巽 浩一郎

OBJECTIVE: Beraprost was developed as the first oral prostacyclin analog to treat patients with pulmonary arterial hypertension (PAH). Although this drug demonstrates improvements in the patient's exercise capacity and symptoms, it carries a weak recommendation in the PAH evidence-based treatment algorithm due to a lack of durability of effects. However, this therapy remains a major treatment method in Japan due to its availability and inexpensive cost. The purpose of this study was to elucidate whether this drug exhibits durable effects on sustained overall survival. METHODS: A comparison of survival benefits was completed among patients undergoing treatment with beraprost (n=35) or conventional therapy (n=44). In addition, the estimated survival calculated using the equation developed by the National Institutes of Health Registry was used for the analysis. RESULTS: Although no significant differences were observed between the two groups using the Kaplan-Meier survival curve, a statistical difference was observed between the patients receiving high-dose beraprost therapy (>120 μg) and those receiving conventional therapy (5- and 10-year survival: 71.1% and 49.4% vs. 37.7% and 21.2%, respectively; p=0.0466). Moreover, the cumulative survival rates in the patients receiving beraprost were slightly better than the estimated survival rates. In the PAH patients with connective tissue diseases, a tendency towards better survival outcomes was observed in the group treated with beraprost. CONCLUSION: This study suggests the survival benefits of high-dose beraprost therapy for patients with PAH. The retrospective nature of this study, however, makes it difficult to conclude definitively that beraprost exerts significant beneficial effects on survival.

BACKGROUND: Pentraxin3 (PTX3) is a protein, which has multifaceted effects on innate immunity, angiogenesis, and vascular remodeling then could be a disease marker of acute myocardial infarction, heart failure, vasculitis. In addition, PTX3 has been recognized as a biomarker for pulmonary arterial hypertension, however whether it is the case in chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. Therefore, we investigated whether PTX3 would be a useful biomarker for detecting CTEPH with respect to differentiation from stable pulmonary thromboembolism (PTE), in comparison to other biomarkers. METHODS: Plasma PTX3 and brain natriuretic peptide (BNP) levels were measured in 70 patients with CTEPH at their first diagnostic right heart catheterization (CTEPH group) and in 20 patients with clinically stable PTE more than three months after the acute episode (control group). The levels of plasma C-reactive protein (CRP) and heart-type fatty acid-binding protein (H-FABP) were also analyzed to compare the diagnostic ability of these biomarkers. RESULTS: The mean level of PTX3 (ng/mL) was significantly higher in the CTEPH group than in the control group (5.51±4.53 versus 2.01±0.96, respectively), and PTX3 levels had mild negative correlation with cardiac output. BNP levels were also higher in the CTEPH group and better correlated with pulmonary hemodynamics than PTX3. However, a receiver operating characteristic (ROC) curve showed PTX3 levels were better for detecting CTEPH, and could detect CTEPH patients with less severe pulmonary hemodynamics and low plasma BNP levels. There was no significant increase in CRP and H-FABP levels in the CTEPH patients. CONCLUSIONS: Plasma PTX3 level was the most sensitive biomarker of CTEPH. Although plasma PTX3 levels did not correlate with the severity of the pulmonary hemodynamics compared to BNP, high levels in clinically stable patients following PTE should prompt a further work-up for CTEPH, which may lead to an early diagnosis.

OBJECTIVE: We aimed to investigate the incidence and clinical characteristics of nontuberculous mycobacterial (NTM) pulmonary disease as a complication of chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: We conducted a retrospective study of 10 cases (5.6%) complicated by NTM pulmonary disease among 180 CTEPH patients. RESULTS: Isolated species of avium (n=5), kansasii (n=2), intracellulare (n=1), abscessus (n=1) and fortuitum (n=1) were detected. NTM-infected lesions were observed in 33 of 180 (18.3%) lung segments obtained from the 10 patients, and complete obstruction due to chronic pulmonary thromboembolism was detected in 65 of the 180 segmental pulmonary arteries (36.1%). The NTM-infected segments in the CTEPH patients were significantly associated with obstructed rather than unobstructed pulmonary artery segments [25 of 65 (38.5%) vs. 8 of 115 (6.9%), p<0.01]. Cavitary, nodular, ectatic and ground-glass lesions were seen in 14, 22, seven and four of the 180 segments, respectively. Thirteen of the 14 cavitary (92.9%) lesions were located in non-perfused segments. Five patients with NTM disease underwent pulmonary endarterectomy (PEA). Of the 18 assessable NTM-infected segments in six NTM-treated patients, 17 were located in non-perfused segments and one was located in a previously perfused segment. All NTM-infected segments improved among three segments reperfused with PEA. In contrast, only eight (57.1%) NTM-infected segments improved among 14 continuously non-perfused segments. A lower body mass index was found to be a significant risk factor for NTM disease in the CTEPH patients. CONCLUSION: This is the first report to document NTM-disease complications in patients with CTEPH. Reperfusion in cases of NTM lesions may improve the response to NTM drug therapy.

BACKGROUND: It is unclear whether abnormalities of coagulation or fibrinolysis are associated with disease progression of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to investigate the association of these factors with the severity and prognosis of CTEPH. METHODS AND RESULTS: Between 1986 and 2011, plasma fibrinogen and plasminogen were measured in 89 of 106 consecutive patients with inoperable CTEPH (17 men; mean age, 55.9±14.1 years old; mean pulmonary arterial pressure, 44.0±12.4 mmHg) and the association of level with severity and prognosis were also examined. Seventeen patients had high fibrinogen and low plasminogen (medians, ≥291 mg/dl and <101%, respectively). These patients had significantly lower cardiac index (2.26±0.68 vs. 2.70±0.57 L·min(-1)·m(-2), P=0.007), higher pulmonary vascular resistance (PVR; 13.29±7.54 vs. 9.15±4.14 Wood units, P=0.003), and poor survival (5-year survival, 35.3% vs. 88.0%, P<0.001) compared to the other 72 patients. Additional analysis showed significantly poor survival in these patients compared with the other patients who did not have modern therapy. On multivariate analysis plasma fibrinogen, plasminogen and PVR were independent predictors of survival in medically treated patients. CONCLUSIONS: High plasma fibrinogen and low plasminogen are associated with poor survival in CTEPH patients without modern therapy.

BACKGROUND: We aimed to study whether pulmonary arterial distensibility (PAD) correlates with hemodynamic parameters in chronic thromboembolic pulmonary hypertension (CTEPH) using electrocardiogram (ECG)-gated 320-slice multidetector computed tomography (MDCT). METHODS AND FINDINGS: ECG-gated 320-slice MDCT and right heart catheterization (RHC) was performed in 53 subjects (60.6±11.4 years old; 37 females) with CTEPH. We retrospectively measured the minimum and maximum values of the cross sectional area (CSA) of the main pulmonary artery (mainPA), right pulmonary artery (rtPA), and left pulmonary artery (ltPA) during one heartbeat. PAD was calculated using the following formula: PAD = [(CSAmaximum-CSAminimum)/CSAmaximum]×100(%). The correlation between hemodynamic parameters and PAD was assessed. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were 40.8±8.7 mmHg and 8.3±3.0 wood units, respectively. PAD values were as follows: mainPA (14.0±5.0%), rtPA (12.8±5.6%), and ltPA (9.7±4.6%). Good correlations existed between mainPAD, with mPAP (r = -0.594, p<0.001) and PVR (r = -0.659, p<0.001). The correlation coefficients between rtPAD and ltPAD with pulmonary hemodynamics were all lower or equal than for mainPAD. CONCLUSIONS: PAD measured using ECG-gated 320-slice MDCT correlates with pulmonary hemodynamics in subjects with CTEPH. The mainPA is suitable for PAD measurement.

A 48-year-old woman was diagnosed with idiopathic pulmonary arterial hypertension (PAH) and administered PAH-specific therapies, including bosentan. Four years after the initiation of treatment with bosentan, liver dysfunction appeared, and ambrisentan was substituted for bosentan. One-and-a half years later, a second episode of liver dysfunction occurred. The pathological findings of a liver biopsy specimen were not definitive, although drug-induced hepatotoxicity caused by ambrisentan was considered. However, the patient's liver dysfunction did not improve even after the discontinuation of ambrisentan. Finally, we diagnosed her with autoimmune hepatitis (AIH). Providing careful observation with a suspicion of AIH is important when treating PAH patients with autoantibodies.

A 47-year-old woman with idiopathic pulmonary arterial hypertension (IPAH) was referred to our hospital for treatment of an ovarian tumor. Although chest contrast-enhanced CT scans obtained on admission revealed pulmonary arterial thrombosis, she was diagnosed with IPAH with central pulmonary thrombosis based on a normal perfusion lung scan. We initiated upfront triple combination therapy with pulmonary vasodilators. After one month of the therapy, the patient's pulmonary hemodynamics improved. Gynecological surgery was performed under general anesthesia without any perioperative complications. Providing careful intensive management of patients with severe PAH can reduce the perioperative risks of non-cardiac and non-obstetric surgery.

OBJECTIVE: Laboratory-based polysomnography (PSG) is the gold standard for diagnosing obstructive sleep apnea-hypopnea syndrome (OSAHS), but it is expensive and requires overnight hospitalization. Recently, a sheet-shaped breath detection monitor, the SD-101, has been developed, and several reports have so far demonstrated the screening accuracy of this device. The aim of this study was to assess the accuracy and the uncertainty of this device. METHODS: A total of 101 suspected OSAHS patients underwent simultaneous examinations with PSG and the SD-101. RESULTS: There was a statistically significant relationship between the respiratory disturbance index (RDI) by the SD-101 and the apnea-hypopnea index (AHI) by PSG. At an RDI cutoff of 14 episodes per hour, the sensitivity and specificity to detect an AHI ≥20 episodes per hour were 90.2% and 90.0%, respectively. To reduce the influence of sleep efficiency, the time in bed (TIB) obtained from PSG, instead of the total seep time (TST), was used to calculate the AHI from the PSG data. There was also a statistically significant relationship between the RDI and AHI for the TIB. Moreover, it was suggested that arousal index and TIB were likely associated with false-negative and/or false-positive results. CONCLUSION: Although the present study demonstrated a close relationship between the RDI and the AHI, use of the SD-101 to examine symptomatic OSAHS patients should be performed with a full understanding of its incapability to detect the sleep state, including arousal reaction and the existence of false respiratory events caused by body movements.

A 17-year-old Japanese girl visited our hospital for an evaluation of exertional dyspnea. A diagnosis of pulmonary arterial hypertension (PAH) was confirmed based on the findings of right heart catheterization. Detailed questioning revealed a family history of hereditary hemorrhagic telangiectasia (HHT), and a genetic mutation analysis disclosed a mutation in the activin receptor-like kinase 1 gene (ACVRL1). The patient was finally diagnosed with HHT according to the Curaçao diagnostic criteria eight years after the diagnosis of PAH. This case supports previous reports indicating that signs of PAH can be the first manifestation of disease in ACVRL1 mutation carriers.

Cancer chemotherapy, including molecular targeted therapy, has major limitations because it does not kill all the cancer cells; the residual cells survive until they acquire chemoresistance. In the present study, the combined effects of metformin and gefitinib were examined in vivo in a mouse xenograft model, inoculated with a human lung adenocarcinoma cell line that possesses an activating epidermal growth factor receptor mutation. The mechanism of the interaction was further elucidated in vitro. Metformin did not suppress the growth of already established tumors, nor did metformin augment tumor shrinkage by gefitinib. However, metformin significantly suppressed the regrowth of the tumor after effective treatment with gefitinib, suggesting the specific effect of metformin on the residual cells. Cytotoxicity of metformin was characterized by the absence of apoptosis induction and unremarkable cell cycle shift in vitro. The residual cell population after treatment with gefitinib was characterized by enriched cells with high expression of CD133 and CD24. Metformin was still effective on this specific cell population. Targeting residual cells after chemotherapy may represent an effective novel strategy for the treatment of cancer. Elucidating the mechanism of metformin cytotoxicity provides insights into future development of anticancer therapeutics.

OBJECTIVES: Structural and functional changes in pulmonary vessels are prevalent at the initial stages of chronic obstructive pulmonary disease (COPD). These vascular alterations can be assessed using cross-sectional area (CSA) of small pulmonary vessels. However, neither in non-COPD smokers nor in COPD patients it has been defined whether the structural changes of pulmonary vessels detected by paired inspiratory and expiratory CT scans are associated with emphysematous changes. We quantified the CSA and low attenuation area (LAA) and evaluated the changes in these parameters in the inspiratory and expiratory phases. MATERIALS AND METHODS: Fifty consecutive non-COPD smokers and COPD patients were subjected to multi detector-row CT and the percentage of vessels with a CSA less than 5 mm(2) as well as the percentage LAA for total lung area (%CSA<5, %LAA, respectively) were calculated. RESULTS: The %CSA<5 correlated negatively with %LAA. The %CSA<5 was lower in COPD patients with emphysema as compared with non-COPD smokers and COPD patients with or without mild emphysema. In addition, the %CSA<5 was lower in the no/mild emphysema subgroup as compared with non-COPD smokers. The respiratory phase change of %CSA<5 in COPD patients was greater than that in non-COPD smokers. CONCLUSION: The percentage of small pulmonary vessels decreased as emphysematous changes increase, and this decrease was observed even in patients with no/mild emphysema. Furthermore, respiratory phase changes in CSA were higher in COPD patients than in non-COPD smokers.

OBJECTIVES: To pathologically distinguish mesothelioma from lung carcinoma, particularly adenocarcinoma. METHODS: We conducted immunohistochemical analyses on clinical specimens, including 26 cases of mesothelioma, 28 cases of lung adenocarcinoma, and 33 cases of lung squamous cell carcinoma. RESULTS: We found that CD90 expression was useful in making a differential diagnosis between epithelioid mesothelioma and lung adenocarcinoma, whereas sarcomatoid mesothelioma and lung carcinoma specimens, irrespective of the histologic types, were negative in general. The sensitivity and specificity of CD90 expression in epithelioid mesothelioma and lung adenocarcinoma were comparable to those of well-established markers used for the differential diagnosis. CONCLUSIONS: These data collectively indicate that CD90 is a novel diagnostic marker that contributes to a diagnosis of epithelioid mesothelioma.

BACKGROUND: Cigarette smoking is the primary causative factor for lung carcinoma and respiratory bronchiolitis (RB), particularly RB-associated interstitial lung disease (RB-ILD). However, the link between lung cancer and RB/RB-ILD remains undefined. We examined whether pathological fibrosis lesions exist simultaneously in patients with lung carcinoma because the fibrous lesions could be precancerous. METHODS: Clinical, radiological, and pathological features were consecutively evaluated in 67 current smokers, 22 ex-smokers, and 35 nonsmokers who underwent surgical resection for lung carcinoma. The presence of interstitial changes was evaluated by high-resolution computed tomography (HRCT). The pathological examination focused on RB, RB with fibrosis, and coexistent interstitial changes. RESULTS: RB with fibrosis was observed in 13/67 current smokers with centrilobular nodular and/or patchy ground-glass opacities patterns or emphysema on HRCT. RB without fibrosis was observed in 12/67 current smokers with a centrilobular pattern, emphysema, or a normal pattern on HRCT. The Brinkman smoking index was significantly higher in the RB with fibrosis group (1278±133) than in the RB without fibrosis group (791±131). No RB with/without fibrosis features were noted in nonsmokers or ex-smokers. Squamous cell carcinoma was observed in 11/13 patients with RB with fibrosis, whereas adenocarcinoma was observed in 7/12 patients with RB without fibrosis. CONCLUSIONS: Squamous cell carcinoma located in peripheral areas was primarily observed in patients with RB with fibrosis, whereas adenocarcinoma was primarily observed in patients with RB without fibrosis. Interstitial fibrosis with RB caused by continuous heavy cigarette smoking may increase the risk of developing squamous cell carcinoma.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by non-resolving thromboembolisms of the pulmonary arteries. In Japan, in contrast to Western countries, CTEPH is more prevalent in women. A Japanese multicenter study reported that a form of CTEPH unrelated to deep vein thrombosis is associated with HLA-B⁎5201, suggesting that this form of CTEPH may be associated with vasculopathy. CTEPH can be cured by pulmonary endarterectomy, provided that the thrombi are surgically accessible; thus, early diagnosis is important, and all patients with exertional dyspnea should be evaluated for pulmonary hypertension. Ventilation/perfusion scans provide an excellent non-invasive means to distinguish CTEPH from pulmonary arterial hypertension. Similarly, computed tomographic pulmonary angiograms allow for the detection of thrombi and evaluation of pulmonary hemodynamics in a minimally invasive manner. Importantly, the absence of subpleural perfusion on pulmonary angiograms can suggest the presence of small vessel disease. Small vessel disease might be involved in the pathogenesis of CTEPH, and its detection is essential in preventing operative death. Although no modern therapies for pulmonary arterial hypertension have been approved for treatment of CTEPH, a recent randomized control trial of riociguat in patients with CTEPH demonstrated that riociguat significantly improved 6-min walking distance. Further investigations into treatments that target endothelial dysfunction and hyperproliferative CTEPH cells are needed. Recently, balloon pulmonary angioplasty has emerged as a promising treatment modality in Japan. A specialized medical team, including at least one expert surgeon, should make decisions regarding patients' candidacy for pulmonary endarterectomy and/or balloon pulmonary angioplasty.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) has been considered to be caused by single or recurrent pulmonary embolism (PE) arising from deep vein thrombosis (DVT). In Japan, female predominance and association of HLA-B*5201 with CTEPH unrelated to DVT were reported. In acute PE residual proximal DVT is associated with larger obstruction of pulmonary arteries. However, it remains uncertain whether DVT and the type of DVT are associated with clinical phenotype of CTEPH. PURPOSE: To clarify the association of DVT and DVT type with clinical phenotype of CTEPH. METHODS: Among 98 consecutive patients who underwent 16 or 64-slice multidetector CT angiography and indirect venography, 91 patients (66% female, age: 56±3 years) with adequate images were enrolled. The associations of DVT and DVT type with pulmonary hemodynamics, CT obstruction index and other clinical parameters were analyzed. RESULTS: DVT was found in 45 patients (49.5%) (distal: 12, proximal: 33), and was significantly associated with male gender and recurrent type. Furthermore, it was more frequent in HLA-B*5201-negative, and d-dimer positive patients. Compared with distal DVT, proximal DVT was associated with male gender, larger CT obstruction index (48.6±13.0 vs. 34.1±13.2%, p=0.004), and higher mean pulmonary arterial pressure (48.2±12.8 vs. 40.8±7.9 mmHg, p=0.03). Proximal DVT was significantly associated with the central type of CTEPH only in HLA-B*5201-negative patients. CONCLUSIONS: The existence and type of DVT were associated with clinical phenotype of CTEPH, and proximal DVT might contribute to the central type of CTEPH in only HLA-B*5201-negative patients.

BACKGROUND: Right-sided heart catheterization (RHC) and pulmonary digital subtraction angiography (PDSA) are the standard methods used in diagnosing suspected or defi nite chronic thromboembolic pulmonary hypertension (CTEPH). We studied the ability of 320-slice CT imaging to detect simultaneously chronic thromboembolic fi ndings in the pulmonary arteries and pulmonary hemodynamics based on the curvature of the interventricular septum (IVS) in CTEPH . METHODS: Forty-four patients with high clinical suspicion of CTEPH underwent RHC, PDSA, and enhanced double-volume retrospective ECG-gated 320-slice CT scan. We measured the sensitivity and specificity of CT imaging to detect thrombi in the pulmonary arteries compared with PDSA. We also compared IVS bowing (expressed as curvature) measured on the short-axis cine heart image with pulmonary arterial pressure (PAP) obtained by RHC. RESULTS: Compared with PDSA, the sensitivity and specificity of CT imaging to detect chronic thromboembolic findings were 97.0% and 97.1% at the main/lobar level and 85.8% and 94.6% at the segmental level, respectively. The correlation coefficients of IVS curvature with systolic PAP and mean PAP were 2 0.79 ( P , .001) and 2 0.86 ( P , .001), respectively. CONCLUSIONS: The use of 320-slice CT imaging allows for less invasive and simultaneous detection of thrombi and evaluation of pulmonary hemodynamics for the diagnostic work-up of CTEPH.

気管支喘息と慢性閉塞性肺疾患(COPD)の発症機序,治療法は異なるが,呼吸器の慢性疾患のなかでいずれもその罹患率は高く,近年,両疾患の合併例も増加している.本症例は,53年間喫煙歴のある75歳女性で,2年前より体動時の息切れを自覚し,当院を精査のため受診.閉塞性換気障害と肺気腫病変を認めたため,喫煙歴よりCOPDと診断し,チオトロピウム投与を開始した.その後,症状は改善するも残存しており,朝方の喘鳴や狭窄音を聴取することから,COPD合併喘息と診断した.ブデソニド/ホルモテロール配合剤(BUD/FM)を追加投与後,ピークフロー日内変動,喀痰や咳嗽などの自覚症状の改善を認め,多少,労作時の息切れは自覚するも経過は良好となった.COPDと喘息は主体となる炎症細胞,病態の違いから治療薬の選択順序は異なるが,喘息症状がみられる場合には抗炎症効果を期待できるBUD/FM投与も考慮すべきと考えられた.(著者抄録)

It is generally accepted that chronic thromboembolic pulmonary hypertension (CTEPH) results from pulmonary emboli originating from deep vein thrombosis. However, this consensus opinion has been challenged, and the concept that some aspects of CTEPH exacerbation might result from a small-vessel disease leading to secondary thrombosis has been suggested. In addition to the effect of recurrent thrombo-embolism, a number of lines of clinical evidence indicate that progressive worsening is contributed to by remodeling in the small pulmonary arteries. Histopathological studies of the microvascular changes in CTEPH have identified vascular lesions similar to those seen in idiopathic pulmonary arterial hypertension (IPAH). Especially in in vitro and ex vivo experiments, pulmonary artery endothelial cells (ECs) in pulmonary hypertensive diseases are suggested to exhibit an unusual hyperproliferative potential with decreased susceptibility to apoptosis, indicating that dysfunctional ECs may contribute to the progression of the diseases. Although the degree and mechanisms of EC dysfunction as a contributor to CTEPH are unclear, EC dysfunction may occur in small arteries. Indeed, the cells stimulated by the microenvironment created by the unresolved clot may release substances that induce EC dysfunction. The EC dysfunctions in CTEPH may lead to disorders of the anti-coagulation properties in ECs and may result in additional clots in situ. Moreover, these may lead to the progression, not only of distal thrombus, but also of proximal clotting. This article reviews the pathobiological concepts of CTEPH and explains a crosstalk between EC dysfunction and in situ thrombi which may contribute to the vascular lesions of CTEPH.

A 50-year-old man with chronic renal failure (hemodialysis treatment) and interstitial pneumonia (IP) was referred to our hospital for exacerbation of IP. We immediately administered a mechanical ventilation, broad spectrum antibiotics, steroid pulse therapy, and endoxan pulse therapy in the intensive care unit, but alveolar opacities became worse. Subsequently, an intrapulmonary cavity appeared in the left middle lung field on the chest X-ray and we also administered amphotericin B. However he died of tension pneumothorax on the tenth day of hospitalization. In an autopsy the rupture of the intrapulmonary cavity of the left S3 region was detected and we diagnosed as invasive pulmonary mucormycosis by Grocott stain of the cavitary lesion. We report a rare case that complicated by fatal tension pneumothorax during treatment with a ventilator in invasive pulmonary mucormycosis and review the literature.

Interferons (IFNs) have been tested for the therapeutic effects in various types of malignancy, but mechanisms of the anti-tumors effects and the differential biological activities among IFN members are dependent on respective cell types. In this study, we examined growth inhibitory activities of type I and III IFNs on 5 kinds of human mesothelioma cells bearing wild-type p53 gene, and showed that type I IFNs but not type III IFNs decreased the cell viabilities. Moreover, growth inhibitory activities and up-regulated expression levels of the major histocompatibility complexes class I antigens were greater with IFN-β than with IFN-α treatments. Cell cycle analyses demonstrated that type I IFNs increased S- and G2/M-phase populations, and subsequently sub-G1-phase fractions. The cell cycle changes were also greater with IFN-β than IFN-α treatments, and these data collectively showed that IFN-β had stronger biological activities than IFN-α in mesothelioma. Type I IFNs-treated cells increased p53 expression and the phosphorylation levels, and activated apoptotic pathways. A combinatory use of IFN-β and cisplatin or pemetrexed, both of which are the current first-line chemotherapeutic agents for mesothelioma, produced synergistic anti-tumor effects, which were also evidenced by increased sub-G1-phase fractions. These data demonstrated firstly to our knowledge that IFN-β produced synergistic anti-tumor effects with cisplatin or pemetrexed on mesothelioma through up-regulated p53 expression.

We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

A 52-year-old Japanese woman presented with optical symptoms, including left-sided myodesopsia, blurred vision, narrowed visual field, and diminished visual acuity. Ocular evaluation revealed a metastatic tumor in the choroid. Further examinations identified pulmonary adenocarcinoma as the primary tumor. Because an epidermal growth factor receptor gene (EGFR) mutation was detected in a biopsy specimen, gefitinib treatment was initiated. Dramatic responses were obtained in the primary tumor and metastatic foci. Optical symptoms improved and remained stable for 5 months during the treatment, until relapse. This report demonstrates that gefitinib is effective for choroidal metastasis of pulmonary adenocarcinoma harboring an EGFR mutation.

OBJECTIVE: Methotrexate (MTX) is a cytotoxic agent that is commonly employed as an alternative to corticosteroids to treat sarcoidosis, although the proper use and efficacy of MTX as a single agent remain unclear. METHODS: The clinical records of patients newly diagnosed with sarcoidosis who were admitted to our institution between 2000 and 2009 were reviewed. Among these patients, 26 received 7.5 mg of MTX per week as a single agent, and the independent effects of MTX were analyzed. RESULTS: Six of the 26 patients (23%) exhibited an improvement of sarcoidosis-related lesions. The skin lesions demonstrated a relatively higher response rate (37%) than the pulmonary lesions (9%). Ten of the 26 patients (39%) experienced adverse effects, mostly mild hepatotoxicity. No severe adverse effects, including irreversible hepatotoxicity, were observed. CONCLUSION: Although the efficacy of low-dose MTX monotherapy for sarcoidosis in this study was not high (23%), some patients exhibited definite improvements, and the drug proved to be safe, suggesting its possible benefits as a single agent for treating sarcoidosis.

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.

BACKGROUND: The surgical indication for chronic thromboembolic pulmonary hypertension (CTEPH) has been modified due to recognition of peripheral type CTEPH and changes in surgical methods and skill. Bosentan and sildenafil are used as modern oral therapy (mod Tx) in patients with inoperable CTEPH, although it remains unknown whether they have positive effects on survival. METHODS AND RESULTS: A total of 202 patients were diagnosed with CTEPH at Chiba University Hospital between 1986 and 2010, 100 of whom underwent pulmonary endarterectomy. Seven medically treated patients with pulmonary vascular resistance (PVR) ≤ 300 dyn·s·cm(-5) were regarded as having mild disease. Survival rate was stratified by date of diagnosis (group 1, 1986-1998; group 2, 1999-2004; group 3, 2005-2010), and prognostic factors in the remaining 95 medically treated patients were investigated. Group 3 included the most patients treated with mod Tx (group 1, 9.1%; group 2, 24.2%; group 3, 65.0%) and had significantly better survival than either group 1 or 2 (5-year survival: group 1, 54.6%; group 2, 69.7%; group 3, 87.3%). Patients receiving mod Tx had significantly better survival than those not on mod Tx (5-year survival: 88.9% vs. 60.2%). Multivariate analysis showed that mod Tx, lower PVR, and lack of comorbidity were significant predictors of better outcome. CONCLUSIONS: Medically treated patients with CTEPH had a better survival rate, and the use of mod Tx contributed to improved survival.

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.

INTRODUCTION: Genetic characterization of malignant mesothelioma shows a homozygous deletion of the INK4A/ARF locus, which results in inactivation of the p53 pathways. METHODS: We examined possible antitumor effects of adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55) on mesothelioma and investigated combinatory actions with the first-line chemotherapeutic agents. RESULTS: Ad-delE1B55 produced cytotoxicity on mesothelioma cells, which was associated with p53 phosphorylation, pRb dephosphorylation, and cleavage of caspases. Ad-delE1B55-infected cells displayed hyperploidy at the cell-cycle analysis and showed enlarged nuclear configurations. Combination of Ad-delE1B55 plus cisplatin or pemetrexed produced antitumor effects in vitro. Furthermore, Ad-delE1B55 and cisplatin showed combinatory effects in an orthotopic animal model. CONCLUSIONS: Cell death caused by Ad-delE1B55 is attributable to cell-cycle arrest at M-phase checkpoint followed by activated apoptotic pathways, and combination of the first-line chemotherapeutic agents and the oncolytic adenovirus is a potential therapeutic for mesothelioma.

Lung-specific toxicity induced by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer (NSCLC) has emerged as a critical side-effect. Although the clinical features of the pulmonary side-effects of TKIs have been characterized, the details of the molecular mechanisms in the development of this lung-specific toxicity remain to be elucidated. EGFR-dependent epithelial regeneration and restoration plays an important role in the recovery process from lung injury. The lung comprises a unique environment where epithelial cells are exposed to internal agents in the systemic circulation and to airborne particles through the mouth and nose. This unique environment may also be associated with the development of lung-specific toxicity induced by EGFR-TKIs. Therefore, the aim of this review was to provide further insight into the molecular mechanisms of lung-specific toxicity in the context of treatment with EGFR-TKIs.

Proteomics is one of the strategies to evaluate molecular mechanisms underlying obstructive sleep apnea syndrome (OSAS). To examine the pathophysiological significance of plasma proteomics in OSAS, the plasma samples from severe OSAS patients (n= 6) with obese (BMI &gt; 30) and non-OSAS patients (n= 6) with non-obese (BMI &lt; 30) were subjected to proteomic profiling. Many proteins regarding inflammation and immune response, including complement proteins, two acute-phase reactants ceruloplasmin and serum amyloid P-component, were found to be highly expressed in severe OSAS patients. Protein changes responsible for immune modulation and inflammation may be a feature of OSAS patients.

The immunogenicity of pandemic influenza A H1N1 virus (A/H1pdm) vaccine might be modified by prior seasonal trivalent influenza vaccine (sTIV) administration. We conducted a retrospective analysis of immunogenicity of 243 health care workers (number of sTIV-positive [sTIV(+)] subjects, 216; number of sTIV(-) subjects, 27) by hemagglutination inhibition. There was no significant difference in the ratios of antibody titers of ≥40 (41.2% versus 48.1%; P = 0.49) and fold increases in geometric mean titer (3.8 versus 4.5; P = 0.37). sTIV injected 7 to 10 days prior to A/H1pdm vaccine administration did not interfere with the immunogenicity of the latter.

BACKGROUND: It has been generally accepted that chronic thromboembolic pulmonary hypertension (CTEPH) results from pulmonary embolism arising from deep vein thrombosis. An unresolved question regarding the etiology of CTEPH is why pulmonary thromboemboli are stable and resistant to effective anticoagulation. Recently non-resolving pulmonary thromboemboli in CTEPH have been shown to include myofibroblasts. This study investigates the cellular characteristics of myofibroblasts included in the organized thrombotic tissues of CTEPH. METHODS: Organized thrombotic tissues of patients with CTEPH were obtained following pulmonary endarterectomy. We isolated cells from endarterectomized tissue from patients with CTEPH and identified them as endothelial-like cells and myofibroblast-like cells. RESULTS: Myofibroblast-like cells were characterized as hyperproliferative, anchorage-independent, invasive and serum-independent. CONCLUSIONS: Here we report the presence of active myofibroblast-like cells in endarterectomized tissue of CTEPH. We suggest that the formation of myofibroblasts with a high growth potential in the organized thrombotic tissues may be an important event in the pathobiology of this disease.

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.