Kazuhiko Fujii

Diffuse alveolar damage after ZD1839 therapy in a patient with non-small cell lung cancer

ZD1839 is an orally active inhibitor selective for the epidermal growth factor receptor tyrosine kinase and has shown promise in the treatment of non-small cell lung cancer (NSCLC). We now present a case of diffuse alveolar damage (DAD) that developed in a 67-year-old man treated with ZD1839. On day 8 of ZD1839 administration, the patient complained of dyspnea and a new-ground glass opacity was apparent on a chest X-ray and computed tomography scan. Despite high-dose steroid therapy, the patient died 13 days after the first administration of ZD1839. Postmortem analysis of lung tissue revealed a pattern of DAD. No evidence of infection or of other specific etiologies was apparent. This case is the first reported of respiratory failure after ZD1839 treatment in a patient with NSCLC. Physicians should therefore be aware of the potential pulmonary toxicity of ZD1839.

Pulmonary tumor thrombotic microangiopathy resulting from metastatic signet ring cell carcinoma of the stomach.

Pulmonary tumor thrombotic microangiopathy is an unusual malignancy‐related respiratory complication characterized by multiple microthrombi and intimal myofibroblast proliferation. Its clinical manifestation is subacute respiratory failure with pulmonary hypertension. Herein is reported a case of pulmonary tumor thrombotic microangiopathy associated with gastric signet ring cell carcinoma. A 51‐year‐old woman with gastric cancer died of subacute respiratory failure. Autopsy showed gastric signet ring cell carcinoma with diffuse metastasis of pulmonary lymphatics and pleurae; every organ examined lacked a space‐occupying tumor mass. Histologically, proliferated intimal myofibroblasts obliterated most of the pulmonary vascular lumen, and a few stenosed vascular lumina contained cancer cells. In addition, pulmonary vasculature associated with intimal proliferation contained microthrombi. Most cancer cells in the stomach and pulmonary lymphatics were typical signet ring cells, whereas those in vascular lesions were cells of poorly differentiated adenocarcinoma without mucous production. Consistent with a previous report, the latter expressed vascular endothelial growth factor (VEGF) and tissue factor (TF). The proliferated intimal myofibroblasts also expressed type 2A serotonin receptor (5‐HT2A). These findings suggest that local expression of VEGF, TF, and 5‐HT2A may be linked to the pathogenesis of this unusual pulmonary complication.

Favorable outcome with hemoperfusion of polymyxin B-immobilized fiber column for rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis: report of three cases

We present 3 cases of rapidly progressive interstitial pneumonia (RPIP) associated with clinically amyopathic dermatomyositis (C-ADM) that were treated with two courses of direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP). Despite initial treatment with high-dose corticosteroids, pulsed cyclophosphamide, and cyclosporine, the lung disease and hypoxemia deteriorated in all the patients. After PMX-DHP treatment, the PaO2/FiO2 ratio and serum LDH and KL-6 were improved, the abnormal shadows in chest high-resolution computed tomography (HRCT) scans gradually decreased, and, finally, all patients survived. These findings indicate that PMX-DHP treatment could be effective in the management of RPIP in patients with C-ADM in combination with conventional therapy.

The role of cysteinyl leukotrienes in the pathogenesis of asthma: Clinical study of leukotriene antagonist pranlukast for 1 year in moderate and severe asthma

Clinical studies have shown that pranlukast (Ono Pharmaceutical Co., Osaka, Japan) is effective for mild and moderate asthma. However, it is not well known that pranlukast is also effective on moderate and severe persistent asthma in the long term. We studied the effect of pranlukast on moderate and severe asthmatics by evaluating the change of peak expiratory flow (PEF) and therapeutic scores for 1 year before and during pranlukast therapy. We gave pranlukast 225 mg twice daily orally to 25 patients who were receiving more than 400 μg/day beclomethasone inhalation and β2 stimulant inhalation with or without oral corticosteroid. Pranlukast increased PEF more than 10 L/min in 14 patients in the first 4 weeks. In these 14 patients, 10 patients continued to monitor PEF and kept asthma diaries for 1 year. We compared the data for 1 year before and during the pranlukast therapy. During the pranlukast therapy, PEF significantly increased, puffs of β2 stimulant inhalation significantly decreased. The incidence of oral corticosteroid rescue therapy reduced, and the mean daily dose of oral corticosteroid decreased; however, they were not statistically significant. During treatment with pranlukast, no side effect was observed. From these results, we suggest that pranlukast is effective for more than half of the moderate and severe persistent asthmatics, and that the effectiveness continues for more than 1 year.

The role of substance P release in the lung with esophageal acid

To investigate whether tachykinins are released in the airways by stimulating the esophagus, airway plasma extravasation induced by intraesophageal hydrochloric acid (HCl) in the presence or absence of the neutral endopeptidase (NEP) inhibitor phosphoramidon and the neurokinin-1-receptor antagonist FK888 was studied in anesthetized guinea pigs. Airway plasma extravasation also was studied in the presence of the NEP inhibitor in guinea pigs pretreated with capsaicin or bilateral vagotomy. Propranolol and atropine were used in all animals to block adrenergic and cholinergic nerve effects. Airway plasma leakage was evaluated by measuring extravasated Evans blue dye. One normal HCl infusion into the esophagus significantly increased plasma extravasation in the trachea. Phosphoramidon significantly potentiated plasma extravasation induced by HCl infusion into the esophagus in the trachea and main bronchi, and FK888 significantly inhibited extravasation in a dose-related manner. In capsaicin-treated animals, airway plasma extravasation was completely inhibited even in the presence of phosphoramidon. Tracheal plasma extravasation potentiated by phosphoramidon was significantly inhibited in the bilaterally vagotomized animals. These results suggest that locally acting substances are released by intraesophageal HCl stimulation that cause airway plasma extravasation. These substances are generated through activation of neural pathways, including some that traffic through the vagus nerves that link the esophagus or airways.

Relationship Between Functional Preservation after Segmentectomy and Volume-Reduction Effects after Lobectomy in Stage I Non-small Cell Lung Cancer Patients with Emphysema

Objectives: To evaluate whether functional preservation after segmentectomy has a greater advantage of pulmonary functions than volume-reduction effects after lobectomy in patients with emphysema with clinical T1N0 non-small cell lung cancer (NSCLC). Patients and Methods: Between January 2000 and December 2006, 47 cases of lobectomy and 71 cases of segmentectomy were performed in patients with stage I NSCLC using intraoperative sentinel node identification. The postoperative change of the forced expiratory volume in 1 second (&dgr;FEV1) 6 months after segmentectomy was compared with that of 6 months after lobectomy. The difference in the &dgr;FEV1 between after segmentectomy and after lobectomy was evaluated according to the ratio of the estimated postoperative FEV1 to the predicted normal value of FEV1 (%ppoFEV1). Results: In 50 patients with the preoperative FEV1% less than 70%, there was no difference in the &dgr;FEV1 between the segmentectomy group (n = 30) and the lobectomy group (n = 20). In 36 patients with emphysema diagnosed by high-resolution chest computed tomography, a negative linear correlation between the %ppoFEV1 and the &dgr;FEV1 was found in the lobectomy subgroup (n = 16, r2 = 0.508, p = 0.0012), but not in the segmentectomy subgroup (n = 20). When patients with emphysema had the %ppoFEV1 more than or equal to 70%, the &dgr;FEV1 had a tendency to be smaller in the segmentectomy subgroups than in the lobectomy subgroups. Conclusion: Segmentectomy should be considered in patients with cT1N0 NSCLC with a normal (>80%) predicted postoperative FEV1. In patients with a %ppoFEV1 under 70%, segmentectomy offers no functional advantages over lobectomy.

CD8 and CD103 Are Highly Expressed in Asthmatic Bronchial Intraepithelial Lymphocytes

Background: Although characteristics of intraepithelial lymphocytes (IELs) in mucosal immunity have been well defined in the intestine, bronchial IELs have been little investigated. Recently, we showed that bronchial IELs have a distinct function that partly resembles that of intestinal IELs; however, surface antigen expression of bronchial IELs and the relationship of that expression to airway disease have not been studied. Methods: We analyzed phenotypic profiles of human bronchial IELs and lamina propria lymphocytes (LPLs) by double-staining immunohistochemistry using full-thickness bronchial specimens (10 nonasthmatic controls and 7 asthmatics) from lung resections. Results: In controls, the percentage of CD4+ cells was lower, and the percentage of CD8+ cells was higher in IELs compared to LPLs (CD4: median 50.0% in IELs vs. 65.9% in LPLs, p = 0.01; CD8: 50.9% in IELs vs. 34.4% in LPLs, p = 0.007). The percentage of cells positive for CD103 (αE-integrin) was higher in IELs than that in LPLs (median 60.1% in IELs vs. 16.9% in LPLs; p < 0.001). In IELs from asthmatics, these characteristics were particularly significant (CD4: median 26.2%, p = 0.008; CD8: 79.8%, p = 0.007; CD103: 76.2%, p = 0.019; all compared with IELs from nonasthmatics). Conclusions: These results suggest that human bronchial IELs have roles distinct from subsets of other lymphocytes, and that CD8+ cells and CD103+ cells have potentially important functions in the bronchial epithelium.

Tachykinin antagonist FK224 inhibits neurokinin A‐, substance P‐ and capsaicin‐induced human bronchial contraction

Summary— To determine the roles of endogenously released tachykinins (substance P [SP] and neurokinin A [NKA]) in the human bronchial tissues, we studied the effects of tachykinin antagonist FK224 on bronchial smooth muscle contraction induced by SP, NKA and capsaicin in an organ bath. FK224 (10−6 M and 10−5 M, respectivly) significantly inhibited NKA‐induced contraction and 10−5 M FK224 shifted the dose‐response curve to more than one log unit higher concentration. Because SP‐ and capsaicin‐induced contractions were small, we pretreated the tissues with the neutral endopeptidase inhibitor phosphoramidon (10−5 M), which inhibits degradation of exogenous tachykinins in order to potentiate the contractions. FK224 (10−5 M) significantly inhibited SP‐induced contraction and it shifted the dose‐response curves to about one log unit higher concentration. FK224 (10−5 M) also significantly inhibited capsaicin‐induced contraction and it shifted the dose‐response curves to more than one log unit higher concentration. In contrast, FK224 (10−5 M) did not affect on acetylcholine‐, histamine‐, and leukotriene D4‐induced contraction. These results suggest that FK224 is a tachykinin receptor antagonist in the human bronchial smooth muscle, and that capsaicin‐induced contraction is due to endogenously released tachykinin‐like substances in the human bronchus.

T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice

T cells play an important role in the pathogenesis of bronchial asthma. However, it is not completely known how circulating lymphocytes infiltrate into the airways of asthmatic patients. Because SCID mice are unable to reject xenogenic transplants, many xenotransplant models using various human tissues have been developed. Therefore, to examine the interaction between bronchi and T lymphocytes of asthma, it may be possible to use the human bronchial xenograft and PBMC xenograft in SCID mice. We transplanted human bronchi into the subcutaneum of SCID mice and i.p. injected PBMCs that were obtained from patients with atopic asthma, atopic dermatitis and rheumatoid arthritis, and normal subjects (asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice). There was no difference in the percentage of CD3-, CD4-, CD8-, CD25-, CD45RO-, CD103-, and cutaneous lymphocyte Ag-positive cells in PBMCs among the patients with asthma, dermatitis, rheumatoid arthritis, and normal subjects, and CD3-positive cells in peripheral blood of asthmatic, dermatitis, rheumatic, and normal huPBMC-SCID mice. The number of CD3-, CD4-, and CD8-positive cells in the xenografts of asthmatic huPBMC-SCID mice was higher than those of dermatitis, rheumatic, and normal huPBMC-SCID mice. IL-4 mRNA and IL-5 mRNA were significantly higher in the xenografts of asthmatic huPBMC-SCID mice than those in the xenografts of normal huPBMC-SCID mice, but there were no significant differences in the expressions of IL-2 mRNA or IFN-γ mRNA between them. These findings suggest that T cells, especially Th2-type T cells, of asthmatics preferentially infiltrate into the human bronchi.

Evidence that allergen-induced contraction of guinea pig bronchi is mediated in part by the release of tachykinins

To study the role of tachykinins in allergic responses in the airways of guinea pigs sensitized to ovalbumin (OVA), we examined the bronchial contractile response to allergen in the presence or absence of the tachykinin antagonist FK224 in vitro. Because neutral endopeptidase (NEP) effectively cleaves tachykinins, we incubated bronchial tissues with the NEP inhibitor phosphoramidon (10(-5) M) to maintain the activity of endogenously released tachykinins. Then we added 10(-5)% (10 microns/ml) OVA in the presence or absence of FK224 (10(-5) M). FK224 significantly inhibited OVA-induced contraction plateaued and began to relax, we added 10(-5) M phosphoramidon. In the tissue without FK224, phosphoramidon blocked the relaxation and enhanced the contraction. In contrast, in the tissues treated with FK224, phosphoramidon did not enhance the OVA-induced contraction. The enhancement of the contraction induced by phosphoramidon was not inhibited by the sodium channel blocker tetrodotoxin. These results suggest that (1) allergic response causes release of tachykinin-like substances to induce bronchial contraction in part, (2) these responses are blocked by tachykinin antagonist FK224 and (3) nerve conduction is not necessary for the release of tachykinin-like substances induced by allergic response in the guinea pig bronchus.