We have shown that phospholipase Cε (PLCε), an effector of Ras and Rap1 small GTPases, plays pivotal roles in inflammation and inflammation-associated carcinogenesis by augmenting proinflammatory cytokine production from epithelial cells of various organs. The purpose of this study is to analyze its role in neutrophilic alveolar inflammation accompanying acute lung injury (ALI), focusing on that in alveolar epithelial cells (AECs), which are known to make a major contribution to the pathogenesis of ALI.We examine the effect of the PLCε genotypes on the development of ALI induced by intratracheal administration of lipopolysaccharide (LPS) to PLCε wild-type (PLCε+/+) and knockout (PLCεΔX/ΔX) mice. Pathogenesis of ALI is analyzed by histological examination of lung inflammation and measurements of the levels of various cytokines, in particular neutrophil-attracting chemokines such as Cxcl5, by quantitative reverse transcription-polymerase chain reaction and immunostaining. Primary cultures of AECs, established from PLCε+/+ and PLCεΔX/ΔX mice, are used to analyze the roles of PLCε, protein kinase D (PKD) and nuclear factor-κB (NF-κB) in augmentation of LPS-induced Cxcl5 expression.Compared to PLCε+/+ mice, PLCεΔX/ΔX mice exhibit marked alleviation of lung inflammation as shown by great reduction in lung wet/dry weight ratios, accumulation of inflammatory cells in the alveolar space and thickening of alveolar walls as well as the number of neutrophils and the protein concentration in bronchoalveolar lavage fluid. Also, LPS-induced expression of the CXC family of chemokines, in particular Cxcl5, is substantially diminished in the total lung and AECs of PLCεΔX/ΔX mice. Moreover, LPS-induced Cxcl5 expression in primary cultured AECs is markedly suppressed on the PLCεΔX/ΔX background (p < 0.05 versus PLCε+/+ AECs), which is accompanied by the reduction in phosphorylation of inhibitor κB (IκB), PKD and nuclear translocation of NF-κB p65. Also, it is suppressed by the treatment with inhibitors of PKD and IκB kinase, suggesting the involvement of the PLCε-PKD-IκB-NF-κB pathway.PLCε-mediated augmentation of the production of the CXC family of chemokines, in particular Cxcl5, in AECs plays a crucial role in neutrophilic alveolar inflammation accompanying ALI, suggesting that PLCε may be a potential molecular target for the treatment of acute respiratory distress syndrome.
背景．同一腫瘍細胞内にthyroid transcription factor 1（TTF-1）とp40が共発現した非小細胞肺癌において抗TTF-1抗体のクローンを変更したことで扁平上皮癌に診断が変わった経験をしたので報告する．症例．症例1：82歳男性．左背部痛を主訴に胸部CTで左S6に41 mm大の腫瘤を認めた．非小細胞肺癌c-stage IIAと診断し左下葉切除術を施行した．術後病理検査でnon-small cell carcinoma with co-expression of TTF-1 and p40と診断した．症例2：65歳男性．呼吸困難感と嚥下障害を主訴に胸部CTで腫瘍と一塊になった気管分岐部リンパ節腫大を認め，生検でnon-small cell carcinoma with co-expression of TTF-1 and p40と診断した．しかし，後日抗TTF-1抗体のクローンを変更して再検したところ2例ともTTF-1は陰性で扁平上皮癌と診断した．結論．TTF-1は抗体のクローンにより発現が異なり，腺癌と扁平上皮癌の判別にはSPT24は用いず，8G7G3/1を利用すべきである．
Objectives: The combination of chemotherapy and immune checkpoint inhibitor (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. Data on the incidence rate of drug-induced interstitial lung disease (D-ILD) in daily practice and the association between the development of D-ILD and ILA in the baseline computed tomography (CT) are limited in ES-SCLC patients treated with chemo-ICIs.Materials and Methods: We conducted a multicenter retrospective study to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICIs between August 2019 and November 2021.Results: Seventy patients (median age, 71 years; including 58 men) from nine institutions in Japan were included. Sixty-two patients (89%) received carboplatin/etoposide/atezolizumab, and eight received carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine (41.4%) patients had ILA on baseline CT. Eleven (15.7%) patients developed D-ILD. The proportion of patients with ILA was significantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P=0.0057). In addition, ground glass and reticular abnormalities were more frequent in the patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5–9.5) months vs. 5.0 (95% CI, 4.5–5.6) months, respectively, P=0.11 and median OS, not reached (NR) (95% CI, 8.7–NR) vs. 18.2 (95% CI, 13.2–NR) months, respectively, P=0.20).Conclusion: The incidence of D-ILD in ES-SCLC patients treated with chemo-ICIs in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD.
Objectives: The combination of chemotherapy and immune checkpoint inhibitor (chemo-ICI) has become the new standard of treatment for extensive-stage small cell lung cancer (ES-SCLC). Recently, slight changes in interstitial shadows, defined as interstitial lung abnormalities (ILA), have been identified. Data on the incidence rate of drug-induced interstitial lung disease (D-ILD) in daily practice and the associationbetween the development of D-ILD and ILA in the baseline computed tomography (CT) are limited in ES-SCLC patients treated with chemo-ICIs.Materials and Methods: We conducted a multicenter retrospective study to investigate the incidence of D-ILD, the risk factors for developing D-ILD, progression-free survival (PFS), and overall survival (OS) in patients with ES-SCLC who received chemo-ICIsbetween August 2019 and November 2021.Results: Seventy patients (median age, 71 years; including 58 men) from nine institutions in Japan were included. Sixty-two patients (89%) received carboplatin/etoposide/atezolizumab, and eight received carboplatin or cisplatin/etoposide/durvalumab. Twenty-nine (41.4%) patients had ILA on baseline CT. Eleven (15.7%) patients developed D-ILD. The proportion of patients with ILA wassignificantly higher in the group who developed D-ILD than in the group who did not (9/11 (81.8%) vs. 20/59 (33.9%), respectively, P=0.0057). In addition, ground glass and reticular abnormalities were more frequent in the patients who developed D-ILD. There was no significant difference in PFS and OS between patients who developed D-ILD and those who did not (median PFS, 8.0 (95% confidence interval (CI), 5.5–9.5) months vs. 5.0 (95% CI, 4.5–5.6) months, respectively, P=0.11 and median OS, not reached (NR) (95% CI, 8.7–NR) vs. 18.2 (95% CI, 13.2–NR) months, respectively, P=0.20).Conclusion: The incidence of D-ILD in ES-SCLC patients treated with chemo-ICIs in clinical practice was higher than that in clinical trials. Patients with pre-existing ILA were more likely to develop D-ILD.
Annexin A10 (ANXA10) is a member of the annexin family and a calcium-dependent phospholipid-binding protein. The aim of this study was to clarify the clinical significance of ANXA10 expression in lung adenocarcinoma.ANXA10 expression was immunohistochemically examined in surgical specimens of lung adenocarcinoma obtained from 74 consecutive patients who underwent complete resection from January 2014 to December 2014. Expression of ANXA10 was down-regulated in A549 cells via siRNA transfection and the effect of ANXA10 on cell migration was assessed by the wound healing assay. Expression of ANXA10 was examined by immunocytochemistry and polymerase chain reaction.High ANXA10 expression was significantly correlated with poor overall survival (p=0.00705). Multivariate analysis with the Cox proportional hazard model demonstrated that ANXA10 expression was an independent prognostic factor. Cell migration was suppressed in ANXA10-down-regulated A549 cell lines.ANXA10 has a role in cancer cell migration and high ANXA10 expression is a novel prognostic marker in lung adenocarcinoma.
Objective Bronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe asthma. Although it has been suggested that BT works by reducing airway smooth muscle, the detailed mechanism underlying its effects is still unknown.
Purpose: Caspase recruitment domain-containing protein 9 (CARD9) is expressed at high levels in bone marrow cells and has a crucial role in innate immunity. Current studies indicate that CARD9 also plays a key role in tumor progression, but there are few reports on the role of CARD9 in lung cancer. The aim of this study was to clarify the role of CARD9 in lung adenocarcinoma. Patients and Methods: Lung adenocarcinoma tumor samples from 74 patients who underwent complete resection at Kobe University Hospital from January 2014 to December 2014 were analyzed by immunohistochemistry. The role of CARD9 in cancer cells was analyzed using lung cancer cell lines treated with CARD9 siRNA. Results: High expression of CARD9 was observed in 32.4% of tumors, and compared to low expression of CARD9, high expression was associated with poorer overall survival (P = 0.0365). Univariate and multivariate analyses showed that high expression of CARD9 was an independent prognostic factor. Knockdown of CARD9 in lung adenocarcinoma cells inhibited proliferation but did not increase apoptosis. In addition, CARD9 activated the NF-κB pathway in a lung adenocarcinoma cell line. Conclusion: CARD9 was shown to be an independent prognostic factor of poor outcome for lung cancer and may represent a molecular target for treatment. Keywords: CARD9, lung adenocarcinoma, spiral array, immunohistochemistry
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