Effects on asthma and induction of interleukin-8 caused by Asian dust particles collected in western Japan.

OBJECTIVE: Asian dust storms (ADS) contain various airborne particles that may augment airway inflammation by increasing the level of interleukin-8. The objective of the study was to investigate the association of exposure to an ADS with worsening of symptoms of adult asthma and the effect of ADS particles on interleukin-8 transcriptional activity. METHODS: The subjects were 112 patients with mild to moderate asthma who recorded scores for their daily upper and lower respiratory tract symptoms and measured morning peak expiratory flow (PEF) from March to May 2011. Interleukin-8 transcriptional activity was assessed in THP-G8 cells that were exposed to airborne particles collected during days of ADS exposure. RESULTS: Of the 112 patients, 31 had comorbid allergic rhinitis (AR) and/or chronic sinusitis (CS), and had worsened scores for upper respiratory tract symptoms on ADS days compared to non-ADS days. Scores for lower respiratory tract symptoms during ADS days were higher than non-ADS days in all patients. Three patients also had unscheduled hospital visits for exacerbation of asthma on ADS days. However, there was no significant difference in daily morning PEF between ADS and non-ADS days. Airborne particles collected on ADS days induced interleukin-8 transcriptional activity in THP-G8 cells compared to the original soil of the ADS. CONCLUSION: Exposure to an ADS aggravates upper and lower tract respiratory symptoms in patients with adult asthma. ADS airborne particles may increase airway inflammation through enhancement of interleukin-8 transcriptional activity.

Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma.

Epidermal growth factor receptor (EGFR) is commonly overexpressed in malignant pleural mesothelioma (MPM). Cetuximab is a chimeric mouse-human antibody targeted against EGFR and induces potent antibody-dependent cellular cytotoxicity (ADCC). The action of cetuximab against MPM cells has not been well studied. Therefore, in this study, we investigated the antitumor activity of cetuximab against MPM cell lines, particularly with respect to ADCC activity in vitro and in vivo. EGFR expression of MPM cells was measured by a quantitative flow cytometric analysis and immunohistochemistry. The effect of cetuximab on growth inhibition was assessed using a modified MTT assay. The ADCC activity was measured by a 4-h 51Cr release assay using fresh or IL-2-activated peripheral blood mononuclear cells. In vivo antitumor activity of cetuximab was evaluated using an orthotopic implantation mouse model. Cetuximab-mediated ADCC activity against MPM cells was observed at low concentration (0.25 mg/ml) and was enhanced by IL-2, whereas no direct effect on growth inhibition was detected. A logarithmic correlation was observed between the number of EGFRs on MPM cells and ADCC activity. Low EGFR expression on the MPM cells, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity. In the mouse model, cetuximab treatment with or without IL-2 significantly inhibited intrathoracic tumor growth and prolonged their survival. Our study shows that cetuximab has potent anti-MPM activity both in vitro and in vivo, mainly through the immunologic mechanism of ADCC. Cetuximab has the potential to be used as a novel therapy for MPM patients.

Influence of Asian Desert Dust on Lower Respiratory Tract Symptoms in Patients with Asthma over 4 Years.

The Asian Dust Storm (ADS) aggravates symptoms and pulmonary dysfunction in adult asthma patients. Our objective was to investigate the association of air pollutants and metals in desert dust with worsening of asthma symptoms during the ADS. A telephone survey was performed to investigate the upper and lower respiratory tract symptoms, ocular symptoms and skin symptoms of asthma patients during the ADS in March between 2007 and 2010. Four surveys were conducted in 46 patients. Two patients noted worsening of lower respiratory tract symptoms in all four surveys, as well as 2 patients in three surveys, 7 patients in two surveys, and 9 patients in one survey. There was no worsening of lower respiratory tract symptoms in 26 patients. In each patient, the influence of the ADS on lower respiratory tract symptoms varied between surveys. In 2010, the level of suspended particulate matter was highest in all four years, but the smallest number of patients noted worsening of lower respiratory tract symptoms. Among pollutants, only the maximum concentration of nitrogen dioxide during the ADS was significantly associated with the worsening of lower respiratory tract symptoms. The influence of the ADS on lower respiratory tract symptoms of adult asthma patients is variable.

Pollen augments the influence of desert dust on symptoms of adult asthma patients.

BACKGROUND: East Asian desert dust storms that occur during mainly spring are called Asian dust storms (ADS). Our objective was to study the association of pollen and ADS with symptoms of adult asthma patients in Japan. METHODS: We designed a telephone survey to investigate the upper and lower respiratory, ocular, and skin symptoms of asthma patients during ADS in February, March, and December on 2009. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: We surveyed 106 patients in February, 101 patients in March, and 103 patients in December. In February and March, Japanese cedar and/or cypress pollen was also in the atmosphere during ADS, but no pollen was identified during December survey. Worsening of upper or lower respiratory, ocular, or skin symptoms was noted by 20.8% of patients in February, 33.7% in March, and 16.5% in December. Worsening of symptoms was significantly more common in March than in February or December. Two patients needed emergency treatment for exacerbation during ADS in March, but no patient needed hospitalization in any period. There was no significant difference of the daily morning PEF/personal best PEF ratio between ADS days and control days. However, in patients with worsening of upper and/or lower respiratory tract symptoms, the daily morning PEF/personal best ratio was significantly associated with the atmospheric level of particulate matter, but not with levels of pollen or other air pollutants. CONCLUSIONS: Pollen augmented symptoms in adult asthma patients, but ADS on its own also were able to aggravate symptoms and pulmonary function.

Correlation between Asian dust storms and worsening asthma in Western Japan.

BACKGROUND: Severe wind storms during spring in East Asia, called Asian dust storms (ADS), have been assessed in the past for their effect on health in Asian countries. Our objective was to study the ADS association with asthma symptoms in adult patients in Japan. METHODS: We designed a telephone survey to assess ADS influence on upper and lower respiratory, ocular and cutaneous symptoms in 98 patients with adult asthma from April to May 2007. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: Worsening lower respiratory symptoms were noted by 22 of 98 patients during ADS in April, when Japanese cedar pollen levels also increased. During ADS in May, however, Japanese cedar and cypress pollen levels were not elevated, 11 patients had worsening of lower respiratory symptoms. None required emergency treatment for the exacerbation. Lower respiratory symptoms worsening most were cough and sputum; this was more common in patients with allergic rhinitis or atopy than in those without (P < 0.05). Min%Max differed significantly at 88.7 ± 6.6% during dust dispersion period, defined as the ADS day plus the next 6 days, versus 92.0 ± 5.3% during the 7-day period before a dust storm. CONCLUSIONS: We found that ADS aggravated lower respiratory symptoms in adult patients with asthma, but this influence was mild.

Asthma: Chronopharmacotherapy and the molecular clock.

Bronchial asthma is characterized by chronic airways inflammation and reversible airflow limitation. In patients with asthma, symptoms generally worsen during the early hours of the morning, and pulmonary function often deteriorates at the same time, suggesting a role for chronopharmacotherapy. Several drugs for asthma have been developed based on chronopharmacology. Most medications employed for the chronotherapy of asthma are administered once at night with the goal of preventing chronic airway inflammation or development of airflow limitation. In addition to bronchodilators, the inhaled glucocorticosteroid ciclesonide is now available with once-daily dosing, which also improves patients' compliance. Numerous investigations have demonstrated the usefulness of chronotherapy for asthma, especially for patients with nocturnal asthma. This review focuses on chronotherapy of asthma, and also provides a molecular biological explanation for the influence of asthma medications on the clock genes.

UFT plus vinorelbine in advanced non-small cell lung cancer: a phase I and an elderly patient-directed phase II study.

PURPOSE: The combination of tegafur-uracil (UFT) with vinorelbine has provided synergistic activity against non-small cell lung cancer (NSCLC) in experimental models. The recommended dose of UFT in combination with vinorelbine in NSCLC was determined in a phase I study. The phase II study evaluated efficacy and tolerability of this combination in elderly patients. METHODS: Vinorelbine was infused on days 1 and 8, and UFT was administered twice daily on days 2 to 6 and days 9 to 13 of a 3-week cycle. UFT and vinorelbine were increased during the phase I study from 400 to 600 mg/d and 20 to 25 mg/m(2), respectively, in 12 patients. In the phase II portion, previously untreated elderly patients were treated with 600 mg/d UFT and 20 mg/m(2) vinorelbine. RESULTS: At the dose level of 600 mg/d UFT and 25 mg/m(2) vinorelbine, dose-limiting toxicity of neutropenia or neutropenic fever was observed in two of three patients, determining the recommended dose of 600 mg/d UFT and 20 mg/m(2) vinorelbine. In 30 evaluable elderly patients of the phase II study, the response rate was 27% (8/30). The median survival and progression-free survival time was 11.8 (range 2.7-34.8) and 5.0 (range 0.5-32.5) months, respectively. Grade 3 or grade 4 neutropenia and grade 3 anemia occurred in 40% and 7% of phase II patients, respectively. Gastrointestinal toxicity was frequent but mild. As the most serious toxicity, pneumonitis was observed in three patients. CONCLUSION: This combination of UFT and vinorelbine is both feasible and active in the treatment of elderly patients with advanced NSCLC.

Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.

PURPOSE: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines. EXPERIMENTAL DESIGN: We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h (51)Cr release assay. Peripheral blood mononuclear cells, purified T cells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells. RESULTS: Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 microg/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients. CONCLUSIONS: These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.

Acute eosinophilic pneumonia caused by calcium stearate, an additive agent for an oral antihistaminic medication.

A 70-year-old man was admitted to our hospital because of dyspnea after taking an antihistaminic agent (homochlorcyclizine hydrochloride) for itching. Chest roentgenogram showed infiltration in the left lung field, and laboratory data revealed eosinophilia. Examination of the bronchoalveolar lavage fluid revealed an increased eosinophil count. A drug lymphocyte stimulation test was positive only for calcium stearate, an additive contained in the homochlorcyclizine hydrochloride tablet. The pulmonary infiltration and clinical symptoms subsided after withdrawal of all drugs and initiation of glucocorticoid therapy. Therefore, we concluded that this patient's pulmonary disease was caused by calcium stearate, an additive for an antihistaminic drug. An allergic reaction to a drug's additive material should be considered as a rare cause of drug-induced acute eosinophilic pneumonia.

Phase II study of weekly paclitaxel in patients with non-small cell lung cancer who have failed previous treatments.

OBJECTIVE: New effective therapy is desirable for patients with non-small cell lung cancer (NSCLC) who have failed previous treatments. Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for NSCLC in a second-line setting. METHODS: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and one or more prior therapies were enrolled. We administered weekly infusions of 80 mg/m2 paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, each patient was treated for a minimum of 4 cycles. RESULTS: Of 39 patients enrolled, 1 patient achieved complete response and 11 patients achieved partial response (response rate, 31%: 95% confidence interval, 17-48%). The median survival time was 43 weeks (range, 7-128 weeks). Grade 3 or 4 leukopenia occurred in only 7 patients (18%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2.26 and 5%, respectively). Although all patients recovered rapidly with corticosteroid treatment, drug-induced pneumonitis was observed in 3 patients (8%). CONCLUSION: Low-dose weekly paclitaxel is a promising therapy with high effectiveness for advanced NSCLC in patients with NSCLC who have failed previous treatments.

Cellular immune profile in patients with non-small cell lung cancer after weekly paclitaxel therapy.

Paclitaxel is a new agent for advanced non-small cell lung cancer (NSCLC). Weekly doses may enhance antitumor activity while minimizing toxicity, but little is known about immune recovery. Paclitaxel (80 mg/m2) was administered to 10 patients with NSCLC, weekly during 3-week cycles. Natural killer (NK) activity, CD3-CD16+CD56+ NK cells, and differential counts were monitored. NK activity appeared in all patients after treatment with paclitaxel therapy NK activity showed a 27 +/- 9% decrease (mean +/- SE) on protocol day 8 and a 37 +/- 7% decrease on day 15 (p < 0.05) recovering to 89 +/- 5% of baseline on day 29. With weekly paclitaxel, a decrease in NK cell function persisted through the first cycle but then recovered. Weekly paclitaxel may be less immunosuppressive than agents such as cisplatin.

Phase II trial of weekly paclitaxel in previously untreated advanced non-small-cell lung cancer.

OBJECTIVE: New effective therapy is desirable for outpatients with advanced non-small-cell lung cancer (NSCLC). Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for chemotherapy-naive NSCLC. METHODS: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and no prior therapy were enrolled. We administered weekly infusions of 80 mg/m(2) paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, we treated each patient for a minimum of four cycles. RESULTS: Of 35 patients enrolled, 17 patients achieved partial response, although no complete responses were observed (response rate 49%; 95% confidence interval 32-66%). The median survival time was 55 weeks (range 6-93 weeks). Grade 3 or 4 leukopenia occurred in only 1 patient (3%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2, 26 and 3%, respectively). Serious toxicity, observed in 2 patients (6%), was interstitial pneumonia, and 1 patient died from sequela. CONCLUSION: Low-dose weekly paclitaxel is a promising therapy for advanced NSCLC with high effectiveness and low toxicity.

Elevated urinary 8-hydroxydeoxyguanosine, a biomarker of oxidative stress, and lack of association with antioxidant vitamins in chronic obstructive pulmonary disease.

OBJECTIVE: The purpose of this study was to investigate whether patients with COPD are under oxidative stress and to elucidate the relationship between the level of oxidative stress and antioxidant vitamins. METHODOLOGY: Nineteen male patients with COPD and 13 age- matched male control subjects were studied. Urinary 8-hydroxydeoxyguanosine (8-OHdG) concentrations were determined using an enzyme-linked immunosorbent assay kit and corrected for creatinine concentrations. Serum levels of vitamin C, alpha-tocopherol, and beta-carotene were determined by high performance liquid chromatography. RESULTS: The median (interquartile range) 8-OHdG excretion was 8.1 ng/mg (5.3-10.9 ng/mg) in control subjects and 12.2 ng/mg (9.8-15.5 ng/mg) in COPD patients (P < 0.01). Urinary 8-OHdG levels were significantly elevated in ex-smokers in the COPD group compared with ex-smokers in the control group. Urinary 8-OHdG level was negatively correlated with FVC (r = -0.42, P = 0.016), FEV1 (r = -0.49, P = 0.0048), and oxygen tension in arterial blood (r = -0.41, P = 0.0005). No significant differences in antioxidant levels were demonstrated between the two groups. There were no significant correlations between urinary 8-OHdG excretion and the serum concentrations of antioxidant vitamins. CONCLUSION: The burden of oxidative stress was observed to increase in COPD patients as judged by urinary 8-OHdG. A depletion of antioxidant vitamins in serum was not essential for this phenomenon. Elevated urinary 8-OHdG level may not be attributable to smoking status or to antioxidant vitamins in COPD.

Reduction of correlation dimension in human respiration by inhaling a mixture gas of 5% carbon dioxide and 95% oxygen.

In order to investigate the effect of the respiratory control system on deterministic behavior in respiration, we used nonlinear analysis in subjects breathing a mixture gas of 5% carbon dioxide (CO2) and 95% oxygen (O2) (CO2-mixed gas). The respiratory movements during breathing air or CO2-mixed gas in eight healthy volunteers were measured. We estimated the values of the correlation dimension (D2) in respiratory movement using Grassberger-Procaccia algorithm. The respiratory movements during inhaling either air or CO2-mixed gas showed a nonlinear behavior using surrogate data method. The values of D2 in respiratory movement during inhaling CO2-mixed gas (1.77 +/- 0.17) were significantly smaller than those during inhaling air (2.52 +/- 0.60) (P < 0.05). This might be related to a prompt change in the nonlinear signal from the central respiratory chemical system.

[A case with advanced non-small cell lung cancer showing long-term partial response to weekly chemotherapy with paclitaxel in outpatient treatment].

A 57-year-old man who is a general physician was admitted to our hospital. A chest X-ray and CT showed a large pulmonary nodule in the right lower lobe. A percutaneous transthoracic fine needle aspiration biopsy under computed tomographic guidance revealed an advanced lung cancer (adenocarcinoma T4N3M1 Stage IV). He was treated with chemotherapy of weekly paclitaxel as an outpatient because he desired to continue working. After the chemotherapy, good partial response of all lesions was achieved. He is now working as a doctor every day. The regimen of weekly paclitaxel is useful and improves QOL of patients who desire to have outpatient treatment.

[Cavitary pulmonary metastasis from bladder cancer: a case report].

A 69 year-old [correction of 63] man who had had a radical cystectomy for bladder cancer was admitted to our hospital because of hemosputum and right femoral pain. His chest radiograph and computed tomogram showed a mass shadow with a cavity in the left upper lung field. Sputum cytology showed class V squamous cell carcinoma and a bone scintigram showed right femoral metastasis. Despite radiotherapy to the left upper lung and the right femur, the patient's condition worsened, and he died of respiratory failure after hospitalization for about 1 month. At autopsy, pathologic studies of lung cancer revealed mixed-type transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma. A diagnosis of metastatic lung cancer from bladder cancer was made. Cavitating pulmonary metastasis is uncommon. We report a rare case of pulmonary metastasis from bladder cancer, with mixed-type histopathology at both primary and metastatic sites.

[Cost-effectiveness of weekly paclitaxel for patients with advanced non-small cell lung cancer].

Paclitaxel is known to be efficacious in treating non-small cell lung cancer (NSCLC). We initiated a phase II trial of weekly paclitaxel (W-PTX) therapy in advanced NSCLC, and found that W-PTX was feasible for advanced NSCLC patients. We evaluated the cost of W-PTX from receipts and compared it with a standard cisplatin-vinorelbine (VC) regimen. The aim of this study was to assess the cost of W-PTX therapy. Previously untreated patients with stage IV NSCLC and patients with stage III B/IV NSCLC after at least one previous cisplatin based regimen were eligible if they had preserved organ function for treatment. Paclitaxel was administered at a dose of 80 mg/m2 for 3 consecutive weeks on a 4-week cycle. Patients received at least 1 course of W-PTX in our hospital and then, if possible, were treated on outpatients basis. All patients receiving the VC regimen were treated in the hospital. The mean cost of W-PTX for one month was approximately 699,000 yen per inpatient and 236,000 yen per outpatient. On the other hand, the mean cost of VC for one month was approximately 816,000 yen per patient. Although the cost of W-PTX for inpatient did not differ greatly from the cost of VC, the cost of W-PTX for outpatients was significantly lower than that of VC. The findings of this study suggest that W-PTX is feasible as a cost-effective chemotherapy for patients with advanced NSCLC.

Approximate entropy of human respiratory movement during eye-closed waking and different sleep stages.

STUDY OBJECTIVE: The breath-to-breath variability of respiratory parameters changes with sleep stage. This study investigates any alteration in the approximate entropy (ApEn) of respiratory movement as a gauge of complexity in respiration, by stage of consciousness, in the light of putative brain interactions. PARTICIPANTS: Eight healthy men, who were between the ages of 23 and 29 years, were investigated. MEASUREMENTS AND RESULTS: The signals of chest wall movement and EEG were recorded from 10:30 PM to 6:00 AM. After analog-to-digital conversion, the ApEn of respiratory movement (3 min) and EEG (20 s) were computed. Surrogate data were tested for nonlinearity in the original time series. The most impressive reduction in the ApEn of respiratory movement was associated with stage IV sleep, when the ApEn of the EEG was also statistically significantly decreased. A statistically significant linear relation is found between the ApEn of both variables. Surrogate data indicated that respiratory movement had nonlinear properties during all stages of consciousness that were investigated. CONCLUSION: Respiratory movement and EEG signals are more regular during stage IV sleep than during other stages of consciousness. The change in complexity described by the ApEn of respiration depends in part on the ApEn of the EEG, suggesting the involvement of nonlinear dynamic processes in the coordination between brain and lungs.

Daily expression of mRNAs for the mammalian Clock genes Per2 and clock in mouse suprachiasmatic nuclei and liver and human peripheral blood mononuclear cells.

The mammalian circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and in most peripheral tissues. Clock genes drive the biological clock. However, circadian expression variations of the human clock genes are still unclear. In this study, we analyzed the daily variations of mPer2 and mClock mRNA expression in both the mouse SCN and liver to evaluate the central and peripheral alterations in the rodent clock genes. We also examined whether there are the daily variations of the clock genes hPer2 and hClock in human peripheral blood mononuclear cells (PBMCs). The daily variation of mClock and mPer2 mRNA expression in mouse SCN and liver were determined at ZT2, ZT6, ZT10, ZT14, ZT18 or ZT22. We isolated PBMCs from 9 healthy volunteers at 9:00 and 21:00 and examined the expression of hPer2 and hClock mRNA by RT-PCR analysis. The animals exhibited a robust daily rhythm in the RNA levels of mPer2 in the SCN and liver (P<0.01, respectively). In humans, hPer2 mRNA expression also had daily variation, and the hPer2 mRNA levels at 9:00 were significantly larger than those at 21:00 (P<0.01). While, the Clock mRNA in both mice and humans exhibited no daily variation. These findings suggest that the variation in hPer2 mRNA expression may be useful for assessing human peripheral circadian systems.

Non-linear behaviour of respiratory movement in obstructive sleep apnoea syndrome.

In this study we investigated the non-linear properties of respiratory movement in patients with obstructive sleep apnoea syndrome (OSAS) during sleep without and with nasal continuous positive airway pressure (nCPAP). To calculate the correlation dimension (D2) in respiratory movement we applied an algorithm proposed by Grassberger and Procaccia. Non-linearity in respiratory movement was tested by comparing D2 for the original data with that for surrogate data. Respiratory movement was recorded from 10 patients with OSAS. D2 during both wakefulness with eyes closed and during sleep with nCPAP at 8 cm H2O could be computed in all subjects (2.50 +/- 0.69 and 1.68 +/- 0.17, respectively). On the other hand, D2 during sleep with apnoea could not be computed in patients with severe OSAS. These results indicate the abnormal properties of respiratory movement during apnoeic sleep in severe OSAS. Moreover, respiratory movement with nCPAP was shown to be non-linear deterministic behaviour in respiratory movement during sleep. Analysis of D2 for respiratory movement may be useful in adjusting (titrating) nCPAP and classifying severity in OSAS.