Pulmonary manifestation of inflammatory bowel disease: Two case reports.

Pulmonary involvement associated with inflammatory bowel disease (IBD) are a rare extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), we herein presented two cases. Case 1: 53-year-old man with Crohn's disease treated with mesalazine and azathioprine. Pulmonary nodular shadows were incidentally detected on chest imaging, and revealed granulomas through transbronchial lung biopsy. Case 2: 68-year-old man with ulcerative colitis treated with mesalazine. He presented with fever and respiratory symptoms, and chest imaging showed multiple nodular infiltrates. He was diagnosed with organizing pneumonia by lung biopsy. Both cases were diagnosed to have pulmonary involvement associated with inflammatory bowel disease (IBD) according to multidisciplinary examination including positron emission tomography-computed tomography (FDG-PET) and pathological test. Pulmonary manifestations with IBD may not always require discontinuation of drugs or additional use of steroids or immunosuppressants.

Active Tuberculosis in a Patient Receiving Adalimumab for Psoriatic Arthritis and Chemoprophylaxis for Latent Tuberculosis Infection.

Tumor necrosis factor (TNF) inhibitors, including adalimumab, are widely used to treat refractory psoriatic arthritis (PsA). Although isoniazid chemoprophylaxis is generally effective in preventing reactivation of latent tuberculosis infection (LTBI), prophylactic measures do not fully protect against development of active tuberculosis. We report a rare case of active tuberculosis despite chemoprophylaxis for LTBI in a patient receiving adalimumab for PsA. A 60-year-old Japanese woman who had received a diagnosis of psoriasis at age 35 years presented with arthralgia of the right hand, which she first noticed 2 months previously. Physical examination showed scattered erythematous papules and plaques with scales on her trunk, extremities, and scalp. Her right metacarpophalangeal and proximal interphalangeal joints were swollen and painful, and her right wrist and elbow were painful. PsA was diagnosed and adalimumab was initiated. Because an interferon-γ release assay (IGRA) showed a borderline result at screening, isoniazid was administered as chemoprophylaxis for LTBI. At 22 months after initiation of adalimumab, IGRA was positive and chest CT disclosed centrilobular nodules in both lungs and swelling of multiple lymph nodes. Culture of sputum at 24 months demonstrated Mycobacterium tuberculosis. Active tuberculosis was diagnosed, and treatment with a combination of isoniazid, rifampicin, ethambutol hydrochloride, and pyrazinamide was started. To ensure timely diagnosis and treatment of active tuberculosis, a tuberculosis expert should be consulted at an early stage, with regular screening and monitoring.

The respiratory microbiome associated with chronic obstructive pulmonary disease comorbidity in non-small cell lung cancer.

BACKGROUND: Research has shown that some microbiomes are linked to cancer. Hence, we hypothesize that alterations in the respiratory microbiome might be associated with lung cancer. METHODS: Through droplet digital polymerase chain reaction analysis, we investigated the abundance of Acidovorax in surgically resected primary tumors and corresponding nontumor lung tissues obtained from 50 Japanese patients with non-small cell lung cancer. RESULTS: The rate of positivity for Acidovorax in tumor and nontumor tissues was 44 and 26%, respectively. The abundance of Acidovorax in tumor tissues was significantly higher in patients with nonsquamous cell carcinoma complicated by chronic obstructive pulmonary disease (COPD) and those who relapsed after surgical resection (p < 0.05). In tumor tissues, the results of the univariate and multivariate analyses revealed that only COPD exerted a direct effect on the abundance of Acidovorax (p < 0.05). Furthermore, the presence of Acidovorax was high in lung cancer patients with COPD comorbidity (65%) and TP53 gene mutation; only one of the nontumor tissues was positive for Acidovorax. In patients with lung cancer complicated by COPD, Acidovorax tended to be present in both the tumor and nontumor areas. CONCLUSIONS: This study identified novel microbiota involved in lung cancer with COPD comorbidity. The results suggested that Acidovorax may be a useful biomarker in the screening for lung cancer. Further studies are warranted to validate the clinical significance of the microbiome in a larger independent patient cohort.

Rictor-targeting exosomal microRNA-16 ameliorates lung fibrosis by inhibiting the mTORC2-SPARC axis.

Idiopathic pulmonary fibrosis (IPF), a progressive disorder of unknown etiology, is characterized by pathological lung fibroblast activation and proliferation resulting in abnormal deposition of extracellular matrix proteins within the lung parenchyma. The pathophysiological roles of exosomal microRNAs in pulmonary fibrosis remain unclear; therefore, we aimed to identify and characterize fibrosis-responsive exosomal microRNAs. We used microRNA array analysis and profiled the expression of exosome-derived miRNA in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. The effect of microRNAs potentially involved in fibrosis was then evaluated in vivo and in vitro. The expression of exosomal microRNA-16 was increased by up to 8.0-fold on day 14 in bleomycin-treated mice, compared to vehicle-treated mice. MicroRNA-16 mimic administration on day 14 after bleomycin challenge ameliorated pulmonary fibrosis and suppressed lung and serum expression of secreted protein acidic and rich in cysteine (SPARC). Pretreatment of human lung fibroblasts with the microRNA-16 mimic decreased the expression of rapamycin-insensitive companion of mTOR (Rictor) and TGF-ß1-induced expression of SPARC. This is the first study reporting the anti-fibrotic properties of microRNA-16 and demonstrating that these effects occur via the mTORC2 pathway. These findings support that microRNA-16 may be a promising therapeutic target for IPF.

Acinetobacter baumannii can be transferred from contaminated nitrile examination gloves to polypropylene plastic surfaces.

BACKGROUND: Several observational studies suggest that gloves of health care workers are major routes of multidrug-resistant Acinetobacter baumannii transmission. However, limited experimental data are available assessing Acinetobacter transmission from gloves to environmental surfaces. This study determined whether A baumannii was easily transferred from nitrile gloves to polypropylene plastic compared with other gram-negative bacteria that cause health care-associated infections in laboratory-controlled experiments. METHODS: Gloved fingerpad-to-fomite transfer efficiency was determined for drug-resistant and -sensitive strains of A baumannii, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. RESULTS: Only A baumannii transferred from gloves to fomites 3 minutes after the bacterial transfer event. Transfer efficiency of A baumannii was 0.1%-33% at that time point. DISCUSSION: Bacterial transfer from contaminated gloves to the hospital environment may be related to the type of contaminating bacteria, inoculated bacterial level, fomites, and glove materials. Therefore, it is important to need a comprehensive assessment of the transfer efficiency. CONCLUSIONS: A baumannii can transfer easily from nitrile gloves to fomite compared with other gram-negative bacteria that cause health care-associated infections. These findings support data from previous observational studies that gloves of health care workers can be major routes of A baumannii transmission in clinical settings.

Prognostic Factors in the Acute Exacerbation of Idiopathic Pulmonary Fibrosis: A Retrospective Single-center Study.

Objectives Acute exacerbation of idiopathic pulmonary fibrosis (IPF-AE) has been recognized as a fatal pulmonary disorder, but the exact prognostic factors are unknown. The aim of the present study was to analyze the clinical characteristics of patients with IPF-AE and identify the prognostic factors. Methods The medical records of 59 cases of IPF-AE were retrospectively reviewed. Clinical data, laboratory data, radiographic findings, treatment, and time from the onset of symptoms to the initiation of corticosteroid pulse therapy, i.e. symptom duration, and outcome were analyzed. Results The IPF Stage, Gender-Age-Physiology (GAP) Index, symptom duration, and the high-resolution computed tomography (HRCT) score were significantly related to the prognosis in the univariate analysis. In the multivariate analysis, the symptom duration remained a significant prognostic factor (hazard ratio of 1-day increase, 1.11; 95% confidence interval, 1.01-1.15; p=0.0427). The area under the receiver operating characteristics curve of symptom duration was statistically significant for survivors versus non-survivors (area under the curve, 0.73; p=0.012). The survival period was significantly shorter in the late-treatment groups (≥5 days; n=30) than in the early-treatment groups (<5 days; n=29; log-rank test; p<0.0001). Conclusion The time interval between the onset of symptoms and the initiation of corticosteroid pulse therapy may be an independent prognostic factor in patients with IPF-AE.

XPLN is modulated by HDAC inhibitors and negatively regulates SPARC expression by targeting mTORC2 in human lung fibroblasts.

Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-ß1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates SPARC expression remains unknown. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts. Effect of XPLN on mTORC2 activity was evaluated by silencing XPLN in human foetal lung fibroblasts (HFL-1 cells), using small interfering RNA. SPARC expression was quantified by quantitative real-time RT-PCR and western blotting. Fibroblasts were treated with TGF-ß1, histone deacetylase (HDAC) inhibitors, entinostat, or vorinostat, to assess their effects on XPLN expression. Moreover, the effect of mTORC1 inhibition on SPARC and XPLN was examined. XPLN depletion stimulated SPARC expression and Akt phosphorylation on Ser473. TGF-ß1 treatment down-regulated XPLN via Smad 2/3. XPLN mRNA expression was up-regulated upon treatment with HDAC inhibitors in a concentration-dependent manner, and TGF-ß1-induced SPARC expression was reversed by entinostat treatment. mTORC1 inhibition by rapamycin and Raptor depletion stimulated SPARC expression. In conclusion, this is the first study describing the involvement of XPLN in the regulation of SPARC. These findings may help uncover the regulatory mechanisms of the mTORC2-SPARC axis. The up-regulation of XPLN by HDAC inhibitors may be a novel therapeutic approach in patients with IPF.

Nintedanib modulates surfactant protein-D expression in A549 human lung epithelial cells via the c-Jun N-terminal kinase-activator protein-1 pathway.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a high mortality rate. Signalling pathways activated by several tyrosine kinase receptors are known to be involved in lung fibrosis, and this knowledge has led to the development of the triple tyrosine kinase inhibitor nintedanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), for the treatment of IPF. Pulmonary surfactant protein D (SP-D), an important biomarker of IPF, reportedly attenuates bleomycin-induced pulmonary fibrosis in mice. In this study, we investigated whether nintedanib modulates SP-D expression in human lung epithelial (A549) cells using quantitative real-time reverse transcriptase polymerase chain reaction and western blotting. To investigate the mechanisms underlying the effects of nintedanib, we evaluated the phosphorylation of c-Jun N-terminal kinase (JNK) and its downstream target c-Jun. The effect of the JNK inhibitor SP600125 on c-Jun phosphorylation was also tested. Activation of activator protein-1 (AP-1) was examined using an enzyme-linked immunosorbent assay-based test, and cell proliferation assays were performed to estimate the effect of nintedanib on cell proliferation. Furthermore, we treated mice with nintedanib to examine its in vivo effect on SP-D levels in lungs. These experiments showed that nintedanib up-regulated SP-D messenger RNA expression in a dose-dependent manner at concentrations up to 5 µM, with significant SP-D induction observed at concentrations of 3 µM and 5 µM, in comparison with that observed in vehicle controls. Nintedanib stimulated a rapid increase in phosphorylated JNK in A549 cells within 30 min of treatment and stimulated c-Jun phosphorylation, which was inhibited by the JNK inhibitor SP600125. Additionally, nintedanib was found to activate AP-1. A549 cell proliferation was not affected by nintedanib at any of the tested concentrations. Moreover, blocking FGFR, PDGFR, and VEGFR function did not affect nintedanib-induced SP-D expression, suggesting that nintedanib mediates its effects through a mechanism that is distinct from its known role as a tyrosine kinase inhibitor. Nintedanib is also reported to inhibit Src kinase although pre-treatment of cells with a Src kinase inhibitor had no effect on nintedanib-induced SP-D expression. Increased expression of SFTPD mRNA and SP-D protein in the lungs of nintedanib-treated mice was also observed. In this work, we demonstrated that nintedanib up-regulated SP-D expression in A549 cells via the JNK-AP-1 pathway and did not affect cell proliferation. This is the first report describing SP-D induction by nintedanib.

Successful treatment of histiocytic sarcoma and concurrent HIV infection using a combination of CHOP and antiretroviral therapy.

Histiocytic sarcoma (HS) is a rare malignancy of soft tissues with an unknown etiology. The CHOP (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride and prednisolone) regimen is often adopted as first-line chemotherapy; however, its therapeutic efficacy against HS is usually low. We herein first present the case of a patient with HS who was infected with human immunodeficiency virus-1 (HIV) in whom treatment with a combination of CHOP and antiretroviral therapy (ART) was successful. The patient has been in complete remission for 12 months following the discontinuation of chemotherapy under continuous ART. This case report may help to promote further investigation of both HS and HIV-related malignancy.

Fatal pneumonia associated with temozolomide therapy in patients with malignant glioma.

This report presents the cases of three patients with fatal pneumonia that was highly suspected to be Pneumocystis pneumonia (PCP) based on serological diagnosis. Their chest radiographs showed bilateral pneumonia and each had presented with severe respiratory failure requiring mechanical ventilation when they arrived at the hospital. Although bronchoscopical sampling could not be performed, their chest computed tomography imaging and a marked elevation of serum KL-6 and ß-D-glucan levels were characteristic of Pneumocystis pneumonia. All three were found to have been treated with temozolomide after surgery for malignant glioma. Temozolomide can cause Pneumocystis pneumonia. The three patients did not receive prophylactic medication against Pneumocystis pneumonia during treatment with temozolomide, and their histories suggested that all had delayed seeking treatment. It may be difficult to diagnose Pneumocystis pneumonia because the symptoms are not specific for Pneumocystis pneumonia and they tend to be similar to those of common respiratory infectious diseases. Therefore, patients who receive temozolomide therapy have the potential to develop fatal pneumonia and should be carefully observed. The patients should also be adequately informed about Pneumocystis pneumonia, and prophylaxis against Pneumocystis pneumonia should be considered proactively before treatment with temozolomide is initiated.

Identification of a novel SEREX antigen family, ECSA, in esophageal squamous cell carcinoma.

BACKGROUND: Diagnosis of esophageal squamous cell carcinoma (SCC) may improve with early diagnosis. Currently it is difficult to diagnose SCC in the early stage because there is a limited number of tumor markers available. RESULTS: Fifty-two esophageal SCC SEREX antigens were identified by SEREX (serological identification of antigens by recombinant cDNA expression cloning) using a cDNA phage library and sera of patients with esophageal SCC. Sequence analysis revealed that three of these antigens were similar in amino acid sequences, and they were designated as ECSA (esophageal carcinoma SEREX antigen)-1, -2 and -3. The ECSA family was also similar to an EST clone, hepatocellular carcinoma-associated antigen 25a (HCA25a). Serum antibody levels to ECSA-1, -2 and -3 were significantly higher in patients with esophageal SCC than in healthy donors. Based on the conserved amino acid sequences, three peptides were synthesized and used for enzyme-linked immunosorbent assays (ELISA). The serum antibody levels against one of these peptides were significantly higher in patients with esophageal SCC. This peptide sequence was also conserved in FAM119A, GOSR1 and BBS5, suggesting that these are also ECSA family members. Reverse transcription followed by quantitative PCR analysis showed that the mRNA expression levels of ECSA-1, -2 and -3 and FAM119A but not of HCA25a, GOSR1 and BBS5 were frequently elevated in esophageal SCC tissues. CONCLUSIONS: We have identified a new gene family designated ECSA. Serum antibodies against the conserved domain of the ECSA family may be a promising tumor marker for esophageal SCC.

Sequential changes of Legionella antigens and bacterial load in the lungs and urines of a mouse model of pneumonia.

Legionella pneumophila is an important cause of community- and hospital-acquired pneumonia. In spite of the introduction of the urinary antigen detection method, Legionella pneumonia may be still underdiagnosed. We performed kinetic and quantitative analysis of diagnostic markers, such as bacterial loads, DNA assays, and antigen titers, in a 28-day time course murine model of L. pneumophila pneumonia. L. pneumophila replicated approximately 100-fold in the lungs of A/J mice in the first 48 h, and then became undetectable on day 14. Unexpectedly, pathogens other than L. pneumophila were consistently recovered from the lungs and livers at the acute phases, although those numbers were far below Legionella loads in the lungs. The peaks of specific antigen titer were observed on 48 h in the lungs, bronchoalveolar lavage (BAL) fluids, and urines and sustained positive even at 28 days after the infection. Especially, the lung homogenates and BAL fluids demonstrated 16 to 64 times higher levels of antigen titer than the urines by the end of observation. Legionella-specific DNA in the lungs was detected by polymerase chain reaction and loop-mediated isothermal amplification methods until 7 and 14 days after the infection, respectively. The inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin 6, and MIP-2, exhibited a peak on the acute phase, whereas the maximal production of high mobility group box 1 in the serum was observed on day 7. These results characterized the kinetic nature of diagnostic markers in L. pneumophila pneumonia. The present data suggested prolonged and compartmentalized deposition of antigen in the lungs, which may have an impact on the diagnosis of L. pneumophila pneumonia, especially in missed cases even after recovery from disease.

[A case of allergic granulomatosis and angiitis (Churg-Strauss syndrome) in a 15-year-old girl].

A 15-year-old girl with a 6-month history of bronchial asthma was admitted to our hospital because of fever, dyspnea, weight loss, dysesthesia, muscle weakness, gait disturbance and purpuric rash. In addition, leukocytosis, hypereosinophilia and elevation of CRP were observed. Chest radiograph and computed tomography on admission showed non-segmental patchy air-space consolidation in both lung fields. Skin biopsy was performed and the pathologic diagnosis was necrotizing arteritis with eosinophilic infiltration. Transbronchial lung biopsy revealed eosinophilic pneumonia. From the clinical course, laboratory data and pathologic findings, the diagnosis of allergic granulomatosis and angiitis (Churg-Strauss syndrome) was made. Following the skin and lung biopsies, intravenous pulse corticosteroid and oral prednisolone treatment was started and her clinical findings improved. Angiitis with allergic granulomatosis is a vasculitis that is found in adults. This is an extremely rare and interesting case of angiitis with allergic granulomatosis in childhood.

[A case of poorly differentiated lung adenocarcinoma showing air-space consolidation caused by aerogenic metastasis].

A 78-year-old woman was admitted to our hospital because of dyspnea. A chest radiograph and a computed tomogram on admission showed air-space consolidation in the left upper lung field, and so pneumonia was diagnosed. Although antibiotics were administered, the air-space consolidation did not improve. A transbronchial lung biopsy was performed, yielding a pathologic diagnosis of poorly differentiated lung adenocarcinoma. Despite combination chemotherapy with docetaxel and UFT, the air-space consolidation expanded, and the patient finally died of respiratory failure 3 months after diagnosis. Autopsy revealed air-space consolidation due to poorly differentiated lung adenocarcinoma, with large atypical cells diffusely floating in the alveolar spaces. It has been recognized that bronchiolo-alveolar carcinoma and well-differentiated lung adenocarcinoma present with air-space consolidation, reflecting the cancer cells lining the alveolar walls. However, in this case, the air-space consolidation was due to cancer cells diffusely floating in the alveolar spaces in aerogenic metastasis. It was considered that this is a rare case, which presented with a very interesting development pattern.

Changes in serum KL-6 after intravenous fosfomycin administration in idiopathic interstitial pneumonia.

Changes in serum KL-6 levels after intravenous fosfomycin (FOM) administration in idiopathic interstitial pneumonia (IIP) were studied. Seventeen patients who were diagnosed with usual interstitial pneumonia by surgical lung biopsy were selected as subjects. In these patients, FOM was administered intravenously, at a dose of 2 g twice daily, for 14 days, and serum KL-6 was determined before and after its administration. FOM administration resulted in a reduction of serum KL-6 in all 17 patients (1273 +/- 132 U/ml [mean +/- SEM] to 1023 +/- 101 U/ml; P < 0.01). FOM may reduce serum KL-6 in IIP and may be an appropriate therapeutic drug for this condition.

[A case of loxoprofen sodium-induced bronchiolitis obliterans organizing pneumonia (BOOP)].

A 78-year-old man was referred to our department because of an abnormal shadow on the chest radiograph and liver dysfunction after lung resection for lung cancer. Following the operation, loxoprofen sodium was administered to control his chest pain. A chest radiograph on admission showed airspace consolidation in the right lower lung field. In addition, leukocytosis and elevation of CRP were observed. Although piperacillin sodium was given to him, airspace consolidation on a chest radiograph was increased. A bronchoalveolar lavage fluid study showed that total cell counts and proportion of lymphocytes were increased, and the CD4/CD8 ratio was 1.77. A transbronchial lung biopsy specimen revealed organizing pneumonia with Masson bodies. Furthermore, a lymphocyte stimulation test for loxoprofen sodium was positive. From the clinical course, laboratory data and pathologic findings, we considered this case to be loxoprofen sodium-induced BOOP. Withdrawal of loxoprofen sodium and treatment with corticosteroid resulted in marked improvement of the clinical findings. Although a rare occurrence, it is important to recognize that BOOP can be caused by loxoprofen sodium.

[Diagnosis of bacterial pneumonia by serum beta-globulin demarcation].

We studied whether the consolidation whose serum beta-globulin demarcation showed more than 12% was bacterial pneumonia or not. The materials were the patients with fever (> or = 37 degrees C) and the consolidation on chest-X ray film, the value of serum beta-globulin demarcation was more than 12% from 1995 to 2000. There were 5 cases with drug-induced pneumonitis, 5 cases with BOOP, 2 cases with eosinophilic pneumonia, 1 case with lung cancer (adenocarcinoma), and 1 case with interstitial pneumonia with dermatomyositis. No one had bacterial pneumonia. These results suggested the consolidation with fever whose serum beta-globulin demarcation showed more than 12% was not bacterial pneumonia.