田邉 信宏

A 40 year-old woman suggestive of having pulmonary hypertension by echocardiography was referred to our hospital. She had a history of chest pain for one year. The multi-detector computed tomography (MD-CT) showed that the right upper pulmonary vein connected to the superior vena cava. Therefore, she was diagnosed with a partial anomalous venous return (PAPVR). Cardiac catheterization showed a pulmonary flow to systemic flow ratio of 1.57 and left-toright shunting ratio of 38.1%. Consequently, no surgical treatment was required. In this case the MD-CT was useful for confirming PAPVR, and PAPVR should be considered in the differential diagnosis of pulmonary hypertension.

A 66-year-old male treated with everolimus for renal cell carcinoma developed exertional dyspnea. Chest computed tomography revealed diffuse interstitial shadows on both lungs. Bronchoalveolar lavage and the drug-induced lymphocyte stimulation test confirmed the diagnosis of drug-induced interstitial lung disease due to everolimus therapy. However, discontinuation of everolimus in combination with corticosteroid therapy did not prevent disease progression. On the basis of a PCR assay for Pneumocystis jirovecii and elevated β-D-glucan levels, trimethoprim-sulfamethoxazole was administered immediately, resulting in a dramatic improvement. This case demonstrated that pneumocystis pneumonia should always be considered and treated during everolimus therapy, even when drug-induced interstitial lung disease is suspected.

Although the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs has already been identified, we herein present the first case of herbal medicine-associated PAH in which the patient demonstrated spontaneous remission. A 38-year-old woman took the herbal medicine "bofutsushosan" for two weeks then stopped taking it due to exertional dyspnea. However, her dyspnea continued, and right heart catheterization revealed a mean pulmonary arterial pressure of 41 mmHg with a normal wedge pressure. Several months after treatment with oxygen therapy, the patient's dyspnea disappeared, and her pulmonary arterial pressure normalized. Further studies focusing on susceptibility factors to drug-induced pulmonary arterial hypertension are needed.

Background: We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-kinase inhibitor (AT-877ER) on PAH. Methods and Results: 23 PAH patients were treated with either placebo (10/2 females/males, 51±16 years, idio-pathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47±14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4) 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hy-droxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. Conclusions: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynam-ics in patients with PAH.

Objectives: Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. Although several reports demonstrated excellent medium-term survival after pulmonary endarterectomy, long-term outcomes remain unclear. We reviewed long-term outcomes and determined risk factors for early and late adverse events. Methods: Seventy-seven patients were studied. Mean pulmonary arterial pressure was 47 +/- 10 mm Hg and pulmonary vascular resistance was 868 +/- 319 dyne . s . cm(-5). Disease was classified as chronic thromboembolic pulmonary hypertension type 1 (n = 61), type 2 (n = 12), or type 3 (n = 4). Median and maximum follow-up periods were 5.6 and 20 years, respectively. Results: There were 11 in-hospital deaths. Nonsurvivors had significantly higher mean pulmonary arterial pressure and pulmonary vascular resistance than did survivors (54 +/- 10 vs 46 +/- 10 mm Hg; P=.02; 1124 +/- 303 vs 824 +/- 303 dyne . s . cm(-5); P<.01). In multivariate analysis, preoperative pulmonary vascular resistance was associated with in-hospital death (odds ratio, 1.003; 95% confidence interval, 1.001-1.005; P < .01). During follow-up, there were 10 all-cause deaths, including 5 related to chronic thromboembolic pulmonary hypertension. Freedom from adverse events, including disease-specific death or New York Heart Association functional class III, was 70% at 10 years. In the Cox proportional hazard model, postoperative mean pulmonary arterial pressure was associated with adverse events (hazard ratio, 1.12; 95% confidence interval, 1.03-1.21; P < .01). Receiver operating characteristic curve analysis showed mean pulmonary arterial pressure of 34 mm Hg as cutoff for adverse events. Conclusions: Pulmonary endarterectomy had sustained favorable effects on long-term survival. High pulmonary vascular resistance was associated with in-hospital death, and postoperative mean pulmonary arterial pressure was an independent predictor of adverse events. (J Thorac Cardiovasc Surg 2012;144:321-6)

In general, intravascular thrombus formation in the pulmonary arteries is considered to be the most common cause of chronic thromboembolic pulmonary hypertension (CTEPH). The current mainstay of therapy for patients with CTEPH is pulmonary endarterectomy (PEA). Recently, the existence of myofibroblast-like cells in endarterectomized tissues has been demonstrated. At the 2nd passage of these myofibroblast-like cells, a pleomorphic cell type was isolated. Pulmonary intimal sarcoma is a very uncommon neoplastic tumor thought to originate from subendothelial-mesenchymal cells of the pulmonary vascular wall. Because these pleomorphic cells were isolated from the pulmonary vascular beds, it is believed that the analysis of these cells may contribute to the understanding of pulmonary intimal sarcoma. We isolated cells from the endarterectomized tissue from patients with CTEPH and identified one type as sarcoma-like cells (SCLs). The SCLs were characterized as hyperproliferative, anchorage-independent, invasive and serum-independent. Moreover, C.B-17/lcr-scid/scidJcl mice injected subcutaneously with SCLs developed solid, undifferentiated tumors at the site of injection, and those injected intravenously with SCLs via the tail vein developed tumors which grew along the intimal surface of the pulmonary vessels, thus, demonstrating the high tumorigenic potential of these cells. The behavior of SCLs indicated that these cells may have a vascular cell-like potential which can affiliate them with the intimal surface of the pulmonary artery, and which may be shared with pulmonary intimal sarcoma. A further investigation of this mouse model with SCLs may elucidate the mechanism(s) underlying the development of pulmonary intimal sarcoma.

Although cisplatin and pemetrexed are key drugs in the treatment of malignant pleural mesothelioma, their drug-drug interactions, cross-resistance and resistance mechanisms in malignant pleural mesothelioma are not well understood. In the present study, the interaction of these 2 agents was determined by clonogenic assays followed by isobologram analysis of 4 human malignant pleural mesothelioma cell lines. The cell lines were exposed to the agents using a stepwise dose-escalation method to establish drug-resistant sublines. Thymidylate synthase mRNA expression was evaluated in the drug-resistant sublines. As a consequence, cisplatin and pemetrexed had synergistic effects in 3 cell lines and an additive effect in the fourth cell line. The former 3 cell lines showed similar pemetrexed sensitivity in the parental cells and their cisplatin-resistant sublines, whereas the fourth cell line exhibited cross-resistance. In contrast, cisplatin had diverse effects on pemetrexed-resistant sublines. High thymidylate synthase expression did not correlate with natural pemetrexed resistance. Elevated thymidylate synthase expression correlated with acquired pemetrexed resistance in 2 sublines. In conclusion, cisplatin and pemetrexed showed synergistic activity and no cross-resistance in 3 of the 4 malignant pleural mesothelioma cell lines, suggesting the clinical relevance of their combination in chemotherapy. Thymidylate synthase expression did not necessarily correlate with pemetrexed resistance. The information together with the experimental model presented here would be useful for further investigating therapeutic targets of malignant mesothelioma.

The oral antidiabetic agent metformin has anticancer properties, probably via adenosine monophosphate-activated protein kinase activation. In the present study, growth inhibition was assessed by a clonogenic and by a cell survival assay, apoptosis induction was assessed by Hoechst staining and caspase activities and cell cycle alteration after exposure to metformin, and the interaction of metformin with cisplatin in vitro were elucidated in four human lung cancer cell lines representing squamous, adeno-, large cell and small cell carcinoma. Clonogenicity and cell proliferation were inhibited by metform in in all the cell lines examined. This inhibitory effect was not specific to cancer cells because it was also observed in a non-transformed human mesothelial cell line and in mouse fibroblast cell lines. Inhibition of clonogenicity was observed only when the cells were exposed to metformin for a long period, (10 days) and the surviving fraction, obtained after inhibiting proliferation by increasing the dose, reached a plateau at approximately 0.1-0.3, indicating the cytostatic characteristics of metformin. Metformin induced significant apoptosis only in the small cell carcinoma cell line. A tendency of cell cycle accumulation at the G0/G1 phase was observed in all four cell lines. Cisplatin, in a dose-dependent manner, severely antagonized the growth inhibitory effect of metformin, and even reversed the effect in three cell lines but not in the adenocarcinoma cell line. The present data obtained using various histological types of human lung cancer cell lines in vitro illustrate the cytostatic nature of metformin and its cytoprotective properties against cisplatin.

Shigeta A, Tada Y, Wang J-Y, Ishizaki S, Tsuyusaki J, Yamauchi K, Kasahara Y, Iesato K, Tanabe N, Takiguchi Y, Sakamoto A, Tokuhisa T, Shibuya K, Hiroshima K, West J, Tatsumi K. CD40 amplifies Fas-mediated apoptosis: a mechanism contributing to emphysema. Am J Physiol Lung Cell Mol Physiol 303: L141-L151, 2012. First published May 18, 2012; doi:10.1152/ajplung.00337.2011.-Excessive apoptosis and prolonged inflammation of alveolar cells are associated with the pathogenesis of pulmonary emphysema. We aimed to determine whether CD40 affects alveolar epithelial cells and endothelial cells, with regard to evoking apoptosis and inflammation. Mice were repeatedly treated with agonistic-anti CD40 antibody (Ab), with or without agonistic-anti Fas Ab, and evaluated for apoptosis and inflammation in lungs. Human pulmonary microvascular endothelial cells and alveolar epithelial cells were treated with agonistic anti-CD40 Ab and/or anti-Fas Ab to see their direct effect on apoptosis and secretion of proinflammatory molecules in vitro. Furthermore, plasma soluble CD40 ligand (sCD40L) level was evaluated in patients with chronic obstructive pulmonary disease (COPD). In mice, inhaling agonistic anti-CD40 Ab induced moderate alveolar enlargement. CD40 stimulation, in combination with anti-Fas Ab, induced significant emphysematous changes and increased alveolar cell apoptosis. CD40 stimulation also enhanced IFN-gamma-mediated emphysematous changes, not via apoptosis induction, but via inflammation with lymphocyte accumulation. In vitro, Fas-mediated apoptosis was enhanced by CD40 stimulation and IFN-gamma in endothelial cells and by CD40 stimulation in epithelial cells. CD40 stimulation induced secretion of CCR5 ligands in endothelial cells, enhanced with IFN-gamma. Plasma sCD40L levels were significantly increased in patients with COPD, inversely correlating to the percentage of forced expiratory volume in 1 s and positively correlating to low attenuation area score by CT scan, regardless of smoking history. Collectively CD40 plays a contributing role in the development of pulmonary emphysema by sensitizing Fas-mediated apoptosis in alveolar cells and increasing the secretion of proinflammatory chemokines.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease of the lung vasculature for which the molecular etiologies are unclear. Specific metabolic alterations have been identified in animal models and in PAH patients, though existing data focus mainly on abnormalities of glucose homeostasis. We hypothesized that analysis of the entire metabolome in PAH would reveal multiple other metabolic changes relevant to disease pathogenesis and possible treatment. Layered transcriptomic and metabolomic analyses of human pulmonary microvascular endothelial cells (hPMVEC) expressing two different disease-causing mutations in the bone morphogenetic protein receptor type 2 (BMPR2) confirmed previously described increases in aerobic glycolysis but also uncovered significant upregulation of the pentose phosphate pathway, increases in nucleotide salvage and polyamine biosynthesis pathways, decreases in carnitine and fatty acid oxidation pathways, and major impairment of the tricarboxylic acid (TCA) cycle and failure of anaplerosis. As a proof of principle, we focused on the TCA cycle, predicting that isocitrate dehydrogenase (IDH) activity would be altered in PAH, and then demonstrating increased IDH activity not only in cultured hPMVEC expressing mutant BMPR2 but also in the serum of PAH patients. These results suggest that widespread metabolic changes are an important part of PAH pathogenesis, and that simultaneous identification and targeting of the multiple involved pathways may be a more fruitful therapeutic approach than targeting of any one individual pathway.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic value in sarcoidosis if the obtained histological specimen is indicative of a non-caseating epithelioid-cell granuloma. However, EBUS-TBNA in sacoidosis sometimes affords solely cytological specimens. Objective: To investigate the relevance of EBUS-TBNA cytology specimens in diagnosing sarcoidosis. Design: The study population comprised 72 patients with sarcoidosis and 116 patients who had thoracic malignancies and intrathoracic lymphadenopathy but were eventually proven to be metastasis-free (controls). The EBUSTBNA samples obtained for these subjects were blindly evaluated for the presence of epithelioid cell clusters by 2 independent cytoscreeners and a pathologist. Results: Interobserver variability in the specimen grading was minimal. The sensitivity and specificity were 65.3% and 94.0%, respectively. The sensitivity was high, at 87.5%, for the combined cytological and histological examinations. Of 7 controls whose cytological specimens showed epithelioid cell clusters, 3 were also deemed positive for sarcoidosis on histological examination, which indicated that they had sarcoid reaction to cancer. Conclusions: Cytological evaluation of the EBUS-TBNA specimens had higher sensitivity than histological evaluation alone for intrathoracic lymphadenopathy due to sarcoidosis. It should be recognized, however, that up to 6% of patients with thoracic malignancy may have sarcoid reaction in non-metastatic lymph nodes. © Mattioli 1885.

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.

Yasuda T, Tada Y, Tanabe N, Tatsumi K, West J. Rho-kinase inhibition alleviates pulmonary hypertension in transgenic mice expressing a dominant-negative type II bone morphogenetic protein receptor gene. Am J Physiol Lung Cell Mol Physiol 301: L667-L674, 2011. First published August 19, 2011; doi:10.1152/ajplung.00423.2010.-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/Rhokinase 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: 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: There is evidence that phosphodiesterase type-5 is effective for the treatment of pulmonary arterial hypertension (PAH). Methods and Results: A phase III, multicenter, open-label clinical trial of sildenafil 20 mg t.i.d. was conducted in 21 Japanese patients with PAH to examine its efficacy, safety, and pharmacokinetics. The present trial consisted of a screening period and 12-week treatment. Patients who were enrolled in the present trial increased their 6-min walking distance of administration increased at week 12 by 84.2m from baseline. Hemodynamic parameters (eg, mean pulmonary artery pressure and pulmonary vascular resistance), Borg dyspnea scores, and plasma brain natriuretic peptide concentrations also improved compared to baseline. Most patients improved or sustained WHO functional class. Seven subjects, who were examined for the pharmacokinetics of sildefanil, showed relatively large interindividual variations in the C-max, AUC(0-8), C-ss,C-av, and C-trough of the drug. Any serious adverse events, severe adverse events, and deaths were not observed. Most of events of undeniable causality were mild or moderate in severity. Sildefanil was well tolerated by the subjects. Conclusions: Sildenafil 20 mg t.i.d. was effective and safe for Japanese patients with PAH. (Circ J 2011; 75: 677-682)

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.

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.

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.

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.

The long-acting beraprost preparation TRK-100STP is formulated to provide sustained release of an orally active prostacyclin derivative to maintain the optimal plasma concentration for a longer period of time compared with the currently used conventional beraprost sodium. In the present Study, we evaluated the efficacy of this newly developed formulation for pulmonary arterial hypertension (PAH). An open-label, 12-week multicenter clinical trial was performed in 46 patients with PAH. They were initially treated with 120 mu g of TRK-100STP divided into 60 mu g twice daily, followed by a stepwise increase to 360 jig given as 180 mu g twice daily. The 6-minute walking distance showed a significant increase by 33.4 +/- 66.0 m (95% confidence interval [CI], 13.4 to 53.5) from the baseline measurement. Mean Pulmonary artery pressure, total Pulmonary vascular resistance, and pulmonary vascular resistance decreased by -2.8 +/- 5.5 mmHg (95% CI, -4.6 to -1.0), by -0.92 +/- 2.63 mmHg.L(-1).min (95% CI, -1.78 to -0.05), and by -0.89 +/- 2.81 mmHg.L(-1).min (95% CI, -1.84 to 0.06), respectively, from the baseline measurements. A higher efficacy was observed in patients with a maximum tolerated dose of 360 mu g daily than those of 240 mu g daily or less. Treatment with TRK-100STP for a 12-week period improved the exercise capacity, mean Pulmonary artery pressure, and total pulmonary vascular resistance. TRK-100STP was effective for Japanese patients with PAH. (Int Heart J 2009; 50: 513-529)

Purpose: We evaluated right atrial (RA) contractility and right ventricular (RV) diastolic function in adult patients with acquired chronic pulmonary hypertension (PH) by pulsed Tissue Doppler Imaging (TDI) and assessed their relationship with serum brain natriuretic peptide (BNP). Materials and methods: Systolic myocardial wave (Sa), early diastolic myocardial wave (Ea), and late diastolic myocardial wave (Aa) at the tricuspid annulus were recorded in 77 consecutive patients with acquired PH. Early (E) RV inflow waves were recorded from 4-chamber views. RVAa was regarded as the parameter of RA contractility and RV E/Ea was taken as the parameter of RV diastolic function using TDI. Results: All subjects had elevated BNP (mean 188.9 +/- 244.0 pg/dl) and pulmonary arterial systolic pressure (PASP) estimated at 62.9 +/- 26.7 mm Hg. BNP levels were positively correlated with RV E/Ea, Aa and PASP (r=0.47, p<0.0001 and r= 0.35, p<0.01, respectively) but negatively with Aa (r=-0.29, p<0.05). Next, all predictor variables were used in a multiple regression model with serum BNP values as dependent variables, refined to include 3 predictors: RV E/Ea, Aa, and PASP, which were all found to influence serum BNP values ( pb0.0001) by the formula Y=34.1X1**-19.11X2**+2.95X3* (**p<0.001, *p<0.01) where Y= BNP, X1= E/Ea of RV, X2=Aa, and X3=PASP ( standard regression coefficients were 0.37, -0.34 and 0.34, respectively). Conclusion: Serum BNP correlates with RA contractility and RV diastolic dysfunction by RV TDI in adults with acquired PH. Increased BNP may be related to decreased RA systolic function and RV diastolic function in these patients. (C) 2008 Published by Elsevier Ireland Ltd.

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.

Purpose: We evaluated whether right ventricular (RV) diastolic dysfunction assessed by pulsed tissue Doppler imaging (TDI) predicts cardiac events in patients with chronic pulmonary thromboembolism (CPTE). Materials and methods: In 63 consecutive patients with CPTE, early diastolic myocardial velocity (Ea) at the tricuspid annulus by TDI and early diastolic tricuspid inflow (E) by conventional pulsed Doppler were obtained, and E/Ea was calculated as an indicator of RV diastolic dysfunction. Brain natriuretic peptide (BNP) and other echo parameters were also obtained. A cardiac event (rehospitalization caused by congestive heart failure or cardiac death) was the study endpoint. Incidence of cardiac events was determined over a 374 +/- 451 day follow-up period. Results: In the follow-up period twelve patients had cardiac events. We divided patients into group A with cardiac events and group B without events. E/Ea was significantly increased in group A as compared with group B (8.3 +/- 4.1 vs. 5.7 +/- 2.6, p < 0.01). BNP was higher in group A than group B (221 +/- 191 vs. 121 +/- 140 mg/dl, p < 0.05), and in addition E/Ea was significantly positively correlated with BNP (r=0.48, p < 0.001). A logistic regression model for predicting cardiac events was constructed and E/Ea was associated with an increased incidence of cardiac events (relative risk=1.33, 95% CI 1.00-1.75). Conclusion: Elevated values of E/Ea obtained by TDI may predict cardiac events in patients with CPTE. BNP may also be a significant predictor. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

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. 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. 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. 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.

As multi-slice CT develops, there are great expectations for an automatic and computer-support diagnoses. This research is on bronchial area which is composed of the bronchial wall regions and the air regions in the internal bronchial tube. Since to diagnose this is difficult, support diagnosis using CT images is desired. The thickness of bronchial wall changes as the airway of early lung cancer, bronchial asthma and the bronchial enhancing syndrome and others change into a malignant state. These changes are detected and the thickness of bronchial wall becomes important information. In this research, the extraction accuracy of the algorithm for bronchial wall evaluation is good. © 2009 SPIE.

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.