[A Case of Solitary Metastasis to the Small Intestine from Sigmoid Colon Cancer after Treatment of Seven Multiple Cancers].

A 75-year-old woman who had undergone a Hartmann's operation for sigmoid colon cancer 2 years ago was hospitalized because she experienced small bowel obstruction several times. She had a treatment history of 6 other cancers, including 5 gastrointestinal tract cancers. However, the obstruction was relieved by conservative therapy each time. In September 2015, she was hospitalized for ileus. Abdominal computed tomography revealed that the lumen of intestine was partially dilated. Subsequently, a long tube was inserted, but the dilatation of the small intestine was not fully recovered. She was diagnosed with small intestinal obstruction due to adhesion, and she underwent an operation in October 2015. During the laparotomy, she was diagnosed with adhesion due to an intestinal tumor, and a partial intestinal resection, including the entire tumor, was performed. Because the tumor appearance and histological findings were very similar to those of sigmoid colon cancer, the tumor was diagnosed as a solitary metastasis of sigmoid colon cancer to the small intestine. Generally, peritoneal dissemination causes metastasis of colon cancer to the small intestine. However, this is a rare case because the lymphatic system or extra-wall invasion was the most likely cause of metastasis. Ileus repeating the improvement exacerbation, an examination must be performed while considering possible intestinal tumors, especially for a patient previously treated for multiple gastrointestinal cancers.

Elevated tenascin-C levels in bronchoalveolar lavage fluid of patients with sarcoidosis.

BACKGROUND: Sarcoidosis is a disease characterized by granulomatous lesions involving multiple organ systems. The etiology of sarcoidosis remains unknown, and reliable biomarkers have not been identified. Tenascin-C is an extracellular matrix molecule expressed during wound healing in various tissues. The present study aimed to investigate the role of tenascin-C in sarcoidosis. METHODS: Enzyme-linked immunosorbent assays were used to measure tenascin-C levels in serum and bronchoalveolar lavage fluid (BALF) from 31 patients with sarcoidosis and 15 healthy individuals. Relationships between tenascin-C concentrations in BALF and serum samples and clinical parameters in patients with sarcoidosis were evaluated. RESULTS: BALF tenascin-C levels were significantly higher in patients with sarcoidosis than in healthy individuals, but serum levels were no different. BALF tenascin-C levels showed positive correlations with serum lactic dehydrogenase levels and the ratio of lymphocytes in BALF. BALF tenascin-C levels were also higher in patients with parenchymal infiltration on chest radiographs than in those without. CONCLUSIONS: The present results demonstrated that the BALF tenascin-C level was correlated with pulmonary infiltrates on chest radiographs in patients with sarcoidosis. Although measurement of serum tenascin-C levels has a limited role and measurement of BALF tenascin-C levels might be impractical, tenascin-C in the lung might play a role in the pathogenesis of sarcoidosis. Further studies are necessary to determine the role of BALF tenascin-C in sarcoidosis.

Pirfenidone inhibits TGF-ß1-induced over-expression of collagen type I and heat shock protein 47 in A549 cells.

BACKGROUND: Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis (IPF). We previously showed that pirfenidone inhibits the over-expression of collagen type I and of heat shock protein (HSP) 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor (TGF)-ß1 in vitro. The increased numbers of HSP47-positive type II pneumocytes as well as fibroblasts were also diminished by pirfenidone in an animal model of pulmonary fibrosis induced by bleomycin. The present study evaluates the effects of pirfenidone on collagen type I and HSP47 expression in the human alveolar epithelial cell line, A549 cells in vitro. METHODS: The expression of collagen type I, HSP47 and E-cadherin mRNAs in A549 cells stimulated with TGF-ß1 was evaluated by Northern blotting or real-time PCR. The expression of collagen type I, HSP47 and fibronectin proteins was assessed by immunocytochemical staining. RESULTS: TGF-ß1 stimulated collagen type I and HSP47 mRNA and protein expression in A549 cells, and pirfenidone significantly inhibited this process. Pirfenidone also inhibited over-expression of the fibroblast phenotypic marker fibronectin in A549 cells induced by TGF-ß1. CONCLUSION: We concluded that the anti-fibrotic effects of pirfenidone might be mediated not only through the direct inhibition of collagen type I expression but also through the inhibition of HSP47 expression in alveolar epithelial cells, which results in reduced collagen synthesis in lung fibrosis. Furthermore, pirfenidone might partially inhibit the epithelial-mesenchymal transition.

S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, and the prognosis remains poor. On the other hand, other fibrotic interstitial pneumonias such as idiopathic nonspecific interstitial pneumonia (I-NSIP) and collagen vascular disease-associated interstitial pneumonia (CVD-IP) resemble IPF, but they respond to therapy and the prognosis is better. We searched for biomarkers to distinguish IPF from other fibrotic interstitial pneumonias and investigated whether S100A9 could be useful for discriminating types of fibrotic interstitial pneumonia based on our preliminary proteomic findings. METHODS: We measured S100A9 levels in serum and bronchoalveolar lavage fluid (BALF) from 28 patients with IPF, 15 with I-NSIP, 20 with cryptogenic organizing pneumonia (COP), 35 with CVD-IP and 23 healthy individuals (controls) using enzyme-linked immunosorbent assays. S100A9 in the lung was also immunohistochemically localized. RESULTS: S100A9 levels in BALF, but not in serum, were significantly elevated in patients with IPF compared with I-NSIP, COP, CVD-IP and healthy individuals. S100A9 immunoreactivity was localized mainly in macrophages and neutrophils in lung specimens from patients with IPF. The results of receiver operating characteristic (ROC) curve analysis showed that BALF S100A9 levels had sufficient specificity and sensitivity to distinguish IPF from I-NSIP and CVD-IP. CONCLUSION: S100A9 in BALF might serve as a candidate biomarker to discriminate between IPF and other fibrotic interstitial pneumonias.

A case of acute sarcoid myositis treated with weekly low-dose methotrexate.

A 25-year-old man was referred to our hospital with a 2-month history of progressive proximal extremity weakness. His serum creatine kinase (CK) level was extremely elevated, and chest X-ray revealed bilateral hilar lymphadenopathy and small nodules in bilateral lung fields. Biopsy specimens obtained from muscle and lung revealed non-caseating epithelioid cell granulomas. On the basis of these findings, the patient was diagnosed with sarcoidosis and acute sarcoid myositis. Although steroid pulse therapy was administered repeatedly, the muscle symptoms did not improve, and the serum CK level remained high. We added 7.5 mg oral methotrexate once per week to oral prednisolone, and this improved both the muscle weakness and the CK level. Concurrent administration of methotrexate could be a therapeutic option for cases with acute sarcoid myositis refractory to steroid therapy.

Immediate single lobar retransplantation for primary graft dysfunction after living-donor lobar lung transplantation: Report of a case.

A 24-year-old man with cystic fibrosis underwent living-donor lobar lung transplantation (LDLLT) with grafts donated from his father, who had mild cirrhosis, and his uncle. The graft from his father failed, and retransplantation was required 44 h after LDLLT, using his sister's left lower lobe. The retransplantation was successful; 18 months postoperatively, the recipient and all three donors are doing well. The favorable outcome was achieved owing to the complete assessment of all potential donors in advance, and the appropriate decision to perform retransplantation in a timely manner. Whether this life-saving retransplant procedure for unexpected primary graft dysfunction after LDLLT can be justified requires further experience and a longer follow-up.

Anti-inflammatory effects of garenoxacin on IL-8 production and ERK1/2 activation induced by lipopolysaccharides in A549 and THP-1 cells.

The anti-inflammatory properties of macrolides have been applied to the treatment of inflammatory airway diseases. Although the anti-inflammatory properties of fluoroquinolones have been reported, no reports are available regarding a newly developed fluoroquinolone, garenoxacin (GRNX). To examine the immunomodulatory effect of GRNX, we examined the transcription and secretion of inflammatory cytokines by human airway epithelial cells and monocytes stimulated with lipopolysaccharide (LPS). A human lung epithelial cell line (A549) and a human monocyte cell line (THP-1) were stimulated with LPS and exposed to different concentrations of GRNX. The transcription and secretion of interleukin 8 (IL-8) in both A549 and THP-1 cells was measured by real-time PCR and an enzyme-linked immunosorbent assay, respectively. Treatment with GRNX significantly inhibited the transcription and secretion of IL-8 induced by LPS-stimulated cells through inhibitory ERK1/2 phosphorylation. GRNX has anti-inflammatory activity through its capacity to alter the secretion of IL-8 from A549 and THP-1 cell lines. Our findings suggest that GRNX is suitable for the treatment of LPS-induced respiratory infection and inflammatory airway diseases.

Effects of doxycycline on production of growth factors and matrix metalloproteinases in pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrosis and a poor prognosis. Alveolar epithelial cells (AECs) are considered to play important roles by releasing growth factors and matrix metalloproteinases (MMPs) and by being involved in epithelial mesenchymal transition in IPF. Doxycycline hydrochloride (DOXY), an inhibitor of MMPs, attenuates pulmonary fibrosis in models and in patients with IPF; however, the mechanism of this action remains obscure. OBJECTIVES: The present study investigated the effect of DOXY on growth factors and MMP production in AECs. METHODS: Bleomycin (BL)-induced murine pulmonary fibrosis was treated with DOXY and examined by pathological and immunohistochemical staining. The human alveolar epithelial cell line A549 was stimulated with transforming growth factor (TGF)-ß1 and incubated with DOXY, and then the expression of growth factors, MMPs, and collagen type I was evaluated at the mRNA and protein levels. We also evaluated the effects of DOXY on the TGF-ß1-induced Smad signaling pathway. RESULTS: DOXY reduced fibrosis scores and the production of collagen type I, connective tissue growth factor (CTGF), and TGF-ß1 in BL models. DOXY inhibited the mRNA expression of MMP-2, MPP-9, CTGF, and collagen type I as well as the production of MMP-2 and platelet-derived growth factor-AA protein induced in A549 cells by TGF-ß1 but not by Smad2 and Smad3 phosphorylation. We did not find a similar effect of DOXY in normal lung fibroblasts. CONCLUSIONS: Our results suggest that DOXY could be useful for attenuating pulmonary fibrosis through the inhibition of growth factors and MMP production in AECs.

Importance of controlling drug-resistant Pseudomonas aeruginosa infection: experience from lung transplantation in a cystic fibrosis case.

Cystic fibrosis (CF) is rare in Japan. We encountered a CF case with drug-resistant Pseudomonas aeruginosa infection and successfully performed lung transplant from living related donors. A combination of beta-lactams and aminoglycosides for drug-resistant P. aeruginosa infection was administered before lung transplantation. Intravenous colistin was also used immediately before and after transplant surgery. Gram staining of respiratory specimens was performed every day after surgery and it was useful in monitoring infection status. Strict monitoring of infections by the Gram staining and culture of respiratory specimens is considered to be effective in preventing lower respiratory infection in lung transplantation.

Two cases with pulmonary mucosa-associated lymphoid tissue lymphoma successfully treated with clarithromycin.

A 70-year-old woman with a history of sinobronchial syndrome was admitted to the hospital because of a cough, sputum, and abnormal chest shadow. She was diagnosed with pulmonary mucosa-associated lymphoid tissue lymphoma (p-MALToma) based on results of a pathologic examination and the gene rearrangements in the Ig heavy chain on Southern blot hybridization. Although p-MALToma did not regress with conventional therapy, it was reduced after long-term treatment with clarithromycin (CAM) (200 mg/d). A 57-year-old woman with a history of Sjögren syndrome and lymphocytic interstitial pneumonia had a mass lesion in the left lower lung field. CT image-guided biopsy established a diagnosis of p-MALToma. The p-MALToma regressed with long-term treatment with CAM (200 mg/d), whereas Helicobacter pylori (HP) eradication therapy was not effective in concurrent atrophic gastritis with HP. It is suggested that CAM, a macrolide antibiotic, may be effective in some patients with p-MALToma.

Sarcoidosis in a patient with systemic sclerosis and primary biliary cirrhosis.

A 73-year-old woman who had been diagnosed with systemic sclerosis was admitted for further examination of bilateral hilar lymphadenopathy. Sarcoidosis was confirmed based on elevated serum levels of angiotensin-converting enzyme, a high proportion of lymphocytes and a high CD4/CD8 ratio in bronchoalveolar lavage fluid, abnormal (67)Gallium uptake in the mediastinum and noncaseating granulomas in skin biopsy specimens. In addition, high levels of antimitochondrial M2 antibodies and alkaline phosphatase indicated primary biliary cirrhosis (PBC). Here we describe a rare triplex of sarcoidosis, SSc and PBC. Although the etiology of this complex remains unknown, these three diseases might share some pathogenesis.

Differential effects of human neutrophil peptide-1 on growth factor and interleukin-8 production by human lung fibroblasts and epithelial cells.

alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of lung diseases, including idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and diffuse panbronchiolitis (DPB). In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in IPF and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to IPF, CF, and DPB. alpha-Defensins are known to induce interleukin (IL)-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide (HNP)-1 (a subtype of alpha-defensin) on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of IPF, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced.

Drug-induced eosinophilic pneumonia with pulmonary alveolar hemorrhage caused by benzbromarone.

A 51-year-old man was admitted to our hospital with cough, hemosputum, dyspnea and chest pain. Chest high-resolution computed tomography (HRCT) revealed diffuse ground-glass opacities in both lungs with peripheral predominance. Bronchoalveolar lavage fluid was fresh-bloody and analysis indicated an increase in the eosinophil proportion. Benzbromarone-induced lymphocyte stimulation test was positive. Therefore, the patient was diagnosed as having drug-induced eosinophilic pneumonia with pulmonary alveolar hemorrhage caused by benzbromarone. After discontinuation of benzbromarone and administration of corticosteroids, chest HRCT images and respiratory manifestation improved. Here, we report this rare case of benzbromarone-induced eosinophilic pneumonia with pulmonary alveolar hemorrhage.

HSP47 in lung fibroblasts is a predictor of survival in fibrotic nonspecific interstitial pneumonia.

BACKGROUND: The histopathologic pattern is currently the most important prognostic marker for idiopathic interstitial pneumonia (IIP). However, more highly sensitive markers are now required. Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagens, and it has been demonstrated that HSP47 expression is significantly higher in the lung specimens of idiopathic UIP than in UIP associated with collagen vascular diseases (CVD). However, its expression in nonspecific interstitial pneumonia (NSIP), the other common pathological pattern of IIP, has not been well investigated. Therefore, the association between lung fibroblast HSP47 expression and prognosis in fibrotic NSIP was evaluated. METHODS: Surgical lung biopsy specimens of 63 patients [idiopathic fibrotic NSIP=19, fibrotic NSIP associated with CVD=9, idiopathic UIP=26, and UIP associated with CVD=9] were reviewed, and a score for lung fibroblast HSP47 expression was assigned. These patients' clinical features and survival were also analyzed. RESULTS: There was no significant difference in HSP47 expression between idiopathic fibrotic NSIP and fibrotic NSIP associated with CVD. The idiopathic fibrotic NSIP patients with higher HSP47 expression levels in their lung specimens had a poorer prognosis than patients with lower HSP47 expression levels. CONCLUSIONS: The present results suggest that lung fibroblast HSP47 expression may be a useful new prognostic marker for idiopathic fibrotic nonspecific interstitial pneumonia.

Elevated levels of tenascin-C in patients with cryptogenic organizing pneumonia.

OBJECTIVE: Idiopathic interstitial pneumonias (IIPs) comprises a group of diffuse parenchymal lung diseases of unknown etiology with varying degrees of inflammation and fibrosis including cryptogenic organizing pneumonia (COP), idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). Tenascin-C is an extracellular matrix molecule that is expressed during wound healing in various tissues. The present study was aimed to investigate the role of tenascin-C in the pathogenesis of IIPs. METHODS: We used enzyme-linked immunosorbent assays to measure levels of tenascin-C in serum and bronchoalveolar lavage fluid (BALF) from 17 patients with IPF, 12 with NSIP, 15 with COP and from 23 healthy individuals. RESULTS: Serum levels of tenascin-C were significantly elevated in patients with COP compared with those in all other participants, whereas those in patients with IPF and NSIP were not significantly elevated compared with healthy individuals. The levels of tenascin-C in BALF from patients with COP and NSIP were significantly higher than those of healthy individuals. In addition, serum tenascin-C was significantly correlated with levels of serum C-reactive protein, which is a serum acute phase protein. CONCLUSION: Systemic inflammation in the lung with IIPs might be associated with tenascin-C. These results suggest that tenascin-C is responsible for the pathogenesis of IIPs especially via inflammation, and that it might serve as a serum marker of COP.

Different effects of telithromycin on MUC5AC production induced by human neutrophil peptide-1 or lipopolysaccharide in NCI-H292 cells compared with azithromycin and clarithromycin.

OBJECTIVES: Mucus hypersecretion is a prominent feature in patients with chronic respiratory tract infections such as cystic fibrosis and diffuse panbronchiolitis, and the clinical effectiveness of macrolide antibiotics has been reported in these patients. Because human neutrophil peptide-1 (HNP-1), an antimicrobial peptide in neutrophils, exists in high concentrations in the airway fluid of these patients, we examined the direct effect of HNP-1 on MUC5AC mucin production using NCI-H292 cells. The effects of macrolide antibiotics on the response were also examined. METHODS: MUC5AC synthesis was assayed using RT-PCR and ELISA. Phosphorylation of ERK1/2 was determined by western blotting. RESULTS: Stimulation with HNP-1 or lipopolysaccharide (LPS) derived from Pseudomonas aeruginosa increases the production of MUC5AC mRNA and protein, and an additive effect was found upon co-stimulation with both HNP-1 and LPS. Azithromycin and clarithromycin had inhibitory effects on overproduction of MUC5AC induced by HNP-1 or LPS stimulation. Telithromycin also had an inhibitory effect on MUC5AC production induced by LPS, but not on production by HNP-1. Phosphorylation of ERK1/2 was induced by HNP-1 or LPS stimulation, and azithromycin, clarithromycin and telithromycin had inhibitory effects on ERK1/2 phosphorylation induced by LPS, but not by HNP-1. CONCLUSIONS: These findings suggest that neutrophil-derived defensins as bacterial components contribute to excessive mucus production in patients with respiratory tract infections, and that macrolide and ketolide antibiotics directly inhibit these actions by interfering with intracellular signal transduction. However, the mechanism of telithromycin inhibition of MUC5AC synthesis may differ from the response induced by azithromycin and clarithromycin.

[Case of acute exacerbation after video-assisted thoracoscopic surgery in a patient with chronic hypersensitivity pneumonitis].

A 65-year-old man had been admitted with exertional dyspnea 2 years previously. Reticular shadows in bilateral lower lung fields were detected on chest roentogenogram and observed the natural course. The clinical symptoms and radiological findings progressed one month later and then he was admitted to our hospital to be examined for diagnosis and treatment. Video-assisted thoracoscopic surgery (VATS) was performed and chronic hypersensitivity pneumonitis was diagnosed. At five days after the surgery, dyspnea and radiological findings deteriorated and we diagnosed acute exacerbation of chronic hypersensitivity pneumonitis. He was treated immediately with steroid pulse therapy, immunosuppressant and polymyxin B-immobilized fiber column-direct hemoperfusion, which relieved his clinical symptoms and radiological findings. Although this is a very rare case, we have to consider the possibility of acute exacerbation of chronic hypersensitivity pneumonitis after VATS, as we do in idiopathic pulmonary fibrosis.

Plectasin has antibacterial activity and no affect on cell viability or IL-8 production.

Animals and plants express endogenous peptide antibiotics called defensins. Defensins show broad-spectrum antimicrobial activity, even against bacteria that have resistance to conventional antibiotics, which has made them viable candidates for new antibiotics. However, human defensins have failed to reach the market because of their cytotoxic effects and non-antimicrobial bioactivities. Plectasin is a defensin that has shown promise but has not had its potentially negative effects clarified. To address this issue, we examined plectasin's cytotoxicity in human cells using an AlamarBlue reduction assay, its interleukin (IL)-8-inducing capacity using real-time PCR and ELISA, and measured its MIC against bacteria. We confirmed that plectasin has specific antibacterial activity against Streptococcus pneumoniae. Plectasin showed no cytotoxicity to A549 cells, normal human bronchial epithelial cells, or lung fibroblasts, and it did not induce IL-8 transcription or production in A549 cells. Our results suggest that plectasin could be an inoffensive alternative antibiotic for clinical application.