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Kenichi Takeda,1 Yuji Kawasaki,2 Kazumasa Yoshida,3 Yoji Nishida,3 Tomoya Harada,1 Kosuke Yamaguchi,2 Shizuka Ito,1 Kiyoshi Hashimoto,1 Shingo Matsumoto,1 Akira Yamasaki,1 Tadashi Igishi,1 Eiji Shimizu1 1Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Japan; 2Department of Regional Medicine, Faculty of Medicine, Tottori University, Yonago, Japan; 3Department of Rehabilitation Medicine, Yoka Hospital, Yabu, Japan Background: Upper-extremity exercise is for pulmonary rehabilitation. The 6-minute pegboard and ring test (6PBRT) was developed to evaluate arm exercise capacity in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to characterize the 6PBRT and evaluate its relationship with upper-extremity activities of daily living (ADLs) in COPD patients. Methods: Twenty outpatients with mild to very severe COPD underwent the 6PBRT and spirometry, and their maximal inspiratory and expiratory pressures and grip strength were measured. For the 6PBRT, subjects were asked to move as many rings as possible in 6 minutes, and the score was the number of moved rings during the 6-minute period. Upper-extremity ADLs were evaluated with the upper extremity activities subdomain of the modified Pulmonary Functional Status and Dyspnea Questionnaire. Upper-extremity ADLs were also measured objectively by using a wrist accelerometer every day for 1 week. Results: There was a positive correlation between 6PBRT score and inspiratory capacity (r = 0.71, P < 0.001), inspiratory capacity/total lung capacity predicted (r = 0.68, P < 0.01), and forced vial capacity (r = 0.57, P < 0.01). There was also a positive correlation between 6PBRT score and accelerometer count (r = 0.54, P < 0.05) and a negative correlation between 6PBRT score and arm activity score (ρ = -0.49, P < 0.05). Conclusion: The 6PBRT may be a predictive test to maintain and improve upper-extremity ADL during pulmonary rehabilitation in patients with COPD. Keywords: pulmonary rehabilitation, inspiratory capacity, COPD, wrist accelerometer, modified Pulmonary Functional Status and Dyspnea Questionnaire

Immune checkpoint inhibitors (ICIs), including nivolumab, have exhibited substantial benefits in the treatment of several types of cancers. However, treatment with ICIs is often accompanied by immune-related adverse events (irAEs), and a clear understanding of the precise indications and management of irAEs is important for harnessing the full potential of these agents. While skin- or gastrointestinal-associated irAEs have been relatively well studied, there are few reports regarding nivolumab-induced cholangitis. We retrospectively reviewed data from patients with advanced or recurrent non-small cell lung cancer who were treated with nivolumab between December 2015 and December 2018 at Tottori University in Japan. Among the 59 patients, we identified four patients who experienced nivolumab-induced cholangitis. Of these four patients, stable disease (SD) was observed in two patients (50%), while partial response (PR) was achieved in two patients (50%) under nivolumab treatment. Patients were treated with corticosteroid alone (n=2) or in combination with mycophenolate mofetil (MMF) (n=2); these treatments resulted in improvements in nivolumab-induced cholangitis in three patients. In conclusion, the present retrospective study identified four cases of nivolumab-induced cholangitis. The combination of corticosteroid and MMF was effective in two cases with grade 4 nivolumab-induced cholangitis. Further reports are needed to establish the optimal management of patients with this irAE., (Copyright: © Izumi et al.)

Background: Weight loss in patients with cancer is caused by cancer cachexia and chemotherapy-induced nausea and vomiting (CINV). Recent developments in antiemetic drugs have substantially improved CINV, but nutritional intervention did not improve body weight. This study aimed to investigate the effects of nutrition intervention with appropriate antiemetic treatment in patients with non-small-cell lung cancer during chemotherapy., Methods: Patients received individualized nutrition counseling by a registered dietitian and were provided with oral supplements for 90 days. Body weight and other parameters were measured at baseline and after 90-day intervention. To evaluate this nutrition intervention, patients were also retrospectively set as control, and then body weight change was compared with inverse probability of treatment weights (IPTW) analysis., Results: Ten patients received individualized nutrition counseling and were provided with oral supplements for 90 days. Of them, 7 patients consumed nutritional supplements, and the mean intake was 130 kcal/day. After 90-day intervention, the patients did not show significant weight and BMI loss during the course of cytotoxic chemotherapy. A total of 38 patients were retrospectively enrolled as controls. The number of the patients who gain the body weight after 90 days in the study cohort was significantly larger than that in the retrospective controls with the IPTW analysis (Odds Ratio (OR) = 8.4; 95% Confidence Interval (CI): 1.6-42; P = 0.01)., Conclusion: Early intensive nutrition intervention with appropriate antiemetic treatment prevents weight loss. Nutrition interventions might be also beneficial for quality of life, treatment response and survival.

Nitrogen-containing bisphosphonates (N-BPs), which are usually used for the treatment of advanced cancer with bone metastasis, occasionally cause fever following the first administration. However, it is unclear as to how the development of fever following the first administration of N-BP is associated with clinical outcome. The aim of the present study was to determine the prognostic value of the development of fever following the first administration of N-BP in advanced non-small cell lung cancer patients with bone metastases. The present study reviewed the data of 46 patients with advanced non-small cell lung cancer who were administered zoledronate (ZOL), an N-BP, for bone metastasis, between March 2009 and March 2011 in the Department of Medical Respirology at Tottori University Hospital. Clinicopathological factors were evaluated using univariate and multivariate analyses, and these factors were compared between the fever and non-fever groups. Of the 46 patients, 15 (32.6%) developed fever following the first administration of ZOL. No significant differences were observed in the clinicopathological characteristics between the two groups. The overall survival in the fever group was significantly longer compared with the non-fever group (median survival time: 33.4 vs. 15.7 months, P=0.04), and the development of fever following the first ZOL administration was independently associated with longer overall survival. The development of fever following the first ZOL administration was an independent prognostic factor in advanced non-small cell lung cancer patients with bone metastases. Thus, ZOL-associated fever may be a predictive factor for an undefined, survival-promoting effect of ZOL.

Background: DNA double-strand breaks (DSBs) are the most cytotoxic form of DNA damage and are induced by ionizing radiation and specific chemotherapeutic agents, such as topoisomerase inhibitors. Cancer cells acquire resistance to such therapies by repairing DNA DSBs. A major pathway for the repair of DNA DSBs is non-homologous end-joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-PK on the chemosensitization of non-small cell lung carcinoma (NSCLC) A549 cells., Methods: The combined effects of chemotherapeutic agents and NU7441 were evaluated by isobologram analysis using Cell Counting Kit-8. DNA DSBs were assessed by immunofluorescence assay. Apoptosis was examined by flow cytometry using an Annexin V apoptosis kit. Activation of DNA-PK was assayed by western blotting., Results: The combination of NU7441 and topoisomerase inhibitors such as amrubicin and irinotecan had a synergistic effect on cell proliferation in A549 cells. NU7441 increased 53BP1 foci and apoptosis induced by topoisomerase inhibitors and decreased phospho-DNA-dependent protein kinase, catalytic subunit (pDNA-PKcs) (S2056) protein expression caused by topoisomerase inhibitors. Interestingly, mitotic inhibitors such as pacritaxel did not cause the pDNA-PKcs (S2056) protein expression and the combination of NU7441 and pacritaxel had an only additive effect., Conclusion: NU7441 inhibited the growth of NSCLC cells and enhanced the chemosensitization to topoisomerase inhibitors by blocking DNA repair. A combination of NU7441 and topoisomerase inhibitor may be a promising treatment for NSCLC.

Background: Chronic obstructive pulmonary disease is a smoking-related disease, and is categorized into the emphysema and airway dominant phenotypes. We examined the relationship between emphysematous changes and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma., Patients and Methods: The medical records for 250 patients with lung adenocarcinoma were retrospectively reviewed. All patients were categorized into the emphysema or non-emphysema group., Results: Wild-type EGFR was detected in 136 (54%) and mutant EGFR in 48 (19%). Emphysematous changes were observed in 87 (36%) patients. EGFR mutation was highly frequent in the non-emphysema group (p=0.0014). Multivariate logistic regression analysis showed that emphysema was an independent risk factor for reduced frequency of EGFR mutation (Odds Ratio=3.47, p=0.005)., Conclusion: Our data showed a relationship between emphysematous changes and EGFR mutation status. There might be mutually exclusive genetic risk factors for carcinogenesis and development of emphysematous changes., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease caused by mutations in SLC34A2 and characterized by intra-alveolar accumulation of microliths. We diagnosed a case of PAM in a 27-year-old Japanese female and identified a novel mutation in SLC34A2 (c.1390 G>C [G464R] in exon 12).

Background: Asian dust (AD) has become a major health concern. The concentration of AD is typically expressed in particulate matter less than 10 μm (PM10) and 2.5 μm (PM2.5). However, PM10 and PM2.5 consist of various substances besides AD. Light detection and ranging (LIDAR) systems can selectively measure the quantity of AD particles to distinguish non-spherical airborne particles from spherical airborne particles. The objective of this study was to investigate the relationship between pulmonary function in adult asthma patients and AD using LIDAR data., Methods: Subjects were 231 adult asthma patients who had their morning peak expiratory flow (PEF) measured from March to May 2012. A linear mixed model was used to estimate the association of PEF with sand dust particles detected by LIDAR., Results: Increases in the interquartile range of AD particles (0.018 km(-1)) led to changes in PEF of -0.42 L/min (95% confidence interval [CI], -0.85 to 0.01). An increase of 11.8 μg/m(3) in suspended particulate matter and 6.9 μg/m(3) in PM2.5 led to decreases of -0.17 L/min (-0.53 to 0.21) and 0.03 L/min (-0.35 to 0.42), respectively. A heavy AD day was defined as a day with a level of AD particles >0.032 km(-1), which was the average plus one standard deviation during the study period, and six heavy AD days were identified. Change in PEF after a heavy AD day was -0.97 L/min (-1.90 to -0.04)., Conclusions: Heavy exposure to AD particles was significantly associated with decreased pulmonary function in adult asthma patients., (Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Light detection and ranging (LIDAR) can estimate daily volumes of sand dust particles from the East Asian desert to Japan. The objective of this study was to investigate the relationship between sand dust particles and pulmonary function, and respiratory symptoms in adult patients with asthma. One hundred thirty-seven patients were included in the study. From March 2013 to May 2013, the patients measured their morning peak expiratory flow (PEF) and kept daily lower respiratory symptom diaries. A linear mixed model was used to estimate the correlation of the median daily levels of sand dust particles, symptoms scores, and PEF. A heavy sand dust day was defined as an hourly concentration of sand dust particles of >0.1 km(-1). By this criterion, there were 8 heavy sand dust days during the study period. Elevated sand dust particles levels were significantly associated with the symptom score (0.04; 95% confidence interval (CI); 0.03, 0.05), and this increase persisted for 5 days. There was no significant association between PEF and heavy dust exposure (0.01 L/min; 95% CI, -0.62, 0.11). The present study found that sand dust particles were significantly associated with worsened lower respiratory tract symptoms in adult patients with asthma, but not with pulmonary function.

Background: Clarithromycin is a macrolide antibiotic that possesses anti-inflammatory and immunomodulatory properties. Although recent data suggests that macrolide antibiotics enhance Pseudomonas aeruginosa clearance from the lung, involving natural killer (NK) T cells in this process by activating the NKG2D-NKG2D ligand system, the precise underlying mechanism is still unclear. In this study, we examined the effect of clarithromycin on a potent NKG2D ligand, UL16-binding protein 2 (ULBP2), in the lung and its shedding mechanism., Methods: The gene expressions of ULBP2 and the shredder proteinases of ULBP2, a disintegrin and metalloproteinase domain 10 (ADAM10) and ADAM17, were measured using real-time PCR. The cell surface ULBP2 expression was measured by flow cytometry. The amount of solubilized ULBP2 (sULBP2) was measured using an ELISA. The activity of ADAM17 was examined by measurement of fluorescence intensity from the fluorescence resonance energy transfer peptide substrate cleaved by ADAM17., Results: Clarithromycin significantly induced transcription of ULBP2 and ADAM17 in both A549 and LCSC #2 cells, which endogenously express minimal and abundant levels of ULBP2, respectively. However, there was no significant change on transcription of ADAM10. The same tendency was observed when LCSC #2 cells were treated with tumor necrosis factoralpha processing inhibitor-2 to inhibit ADAM17 activity. The amount of sULBP2 was significantly decreased in both A549 and LCSC #2 cells by treatment with clarithromycin. Finally, clarithromycin significantly inhibited the activity of ADAM17 in LCSC #2 cells., Conclusion: These findings suggest that clarithromycin induces ULBP2 expression and reduces the amount of sULBP2, by possibly inhibiting the activity of the potent ULBP2-shedding enzyme ADAM17. Because these changes in ULBP2 and sULBP2 levels could activate NKT cells, this finding might indicate a novel mechanism by which clarithromycin improves the clearance of P. aeruginosa in chronic respiratory diseases.

Background: Performing multiple blood culture sets simultaneously is a standard blood culture methodology, although it is often difficult to distinguish true bacteremia from contamination when only one of several blood culture sets is positive. This study clarified the relationship between the number of positive blood culture sets and clinical significance in patients with positive blood culture., Methods: Patients aged 18 years and over with at least 1 positive blood culture were enrolled. Positive blood culture episodes were categorized from clinical records as true bacteremia, contamination, or unknown clinical significance. The associations among episodes of true bacteremia, isolated bacteria, the number of positive blood culture sets from among the performed sets, and the clinical background of patients were analyzed., Results: Among a total of 407 episodes, 262, 67 and 78 were true bacteremia, contamination and unknown clinical significance, respectively. The positive predictive values (PPVs) of 1 out of 1, 1 out of 2 and 2 out of 2 positive sets in cases of Staphylococcus aureus, were 81.3%, 50% and 100% respectively; those in cases of coagulase-negative Staphylococci were 20.5%, 10.8% and 63.5%, respectively. Almost all cases of Escherichia coli, Pseudomonas aeruginosa, Klebsiella species and Candida species were true bacteremia. The probability of true bacteremia was strongly associated with recent surgery in multivariate analysis (P < 0.05)., Conclusion: The probability of true bacteremia based on the number of positive culture sets from among the performed sets varies by microorganism. Therefore, PPVs calculated using this method may help physicians distinguish true bacteremia from contamination.

UL16-binding protein 2 (ULBP2) is one of the ligands for NKG2D (NKG2DL). ULBP2 expression is induced in transformed cells and is recognized by immune effector cells via the activating NKG2D immunoreceptor. Soluble forms of NKG2DL have been reported in the serum of patients with several types of cancer. The present study investigated the diagnostic and prognostic significance of serum-soluble ULBP2 (sULBP2) in lung cancer patients. We used flow cytometry to evaluate the surface expression of NKG2DL by various lung cancer cells, while sULBP2 was measured using our original ELISA. In addition, the immunological effect of sULBP2 on peripheral blood mononuclear cells (PBMC) was examined by the (51) Cr release assay. We found that ULBP2 was highly expressed and that the sULBP2 level was elevated in supernatants of cultured non-small-cell lung cancer (NSCLC) cells as well as in the serum of NSCLC patients. ULBP2 levels were especially high in squamous cell carcinoma (SQ) patients. Clinical stage IIIB and IV NSCLC patients with a sULBP2 level ≥ 8.7 pg/mL showed significantly shorter survival than patients with sULBP2 <8.7 pg/mL. In multivariate analysis, a sULBP2 level ≥ 8.7 pg/mL (hazard ratio [HR], 2.13; P = 0.038) and clinical stage IV (HR, 2.65; P = 0.019) were independent determinants of a poor outcome. As a possible mechanism, we demonstrated that sULBP2 directly suppresses the cytolytic activity of PBMC. In conclusion, ULBP2 is the most significant NKG2DL for lung cancer, and sULBP2 is useful in the diagnosis of SQ and as a prognostic indicator for patients with advanced NSCLC., (© 2012 Japanese Cancer Association.)

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.

Epidermal growth factor receptor (EGFR) mutation is the best marker of sensitivity to the EGFR tyrosine kinase inhibitor gefitinib, but a marker for the anti-EGFR antibody cetuximab has not been identified in lung cancer. The present study investigated markers for sensitivity to cetuximab. Sensitivity to cetuximab and gefitinib was compared with EGFR expression, EGFR and KRAS mutation, and EGFR gene copy numbers in lung cancer cell lines. We also studied the effect of these agents on the activation of EGFR, ERK, AKT, and STAT3 in cetuximab-sensitive and -resistant cell lines. We found one cetuximab-sensitive cell line with EGFR mutation among 19 lung cancer cell lines. Analysis of molecules downstream from EGFR revealed that AKT phosphorylation was suppressed in this cell line. Augmentation of AKT phosphorylation by transfection of a plasmid induced resistance to cetuximab. Acquisition of cetuximab resistance was associated with AKT activation in this cell line, while pharmacological inhibition of AKT markedly enhanced the growth inhibitory effect of cetuximab. Dephosphorylation of AKT in association with EGFR mutation is a candidate marker for sensitivity to cetuximab, and combined use of an AKT pathway inhibitor with cetuximab could be a novel therapeutic strategy for lung cancer.

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.

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.

Objective: Health-care associated pneumonia (HCAP) is a new category of pneumonia. We investigated differences of epidemiology, pathogens, and outcomes between HCAP patients in large hospitals and those in small hospitals., Methods: This was a retrospective observational study of patients hospitalized with HCAP from December 2009 to March 2010. HCAP was defined according to ATS/IDSA criteria. A large hospital was defined as ≥ 200 beds and a small hospital was <200 beds., Results: Of 117 patients, 61 patients were admitted to large hospitals and 56 patients were admitted to small hospitals. There was a significant difference of HCAP diagnostic criteria between the two groups. The A-DROP severity class was worse in the large hospital group than the small hospital group (P<0.05). Respiratory failure and disturbance of consciousness were more frequent in the large hospital group (P<0.05). The mortality rate was 8.2% in the large hospital group versus 1.8% in the small hospital group. Patients in the very severe A-DROP class had a high mortality rate of 33% in both groups., Conclusion: Patients with severe HCAP were more likely to be admitted to large hospitals. Patients in the very severe A-DROP class should receive intensive antibiotic therapy, but not all patients need broad-spectrum therapy.

Extreme caution should be taken to avoid uncontrollable bleeding in treating hypervascular tumors via bronchoscope. We report two cases of endobronchial metastasis of renal cell carcinoma treated with bronchial artery embolization (BAE) before endoscopic treatments. The intraluminal lesions were removed swiftly and safely. Although arterial embolization is not always efficacious in cases of tracheal lesions, BAE is effective for tumors located in the carina, bilateral main bronchus or intermediate bronchus. The addition of BAE before endoscopic tumor removal should be considered a treatment option in patients suffering from airway obstructions due to hypervascular tumors such as renal cell carcinoma.

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death and loss of disability-adjusted life-years. However, many COPD patients are not diagnosed because of underrecognition or underdiagnosis of this disease among many patients and physicians. One possible reason is underrecognition of spirometry. In this study, we examined the prevalence of airflow limitation and underlying disease in patients with airflow limitation., Methodology: From April 2006 to March 2008, patients who had spirometry performed were examined. The original disease of patients, pulmonary function tests, smoking status, and respiratory symptoms were surveyed from their medical records., Results: Of all patients who had spirometry performed, 15.8% showed airflow limitation (FEV(1)/FVC < 0.7). A variety of diseases were observed in patients with airflow limitation. Among all diseases, cardiovascular disease was the highest and gastrointestinal malignant disease had the second highest prevalence in patients with airflow limitation., Conclusion: COPD might be frequent in conditions of comorbidity in patients treated for various diseases. Attention should be paid to the possibility of co-existence of COPD and the influence of COPD on these patients.

Salivary pH is associated with esophageal acid reflux and neutralization of esophageal acid. In this study, we assessed the association between nocturnal decline of salivary pH and airway hyperresponsiveness. Salivary pH was serially assessed in 9 patients with mild asthma (7 men and 2 women; mean age 33.3 years; mean %predicted FEV(1.0) 89.4%) and 10 healthy volunteers (6 men and 4 women; mean age 31.2 years) using a pH indicator tape. The buffering capacity of saliva was defined as the median effective dose (ED(50)) for acidification of saliva with 0.01 N HCl, and airway responsiveness was defined as the dose of methacholine producing a 35% fall in Grs (PD(35)-Grs). There was a significant correlation between the values obtained from the pH indicator tape and those obtained from the electrometric pH meter. Using the indicator tape for sequential monitoring, we observed a nocturnal fall (ΔpH) in salivary pH in all subjects. A significant correlation was found between airway hyperresponsiveness (PD(35)-Grs) and either ΔpH or ED(50) in mildly asthmatic patients. Vagal reflux dysfunction might contribute to nocturnal salivary pH as well as to airway hyperresponsiveness in mild asthmatics.

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.

Bronchial asthma is a chronic inflammatory disorder of the airways, in which inflammation causes bronchial hyper-responsiveness and flow limitation in the presence of various stimuli. Pulmonary function in asthmatic patients frequently deteriorates between midnight and early morning, which has suggested a role for chronotherapy. Although relationships between bronchial asthma and the function of clock genes remain unclear, some medications given for asthma such as glucocorticoids or beta(2)-adrenoceptor agonists may influence clock genes in vivo. In our studies of clock gene mRNA expressions in human bronchial epithelial cells in vitro and peripheral blood cells in vivo, we demonstrated that glucocorticoid or beta(2)-adrenoceptor agonist treatment strongly induced human Per1 mRNA expression both in vitro and in vivo. Human peripheral blood cells provide a useful indication of peripheral clock gene mRNA expression in vivo.

Objective: To determine the role of KL-6 (Krebs von den Lungen-6) in evaluating the disease severity of pulmonary lesions in rheumatoid arthritis (RA) compared with high resolution computed tomography (HRCT) findings., Methods: Fifty serum KL-6 levels and HRCT images were prospectively obtained from 47 RA patients. Eight HRCT findings were classified into five grades. Patients were also divided into two groups according to the KL-6 threshold level and HRCT findings were evaluated., Results: There was a positive correlation between the serum KL-6 level and the total CT score (r = 0.83). Reticular opacity most closely related to the serum KL-6 levels (r = 0.84). In the high KL-6 group (n = 10), the average CTscore was markedly increased (64.6 points) and severe honeycombing expanded into the whole lung. One case revealed diffuse ground glass opacity. In 12 of 40 cases in the normal KL-6 group, CT scores mildly increased compared with the other cases (over 20 points). The predominant finding of these cases could be classified into four types: (1) narrow spread honeycombing; (2) subtle fibrosis; (3) airway diseases; and (4) dense consolidation., Conclusion: KL-6 is a useful marker to detect severe RA lung disease. It is also useful to distinguish non-fibrosis from fibrosis predominant cases. However, it sometimes could not detect early stage RA lung disease.

Cell migration is essential for invasive and metastatic phenotypes of cancer cells. Potential chemopreventive agents of cancer-sulindac sulfide, caffeic acid phenethyl ester (CAPE), curcumin, and (+)-catechin-have been reported to interfere with several types of intracellular signaling. In this study, we examined the effects of these agents on transforming growth factor-beta(TGF-beta)-induced motility and Akt phosphorylation in A549 cells. Judged by gold particle phagokinesis assay, sulindac sulfide, CAPE, and curcumin suppressed the motility of A549 cells promoted by TGF-beta. LY294002, a specific inhibitor of phosphatidylinositol 3-kinase(PI3K)/Akt signaling, also suppressed TGF-beta-induced motility and Akt phosphorylation. Sulindac sulfide and CAPE, but not curcumin, suppressed TGF-beta-induced Akt phosphorylation. We conclude that sulindac sulfide and CAPE suppress the motility promoted by TGF-beta in lung adenocarcinoma cells through the suppression of Akt. Our observations raise the possibility that these agents, except for (+)-catechin, can be applied not only as chemopreventive agents but also as anti-metastatic therapy.

Altered and deregulated cyclin-dependent kinase (cdk) activity is now believed to play a major role in the pathogenesis of head and neck squamous cell carcinomas (HNSCC), thus providing a suitable cellular target for therapeutic intervention. UCN-01 (7-hydroxy-staurosporine), a known protein kinase C and cdk modulator, demonstrates antiproliferative and antitumor properties in many experimental tumor models and may represent a potential candidate to test in HNSCC. In this study, UCN-01 displayed potent antiproliferative properties (IC50 of approximately 17-80 nM) in HNSCC cells. Cell cycle analysis revealed that UCN-01 treatment of HNSCC cells for 24 h leads to a G1 block with a concomitant loss of cells in S and G2-M and the emerging sub-G1 cell population, confirmed to be apoptotic by terminal deoxynucleotidyl transferase-mediated nick end labeling analysis. Additional in vitro studies demonstrated a G1 arrest that was preceded by depletion in cyclin D3, elevation of p21(WAF1) and p27(KIP1) leading to a loss in activity of G1 cdks (cdk2, cdk4), and reduction in pRb phosphorylation. Antitumor properties of UCN-01 were also assessed in vivo by treating HN12 xenografts (7.5 mg/kg/i.p./daily) with UCN-01 for 5 consecutive days. Total sustained abolition of tumor growth (P < 0.00001) was obtained with only one cycle of UCN-01 treatment. Terminal deoxynucleotidyl transferase-mediated nick end labeling staining of xenograft samples revealed a higher incidence of apoptosis in treated tissues when compared with control. Additional tissue analysis demonstrated that elevated p27(KIP1) with minimal increase in p21(WAF1) and reduced cyclin D3 levels were readily detected in those animals treated with UCN-01, similar to those observed in HNSCC cells. Thus, UCN-01 exhibits both in vitro and in vivo antitumor properties in HNSCC models, and these effects are associated with a decrease in cyclin D3 and an increase in p27(KIP1) protein levels, thus providing appropriate surrogate markers to follow treatment efficacy in vivo and, therefore, a suitable drug candidate for treating HNSCC patients.