巽 浩一郎

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.

慢性閉塞性肺疾患・気管支喘息などの慢性呼吸器疾患の増悪を抑制するための戦略は，1）気道炎症を可能な限り改善しておく，2）気道感染を予防する，3）心機能を保つ，に大別される．薬物療法の観点で考えると，気道感染の予防には去痰薬に分類されているカルボシステインが有用である．カルボシステインは，気道上皮細胞に対するウイルスエントリーインヒビターの役割を有しており，臨床的にも増悪抑制に有用である．

To study the role of mutant p53 in the induction and cure of tumors, we generated transgenic mice carrying mutant p53 (mp53) containing a 9 bp deletion in exon 6 in addition to wild-type p53, expressing both p53 and mp53. The mp53 cDNA was cloned from a radiation-induced mouse tumor and ligated to the chicken beta-actin promoter/CMV-IE enhancer in the expression vector. The presence of mp53 suppressed p21 expression in primary fibroblasts after ionizing irradiation, indicating the dominant-negative activity of mp53 in the mice. These mice developed fibrosarcomas after the subcutaneous injection of 3-methylcholanthrene with an incidence 1.7-fold higher than that of wild-type mice (42% excess). The tumors were then treated via a potent atelocollagen delivery system with small interfering RNA (siRNA), that targeted the promoter/enhancer of the expression vector, resulting in the suppression of tumor growth in 30% of 44 autochthonous tumors, including four cures, and their transplants, the total fraction corresponding to the tumor excess. This suppressive effect involved the induction of apoptosis. These results indicate that mp53 activity causes tumors that can be suppressed by subsequent silencing of mp53 in the presence of wild-type p53 alleles. Cancer Gene Therapy (2010) 17, 1-10; doi: 10.1038/cgt.2009.43; published online 26 June 2009

症例１は初診時39歳女性．2003年に眼所見と両側肺門リンパ節腫脹（BHL）で発症した．2009年に疼痛を伴う耳下腺と両鼠径リンパ節の腫脹が出現した．近医でミノサイクリンを使用されたが無効であり，当科に紹介されメトトレキサート（以下MTX）7.5 mg/週の単剤治療を開始したところBHLと表在リンパ節の改善が認められた．症例２は初診時51歳男性，以前より眼，皮膚，肺病変に対してプレドニゾロン（以下PSL）が投与されていた．PSLの中止後に肺病変の増悪と肺アスペルギルス症の合併を認め当科に紹介された．MTX 7.5 mg/週の単剤治療にて肺野陰影の改善が認められた．MTXはsteroid-sparing agentとして位置づけられ単剤治療での有効性を示した報告は少なく，今回２症例を報告した．

Selective right pulmonary arteriography and 3-dimensional computed tomography revealed multiple severe stenoses of the peripheral pulmonary artery associated with poststenotic aneurysms in a 65-year-old woman. She was referred to the hospital for evaluation of dry cough, gradually increasing dyspnea and multiple nodular shadows on a chest radiograph. Echocardiography and cardiac catheterization showed severe pulmonary hypertension, though other structural heart diseases or well-characterized congenital syndromes were ruled out. She was diagnosed as isolated peripheral pulmonary artery branch stenosis. Recent advances in CT technology enable a less-invasive assessment of pulmonary artery, and can be useful in the management of pulmonary arterial hypertension.

A 20-year-old female diagnosed as idiopathic pulmonary arterial hypertension at 7 years of age was referred with worsening dyspnea and chest pain. Several imaging studies and right cardiac catheterization showed multiple stenoses in the peripheral pulmonary arteries with severe pulmonary hypertension and multiple systemic arterial stenoses lacking in systemic hypertension. No evidence of inflammatory or autoimmune disease was detected. Fibromuscular dysplasia was clinically diagnosed because of the narrowed systemic and pulmonary arterial stenoses which included dilatation and aneurysms that appeared similar to a string of beads. Treatment with sildenafil yielded a temporary improvement in her disease state.

Severe pulmonary arterial hypertension, whether idiopathic or secondary, is characterized by structural alterations of microscopically small pulmonary arterioles. The vascular lesions in this group of pulmonary hypertensive diseases show actively proliferating endothelial cells without evidence of apoptosis. In this article, we review pathogenetic concepts of severe pulmonary arterial hypertension and explain the term "complex vascular lesion ", commonly named "plexiform lesion", with endothelial cell dysfunction, i.e., apoptosis, proliferation, interaction with smooth muscle cells and transdifferentiation.

本論文では漢方医学的と同時に西洋医学的観点から，気道系領域疾患の治療として，西洋薬とともにどのように漢方薬を使用するかを考察した。漢方治療では一般的に患者の体力，病態，病気の進展に合わせて薬方を決定することが重要である。喀痰がからまるという患者の病態が去痰薬，気管支拡張薬，吸入ステロイド薬，抗菌薬では十分に改善しない場合，例えば半夏厚朴湯という漢方薬は喀痰がほとんどなく，咽頭部の閉塞感を訴える場合に効果が期待できる。<br>咳嗽反射，嚥下反射の低下は誤嚥性肺炎の誘因になりうる。そのような場合，半夏厚朴湯の投与は咳嗽反射，嚥下反射を改善することにより，誤嚥性肺炎を予防しうる。<br>遷延性あるいは慢性咳嗽は鎮咳薬，抗菌薬，去痰薬，気管支拡張薬，吸入ステロイド薬などの西洋薬を使用しても，十分に改善しない場合がある。麦門冬湯，五虎湯，麻杏甘石湯，越婢加半夏湯などの漢方薬は，そのような場合に有用である可能性がある。西洋医学の薬と漢方薬の併用は，新たな効果を発揮しうると期待する。

We examined phrenic long-term facilitation (LTF) in urethane-anesthetized, vagotomized, paralyzed, and artificially ventilated orexin neuron-ablated mice and their wild-type littermates. Effect of isocapnic single hypoxic episode (SHE, for 45 s) and intermittent hypoxia (IH, 5 times of SHE separated by 5 min) on phrenic nerve activity (PNA) was measured for 1-2h. In wild-type mice, amplitude of PNA gradually increased after cessation of IH and reached 55+/-15% above the baseline (n=7, p<0.05) whereas the burst rate of PNA did not change. Qualitatively similar but significantly attenuated response (16+/-8%) was observed in orexin neuron-ablated mice. SHE did not affect amplitude nor frequency in both animals. We conclude that orexin contributes to eliciting phrenic LTF at least in part in mice. This study also showed, for the first time, phrenic LTF following IH in WT mice. Characteristics of phrenic and ventilatory LTF in mice were similar to those in rats.

A 27-year-old man experienced progressive left hypochondralgia. CT with contrast medium enhancement revealed marked splenomegaly, multiple swollen lymph nodes in the mediastinum and abdominal cavity, and multiple nodules in the spleen, liver, kidneys and lungs. Pathological examinations of the lung and liver lesions showed non-caseating granulomatous lesions, and established the diagnosis of sarcoidosis. The symptom and lesions presented by CT regressed dramatically with administration of corticosteroid (30 mg/day oral prednisolone). Symptomatic splenomegaly in a young Japanese man with sarcoidosis seems very rare especially considering that sarcoidosis lesions completely regress spontaneously within a year in 90% patients of young Japanese men with sarcoidosis.

Racemose hemangioma of the bronchial arteries is a rare abnormality and is characterized by enlarged and convoluted bronchial arteries arranged segmentally along the longitudinal axis of bronchus. Primary racemose hemangioma may arise from inborn malformation, and secondary one may develop following primary inflammatory, stenosing or deforming diseases of the bronchus, the peribronchial tissues and the surrounding lung tissues. The symptom at onset is usually hemoptysis. Although the typical treatments have not been established, various treatments, like embolization or ligation of the bronchial arteries and surgical resection of the involved area of lung, were reported. However the term 'Racemose hemangioma' seems to be used only in Japan, so it is favorable to make a consensus of its definition among countries.

BACKGROUND AND OBJECTIVE: Although lung cancer is frequently accompanied by COPD and interstitial lung disease (ILD), the precise coincidence of these diseases with lung cancer is not well understood. The objectives of this study were to determine the prevalence of abnormal CT and spirometric findings suggestive of COPD or ILD in a population of patients with untreated lung cancer, and to estimate the lung cancer risk in this population. METHODS: The study population consisted of 256 patients with untreated lung cancer and 947 subjects participating in a CT screening programme for lung cancer. Semi-quantitative analysis of low attenuation area (LAA), fibrosis and ground glass attenuation (GGA) on CT was performed by scoring. Gender- and age-matched subpopulations, with stratification by smoking status, were compared using the Mantel-Haenszel projection method. RESULTS: Inter-observer consistency was excellent for LAA, but not as good for fibrosis or GGA scores. Pooled odds ratios for lung cancer risk using LAA, fibrosis, GGA scores and reduced FEV(1)/FVC and %VC were 3.63, 5.10, 2.71, 7.17 and 4.73, respectively (P < 0.0001 for all parameters). Multivariate regression analyses confirmed these results. CONCLUSION: Abnormal CT and spirometric parameters suggestive of COPD and ILD were strong risk factors for lung cancer, even after adjusting for gender, age and smoking status.

Gender differences could exist in the respiratory functions of the upper airway, especially when they relate to sleep and possibly sleep apnea. Particular attention should be given to factors related to upper airway patency, considering the gender difference of anesthesia. The pharyngeal airway is open during wakefulness but occludes during sleep implicating a neural component dependent upon state of vigilance, although anatomical upper airway narrowing in the genesis of airway occlusion during sleep plays an important role. Respiratory disturbances, including sleep apnea syndromes, are less common in women than men until after menopause. Particularly marked is the male predominance among patients with obesity hypoventilation syndrome. While obesity increases the risk of developing sleep-disordered breathing in both sexes, women with sleep apnea syndromes are more massively obese than their male counterparts. Several factors may contribute to the protection in herento premenopausal women, including the presence of female hormones, the absence of male hormones, and the effects of gender or age unrelated to sex hormones. These factors, in turn, appear to influence airway patency and ventilatory control.

Good syndrome, characterized by hypogammaglobulinemia and acquired immunodeficiency, is a rare condition associated with thymoma. A 67-year-old woman, who 4 months previously had a thymoma resected, presented with generalized hypogammaglobulinemia with a severely decreased B cell population as demonstrated by flow cytometry. She was diagnosed as having bacterial mediastinitis associated with Good syndrome. For the subsequent 6 years, she suffered from repeated serious bacterial infections. As this paraneoplastic syndrome is not resolved by tumor removal, careful management with intensive infection-control using antibiotics and intravenous immunoglobulins is required for the long term. Serum immunoglobulin levels should be evaluated for patients with thymoma and suspected vulnerability to infection.

A 52-year-old woman with end-stage renal disease and long-term hemodialysis complained of worsening exertional dyspnea. A chest X-ray showed cardiomegaly. She was admitted to our hospital because an echocardiogram suggested pulmonary hypertension. Right heart catheterization revealed pulmonary hypertension, but pulmonary perfusion scintigraphy with Tc-99m-MAA showed no evidence of pulmonary thromboembolism. We gave her a diagnosis of pulmonary arterial hypertension associated with Sjögren syndrome on the basis of a positive serological test (SS-A. SS-B) and the findings of lip biopsy. After four months of therapy with bosentan, her 6-minute walk distance, estimated pulmonary arterial pressure and brain natriuretic peptide (BNP) improved. Bosentan is mainly cleared by hepatic elimination and its dialysis clearance is low. Bosentan for the treatment of pulmonary hypertension was safe as well as effective in this patient with end-stage renal disease and hemodialysis. In consideration of the relationship between pulmonary hypertension and end-stage renal disease, and hemodialysis, bosentan was considered to be a reasonable and effective treatment.

BACKGROUND: The predominance of chronic thromboembolic pulmonary hypertension (CTEPH) in females and association of HLA-B*5201 with CTEPH have been reported in Japan. However, the clinical characteristics of female CTEPH remain uncertain. The purpose of the present study is to clarify the clinical phenotype of female CTEPH in Japan. METHODS AND RESULTS: The 150 consecutive patients (female 103, male 47; age 52.8+/-12.4 years SD) were admitted to Chiba University Hospital, and diagnosis was confirmed using right cardiac catheterization and pulmonary angiography. Among these patients, 78 underwent pulmonary endarterectomy. Clinical characteristics, pulmonary hemodynamics, extent of central disease and surgical outcome in females were compared with those in males. The female patients were elderly and had less deep vein thrombosis, less acute embolic episodes, better cardiac function, lower arterial oxygen tension and more peripheral thrombi, and showed less improvement through surgery than males. When the patients were identified using HLA-B*5201, HLA-B*5201-positive female patients had less embolic episodes and better cardiac function with lower operative mortality. In contrast, HLA-B*5201-negative female patients had less embolic episodes, and more peripheral thrombi, resulting in less improvement by surgery. CONCLUSION: The clinical phenotype of female CTEPH differed from that of male CTEPH. Additionally, gender differences of HLA-B*5201-positive type were dissimilar to those of HLA-B*5201-negative type.

Remodeling of the lung's vascular structure is the critical abnormality in the various types of pulmonary hypertension, including pulmonary arterial hypertension. Pulmonary hypertension consists of some structural changes and an adaptation to its presence (perhaps reversible component, including vasoconstriction). However, once pulmonary hypertension is a recognizable clinical problem, its basis is structural. The research for mediators of cell injury and tissue remodeling has been one of the most active fields of biomedical study. It offers an embarrassingly wide array of candidates for the cellular events. The normal structure of the lung's vascular bed holds the key to its remodeling. The cast of cells is similar at all levels of the pulmonary vascular bed, yet the various segments have special features and different patterns of response.

Testicular involvement by sarcoidosis is a rare condition. A 23-year-old Japanese man had asymptomatic bilateral testicular lesions, which were detected by gallium scintigram, together with lesions located bilaterally in the uvea, lungs and hilar, and mediastinal lymph nodes and unilateral supraclavicular lymph nodes. Semen analysis demonstrated severely impaired spermatogenesis. Treatment with corticosteroid dramatically improved these lesions and restored spermatogenesis. This case report suggests that testicular sarcoidosis may cause male infertility.

Although mucosa-associated lymphoid tissue (MALT) lymphoma is classified as an indolent lymphoma, it frequently disseminates and recurs to make the disease difficult to cure. The present case had metachronous lesions in the skin, orbit and pleura, and all of them were diagnosed as derived from the same monoclonal tumor cell. A 65-year-old woman was admitted to our hospital because of a pleural tumor with pleural effusion. Two years before, she had undergone surgical resection for skin erythematous lesion and an ocular adnexa tumor, which were diagnosed as lymphoid hyperplasia by histological examination at that time. On admission, thoracoscopy-guided biopsy of the pleural tumor with local anesthesia established a diagnosis of MALT lymphoma. The rearranged immunoglobulin heavy chain of the skin tumor, ocular adnexa tumor, pleural tumor and lymphocytes in the pleural effusion were analyzed using a polymerase chain reaction (PCR)-based assay. This analysis revealed the metachronous MALT lymphoma originated from a distinct B-cell clone. After rituximub and CHOP therapy, complete remission was obtained. Although MALT lymphoma occurs in a wide variety of body sites, the pleural presentation of MALT lymphoma is very rare. Lifelong observation of all patients treated for MALT lymphoma is required because of the high frequency of dissemination and recurrence.

Information concerning the effects of genetic variation between different background strains on hemodynamic, morphometric, and gene expression response to hypoxia would be useful. Three strains of mice were kept in hypoxia and phenotyped followed by gene profiling analysis. Among the variables examined, hematocrit, right heart muscularization, and right ventricular systolic pressure showed a strain-specific effect. Increased gene expression of inflammatory, muscle, and angiogenesis genes were seen in all strains, though the specific genes changed varied among groups. These results suggest that different strains use different gene expression mechanisms to adapt to the challenge of chronic hypoxia, resulting in modified phenotypic changes.

BACKGROUND: Dilatation of the bronchial arteries is a well-recognized feature in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The purpose of the current study was to use computed tomography (CT) to assess the relationship between dilated bronchial arteries and the extent of thrombi, and to evaluate the predictive value of the former for surgical outcome. METHODS AND RESULTS: Fifty-nine patients with CTEPH and 16 with pulmonary arterial hypertension (PAH) were retrospectively evaluated. The total cross-sectional area of bronchial arteries was measured by CT and its relationship with the central extent of thrombi or surgical outcome was assessed. The total area of the bronchial arteries in CTEPH patients was significantly larger than that in PAH patients (median [range], 6.9 [1.7-29.5] mm(2) vs 3.2 [0.8-9.4] mm(2)), with the total area of bronchial arteries correlating with the central extent of thrombi. In patients who had undergone pulmonary thromboendarterectomy (PTE) (n=22), the change in PaO(2) after surgery had a tendency to correlate with the total area of the bronchial arteries. CONCLUSION: The total cross-sectional area of the bronchial arteries correlated with the extent of central disease in patients with CTEPH, and it might predict gas exchange improvement after PTE.

Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vbeta genes were identified in sequential materials obtained at 1-3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vbeta genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients.