Shigenori Nakajima

Phase II study of vinorelbine in heavily previously treated small cell lung cancer

Twenty-four previously treated patients with refractory or relapsed small cell lung cancer (SCLC) were entered into a prospective, multicenter phase II study. All 24 patients had been pretreated with some form of cisplatin-based chemotherapy. The median time of chemotherapy was 4.2 months (range 1.4–9.4 months). Patients were treated with a dose of 25 mg/m2 of vinorelbine weekly. Twenty-four patients were eligible for response and for toxicity. Partial response was observed in 3 out of 24 eligible patients (12.5%; 95% confidence interval, 2.7–32.4%). All 3 patients who responded had previous chemotherapy including vincristine. The most common toxicity was leukopenia (91.7%, 66.7% in WHO 3-4 grade) and anemia (70.8%, 20.8% in WHO 3 grade). Nonhematological toxicities were moderate and mild. These results support a two-stage sequential study design of previously untreated patients for further phase II study in SCLC.

A comparative study of eosinophil isolation by different procedures of CD16-negative depletion

Eosinophils were isolated by the three methods of CD16‐negative depletion: 1) magnetic beads, 2) fluorescence‐activated cell sorter (FACS), and 3) complement reaction. Their purity, yield, and viability were compared. The second procedure produced well purity and viability (94.65 ± 1.51% and 94.98 ± 1.40%, respectively) but low yield of eosinophils (65.47 ± 2.47%). The viability of cells obtained by the third procedure was not efficient (80.83 ± 2.85%), while the purity and the yield were efficient (96.23 ± 1.09% and 90.75 ± 1.72%, respectively). In conclusion, the magnetic beads method (purity: 98.02 ± 0.45%, yield: 91.05 ± 2.43%, viability: 97.57 ± 0.37%) was the most advantageous of these three procedures. Moreover, in the functional assay, radical oxygen products from eosinophils isolated by the procedure with complement reaction were less than with the magnetic beads or FACS procedures.

Assessment of Serum CYFRA 21-1 in Lung Cancer

Cytokeratins are the intermediate filaments of the cytoskeletal protein located in normal epithelia, tumor, and cultured cells. Recently, a fragment of cytokeratin subunit 19, referred to as CYFRA 21‐1, detected in the serum of patients with nonsmall cell lung cancer, has been reported as a new tumor marker. This article reports the results of a study of serum fragment CYFRA 21‐1, measured by immunoradiometric assay, as a marker of lung cancer.

RANTES Augments Radical Oxygen Products from Eosinophils

RANTES, which is released from thrombin-stimulated platelets, is a member of the 8-kD cytokine family that has been shown to possess chemotactic activity for eosinophils. Thus, in this study, we examined the effect of RANTES on radical oxygen products from eosinophils. RANTES treatment resulted in the enhancement of peak value and integrated value of productivity of eosinophil-mediated radical oxygen products determined by luminol-dependent chemiluminescence of EoL-3 cells stimulated with A23187. In addition, the radical oxygen products of EoL-1 or eosinophils showed similar results. Thus, we could conclude that platelets might play an important role in the pathogenesis of allergic inflammation through the involvement in the selective eosinophil infiltration and eosinophil activation by releasing RANTES.

Possible Release of Eosinophil Granule Proteins in Response to Signaling from Intercellular Adhesion Molecule-1 and its Ligands

The presence of a large variety of membrane receptors and the identification of cytotoxic molecules (mainly granule basic proteins) have indicated that eosinophils should br considered as effector cells. It has recently been suggested that adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), play an important role in allergic inflammation, for example in bronchial asthma. This study therefore investigated the possible release of granule protein in response to signaling from ICAM-1 and its ligands. The concentrations of eosinophil cationic protein and eosinophil-derived neurotoxin in supernatants of eosinophils were significantly greater (p < 0.05) in the presence of recombinant soluble ICAM-1 than without it. These results suggest that signaling from ICAM-1 and its ligands might induce eosinophil activation and might be involved in degranulation of eosinophil granule proteins, e.g. eosinophil cationic protein and eosinophil-derived neurotoxin.

Change of Cu,Zn-superoxide dismutase activity of guinea pig lung in experimental asthma.

Correlation between the level of reactive oxygen species (ROS) generated by airway inflammatory cells and superoxide dismutase (SOD) activity of pulmonary tissue during an asthma attach was investigated in a guinea pig model of allergic asthma. In addition, the influence of SOD inhibition by diethyldithiocarbamate (DDC, Cu-chelating agent) on the airway was investigated in terms of pulmonary function during an asthma attach. Relative to controls, the capacity of bronchoalveolar lavage fluid (BAL) cells to release ROS was significantly increased in guinea pigs sensitized with ovalbumin (OA) as the antigen, and significantly increased in guinea pigs with an asthma attack provoked by the inhalation of OA. SOD activity was increased significantly in the antigen-sensitized group. The asthma provocation group showed a tendency for increase in total SOD activity, compared with the sensitization group, whose increase was dependent on the increase in copper, zinc-SOD (Cu, Zn-SOD) activity. Pretreatment with DDC increased the severity and duration of the asthma attack. These results were indicated that Cu, Zn-SOD was closely involved in the asthma process, particularly in the scavenging of oxygen radicals secreted from BAL cells.

Effect of platelet-activating factor and platelet factor 4 on eosinophil adhesion.

The effect of platelet-activating factor (PAF) and platelet factor 4 (PF4) on the adhesion of isolated human eosinophils or eosinophilic cell lines (EoL-1, EoL-3) was examined. Both PAF and PF4 augmented eosinophil adhesion to plates coated with AB plasma or recombinant soluble intercellular adhesion molecule-1 (r-sICAM-1). These findings suggest that PAF and PF4 not only modulate chemotactic activity of eosinophils but also intensify the function of eosinophil adhesion. Since PAF and PF4 induce the expression of adhesion molecules (LFA-1 alpha, LFA-1 beta, CR3) on eosinophils, we could conclude that PAF or PF4 are closely related to eosinophil accumulation not only as chemotactic agents but also as augmentative agents for eosinophil adhesion through involvement in functional eosinophil adherence as well as surface expression of adhesion molecules on eosinophils.

Induction of hypodense eosinophils and nuclear hypersegmentation of eosinophils by various chemotactic factors and lymphokines in vitro

We have previously reported pulmonary eosinophils in eosinophilic pneumonia (PIE syndrome) showed two characteristics: hypodensity and nuclear hypersegmentation. Our present working hypothesis is that the eosinophil chemotactic factor and certain lymphokines may be involved in the induction of these characteristic features. Therefore, we examined whether these stimuli can induce two characteristics in vitro. Results were as follows. 1) Chemoattracts (ECF-A, histamine and PAF) can induce both nuclear hypersegmentation and hypodense eosinophils. 2) Hypodense eosinophils can be induced earlier than induction of hypersegmented nuclei (hypodense eosinophils within three hours, hypersegmented nuclei: 12 hrs). 3) Furthermore, lymphokines can not induce hypodense eosinophil. 4) However, PHA-lymphocyte culture medium (PHALCM), gamma-IFN and IL-3 + GM-CSF can induce hypersegmented nuclei but IL-2 has no effect on nuclear segmentation of eosinophils.

A double‐blind, placebo‐controlled dose–response study with budesonide Turbuhaler in Japanese asthma patients

The aim of this study was to investigate the dose–response for inhaled budesonide via Turbuhaler® in Japanese patients with mild to moderate asthma.

Dual-phase response model for bronchial asthma.

The authors have successfully developed an animal model of dual-phase bronchial responses and very high IgG titer by sensitizing Hartley-strain male guinea pigs. Specific airway resistance, which was determined in a two-chamber body plethysmograph, was elevated to sevenfold during immediate response, followed by a late phase response with a smaller but marked elevation in resistance. Furthermore, hematological and histological examinations revealed that the total cell count increased in BAL obtained during both immediate and late bronchial responses as compared to pre-OVA challenges. A significant increase in BAL eosinophils was present only for the late bronchial samples, and this finding was supported by histological examination.