[A CASE OF ALLERGIC BRONCHOPULMONARY MYCOSIS WITH NONTUBERCULOUS MYCOBACTERIOSIS SUCCESSFULLY TREATED WITH BENRALIZUMAB FOR STEROID WITHDRAWAL].

A 56-year-old woman who had allergic bronchopulmonary mycosis (ABPM) with nontuberculous mycobacteriosis (NTM) was treated with prednisone. After treatment, her respiratory symptoms, eosinophil count, and infiltrative shadow diminished. However, when the dosage of prednisone was tapered and finally stopped, the eosinophil count increased and the infiltrative shadow returned. Since there was a risk of exacerbation of NTM, benralizumab without prednisone was administrated, which improved the patient's respiratory symptoms and eosinophil count, while the infiltrative shadow remained. When the dosage of prednisone was restarted, the shadow disappeared. After prednisone discontinuation, no exacerbation of the shadows nor relapse were observed. In recent years, clinical usefulness of biologics like benralizumab for ABPM has been reported, but evidence to support their use is insufficient. Furthermore, it is expected that the number of the combined cases of NTM and ABPM will increase with the increase in NTM; however, reports of biologics for the management of both cases are extremely rare. The risk of complications of infectious diseases, interaction with antifungal drugs, and steroid sparing effects should be considered when deciding the treatment strategy. Accumulation of more cases in the future may lead to the establishment of a treatment method for the combined cases of NTM and ABPM.

A rare case of gradual enlargement of a multifocal myelolipoma of the posterior mediastinum for 12 years after surgical resection of an adrenal myelolipoma.

INTRODUCTION: A myelolipoma is a rare benign tumor that is composed of adipose tissue and hematopoietic elements. Myelolipomas most commonly occur in the unilateral adrenal gland. Posterior mediastinal myelolipomas are extremely rare. We herein present a rare case of a multifocal myelolipoma of the mediastinum that gradually enlarged over a 12-year period after surgical resection of an adrenal myelolipoma. This is the first report of multifocal myelolipomas of the posterior mediastinum and adrenal gland. PRESENTATION OF CASE: A posterior mediastinal tumor was incidentally found by chest X-ray and computed tomography (CT) examination of a 74-year-old woman. The patient had a medical history of resection of a myelolipoma of the left adrenal gland 12 years earlier. We performed tumor extirpation under video-assisted thoracic surgery (VATS). The size of the tumor was 4.5 cm, and the postoperative diagnosis was a myelolipoma. DISCUSSION: Posterior mediastinal myelolipomas are extremely rare, and only 39 cases of mediastinal myelolipoma have been reported to date. No reports have described a multifocal myelipoma of mediastinal myelolipoma. To our knowledge, this is the first report of multifocal myelipomas of the adrenal gland and posterior mediastinum. CONCLUSION: A differential diagnosis of myelolipoma of the posterior mediastinum is important in patients with a history of myelolipoma of the adrenal gland.

[Pneumonia and Streptococcal Toxic Shock Syndrome Due to Group A Streptococci: A Case Report].

A 71-year-old woman who was undergoing immunosuppressive therapy presented with a 7-day history of productive cough and 2-day history of fever. She was diagnosed with severe pneumonia and septic shock. Meropenem, azithromycin, large amounts of fluids, and noradrenaline were administered, and high-flow nasal cannula oxygen therapy was provided. The gross appearance of the aspirated sputum was ginger-like, and the gram-positive cocci in chains were identified as group A beta-hemolytic streptococci (GAS), Streptococcus pyogenes. The blood sample culture test revealed negative results. Based on Stevens' criteria, the patient was finally diagnosed as having streptococcal toxic shock syndrome (STSS). Antibiotics were switched to ampicillin/sulbactam and clindamycin as an antitoxin treatment, and the patient was discharged on day 33. Serotypes of GAS were T1, M1, and emm1. Superantigens spe A, spe B, and spe F were present, and spe C was absent. These observations were compatible with the clinical features of hypotension. GAS is an uncommon cause of community-acquired pneumonia, which when potentially complicated with STSS can lead to a high mortality rate, and the rapid progression is particularly a striking feature. We should be aware that GAS can cause pneumonia, and antitoxin treatment can play a key role in STSS management.

Lung cancer surgery in patients aged 80 years or older: an analysis of risk factors, morbidity, and mortality.

INTRODUCTION: As the population ages, the age of patients undergoing thoracic surgery increases, and elderly patients often have more comorbidities than younger patients. METHODS: This retrospective study observed preoperative comorbidities, surgical procedures and postoperative morbidity and mortality after lung cancer surgery in patients 80 years of age or older. The medical records of lung cancer patients 80 years of age or older who underwent surgery from January 2003 to December 2012 were reviewed. RESULTS: There were 49 patients (27 males, 22 females), with a median age of 83 years. Thirty patients underwent major pulmonary resection and 18 patients underwent limited pulmonary resection. The median Charlson comorbidity index was 3. Although approximately two-thirds of the patients (20 patients; 40.8%) experienced some kind of postoperative morbidity, more than 80% of the complications were grade 1 or 2 according to the Clavien-Dindo classification. Cerebrovascular disease and chronic obstructive pulmonary disease were significantly associated with moderate-to-severe complications. Postoperative death was observed in two cases (4.1%). In addition, an increased American Society of Anesthesiologists classification score and past history of myocardial infarction, congestive heart failure and/or diabetes mellitus with end-organ damage were significantly associated with mortality. The overall survival rate was 79.6% at 3 years and 53.1% at 5 years. CONCLUSIONS: Thoracic surgery shows acceptable morbidity and mortality in patients 80 years of age or older. Patients 80 years of age or older should be offered the best treatments, including surgery, with careful patient evaluation and selection.

Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor ß to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor ß, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.

Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice.

Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.

[Relationship between the prognosis of interstitial pneumonia and its comorbidities].

BACKGROUND: To investigate the relationship between the prognosis of chronic interstitial pneumonia (IP) and its comorbidities, we conducted a retrospective study for clinically and radiologically diagnosed IP. We assessed comorbidities by using the Charlson Comorbidity Index (CCI). METHODS: We classified 224 patients given clinical diagnoses of chronic IP (excluding the patients who had clear causes such as collagen disease, infection, drugs or radiation) in our institution between April 2000 and June 2010, into 2 groups; those with clinical diagnoses of idiopathic pulmonary fibrosis (IPF:108 cases) and those with other chronic IP but without honeycomb lung (116 cases); and analyzed their backgrounds and comorbidities. We also classified them into survival and non-survival groups to assess their prognostic factors. RESULTS: Although the smoking status of patients with clinically diagnosed IPF was higher, and SpO2 was lower than those with other chronic IP without honeycomb lung, the mean age, comorbidities and CCI did not differ between them. The 5-year overall survival of the clinically-diagnosed IPF group was lower than that of the other chronic IP without honeycomb lung group (50.8% vs. 76.3%, p<0.01). In cases of other chronic IP without honeycomb lung, the CCI of non-survival cases was higher than that of survival cases (4.05 vs. 2.47, p<0.01), although patient backgrounds did not differ between survival and non-survival cases in those with clinically diagnosed IPF (CCI : 2.32 vs. 2.98, p = 0.70). CONCLUSIONS: Our analysis revealed the possibility that comorbidities and CCI were prognostic factors in other chronic IP cases without honeycomb lung, although the prognosis of IPF was not affected by their comorbidity.

[A clinical review of pleurodesis for patients with poor performance status].

BACKGROUND: Although pleurodesis is an effective treatment for malignant pleural effusion, we hesitate to use in patients with poor performance status (PS) because of its side effects. METHODS: Of 46 pleurodesis cases in our institution between 2006 and 2010, 24 poor PS cases (>3) were classified into 2 groups according to survival (beyond 3 months) or non-survival, and 3 groups according to condition: PS improved after pleurodesis, remained stable, or was exacerbated and we analyzed their backgrounds. RESULTS: Among the 24 cases (66.7%), there were 5 and 19 survival and non-survival cases. Patient backgrounds, characteristics of the lesions and examination results did not differ significantly among them. On the other hand, the ratio of successful initial pleurodesis in the exacerbated PS group was lower than in the improved and stable groups (16.7% vs. 100%, 87.5%). The 1- and 3-month survival rates of unsuccessful cases were lower than those of successful cases (33.3% vs. 77.8%, 0% vs. 32.4%). CONCLUSION: Success of initial pleurodesis can affect PS and outcome, thus it is important to improve the number of successful cases of initial pleurodesis.

CCN6 as a profibrotic mediator that stimulates the proliferation of lung fibroblasts via the integrin ß1/focal adhesion kinase pathway.

Idiopathic pulmonary fibrosis is a progressive and lethal disease of the lung that is characterized by the proliferation of fibroblasts and increased deposition of the extracellular matrix. The CCN6/WISP-3 is a member of the CCN family of matricellular proteins, which consists of six members that are involved in many vital biological functions. However, the regulation of lung fibroblasts mediated by CCN6 protein has not been fully elucidated. Here, we demonstrated that CCN6 induced the proliferation of lung fibroblasts by binding to integrin ß1, leading to the phosphorylation of FAK(Y397). Furthermore, CCN6 showed a weak, but significant, ability to stimulate the expression of fibronectin. CCN6 was highly expressed in the lung tissues of mice treated with bleomycin. Our results suggest that CCN6 plays a role in the fibrogenesis of the lungs mainly by stimulating the growth of lung fibroblasts and is a potential target for the treatment of pulmonary fibrosis.

[The efficacy of shortening an administration period with omalizumab].

A 64-year old male who had been treated with oral predisolone for severe bronchial asthma had started the treatment of omalizumab administration every 4 weeks since December 2009 and his symptoms had prominently improved. However, he complained the recurrence of his symptoms 4 weeks after administration of omalizumab and the mean times of SABA use had also increased from 0.61/day (1-2w) to 0.95/day (4w). Therefore, we had shortened the interval of omalizumab to 3 from 4 weeks since April 2010. Consequently, his symptoms have improved with increase of Asthma Control Test (15.67→21.33) and it has been possible to reduce the oral prednisolone. Recently, we can use the omalizumab and have extended the choice of treatment for severe bronchial asthma. However, it is predicted that there are some patients who have clinical problems for continuing the recommendation dose or intervals. We report a case with a brief review of the literature.

Surgical resection of a primary pulmonary epithelioid hemangioendothelioma in bilateral lungs.

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare pulmonary neoplasm that was initially described in 1975 as an intravascular bronchioloalveolar tumor. This report presents the case of a patient with multifocal primary pulmonary PEH (11 tumors) in the bilateral lungs. All of the tumors detected in the preoperative computed tomography scan were surgically resected. The patient has been doing well for 9 years after surgery. No tumor recurred for 8 years after surgery until a single recurrent nodule appeared and was thoracoscopically resected.

Expression of soluble vascular endothelial growth factor receptor-1 in human monocyte-derived mature dendritic cells contributes to their antiangiogenic property.

The soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1) is produced from endothelial cells by alternative splicing of VEGFR-1 mRNA, and can inhibit angiogenesis by blocking the biological effects of VEGF. In this study, we show the expression of a large amount of sVEGFR-1 in human monocyte-derived mature dendritic cells (mDCs). As compared with monocytes and immature DCs, mDCs generated by TNF-alpha or soluble CD40L with IFN-gamma, but not LPS or other stimuli, preferentially produce sVEGFR-1. We also detected the mRNA of sVEGFR-1 generated by alternative splicing of VEGFR-1 mRNA in mDCs induced by TNF-alpha. The production of sVEGFR-1 showed a distinct contrast to those of VEGF in each DC matured with various stimuli. The supernatant of DCs matured with TNF-alpha or soluble CD40L with IFN-gamma showed inhibition of the tube formation of HUVECs, which was neutralized by anti-VEGFR-1 Ab, indicating that sVEGFR-1 secreted from mDCs was biologically active. Interestingly, the supernatant of mDCs generated with LPS increased HUVEC capillary-like formation in vitro. The ratio of sVEGFR-1 to VEGF clearly reflected the net angiogenic property of mDCs. Administration of mDCs induced by TNF-alpha into the s.c. tumor of PC-14 cells implanted in SCID mice demonstrated the inhibition of tumor growth via reduction of the number of CD31-positive vessels, indicating their in vivo antiangiogenic potential. These results suggest that sVEGFR-1 produced by mDCs contribute to their antiangiogenic property, and the ratio of sVEGFR-1 to VEGF might be a useful tool for evaluating their ability to regulate angiogenesis mediated by VEGF.

Role of alpha1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice.

RATIONALE: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect. OBJECTIVES: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(1)-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance. METHODS: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice. MEASUREMENTS AND MAIN RESULTS: Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects. CONCLUSIONS: AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis.

A novel IkappaB kinase-beta inhibitor ameliorates bleomycin-induced pulmonary fibrosis in mice.

RATIONALE: IkappaB kinase-beta is a critical regulator in the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor related to the expression and regulation of proinflammatory cytokines. OBJECTIVE: To evaluate if inhibition of IkappaB kinase-beta ameliorates pneumonitis and pulmonary fibrosis. METHODS: We examined whether a novel IkappaB kinase-beta inhibitor, IMD-0354, attenuates bleomycin-induced pulmonary fibrosis in mice. MEASUREMENTS AND MAIN RESULTS: Administration of IMD-0354 significantly improved the loss of body weight and survival of mice treated with bleomycin, whereas IMD-0354 alone did not cause any morphologic change in the lung. When mice were evaluated 28 d after bleomycin administration, IMD-0354 dose-dependently reduced the collagen content and fibrotic scores as shown by histologic examination. The findings in the bronchoalveolar lavage demonstrated that the proportions of neutrophils and lymphocytes were decreased in mice treated with IMD-0354 on Day 7 and 14, respectively. IMD-0354 treatment was confirmed to inhibit the activation of NF-kappaB, but not activator protein-1, in the lungs treated with bleomycin. The production of inflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta was reduced in the lungs of mice treated with IMD-0354. CONCLUSIONS: These results suggest that IMD-0354 might be useful to ameliorate the inflammation in the lungs induced by fibrotic injury and the subsequent fibrogenesis via inhibiting the expression of profibrotic cytokines related to the activation of NF-kappaB.