Takashi Sumikawa

Expression of functional leukotriene B4 receptors on human airway smooth muscle cells

BACKGROUND Leukotriene B4 (LTB4) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the T(H)2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies suggest that LTB4 may contribute to asthma pathophysiology. However, the direct effects of LTB4 on human airway smooth muscle (ASM) have not been studied. OBJECTIVES We sought to determine the expression of LTB4 receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB4 on these cells. METHODS Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB4 receptors. To determine the effect of LTB4 on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay. RESULTS We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB4 markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB4 also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB4-induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002). CONCLUSIONS These observations are the first to suggest a role for a LTB4-BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma.

Gastric metastasis by primary lung adenocarcinoma

The diagnosis of gastric metastasis from lung cancer is relatively rare in living patients. We describe a case of Type 4 tumor-like metastasis due to primary lung cancer diagnosed with immunohistochemical staining while the patient was alive. A 68-year-old man was admitted to our hospital because of epigastric pain. Gastrointestinal endoscopy revealed a Type 4 tumor and the histological examination showed poorly differentiated adenocarcinoma. His chest X-ray showed mass shadow in the right upper lung field. The resected specimens showed moderately differentiated adenocarcinoma., The diagnosis of gastric metastasis from lung cancer was made by immunohistochemical staining of the lung and gastric tumors which showed positive staining for Thyroid transcriptional factor-1. Diagnosis of gastric metastasis, especially Type 4 metastasis by lung cancer is difficult. However, immunohistochemical staining is very helpful for diagnosis of primary lung cancer metastasis at sites such as the gastrointestinal tract which are not normally prone to metastatis.

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/m2, respectively, in 12 patients. In the phase II portion, previously untreated elderly patients were treated with 600 mg/d UFT and 20 mg/m2 vinorelbine. Results: At the dose level of 600 mg/d UFT and 25 mg/m2 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/m2 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.

Case ReportSquamous Cell Carcinoma Transformation from EGFR-mutated Lung Adenocarcinoma: A Case Report and Literature Review

Epidermal growth factor receptor (EGFR)-mutated nonesmall-cell lung cancer responds dramatically to initial EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance develops in w1 year. Osimertinib, one of the T790M-specific EGFR TKIs, results in a favorable response in EGFR-mutated NSCLC that has developed acquired resistance with a secondary T790M mutation. We report a rare case of EGFR-mutated stage IB lung adenocarcinoma with a point mutation in exon 21 (L858R) in a 68-year-old man that showed histologic transformation to squamous cell carcinoma (SCC) concurrently with secondary T790M mutation and responded to osimertinib. T790M-specific third-generation EGFR TKIs, including osimertinib, could be a promising strategy for EGFR T790M mutation-positive NSCLC, regardless of the histologic findings.

O2-12-4Introduction of cisplatin-containing regimens on an outpatient basis

Hisashi Suyama, Miwako Makima, Naomi Adchi, Takashi Sumikawa, Norihiko Hino, Eiji Shimizu Division of Transfusion, Tottori University Hospital, Department of Pharmacy, Tottori Prefectural Central Hospital, Department of Outpatient Treatment Unit, Tottori Prefectural Central Hospital, Department of Respirology, Tottori Prefectural Central Hospital, Department of Hematology, Tottori University Hospital, Division of Medical Oncology and Molecular Respirology, Tottori University