72 RA/UIP patients, 14 patients (19.4%) had lung cancer. Compared to RA/UIP-only patients, the proportion of smokers (92.6 vs 46.6%, p = 0.002) and total pack-years of smoking (57.1 +/- 37.1 vs 25.4 37.4, p = 0.006) were significantly higher in RA/UIP patients with lung cancer. There was no significant difference in age, sex, and the duration of RA between these two groups. The odds ratio of smoking and total pack-years of smoking over 20 for the development of lung cancer in RA/UIP patients were 14.93 and 21.27, and the differences were statistically significant (p = 0.002 and p < 0.001, respectively). CONCLUSION: 50% of RA patients with lung cancer had RA/UIP and 19.4% of RA/UIP patients had lung cancer. These findings suggest that RA/UIP may be associated with increased risk of development of lung cancer in RA patients. In an RA cohort study to assess the development of lung cancer, RA patients should be divided into two groups, one with RA/UIP and another without RA/UIP. Smokers with RA/UIP should be recommended to cease smoking.

[Pulmonary infections in patients with rheumatoid arthritis].

We studied 149 rheumatoid arthritis (RA) patients (mean age 68.0 years; 68 men, 81 women) with pulmonary infections. The mean age at the onset of RA and the duration of RA was 57.2 +/- 15.2 years and 10.9 +/- 11.5 years, respectively. Pulmonary infections included nontuberculous mycobacteriosis in 59 patients (Mycobacterium avium complex infection, 50 cases : Mycobacterium kansasii infection, 4 cases; others, 5 cases), pneumonia in 46 patients, pulmonary tuberculosis in 28 patients, pulmonary aspergillosis in 12 patients, pulmonary cryptococcosis in 5 patients, Pneumocystis jiroveci pneumonia in 5 patients, lung abscess in 9 patients, exacerbation of bronchiectasis in 7 patients, and empyema in 4 patients. One hundred percent of patients with exacerbation of bronchiectasis, 91.7% of patients with pulmonary aspergillosis, 87% of patients with pneumonia, and 81.4% of patients with nontuberculous mycobacteriosis had underlying lung diseases. The pulmonary infections during therapy with steroids were pulmonary tuberculosis (78.6%), pneumonia (65.2%), and pulmonary aspergillosis (58.3%), while the pulmonary infections during methotrexate treatment were Pneumocystis jiroveci pneumonia (80%), pulmonary cryptococcosis (40%), and pulmonary tuberculosis (28.6%). Pulmonary infections in RA patients who were taking TNFalpha inhibitors included 1 patient each with nontuberculous mycobacteriosis, pneumonia, pulmonary tuberculosis, and Pneumocystis jiroveci pneumonia. Among the RA patients with lung abscess, malignancy was noted in 55.6%, and diabetes mellitus in 22.2%. Pseudomonas aeruginosa was the second-most-common cause of pneumonia and cause of all exacerbations of bronchiectasis. As well as immunosuppressive medications (steroids, methotrexate, TNFalpha inhibitors) and systemic comorbid diseases, underlying lung diseases could be one of the risk factor for pulmonary infections in patients with RA. The dominant risk factor for each pulmonary infection in patients with RA might be different.

[Etiology and outcome of community-acquired pneumonia in relation to age and severity in hospitalized adult patients].

The aim of this study was to determine the etiology and outcome of community-acquired pneumonia (CAP) in relation to age and severity in hospitalized patients. Overall, 652 consecutive patients with CAP were studied retrospectively during a 4-year period from 2002. Severity of pneumonia was classified according to the guidelines of the Japanese Respiratory Society (JRS 2005) and American Thoracic Society (ATS 2001). The etiology was identified in 401 of 652 (61.5%) cases. The four most frequent pathogens were Streptococcus pneumoniae (26.2%), influenza virus (12.4%), Mycoplasma pneumoniae (10.9%), and Haemophilus influenzae (5.9%). The most common pathogen in the younger (15-44 years) group and very severe patients (JRS) was Mycoplasma pneumoniae (38.4%) and influenza virus (28.6%), respectively. The three most frequent pathogens in severe CAP patients (ATS) were Streptococcus pneumoniae (29.0%), influenza virus (17.4%), and Legionella species (13.0%). The overall mortality was 6.4%. The mortality of CAP patients among aged 1544, 45-64, 65-74, and 75 years or older was 1.4%, 3.3%, 6.9% and 9.3%, respectively. The mortality of mild, moderate, severe, and very severe patients (RS) was 0%, 4.1%, 15.5%, and 53.6%, respectively. The mortality of non-severe and severe patients (ATS) was 1.8% and 23.9%, respectively. Age and severity had influence on the prevalence of the main microbial pathogens. Streptococcus pneumoniae remained the most important pathogen that needs consideration in initial antibiotic therapy in patients with CAP of all ages and severities. Pathogens identified in patients with severe CAP in Japan were similar to those of Western countries, except for the high incidence of the influenza virus.

Connective Tissue Disease-related Thoracic Disease.

Pulmonary involvement is a frequent manifestation of connective tissue disease (CTD)-related thoracic disease. It is important to characterize the underlying pattern when pulmonary involvement occurs in a patient with CTD, and to exclude other causes. A systematic approach, evaluating each compartment of the lung (airway, interstitium, pleura, pulmonary vasculature) may be helpful. In complex cases, a multidisciplinary approach should be considered, potentially including the pulmonologist, rheumatologist, radiologist, pathologist, and sometimes the infectious disease specialist or oncologist. New techniques, such as quantitative computed tomography and MRI, are expected to be helpful for evaluation and management of CTD-associated thoracic disease.

Acquired resistance L747S mutation in an epidermal growth factor receptor-tyrosine kinase inhibitor-naïve patient: A report of three cases.

The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.

Azacitidine-induced pneumonitis in a patient with myelodysplastic syndrome: first case report in Japan.

A 74-year-old Japanese man with myelodysplastic syndrome (MDS) received chemotherapy with azacitidine. From the second day after starting the administration, he complained of fever, cough and shortness of breath. Chest roentgenography and computed tomography showed consolidations and ground-glass opacities. His symptoms grew from worse to life-threatening. We diagnosed him with azacitidine-induced pneumonitis and began administering corticosteroids. Thereafter, his symptoms and radiographic abnormalities improved. Azacitidine is a hypomethylating agent that improves the survival of MDS patients. Although this drug is commonly well tolerated and rarely causes severe lung injury, it is important to consider the potentially serious adverse effects of azacitidine-induced pneumonitis.

Photon path distribution in inhomogeneous turbid media: theoretical analysis and a method of calculation.

The photon path distribution (PPD) is a measure that I have developed to express optical responses in inhomogeneous turbid media in the time and frequency domains. The PPD is defined by local photon pathlengths of possible photons having total zigzag pathlengths I between the points of light input and detection. Such a distribution is independent of absorption and is uniquely determined for the medium under quantification. I show that the PPD is derived through the local photon count of the possible photons arising from an optical impulse incident on an imaginary medium having the same optical properties as the medium under quantification, except for the absence of absorption. The formulas derived can be used to calculate the PPD simultaneously with, for example, the numerical calculation of a diffusion equation.

Femtosecond snapshot imaging of propagating light itself.

An ultrafast imaging technique has been developed to visualize directly a light pulse that is propagating in a medium. The method, called femtosecond time-resolved optical polarigraphy (FTOP), senses instantaneous changes in the birefringence within the medium that are induced by the propagation of an intense light. A snapshot sequence composed of each femtosecond probing the pulse delay enables ultrafast propagation dynamics of the intense femtosecond laser pulse in the medium, such as gases and liquids, to be visualized directly. Other examples include the filamentation dynamics in CS2 liquid and the propagation dynamics in air related to the interaction with laser breakdown plasma. FTOP can also be used to extract information on the optical Kerr constant and its decay time in media. This method is useful in the monitoring of the intensity distribution in the nonlinear propagation of intense light pulses, which is a frequently studied subject in the field of physics regarding nonlinear optics and laser processing.