Possibility of using salivary ultra-weak chemiluminescence as a biomarker for feelings of anxiety in hospital settings.

The aim of this study was to assess whether a particular value of noninvasive salivary ultra-weak chemiluminescence (UCL) could be used as a biomarker of psychological stress. Our study covered two groups. Group 1 comprised six healthy volunteers who stayed in a hospital for one night and group 2 comprised 15 patients with lung cancer and 24 patients with respiratory diseases other than lung cancer who were in hospital for an extended stay. First, we evaluated the UCL of saliva from six healthy volunteers before and after one night in hospital. Immunoglobulin A (IgA) concentrations were also measured. The integrated intensity value of UCL was correlated with the IgA concentration (correlation coefficient 0.90). Second, in the case of a long hospital stay, we found that the maximum salivary UCL intensities were higher in patients with lung cancer than in those with respiratory diseases other than lung cancer or in 28 healthy controls. Copyright © 2016 John Wiley & Sons, Ltd.

Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis.

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone.

Efficacy of short-term prednisolone treatment in patients with chronic eosinophilic pneumonia.

In patients with chronic eosinophilic pneumonia (CEP), dramatic improvements are seen in response to corticosteroid therapy; however, relapse is common after treatment has ceased. The optimal duration of corticosteroid therapy remains unclear. In a randomised, open-label, parallel group study, eligible patients with CEP received oral prednisolone for either 3 months (3-month group) or 6 months (6-month group), followed by 2 years observation. All patients were treated with an initial dose of prednisolone of 0.5 mg·kg(-1)·day(-1), which was then tapered and discontinued at either 3 or 6 months. The primary end-point was relapse during the follow-up period. In the final analysis, there were 23 patients in the 3-month group and 21 patients in the 6-month group. All patients showed a good response to prednisolone treatment. There were 12 (52.1%) relapses in the 3-month group and 13 (61.9%) relapses in the 6-month group. No significant difference was found in the cumulative rate of relapse (p=0.56). All relapse cases showed improvement upon resumption of prednisolone treatment. No difference was observed in the rate of relapse between the 3- and 6-month prednisolone treatment groups for patients with CEP.

Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner.

IL-17A, IL-17F, and IL-25 belong to the IL-17 family of cytokines, and are well known to play important roles in the host defense against infection and inflammatory diseases. IL-17C, also a member of the IL-17 family, is highly expressed in the epithelium; however, the function and regulatory mechanism of IL-17C in airway epithelium remain poorly understood. In this study, we demonstrate that polyinosinic-polycytidylic acid (polyI:C), the ligand to Toll-like receptor 3, is a potent inducer of IL-17C mRNA and protein expression in primary normal human bronchial epithelial (NHBE) cells. IL-17C induction by polyI:C was both time dependent and dose dependent, and was attenuated by inhibitors of the Toll-IL-1 receptor domain-containing adaptor-inducing INF-ß (TRIF)-NF-κB pathway, Pepinh-TRIF, BAY11, NF-κB inhibitor III, and NF-κB p65 small interfering RNA, suggesting that IL-17C expression is induced by polyI:C via the Toll-like receptor 3-TRIF-NF-κB pathway. Both IL-17C and polyI:C increased the expression of antimicrobial peptides and proinflammatory cytokines, such as human ß-defensin (hBD) 2, colony-stimulating factor 3 (CSF3), and S100A12 in NHBE cells. Knockdown of IL-17 receptor (IL-17R) E, the specific receptor for IL-17C, using IL-17RE small interfering RNA, attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression, without any reduction of polyI:C-induced IL-17C expression, which suggest that IL-17C enhances hBD2, CSF, and S100A12 expression in an autocrine/paracrine manner in NHBE cells. Knockdown of IL-17C also decreased polyI:C-induced hBD2, CSF3, and S100A12 expression. Thus, our data demonstrate that IL-17C is an essential epithelial cell-derived cytokine that enhances mucosal host defense responses in a unique autocrine/paracrine manner in the airway epithelium.

Switching from salmeterol/fluticasone to formoterol/budesonide combinations improves peripheral airway/alveolar inflammation in asthma.

BACKGROUND: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) in a single inhaler is the mainstay of asthma management. We previously showed that switching from salmeterol/fluticasone combination (SFC) 50/250 µg bid to a fixed-dose formoterol/budesonide combination (FBC) 9/320 µg bid improved asthma control and pulmonary functions, but not fractional exhaled nitric oxide (FeNO), in patients with asthma not adequately controlled under the former treatment regimen. OBJECTIVE: To assess whether switching from SFC to FBC improves peripheral airway/alveolar inflammation in asthma (UMIN000009619). METHODS: Subjects included 66 patients with mild to moderate asthma receiving SFC 50/250 µg bid for more than 8 weeks. Patients were randomized into FBC 9/320 µg bid or continued the same dose of SFC for 12 weeks. Asthma Control Questionnaire, 5-item version (ACQ5) score, peak expiratory flow, spirometry, FeNO, alveolar NO concentration (CANO), and maximal NO flux in the conductive airways (J'awNO) were measured. RESULTS: Sixty-one patients completed the study. The proportion of patients with an improvement in ACQ5 was significantly higher in the FBC group than in the SFC group (51.6% vs 16.7%, respectively, p = 0.003). A significant decrease in CANO was observed in the FBC group (from 8.8 ± 9.2 ppb to 4.0 ± 2.6 ppb; p = 0.007) compared to the SFC group (from 7.4 ± 7.8 ppb to 6.4 ± 5.0 ppb; p = 0.266) although there was no significant difference in the changes in pulmonary functions between the 2 groups. Similar significant differences were found in the CANO corrected for the axial back diffusion of NO (FBC, from 6.5 ± 8.2 ppb to 2.3 ± 2.5 ppb; and SFC, from 4.3 ± 5.3 ppb to 3.9 ± 4.3 ppb). There was no difference in the changes in FeNO or J'awNO between the 2 groups. CONCLUSIONS: Switching therapy from SFC to FBC improves asthma control and peripheral airway/alveolar inflammation even though there is no improvement in pulmonary functions, and FeNO in asthmatic patients.

A study on the management of acute respiratory tract infection in adults.

Antimicrobials are commonly used to treat acute respiratory tract infection in adults. Furthermore, their overuse has raised concern. We conducted a field survey study that included 170 medical institutions from January 2008 to June 2010. The purpose of this study was to clarify the relationship between the rate of antimicrobial use and patient outcomes with each indication. The study included 1753 patients diagnosed with acute respiratory tract infection. Antimicrobials were used for treatment of 1420 of these patients, whereas 333 cases were not treated with antimicrobials. After 3 days of treatment, patients administered antimicrobials experienced a higher improvement rate than those who did not receive antimicrobial treatment (92.2% vs. 83.3%, p < 0.0001). However, after 7 days of treatment, the rates of improvement for patients in both groups were similar (95.0% and 93.4%, respectively, p = 0.2391). In addition, according to the criteria for the usage of antimicrobials described in the Japanese Respiratory Society guidelines for the management of respiratory tract infection in adults, the patients were classified into the 3 categories (6 indication factors for antimicrobial use): Grade 1, ≤ 2 factors; Grade 2, 3-4 factors; Grade 3, 5-6 factors). The indication factors considered were the following: 1) temperature; 2) purulent sputum or nasal discharge; 3) tonsillar enlargement and tonsillolith/white puss; 4) middle otitis/sinusitis; 5) inflammatory reaction; and 6) high-risk patients. The results indicate that the improvement observed after 3 days of treatment in Grade 2 and Grade 3 patients was significantly higher with antimicrobial treatment than without antimicrobial treatment. In conclusion, the administration of antimicrobials is not recommended in younger patients with no underlying disease. However, the use of antimicrobials is required in patients with a higher relative risk that corresponds to the presence of ≥ 3 of the 6 indication factors for antimicrobial use.

Multidetector-row computed tomography assessment of adding budesonide/formoterol to tiotropium in patients with chronic obstructive pulmonary disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT. METHODS: Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD. RESULTS: The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 ± 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment. CONCLUSION: MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.

Alveolar nitric oxide concentration reflects peripheral airway obstruction in stable asthma.

BACKGROUND AND OBJECTIVE: Increased fraction of exhaled nitric oxide (FeNO) has been shown to reflect airway inflammation in asthma. Central airway NO flux (J'awNO; nL/s) and peripheral airway/alveolar NO concentration (CANO; ppb) can be calculated separately. CANO has been reported to reflect small airway inflammation. The aim of the present study is to correlate CANO levels with clinical and physiological parameters in patients with stable asthma. METHODS: Seventy-three well-controlled asthmatics (mean age 61) were enrolled. Measurement of FeNO (at 50, 100, 150 and 200 mL/s) and pulmonary function test were performed. J'awNO(TMAD) and CANO(TMAD) were calculated and corrected by the trumpet shape of the airway tree and axial back-diffusion (TMAD). RESULTS: CANO(TMAD) was significantly correlated with forced expiratory flow between 25-75% of the forced vital capacity (FVC) (FEF(25 -75)), FEF(25 -75) percentage of the predicted value (%pred), forced expiratory flow at 50% of the FVC (FEF(50)) and FEF(50) %pred (R = -0.39 P = 0.002, R = -0.29 P = 0.02, R = -0.39 P = 0.001, R = -0.29 P = 0.02, respectively). CANO(TMAD) was positively correlated with age (R = -0.45 P = 0.0002) and weakly correlated with duration of asthma (R = -0.27 P = 0.03). Forced expiratory volume in 1 s/FVC was negatively correlated with CANO(TMAD), J'awNO(TMAD) and FeNO 50 mL/s. Among these, correlation between forced expiratory volume in 1 s/FVC and FeNO 50 mL/s was the strongest (R = -0.34 P = 0.004). CONCLUSIONS: CANO(TMAD) may be a more specific marker of peripheral airway obstruction than FeNO and J'awNO(TMAD) in stable asthma.

Mouse CD11bhigh lung dendritic cells have more potent capability to induce IgA than CD103+ lung dendritic cells in vitro.

Lung dendritic cells (LDCs) are primary antigen-presenting cells that develop IgA-producing plasma cells in the lung through class switch recombination (CSR) in naive B cells. Recently, the major LDC subsets were found to comprise CD103(-)CD11b(high) LDCs (CD11b(high) LDCs) and CD103(+)CD11b(low or negative) LDCs (CD103(+) LDCs), but their abilities to induce IgA production have not been defined. Under T cell-dependent (T-D) and T cell-independent (T-ID) conditions, we compared the abilities of these two LDC populations to induce IgA. CD11b(high) or CD103(+) LDCs obtained from BALB/c mice were cocultured with naive IgD(+) B cells in the presence of LPS, with or without anti-CD40 monoclonal antibody (mAb) (i.e., T-D and T-ID coculture conditions, respectively). Under both T-D and T-ID conditions, CD11b(high) LDCs induced significantly greater amounts of IgA production, together with a significantly higher mRNA expression of activation-induced cytidine deaminase, than did CD103(+) LDCs. However, the protein expression of a proliferation-inducing ligand, B cell-activating factor of the tumor necrosis family, or retinaldehyde dehydrogenase-1 did not differ between the two LDC subsets. CD11b(high) LDCs displayed a significantly greater capacity to secrete IL-6 and IL-10 in response to LPS, with or without anti-CD40 mAb. Moreover, the IgA production induced by CD11b(high) LDCs in T-D coculture was attenuated by neutralizing both IL-6 and IL-10. These findings suggest that, of the two major LDCs, CD11b(high) LDCs more efficiently induce IgA than do CD103(+) LDCs, possibly through their potent capacity to produce IgA-inducing cytokines.

Mouse lung CD103+ and CD11bhigh dendritic cells preferentially induce distinct CD4+ T-cell responses.

Mouse lung dendritic cells (LDCs) have been recently shown to contain two major subpopulations: CD103(+) CD11b(low or negative) (CD103(+) LDCs) and CD103(-) CD11b(high) LDCs (CD11b(high) LDCs). Although several studies have demonstrated functional differences between them, it is unclear whether the subpopulations induce distinct T helper (Th) cell responses. The present study was conducted to examine whether CD103(+) and CD11b(high) LDCs preferentially generate different Th responses. Naive DO11.10 CD4(+) T cells were primed with CD103(+) or CD11b(high) LDCs obtained from normal BALB/c mice. The primed CD4(+) T cells were restimulated, and their cytokine secretions were assessed. The expression of intracellular cytokines and the mRNA levels of chemokine receptors were also measured. We found that the CD4(+) T cells primed with CD103(+) LDCs secreted significantly larger amounts of IFN-γ and IL-17A, whereas those primed with CD11b(high) LDCs released significantly higher levels of IL-4, IL-6, and IL-10. Intracellular cytokine assay showed that CD103(+) LDCs induced greater frequencies of CD4(+) T cells producing IFN-γ and IL-17A, whereas CD11b(high) LDCs were more efficient at inducing CD4(+) T cells producing IL-4 and IL-10. The mRNA levels of CXCR3 and CCR5, which are expressed preferentially in Th1 cells, were significantly higher in CD4(+) T cells primed with CD103(+) LDCs. The mRNA levels of CXCR4 and CCR4, which are expressed primarily in Th2 cells, were significantly greater in those primed with CD11b(high) LDCs. These data suggest that mouse CD103(+) LDCs predominantly elicit Th1 and Th17 responses, whereas CD11b(high) LDCs primarily provoke a Th2 response under the steady state.

Idiopathic pleuroparenchymal fibroelastosis: consideration of a clinicopathological entity in a series of Japanese patients.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported group of disorders characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes. We report five Japanese cases fulfilling the criteria of IPPFE and address whether it should be considered a separate clinicopathologic entity. And this study was an attempt to identify features in common between IPPFE and previously described idiopathic upper lobe fibrosis (IPUF), allowing IPPFE to be considered as a distinct entity in our Japanese series. METHODS: Five consecutive cases of idiopathic interstitial lung disease confirmed as IPPFE by surgical lung biopsy were studied. RESULTS: There were four males and one female, aged 70±2.76 yr. No associated disorder or presumed cause was found in any case. Lung function tests found a restrictive ventilatory defect (4/5) and/or impairment of DLco (4/5). Chest X-ray showed marked apical pleural thickening in all cases. Computed tomography of the chest in all cases mainly showed intense pleural thickening and volume loss associated with evidence of fibrosis, predominantly in the upper lobes. In all cases in this study, markedly thickened visceral pleura and prominent subpleural fibrosis characterized by both elastic tissue and dense collagen were clearly shown. All cases were alive at the last follow-up, 17.6±13.59 months after diagnosis; however, all had deteriorated both clinically and radiologically. CONCLUSIONS: IPPFE deserves to be defined as a separate, original clinicopathologic entity owing to its uniformity and IPPFE has some features in common with previously described idiopathic upper lobe fibrosis (IPUF). Our limited experience with a cohort of 5 subjects suggests that IPPFE can be rapidly progressive.

Effect of exposure and sensitization to indoor allergens on asthma control level.

BACKGROUND: Reducing risk factors, such as exposure to allergens, and stepwise pharmacotherapy to achieve and maintain control of asthma are the mainstay of asthma care. The purpose of this study was to clarify the effect of exposure and sensitization to indoor allergens, including house dust mites, cats, and dogs, on the asthma control level. METHODS: Dust samples were collected from the mattresses of 101 adult asthma patient homes and the Dermatophagoides mite group 1 (Der 1), Fel d 1, and Can f 1 concentrations were measured using ELISA. Sensitization was determined by positive specific IgE antibodies. The Asthma Control Test (ACT), lowest peak expiratory flow (PEF) during 1 week expressed as a percentage of the highest PEF (Min%Max PEF), and spirometry were measured for the assessment of asthma control. Univariate and multivariate regression analyses were used to assess the relationships. RESULTS: Sixty-nine patients were exposed to high levels (>10µg/g dust for Der 1 and Can f 1 and >8µg/g dust for Fel d 1) of 1 or more allergens and 39 patients were sensitized to at least one allergen. Multivariate logistic regression analyses revealed that the FEV(1) (% of predicted value) was associated with low ACT scores (≤19) and that the number of highly exposed allergens and inhaled corticosteroid dose were associated with a low level of Min%Max PEF (<80%). CONCLUSIONS: The level of exposure to multiple indoor allergens, but not sensitization, is associated with the asthma control level determined by PEF variation.

Effect of switching from salmeterol/fluticasone to formoterol/ budesonide combinations in patients with uncontrolled asthma.

BACKGROUND: Combination therapy with an inhaled corticosteroid (ICS) and a long-acting ß(2)-agonist (LABA) in a single inhaler is the mainstay of asthma management and salmeterol/fluticasone combination (SFC) and fixed-dose formoterol/budesonide combination (FBC) are currently available in Japan; however, there is nothing to choose between the two. The purpose of this study was to clarify the effect of switching from SFC to FBC in patients with asthma not adequately controlled under the former treatment regimen. METHODS: This was a prospective, multicenter, open-label, uncontrolled longitudinal study in 87 adult patients with an Asthma Control Questionnaire, 5-item version (ACQ5) score of greater than 0.75 under treatment with SFC 50/250µg one inhalation twice daily (bid). SFC was switched to FBC 4.5/160µg two inhalations bid. Study outcomes included ACQ5 score, peak expiratory flow (PEF), FEV(1), and fractional exhaled nitric oxide (FeNO) at the end of treatment period. RESULTS: Eighty-three patients completed the study. ACQ5 scores improved and exceeded the clinically meaningful difference after 12 weeks of treatment and well-controlled asthma (ACQ5 score ≤0.75) was attained in 37 (44.6%) patients. Minimum and maximum PEF and FEV(1) values improved significantly, but not FeNO values, after switching from SFC to FBC. CONCLUSIONS: Switching ICS/LABA combination therapy is a useful option in the management of asthma that is not optimally controlled.

Inflammatory markers in active pulmonary tuberculosis: association with Th1/Th2 and Tc1/Tc2 balance.

OBJECTIVE: Few inflammatory markers closely reflect the activity of tuberculosis and only a few surrogate markers are available. The purpose of this study was to clarify the usefulness of measuring the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA), and the association between these markers and T-cell profiles. METHODS: One hundred one patients with active pulmonary tuberculosis were enrolled in this study. The associations between ESR, CRP, and SAA values on admission and microbiological and radiological findings and T-cell profiles were assessed. Th1/Th2 and Tc1/Tc2 were determined by analyzing intracellular cytokine staining for IFN-gamma and IL-4 in blood CD4+ and CD8+ T cells using flow cytometry after stimulation with PMA and ionomycin. RESULTS: There were significant correlations between ESR, CRP, and SAA, of which the correlation between CRP and SAA was strong (r = 0.88). CRP values significantly correlated with the sputum smear scale and the extent of lesions, and were higher in bilateral lesions. SAA values correlated with the sputum smear scale, whereas all markers were higher in patients with pleural effusion. Both CRP and SAA levels negatively correlated with the ratio of Th1/Th2. In contrast, ESR negatively correlated with the ratio of Tc1/Tc2. CONCLUSION: CRP reflected the disease severity before treatment. CRP and SAA values were associated with helper T-cell proportions whereas ESR was associated with cytotoxic T-cell proportions, both being type 2 predominant.

Enhanced anti-tumor immunity by superantigen-pulsed dendritic cells.

Staphylococcal enterotoxins A (SEA) and B (SEB) are classical models of superantigens (SAg), which induce potent T-cell-stimulating activity by forming complexes with MHC class II molecules on antigen-presenting cells. This large-scale activation of T-cells is accompanied by increased production of cytokines such as interferon-γ (IFN-γ). Additionally, as we previously reported, IFN-γ-producing CD8(+) T cells act as "helper cells," supporting the ability of dendritic cells to produce interleukin-12 (IL-12)p70. Here, we show that DC pulsed with SAg promote the enhancement of anti-tumor immunity. Murine bone marrow-derived dendritic cells (DC) were pulsed with OVA(257-264) (SIINFEKL), which is an H-2Kb target epitope of EG7 [ovalbumin (OVA)-expressing EL4] cell lines, in the presence of SEA and SEB and were subcutaneously injected into naïve C57BL/6 mice. SAg plus OVA(257-264)-pulsed DC vaccine strongly enhanced peptide-specific CD8(+) T cells exhibiting OVA(257-264)-specific cytotoxic activity and IFN-γ production, leading to the induction of protective immunity against EG7 tumors. Furthermore, cyclophosphamide (CY) added to SAg plus tumor-antigens (OVA(257-264), tumor lysate, or TRP-2) pulsed DC immunization markedly enhanced tumor-specific T-cell expansion and had a significant therapeutic effect against various tumors (EG7, 2LL, and B16). Superantigens are potential candidates for enhancing tumor immunity in DC vaccines.

Phase II study of erlotinib as third-line monotherapy in patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutations.

OBJECTIVE: There are few standard therapeutic options beyond second-line treatment. We aimed to evaluate the efficacy and safety of erlotinib monotherapy as third-line chemotherapy in patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutations. METHODS: In this phase II trial, patients who did not have epidermal growth factor receptor mutations and who had previously received two cytotoxic chemotherapy regimens containing platinum were treated with erlotinib (150 mg, per os) until disease progression or unacceptable toxicity. RESULTS: Twenty patients were eligible for the assessment of efficacy and safety. Three cases showed a partial response, and eight cases showed stable disease with an overall response rate of 15.0% (95% confidence interval: 5.2-36.0%) and a disease control rate of 55.0% (95% confidence interval: 34.2-74.2%). Median progression-free survival and overall survival time were 2.1 and 6.7 months, respectively. Although dose reduction was required in one patient because of skin toxicity, grade 3/4 toxicity or pulmonary disease was not observed. CONCLUSIONS: Erlotinib as third-line therapy showed an acceptable response rate, survival time and toxicity. It could be a potential third-line therapy for patients without epidermal growth factor receptor mutations.

Nonspecific interstitial pneumonia: prognostic significance of high-resolution computed tomography in 59 patients.

OBJECTIVE: To retrospectively analyze the prognostic implications of high-resolution computed tomography (HRCT) findings for patients with biopsy-proven nonspecific interstitial pneumonia (NSIP). METHODS: Fifty-nine patients with NSIP (25 idiopathic NSIP, 34 collagen-vascular disease-associated NSIP) were included. Two chest radiologists independently evaluated the extent, presence, and distribution of various HRCT findings. Cox hazards analysis was used to evaluate the relationship between HRCT findings and prognosis. RESULTS: The 5-year survival rate was 83% and the 10-year survival rate was 66%. Univariate analysis revealed that the extent of areas with ground-glass attenuation without traction bronchi-bronchiolectasis and that of airs-pace consolidation were associated with favorable outcome, whereas that of intralobular reticular opacities was associated with worse prognosis. Multivariate analysis showed that the extent of air-space consolidation was an independent factor of favorable outcome. CONCLUSION: In NSIP, the extent of areas with ground-glass attenuation without traction bronchi-bronchiolectasis, air-space consolidation, and intralobular reticular opacities correlate with survival.

Evaluation of different perfusion durations in direct hemoperfusion with polymyxin B-immobilized fiber column therapy for acute exacerbation of interstitial pneumonias.

BACKGROUND: Recently, the potential therapeutic effect of direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been reported for acute exacerbation of interstitial pneumonia (AE-IP), a highly morbid clinical event; however, there is no consensus on the appropriate procedure for PMX-DHP. We examined the appropriate perfusion duration of PMX-DHP for AE-IP. METHODS: AE-IP patients receiving PMX-DHP were divided into two groups: short-duration group (≤6 h) (n = 5) and long-duration group (12 h) (n = 12). RESULTS: ThePaO(2)/FiO(2) (P/F) ratio increased immediately after PMX-DHP in the two groups. In the long-duration group, the P/F ratio continued to increase over the following 7 days, while, in the short-duration group, the P/F ratio declined again 3 days after therapy. The survival rate 30 days after PMX-DHP was significantly higher in the long-duration group than in the short-duration group. CONCLUSIONS: A long perfusion duration of PMX-DHP is more efficacious for AE-IP than a short perfusion duration.

Colored 3-dimensional analyses of respiratory resistance and reactance in COPD and asthma.

BACKGROUND: The forced oscillation technique (FOT) is a noninvasive method with which to measure respiratory system resistance (Rrs) and reactance (Xrs) at a wide range of frequencies during breathing at rest in a short time. The purpose of this study was to assess the differences in Rrs and Xrs between patients with chronic obstructive pulmonary disease (COPD) and asthma using a new method of FOT with colored 3-dimensional visualization. METHODS: Fifty-one patients with stable COPD and 49 patients with controlled or partly controlled asthma were enrolled. Whole-breath or within-breath changes of Rrs and Xrs were measured and compared between the diseases. RESULTS: The colored 3-dimensional images clarified the complex oscillatory properties of the respiratory system. Whole-breath resistance (the difference in Rrs at 5 and 20 Hz) and reactance (Xrs at 5 Hz and resonant frequency), and within-breath changes in reactance (Xrs at 5 Hz and resonant frequency) discriminated between patients with COPD and asthma. In multivariate regression analyses, inspiratory-expiratory differences in Xrs at 5 Hz contributed significantly to the differentiation between COPD and asthma, independent of age, gender, body weight, and pulmonary function. CONCLUSION: This new method of FOT is useful in the differential diagnosis of COPD and asthma.

[A case of pulmonary alveolar proteinosis presenting with miniscule ground-glass opacity in the apex of the left lung].

A 66-year-old man was found to have a very small ground-glass opacity in the apex of the left lung. Because the ground-glass opacity had slightly enlarged after 2 years, video-assisted thoracic surgery (VATS) biopsy was performed. The histological findings showed the alveolar spaces to be filled with PAS-positive granular materials, so pulmonary alveolar proteinosis was diagnosed. Although his bronchoalveolar lavage fluid (BALF) did not have a milky appearance, his serum and BALF GM-CSF autoantibody and serum KL-6 levels were elevated. Asymptomatic pulmonary alveolar proteinosis may appear as very small ground-grass opacities.