巽 浩一郎

Background and objective: Japanese pulmonologists, experienced in treating patients with diffuse panbronchiolitis (DPB) prior to the 1980s, have uniformly observed that new incidences of DPB are now a rare event in Japan. However, there is no epidemiological data to support this observation. We examined epidemiological trends of the number of patients with DPB in a large company. Design: The computerized health records of JR East Company employees were used to identify patients with DPB and then these were followed up using the assessments of these patients in JR Tokyo General Hospital and two other JR hospitals. The whole study period was 27 years (1976-2003), although detailed analyses were carried out for three specific periods the first was 1976-1980, the second was 1989-1993, and the third was 1999-2003. Results: In the first period, 11 DPB cases (four incidence, and seven prevalence) were detected among a total of 355,572 workers. In the second period, three DPB cases (one incidence, and two prevalence) were identified from a total of 180,359 workers. In the third period, no case was found in a total of 144,485 workers. Conclusion: This epidemiological trend suggests that both the incidence and prevalence of DPB may have decreased. © Mattioli 1885.

Expression of human interleukin (IL)-24 in tumors achieved anti-tumor effects through apoptosis. IL-24 also induced secretion of proinflammatory cytokines, suggesting the role in immunity. We showed that murine IL-24 transcripts started from the second initiation codon and that expressed mIL-24 in tumors failed to induce apoptosis. Proliferation of murine cells expressing mIL-24 was the same as that of the parent cells and inoculation of the mIL-24-expressing tumors into syngeneic mice did not produce anti-tumor effects. Secretory mIL-24 did not induce the expression of the IL-6, TNF-alpha or IFN-gamma gene in spleen cells. Expression of mIL-24 receptor subunits, IL-22R and IL-20R1, was undetectable in spleen cells even though they were stimulated by anti-CD3, anti-CD40 antibody or concanavalin A. Transduction of murine tumors with adenoviruses expressing the human IL-24 gene however suppressed the viability and decreased the tumor growth. These data suggest that mIL-24 is functionally irrelevant to the human counterpart. (C) 2012 Elsevier Inc. All rights reserved.

OBJECTIVE: Although endothelin receptor antagonists (ERAs) and phosphodiesterase type 5 (PDE5) inhibitors have become the most commonly used treatments for pulmonary arterial hypertension (PAH) since their introduction in 2005, it remains unknown whether these medications play a significant role in the survival of Japanese patients with PAH. METHODS: The cardiac catheterization and survival data of 103 PAH patients were retrospectively reviewed. A comparison of survival benefits with regard to the type of PAH was completed in PAH patients diagnosed between 2005 and 2012 and those diagnosed between 1983 and 2004 and in patients undergoing treatment with ERAs and/or PDE5 inhibitors and those being treated with conventional therapy and/or oral beraprost. Although pulmonary vascular resistance (PVR) at baseline differed, the more recent group showed better survival rates compared with those observed in the early group (5-year survival: 70.1% vs. 44.8) (p<0.05). In addition, the survival of PAH patients treated with ERAs and/or PDE5 inhibitors was superior to that of the patients treated without these medications (5- and 8-year survival: 77.8% and 66.7% vs. 39.0% and 37.0%, respectively) (p<0.05), especially in patient with idiopathic and heritable PAH. CONCLUSION: Superior survival rates are observed in patients with idiopathic and heritable PAH after introduction of ERAs and PDE5 inhibitors, and the use of these drugs provides benefits for survival.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in prolonging progression-free survival time of patients with non-small cell lung carcinoma, typically adenocarcinoma, bearing some active EGFR mutations in their tumors. However, the close relationship between the EGFR mutations and pleomorphic carcinoma of the lung, which is a very rare type of primary lung cancer, has never been elucidated. We present a 60-year-old Japanese woman with pleomorphic carcinoma of the lung that became resistant to cytotoxic chemotherapies including platinum-based chemotherapy, and her general condition seriously deteriorated. Thereafter, treatment with gefitinib was started and resulted in significant tumor shrinkage and a dramatic improvement in her general condition for up to 8.5 months. Analyses of the EGFR mutation in separately microdissected specimens from adenocarcinoma and spindle cell components revealed that both components possessed the L858R point mutation. These findings gave us some insight into the carcinogenesis of pleomorphic carcinoma of the lung in relation to EGFR gene alteration. Testing for EGFR mutation may be important in patients with advanced pleomorphic carcinoma including adenocarcinoma component that is usually chemoresistant.

Cluster of differentiation 69 (CD69) has been identified as a lymphocyte early activation marker, and recent studies have indicated that CD69 mediates intracellular signals and plays an important role in various inflammatory diseases. Cigarette smoke (CS) is a strong proinflammatory stimulus that induces the release of proinflammatory mediators by recruiting macrophages and neutrophils into the lung tissue, and is one of the main risk factors for a number of chronic diseases. However, the potential role of CD69 in CS-induced pulmonary inflammation has not been determined. To address to this question, CD69-deficient (KO) and wild-type (WT) mice were subjected to CS-induced acute pulmonary inflammation. After the exposure with CS, the expression of CD69 in the lung of WT mice was significantly induced, it was predominantly observed in macrophages. In conjunction with this phenomenon, neutrophil and macrophage cell counts, and expression of several cytokines were significantly higher in the bronchoalveolar lavage fluid (BALF) of CS-exposed WT mice compared with air-exposed WT mice. Likewise, the CS-induced accumulation of inflammatory cells and cytokines expression were significantly lower in CD69-KO mice than in WT mice. These results suggest that CD69 on macrophages is involved in CS-induced acute pulmonary inflammation.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a sustained elevation in the pulmonary artery pressure and subsequent right heart failure. The activation of Rho/Rho-kinase activity and the beneficial effect of Rho-kinase inhibition have been demonstrated in several experimental models of pulmonary hypertension. However, it remains unclear whether Rho-kinase inhibitors can also be used against pulmonary hypertension associated with mutations in the type II bone morphogenetic protein receptor (BMPRII) gene. Transgenic mice expressing a dominant-negative BMPRII gene (with an arginine to termination mutation at amino acid 899) in smooth muscle by a tetracycline-gene switch system (SM22-tet-BMPR2(R899X) mice) were examined. They developed an elevated right ventricular systolic pressure (RVSP), right ventricular (RV) hypertrophy, muscularization of small pulmonary arteries, and an associated disturbed blood flow in their lungs. The Rho/Rho-kinase activity and Smad activity were determined by a Western blot analysis by detecting GTP-RhoA and the phosphorylation of myosin phosphatase target subunit 1, Smad1, and Smad2. In the lungs of SM22-tet-BMPR2(R899X) mice, the Rho/Rho-kinase activity was elevated significantly, whereas the Smad activity was almost unchanged. Fasudil, a Rho-kinase inhibitor, significantly decreased RVSP, alleviated RV hypertrophy and muscularization of small pulmonary arteries, and improved blood flow in SM22-tet-BMPR2(R899X) mice, although it did not alter Smad signaling. Our study demonstrates that Rho/Rho-kinase signaling is activated via a Smad-independent pathway in an animal model of pulmonary hypertension with a BMPRII mutation in the cytoplasmic tail domain. Rho-kinase inhibition is therefore a possible therapeutic approach for the treatment of PAH associated with genetic mutation.

Background There is synteny in the CC-type chemokine gene clusters between humans (CCL2/MCP-1, CCL7MCP-3, CCL11/eotaxin, CCL8/MCP-2, CCL13/MCP-4, and CCL1/I-309) and mice (CCL2, CCL7, CCL11, CCL12/MCP-5, CCL8, and CCL1). Objective As many putative Bcl6/STAT-binding sequences are observed in the clusters, we examined the roles of a transcriptional repressor Bcl6 and the regional histone modification in the expression of these chemokine genes in pulmonary epithelium. Methods We generated transgenic (Tg) mice carrying the Bcl6 or the dominant-negative (DN)-Bcl6 gene under the control of the surfactant protein C (SPC) promoter that induces the exogenous gene expression in the distal lung epithelium. For in vitro studies, A549, alveolar type II-like epithelial cell line transfected with the SPC-DN-Bcl6 gene were stimulated with IL-4+TNF-alpha, and Bcl6 or STAT6 binding to and histone modification of the cluster in the transfectants were analysed by chromatin immunoprecipitation assays. Tg mice sensitized with ovalbumin (OVA) were challenged with OVA inhalation. The amounts of mRNAs in each sample were analysed by quantitative RT-PCR. Results The amount of Bcl6 bound to the cluster decreased in A549 cells stimulated with IL-4 and TNF-alpha, whereas STAT6 binding increased in association with regional histone H3-K9/14 acetylation and H3-K4 methylation. The expression of all chemokine genes in the gene cluster was augmented in activated A549 cells transfected with the DN-Bcl6 gene. We also induced allergic airway inflammation in Tg mice. Expression of the chemokine genes and infiltrated cell numbers in the lungs of these Tg mice with allergic airway inflammation were inversely correlated with the amount of Bcl6 in the lungs. Conclusion and Clinical Relevance Expression of the pulmonary epithelium-derived CC-type chemokine genes in the cluster is orchestrated by the conserved machinery related to Bcl6. Thus, Bcl6 in pulmonary epithelium may be a critical regulator for pathogenesis of various pulmonary inflammatory diseases.

BACKGROUND: Cluster of differentiation 69 (CD69), an early activation marker antigen on T and B cells, is also expressed on activated macrophages and neutrophils, suggesting that CD69 may play a role in inflammatory diseases. To determine the effect of CD69 deficiency on bleomycin(BLM)-induced lung injury, we evaluated the inflammatory response following intratracheal BLM administration and the subsequent fibrotic changes in wild type (WT) and CD69-deficient (CD69-/-) mice. METHODS: The mice received a single dose of 3 mg/kg body weight of BLM and were sacrificed at 7 or 14 days post-instillation (dpi). Lung inflammation in the acute phase (7 dpi) was investigated by differential cell counts and cytokine array analyses of bronchoalveolar lavage fluid. In addition, lung fibrotic changes were evaluated at 14 dpi by histopathology and collagen assays. We also used reverse transcription polymerase chain reaction to measure the mRNA expression level of transforming growth factor β1 (TGF-β1) in the lungs of BLM-treated mice. RESULTS: CD69-/- mice exhibited less lung damage than WT mice, as shown by reductions in the following indices: (1) loss of body weight, (2) wet/dry ratio of lung, (3) cytokine levels in BALF, (4) histological evidence of lung injury, (5) lung collagen deposition, and (6) TGF-β1 mRNA expression in the lung. CONCLUSION: The present study clearly demonstrates that CD69 plays an important role in the progression of lung injury induced by BLM.

The clinical concept of COPD initially started in conjunction with American Emphysema and British Bronchitis in CIBA Guest Symposium in 1958. JC Hogg, et al. recognized the peripheral airways as the major site of airflow obstruction in COPD in 1968. Thirty-six years later in 2004, JC Hogg, et al. described the pathological nature of small-airway obstruction in COPD. The GOLD project provided state-of-the-art information about COPD in 2001, in which it is stated that the chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease and parenchymal destruction. Cigarette smoke may accelerate the aging of lung or worsen aging-related events in lung by defective resolution of inflammation. Accelerated decline in lung function is recognized to occur in asthma, especially in those with asthma who smoke. With increasing age, there was a greater increase in the proportion of patients with overlapping COPD and asthma.

It is generally accepted that genetic predisposition plays a role in COPD development in susceptible individuals. Therefore, many candidate genes that could be linked to the development of disease have been examined in COPD. However, inconsistent results in different study populations often limit this approach, suggesting that not only genetics, but also other factors, may be contributed to the susceptibility to COPD. Epigenetic mechanisms can affect the transcriptional activity of specific genes, at different points in time, and in different organs. Moreover, these mechanisms can have an effect on people's health. Recently, there is emerging evidence supporting a role of epigenetics for the regulation of inflammatory genes in diseases such as asthma and COPD. Moreover, recent studies suggest that the currently used treatments including corticosteroids may work through epigenetic mechanisms. Epigenetic regulation can be reprogrammed, potentially affecting the risk, aetiology and treatment of various disease states. The epigenetically influenced phenotype could be reversed with demethylating or deacetylating agents, consistent with epigenetic plasticity. The postnatal reversibility of these methylation or acetylation events may therefore provide good opportunities for intervention. The recognition of the role of genetic and epigenetic mechanisms in the development of COPD may identify novel targets that hatch new therapies for patients with COPD.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intravascular thrombus formation in the pulmonary arteries.Recently, it has been shown that a myofibroblast cell phenotype was predominant within endarterectomized tissues from CTEPH patients. Indeed, our recent study demonstrated the existence of not only myofibroblast-like cells (MFLCs), but also endothelial-like cells (ELCs). Under in vitro conditions, a few transitional cells (co-expressing both endothelial- and SM-cell markers) were observed in the ELC population. We hypothesized that MFLCs in the microenvironment created by the unresolved clot may promote the endothelial-mesenchymal transition and/or induce endothelial cell (EC) dysfunction. METHODS: We isolated cells from these tissues and identified them as MFLCs and ELCs. In order to test whether the MFLCs provide the microenvironment which causes EC alterations, ECs were incubated in serum-free medium conditioned by MFLCs, or were grown in co-culture with the MFLCs. RESULTS: Our experiments demonstrated that MFLCs promoted the commercially available ECs to transit to other mesenchymal phenotypes and/or induced EC dysfunction through inactivation of autophagy, disruption of the mitochondrial reticulum, alteration of the SOD-2 localization, and decreased ROS production. Indeed, ELCs included a few transitional cells, lost the ability to form autophagosomes, and had defective mitochondrial structure/function. Moreover, rapamycin reversed the phenotypic alterations and the gene expression changes in ECs co-cultured with MFLCs, thus suggesting that this agent had beneficial therapeutic effects on ECs in CTEPH tissues. CONCLUSIONS: It is possible that the microenvironment created by the stabilized clot stimulates MFLCs to induce EC alterations.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intravascular thrombus formation in the pulmonary arteries. Recently, it has been shown that a myofibroblast cell phenotype was predominant within endarterectomized tissues from CTEPH patients. Indeed, our recent study demonstrated the existence of not only myofibroblast-like cells (MFLCs), but also endothelial-like cells (ELCs). Under in vitro conditions, a few transitional cells (co-expressing both endothelial-and SM-cell markers) were observed in the ELC population. We hypothesized that MFLCs in the microenvironment created by the unresolved clot may promote the endothelial-mesenchymal transition and/or induce endothelial cell (EC) dysfunction. Methods: We isolated cells from these tissues and identified them as MFLCs and ELCs. In order to test whether the MFLCs provide the microenvironment which causes EC alterations, ECs were incubated in serum-free medium conditioned by MFLCs, or were grown in co-culture with the MFLCs. Results: Our experiments demonstrated that MFLCs promoted the commercially available ECs to transit to other mesenchymal phenotypes and/or induced EC dysfunction through inactivation of autophagy, disruption of the mitochondrial reticulum, alteration of the SOD-2 localization, and decreased ROS production. Indeed, ELCs included a few transitional cells, lost the ability to form autophagosomes, and had defective mitochondrial structure/function. Moreover, rapamycin reversed the phenotypic alterations and the gene expression changes in ECs co-cultured with MFLCs, thus suggesting that this agent had beneficial therapeutic effects on ECs in CTEPH tissues. Conclusions: It is possible that the microenvironment created by the stabilized clot stimulates MFLCs to induce EC alterations.

Human malignant pleural mesothelioma (HMPM) is highly resistant to conventional therapy, and therefore novel therapies are required. We previously reported that overexpression of the FUSE-binding protein-interacting repressor (FIR), a c-myc transcriptional repressor, induces apoptosis via c-Myc suppression, and is thus a suitable cancer therapy. In the current preclinical trial, a fusion gene deleted non-transmissible Sendai virus vector encoding FIR (SeV/ΔF/FIR) was prepared and its cytotoxic activity against an orthotopic xenograft model of HMPM, in combination with cisplatin, was assessed. SeV/ΔF/FIR and a fusion gene deleted non-transmissible Sendai virus vector encoding green fluorescent protein (SeV/ΔF/GFP) were prepared. The transduction efficiency of these agents in terms of dose-dependent cytotoxicity and/or apoptosis induction was then assessed in a few HMPM cells. Combination therapy with SeV/ΔF/FIR plus cisplatin was evaluated in vitro and in a mouse model. SeV/ΔF/FIR significantly reduced cell viability in three HMPM cell lines but was less effective in non-tumor immortalized mesothelial cells. SeV/ΔF/FIR cytotoxicity was partly due to apoptosis induction via c-Myc suppression. In addition, SeV/ΔF/FIR showed synergistic antitumor effects in combination with cisplatin, as was revealed by isobologram analysis in MSTO-211H. Moreover, combination therapy with SeV/ΔF/FIR plus cisplatin demonstrated significant tumor reduction and improvement in survival rate in an animal model. Combination therapy with SeV/ΔF/FIR plus cisplatin has therapeutic potential against HMPM. SeV/ΔF/FIR plus cisplatin will be an attractive modality against HMPM in the future.

Stachybotrys chartarum, a ubiquitous fungus in our environment, has been suspected of causing respiratory symptoms in humans, such as acute infant pulmonary hemorrhage and asthma. We previously established a mouse model in which repeated inhalation of Stachybotrys chartarum spores caused pulmonary hypertension. To further investigate the model, particularly in the pulmonary circulation, mice were intra-tracheally injected with spores, 18 times over 12 weeks. Severe muscularization was observed in the small- to medium-sized pulmonary arteries. Bronchoalveolar lavage fluid revealed an increase in eosinophils accompanied by high concentrations of Th2-associated cytokines, IL-4, IL-5, but not Th1-associated IFN-γ. The remodeling was temporary, resolving after cessation of spore inhalation. Chronic inhibition of the RhoA/Rho-kinase pathway by fasudil attenuated pulmonary arterial remodeling. These data suggest that Stachybotrys-mediated remodeling is caused by Th2-associated inflammation and can be resolved by Rho-kinase inhibition, either through direct effects on smooth muscle hypertrophy or through indirect effects on vascular inflammation. These data also show that extensive pulmonary vascular remodeling, often thought of as a fixed lesion, will spontaneously resolve in the absence of underlying molecular etiology.

Classic Lemierre syndrome is a septic internal jugular venous thrombophlebitis secondary to oropharyngeal anaerobic infection in adolescents and young adults. Upper respiratory tract infection is the most common antecedent. We report a case of Lemierre syndrome as a rare infectious disease. A 20-year-old man complained of high fever, right neck discomfort and chest pain. Chest X-ray revealed infiltrative shadows, suggesting bacterial pneumonia. Although cefcapene pivoxil hydrochloride hydrate (CFPN-PI) was given in a local clinic, his symptoms did not improve. Then he was referred to our hospital. Chest CT findings showed bilateral multiple nodular shadows with small cavities, suggesting septic embolization. Fusobacterium necrophorum was cultured from specimen of the blood, and an enhanced neck CT scan showed thrombosis in the right internal jugular vein. These findings led us to a diagnosis of Lemierre syndrome. Four weeks of antibiotics and anticoagulants ameliorated inflammatory findings in blood, but internal jugular vein thrombosis remained. Currently, there is no consensus opinion on the use of anticoagulation in patients with Lemierre syndrome complicated by septic internal jugular thrombosis and embolism. Early and effective antibiotics therapy may prevent the development of the syndrome and its associated complication, although it is unclear whether the outcome will be favorable.

COPDは労作時呼吸困難を主訴とし，QOLが著しく障害される病態である。経過中に体重減少を認める患者は生命予後が悪く，体重減少は呼吸機能の一指標としての気流制限の程度とは独立した予後因子とされている。体重減少に対する治療法として，食事指導や栄養補助療法が用いられているが，必ずしも十分な効果は得られていない。さらに，栄養障害は易感染性を招き，COPDの増悪発症に関与する可能性も考えられる。COPD患者では増悪の度に呼吸機能が低下していくことが想定され，増悪の頻度を減らすことが呼吸機能の維持に貢献するものと考えられる。またCOPDは全身性炎症性疾患であるという認識が高まってきており，それに対する治療も必要と考えられる。補中益気湯には食欲改善や免疫機能改善作用があり，COPDの栄養障害や易感染性の改善，増悪の抑制により，QOLの改善，重症化移行の遅延化，呼吸機能の維持をもたらしうる。

PURPOSE: To reduce the redundant acquisition range and total radiation dose for planning appropriate "triple rule-out" CT angiography (CTA) for acute chest pain, we evaluated the detailed distribution of pulmonary thromboemboli (PTE) in subjects with acute PTE. MATERIALS AND METHODS: Retrospective review of CTA n 75-subjects (48-females; 57 ± 16 years) with proven acute PTE was performed to determine whether PTE was present solely above the aortic arch or below the heart. RESULTS: 77% had PTE in the right upper lobe but none had PTE that were solely located higher than the aortic arch; 73% had PTE in the right middle lobe; 80% had PTE in the right lower lobe, but none had PTE that were solely located lower than the heart. 81% had PTE in the left upper lobe and 3% of them had PTE solely located higher than the aortic arch; both had PTE in the right upper, middle, and lower, and the left lower lobes. 75% had PTE in the left lower lobe, but none had PTE that were solely located lower than the heart. The acquisition length in limited CTPA in this population was reduced on average by 21.9% compared with full CTPA. CONCLUSIONS: In subjects with acute PTE, there were none whose PTE was located solely in the upper lobes which were higher than the aortic arch, nor solely in the lower lobes which were lower than the heart. A limited range triple rule-out CTA protocol would decrease effective doses approximately 22% relative to full chest CTA and may help the physician find all PE present.

PURPOSE: To reduce the redundant acquisition range and total radiation dose for planning appropriate "triple rule-out" CT angiography (CTA) for acute chest pain, we evaluated the detailed distribution of pulmonary thromboemboli (PTE) in subjects with acute PTE. MATERIALS AND METHODS: Retrospective review of CTA n 75-subjects (48-females; 57 ± 16 years) with proven acute PTE was performed to determine whether PTE was present solely above the aortic arch or below the heart. RESULTS: 77% had PTE in the right upper lobe but none had PTE that were solely located higher than the aortic arch; 73% had PTE in the right middle lobe; 80% had PTE in the right lower lobe, but none had PTE that were solely located lower than the heart. 81% had PTE in the left upper lobe and 3% of them had PTE solely located higher than the aortic arch; both had PTE in the right upper, middle, and lower, and the left lower lobes. 75% had PTE in the left lower lobe, but none had PTE that were solely located lower than the heart. The acquisition length in limited CTPA in this population was reduced on average by 21.9% compared with full CTPA. CONCLUSIONS: In subjects with acute PTE, there were none whose PTE was located solely in the upper lobes which were higher than the aortic arch, nor solely in the lower lobes which were lower than the heart. A limited range triple rule-out CTA protocol would decrease effective doses approximately 22% relative to full chest CTA and may help the physician find all PE present.

Although the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS) are often individually accompanied by small-cell lung carcinoma, simultaneous occurrence of the 2 syndromes is rare. A 61-year-old man was admitted to our hospital because of fatigue and myasthenia in the extremities, and small-cell lung carcinoma with pulmonary metastasis was diagnosed, together with SIADH and LEMS. These syndromes markedly ameliorated following tumor shrinkage, with 4 cycles of chemotherapy consisting of carboplatin and etoposide. On progression of the tumor thereafter, neither syndrome recurred. A literature review disclosed that these syndromes frequently resolve with tumor shrinkage.

Thioredoxin reductase 1 (TrxR1) catalyzes the nicotinamide adenine dinucleotide phosphate-dependent reduction of oxidized thioredoxin (Trx). Trx, which is over-expressed in many human tumors, is a selenocysteine-containing protein associated with cell proliferation and apoptosis inhibition. This selenium-containing redox system regulates the activity of various enzymes and counteracts oxidative stress in cells such as hypoxia and cytotoxic agents. Consequently, TrxR1 could play an important role in tumor progression and resistance to chemotherapy due to its anti-apoptotic functions. To characterize cancer-related gene expression changes in oral squamous cell carcinomas (OSCC), we compared the gene expression profiles in OSCC primary tumors with patient-matched normal oral epithelium. Microarray analysis showed TrxR1 upregulation in primary tumors. Gene ontology analysis showed highly significant cancer-related function. The TrxR1 expression examined by immunohistochemistry was correlated with regional lymph node metastasis (P<0.05) and the clinical stages of 50 patients (P<0.01). Overexpression of TrxR1 could contribute to cancer progression and might be a potential molecular marker for therapy.

Most patients with severe pulmonary arterial hypertension (PAH) demonstrate persistent structural alterations in small pulmonary arterioles at the time of diagnosis, including marked proliferation of pulmonary artery endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts. Rai et al. have recently proposed a paradigm shift to explain the pathobiology of small vessel disease in severe PAH patients as a quasi-neoplastic process. Indeed, the vascular lesions of patients with severe PAH exhibit some cancer-like characteristics: decreased population of apoptotic cells and overexpression of antiapoptotic proteins. Nevertheless they lack the capability for tissue invasion and metastasis. The article reviews pathomechanisms of vascular lesions in PAH comparing them with each of the cancer defining mechanisms and indicates the potential utility of antineoplastic drugs as antiproliferative treatment in PAH. PDGF has been identified as a novel potential therapeutic target and the successful treatment of experimental PAH with a PDGF receptor tyrosine kinase inhibitor has been demonstrated recently. These findings justify further clinical trials concerning thyrosine kinase inhibitors as future PAH therapies. However, the drugs currently developed for malignant neoplasms to target neoplastic proliferation should be tested carefully in PAH patients due to their cardiac and pulmonary toxicity.

In the diagnosis of thrombosis with no specific clinic symptoms, diagnostic imaging plays a greater role. Particularly, contrast Enhanced CT is low invasive diagnostics, and the thrombus in the pulmonary artery can be detected as a low density without the contrast effect. Moreover, because describing the change of concentration in lung field and the decline in lung blood vessel shadow is also possible, it is indispensable to diagnose of thrombosis. As the image diagnosis support, it is necessary to classify the pulmonary artery and vein that relate to the thrombosis, and to analyze the lung blood vessel quantitatively. The technique for detecting the thrombosis by detecting the position of the thrombus has been proposed so far. In this study, it aims to focusing on the dilation of the main pulmonary artery and to detect the thrombosis. The effectiveness of the method is shown by measuring the pulmonary trunk diameter by using the extracted pulmonary artery from contrast Enhanced CT through semi-automated method, and comparing it with a normal case. © 2011 SPIE.

In the diagnosis of thrombosis with no specific clinic symptoms, diagnostic imaging plays a greater role. Particularly, contrast Enhanced CT is low invasive diagnostics, and the thrombus in the pulmonary artery can be detected as a low density without the contrast effect. Moreover, because describing the change of concentration in lung field and the decline in lung blood vessel shadow is also possible, it is indispensable to diagnose of thrombosis. As the image diagnosis support, it is necessary to classify the pulmonary artery and vein that relate to the thrombosis, and to analyze the lung blood vessel quantitatively. The technique for detecting the thrombosis by detecting the position of the thrombus has been proposed so far. In this study, it aims to focusing on the dilation of the main pulmonary artery and to detect the thrombosis. The effectiveness of the method is shown by measuring the pulmonary trunk diameter by using the extracted pulmonary artery from contrast Enhanced CT through semi-automated method, and comparing it with a normal case.

Several lines of evidence indicate that vascular endothelial growth factor (VEGF) plays a prosurvival and antiapoptotic role in endothelial cells. SU5416 is the first VEGF receptor 2 inhibitor to enter clinical development for cancer therapy. A phase I/II study of SU5416 has been completed, and the results show that SU5416 is well tolerated in patients with terminal cancers. It has been shown that VEGF receptor blockade using SU5416 combined with chronic hypoxia results in severe angioproliferative pulmonary hypertension (PAH) with neointimal changes in adult rats. Although classic animal models of pulmonary hypertension (that is, the monocrotaline and hypoxic models) do not form obstructive intimal lesions in the peripheral pulmonary arteries, the SU5416 model has shown pulmonary arterial changes resembling plexiform lesions. Therefore, the SU5416 model of PAH has been used for some time, and it has thus contributed to a better understanding of the pulmonary hypertensive process. However, the mechanism by which SU5416 combined with chronic hypoxia can result in PAH with plexiform-like lesions in adult rats is complex and still remains to be fully elucidated. The most likely explanation is that there is increased apoptosis of endothelial cells in response to the loss of the survival signaling, creating conditions favoring the emergence of apoptosis-resistant cells with increased growth potential, that is, the endothelial cell hyperproliferation that might characterize the plexiform lesions of human PAH. The aim of the present review is to provide information useful for understanding a potent inhibitor of VEGF receptor tyrosine kinase, SU5416, and to better understand its use for generating animal models of PAH.

The patient was a 34-year-old man, who was referred to our hospital because of abnormal shadows in the right lower lung field on a chest radiograph during a medical screening. Chest computed tomography (CT) showed a pulmonary arteriovenous fistula 23 x 17 mm in size in the anterior basal segment of the right lung, together with a single artery and single vein. He had no symptoms and did not have Osler-Weber-Rendu syndrome. Coil embolization was performed in order to decrease the risk of complications associated with right-to-left shunting. Transcatheter embolization using interlocking detachable coils and detachable fibered coils was successfully performed without severe complications. Then, 320-row multidetector CT revealed that the blood flow from the pulmonary artery disappeared just after coil embolization, the blood flow from the pulmonary vein flowed backward, and the fistula was contrasted. The fistula had almost completely disappeared 8 months after embolization. We confirmed that blood flows were interrupted by 320-row CT and pulmonary angiography. 320-row CT was useful for the evaluation of pulmonary arteriovenous fistula and coil embolization.

Vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC). Successful treatment of experimental PAH with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor offers the perspective of "reverse remodeling" (i.e., the regression of established pulmonary vascular lesions). Here we ask the question: which forms of pulmonary vascular remodeling are reversible and can such remodeling caused by angiogenic proliferation of EC be reversed? It is important to emphasize that the report showing reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor showed only a reduction of the pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack the feature of clustered proliferated EC in the lumen of pulmonary arteries. The regression of vascular muscularization is an important manifestation, whereby proliferative adult SMC convert back to a nonproliferative state. In contrast, in vitro experiments assessing the contribution of EC to the development of PAH demonstrated that phenotypically altered EC generated as a consequence of a vascular endothelial growth factor receptor blockade did not reverse to normal EC. Whereas it is suggested that the proliferative state of SMC may be reversible, it remains unknown whether phenotypically altered EC can switch back to a normal monolayer-forming EC. This article reviews the pathogenetic concepts of severe PAH and explains the many forms in PAH with reversible or irreversible remodeling.

We examined possible combinatory antitumor effects of replication-competent type 5 adenoviruses (Ad) lacking E1B-55kDa molecules (Ad-delE1B55) and chemotherapeutic agents in nine human esophageal carcinoma cells. Ad-delE1B55 produced cytotoxic effects on all the carcinoma cells and the cytotoxicity is not directly linked with the p53 status of the tumors or with the infectivity to respective tumors. A combinatory treatment with Ad-delE1B55 and an anticancer agent, 5-fluorouracil (5-FU), mitomycin C or etoposide, produced greater cytotoxic effects than that with either the Ad or the agent. Administration of 5-FU could minimally inhibit the viral replication and a simultaneous treatment with the Ad and 5-FU achieved better cytotoxicity than sequential treatments. We also confirmed the antitumor effects by the combination of Ad-delE1B55 with 5-FU in vivo. Cisplatin, however, did not achieve the combinatory effects in most of the cells tested. These data indicate that the Ad-delE1B55 produce combinatory antitumor effects with a chemotherapeutic agent irrespective of the administration schedule, but the effects depend on an agent in esophageal carcinoma. © 2010 Nature America, Inc. All rights reserved.

We report a 65-year-old man with a 35-year history of occupational asbestos exposure. He presented at a nearby hospital with a complaint of dyspnea in 2002. Bilateral pleural effusion was revealed on a chest x-ray film. Chest CT revealed diffuse thickening of the pleura, bilateral pleural effusions and cardiac effusion, but no abnormal findings in the lung fields. Both pleural effusions were exudative, and lymphocytes were predominant. Antituberculous chemotherapy had no effect on the exudates. Thoracoscopic pleural biopsy was conducted to exclude malignant mesothelioma. No evidence of malignancy was found in pleural samples. The patient's condition was diagnosed as benign asbestos pleurisy with diffuse pleural thickening. He was referred to our hospital in June 2008. Bilateral pleural effusions continued to progress despite pleurodesis and frequent drainage of his pleural effusion. He suffered from respiratory failure and died in December 2008. We investigated the concentration of asbestos bodies in his lung tissue. There were 462 asbestos bodies per 1 g of dry lung tissue, which was relatively low considering the time of asbestos exposure. We report a rare case of benign asbestos pleurisy with diffuse pleural thickening confirmed by autopsy.

We report a case of a 70-year-old man with chronic thromboembolic pulmonary hypertension (CTEPH) in whom bronchial asthma had been clinically diagnosed and treated, and who showed remarkable improvement by pulmonary endarterectomy. He had dyspnea on exertion and had been clinically treated for bronchial asthma for 15 years. However, his symptoms did not improve after oral and inhaled corticosteroid therapy, and he had dyspnea at rest. CTEPH was suspected by echocardiography and computed tomography (CT) and he was admitted to our hospital. Perfusion scans showed multiple segmental perfusion defects with normal ventilation study, and contrast-enhanced CT showed intramural thrombi in both pulmonary arteries. Right cardiac catheterization revealed a mean pulmonary arterial pressure of 70 mm Hg and pulmonary vascular resistance of 1699 dyn.s.cm(-5) with chronic thromboembolic findings on pulmonary angiography. After surgery his pulmonary hemodynamics and symptoms significantly improved. CTEPH is rarely diagnosed at the initial visit because the only symptom is dyspnea on exertion, and it is often misdiagnosed as other respiratory diseases. But it is important to suspect and diagnose CTEPH in patients with unexplained dyspnea because this disease can be cured by surgery.

A 46-year-old man presented with chest pain at a local hospital in July 2007. Chest computed tomography (CT) showed a 48-mm mass in the anterior mediastinum. CT-guided percutaneous tumor biopsy demonstrated large cell neuroendocrine carcinoma of the thymus. He was referred to our hospital in August 2007. Because the tumor had already progressed to stage IVb according to the Masaoka classification of thymic epithelial tumors, the patient was treated with combination chemotherapy of cisplatin and irinotecan, which achieved a partial response. However, the tumor relapsed in February 2008. He died, despite 2 separate cycles of chemotherapy with docetaxel only and amrubicin only in August 2008. We encountered a rare case of large cell neuroendocrine carcinoma of the thymus treated with combination chemotherapy of cisplatin and irinotecan.

Idiopathic pulmonary arterial hypertension (PAH) is a disabling condition characterized by PA vasoconstriction and remodeling as well as in situ thrombosis and eventual right heart failure. Idiopathic PAH occurs more frequently in females than in males. The female:male ratio is 1.64 ∼ 3.88:1. Although endogenous sex hormones including estrogen have been suggested to account for the observed gender differences in PAH, a precise pathobiology for the gender differences remains uncertain. Recent studies demonstrated that estrogen exerts beneficial effects on the pulmonary vasculature. However, it seems to contradict the female predominance that is observed in idiopathic PAH. Moreover, Sweeney and Voelkel (Sweeney L and Voelkel NF. Eur J Med Res 14: 433-442, 2009) showed that early and long-term estrogen exposure might be correlated with an increased risk of the development of PAH. Here we ask the question: Is estrogen a friend or a foe? According to accumulating evidence, we postulate that the different effects of estrogens on different target cells could account for this paradox, i.e., estrogens may exert beneficial effects only on the increased muscularization of vessel walls, but not on phenotypically altered endothelial cells. The effects of estrogens on the pulmonary vasculature are potent and complex, yet not fully understood. A better mechanistic understanding may allow for future therapeutic interventions in patients with PAH.

PURPOSE: Long-acting bronchodilators are recommended as a first-line treatment for chronic obstructive pulmonary disease (COPD), although their effects for postoperative lung cancer patients with COPD are still not well known. A prospective randomized trial was used to examine the efficacy of bronchodilators on postoperative pulmonary function and quality of life (QOL). METHODS: Twenty lung cancer patients with COPD who had lobectomies were randomized. A control group (n = 10) did not receive bronchodilators. An experimental group (n = 10) received tiotropium and salmeterol. Patients were divided into two COPD grades: stage I COPD and stage II-III COPD. Results for pulmonary function, 6-minute walking test, and the St. George's Respiratory Questionnaire (SGRQ) were compared. Diaphragmatic motion on dynamic magnetic resonance imaging was also analyzed. RESULTS: The patient demographics were similar in the two groups. Except for pulmonary function results at 2 weeks, no other parameters were significantly different. However, in stage II-III COPD, forced expiratory volume in 1 second, forced vital capacity, inspiratory capacity, the total score of the SGRQ, and diaphragmatic motion in the experimental group (n = 5) were significantly better than those in the control group (n = 4) at various time points (all P < 0.05). CONCLUSION: The daily inhalation of bronchodilators was effective for maintaining the respiratory function and QOL in lung cancer patients with moderate to severe COPD.

A phase III observational study evaluating a single-dose of an inactivated, split-virus, unadjuvanted AH1pdm vaccine in HCW was conducted. A safe and effective vaccine was needed after the emergence of AH1pdm in April 2009. We analyzed the immunogenicity and safety of the vaccine. A total of 409 subjects were enrolled and given 15 μg hemagglutinin antigen by s.c. injection. Antibody titers were measured using hemagglutination-inhibition antibody assays before vaccination and 28 days after. The co-primary immunogenicity end-points were the proportion of subjects with antibody titers of 1:40 or more, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in geometric mean titer. We collected 389 pair samples. Antibody titers of 1:40 or more were observed in 148 of 389 subjects (38.0%, 95% CI: 33.2-42.9). The immunogenicity was also confirmed in other end-points, but was not sufficient and was lower than in previous reports. A total of 96 of adverse events was reported: 51 local events and 57 systemic events. There were 12 subjects with both local and systemic events. Nearly all events were mild to moderate except in four subjects. A single 15-μg dose of AH1pdm vaccine did not induce sufficient immunogenicity in HCW, with mild-to-moderate vaccine-associated adverse events. We need to consider further improvement of the AH1pdm vaccine program in HCW for the prevention of nosocomial infection, as well as for the benefit of HCW.

The Ministry of Health, Labour and Welfare (Japan) has approved research into primary pulmonary hypertension (PPH) and pulmonary hypertension due to chronic thromboembolic and/or embolic disease (CTE-PH) to examine their epidemiology, pathophysiology, and develop new therapeutic strategies. The Respiratory Failure Research Group, with grant support from the Ministry of Health, Labour and Welfare, changed the diagnostic names of PPH and CTE-PH. The Specific Diseases Control Division in the Health Service Bureau of the Ministry of Health, Labour and Welfare supported our proposal. One of the major purposes of The Respiratory Failure Research Group has been to maintain and, if possible, promote patient quality of life and prognosis in cases of intractable respiratory diseases. The name PPH has been changed to "pulmonary arterial hypertension (PAH)", and the name CTE-PH has been changed to "chronic thromboembolic pulmonary hypertension (CTEPH)", in keeping with recent worldwide research progress in this field. PAH should be subdivided into different pathophysiologic conditions, such as idiopathic and hereditary PAH, PAH associated with connective tissue diseases, portal hypertension, congenital heart disease, persistent pulmonary hypertension in newborn babies, pulmonary veno-occlusive disease etc. Different therapeutic strategies may be adopted for different subgroups. Pulmonary hypertension due to left heart disease, lung disease and/or hypoxia and CTEPH should be excluded from PAH. Continuous monitoring of PAH and CTEPH is required in patients with these conditions, even if the degree of pulmonary hypertension is improved by therapeutic intervention, because these diseases are incurable.

RATIONALE: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. OBJECTIVES: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. METHODS: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk). MEASUREMENTS AND MAIN RESULTS: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. CONCLUSIONS: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).

COPDは呼吸器の炎症性疾患であるが，同時にその機序は明らかではないが全身炎症性疾患である．COPDは主に喫煙が惹起する呼吸器の炎症性疾患と認識されているが，喫煙・加齢も肺および全身に炎症を引き起こすため，それらの病態への影響も常に考慮しておく必要がある．全身炎症性疾患としてのCOPDのバイオマーカーとして高感度CRP・IL-6などが挙げられている．特に高感度CRPはCOPD以外の慢性疾患でも上昇し，COPDでは高感度CRPは心筋梗塞，脳血管障害，末梢動脈疾患などの全身併存症を予想しうるバイオマーカーになりうる．肥満・メタボリックシンドローム・運動不足なども全身性炎症に関与してくるため，それらの影響も考慮にいれておく必要がある．高齢者に対する運動療法は，COPD以外でも必要かもしれない．全身併存症は患者予後およびHRQOLにも影響するため，それらを考慮にいれた対策が必要である．<br>

Background. Lung tumors with rhabdoid features are classified as a variant of large-cell carcinoma of the lung, according to the WHO classification of lung and pleural tumors. In general, they grow aggressively and have a poor prognosis, with no established therapeutic method. Case. A 39-year-old man presented with a primary tumor in the left upper lung lobe, and metastatic lesions in the cervical lymph nodes, right tonsil, bilateral adrenal glands and bone. A biopsy specimen of the tonsil yielded a diagnosis of lung tumor with rhabdoid phenotype. Although initial chemotherapy, including cisplatin/irinotecan and cisplatin/etoposide were ineffective, subsequent chemotherapy with mesna, doxorubicin, ifosfamide and dacarbazine (the MAID protocol) was effective in reducing the tumors and significantly improving his general condition. Conclusion. Features of the present case should be considered when developing therapeutic strategies for lung tumors with rhabdoid phenotype.

OBJECTIVE: To examine the effects of dose-volume factors on the development of radiation pneumonitis in patients with non-small-cell lung cancer who received twice-daily radiotherapy concurrently with carboplatin and paclitaxel chemotherapy. METHODS: Radiotherapy consisted of twice-daily fractionation of 1.2 Gy, to a total dose of 60 Gy. Weekly carboplatin and paclitaxel were used as a concurrent chemotherapy. Effects of radiotherapy parameters on the development of radiation pneumonitis were retrospectively analyzed. RESULTS: Fourteen of 37 patients developed Grade 2 or worse (> or = G2) radiation pneumonitis. Grade 2 or worse radiation pneumonitis occurred in all 5 patients with V5 >40%, all 4 patients with V10 >35%, all 4 patients with V13 >32%, 9 of 14 patients with V20 >24% and 8 of 11 patients with V30 >22%, whereas 9 of 32 patients with V5 <40%, 10 of 33 patients with V10 <35%, 10 of 33 patients with V13 <32%, 5 of 23 patients with V20 <24% and 6 of 26 patients with V30 <22%, with respective P values of 0.0045, 0.015, 0.015, 0.015 and 0.008. Eight of 11 patients with a mean lung dose of >14 Gy developed > or = G2 radiation pneumonitis in contrast to 6 of 26 patients with a mean lung dose of <14 Gy (P = 0.008). CONCLUSIONS: Several cut-off values in the V(dose) and the mean lung dose differentiating probabilities of developing > or = G2 radiation pneumonitis were identified in this combination therapy.