UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Medline ® Abstracts for References 4-8

of '抗肿瘤治疗相关的肺毒性:分子靶向药物'

4
TI
Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study.
AU
Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Ichinose Y, Tsuboi M, Yokota S, Nakagawa K, Suga M, Japan Thoracic Radiology Group, Jiang H, Itoh Y, Armour A, Watkins C, Higenbottam T, Nyberg F
SO
Am J Respir Crit Care Med. 2008;177(12):1348. Epub 2008 Mar 12.
 
RATIONALE: Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib.
OBJECTIVES: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy.
METHODS: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data.
MEASUREMENTS AND MAIN RESULTS: The observed (unadjusted) incidence rate over12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2).
CONCLUSIONS: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.
AD
Nippon Medical School, Tokyo, Japan.
PMID
5
TI
Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib.
AU
Takano T, Ohe Y, Kusumoto M, Tateishi U, Yamamoto S, Nokihara H, Yamamoto N, Sekine I, Kunitoh H, Tamura T, Kodama T, Saijo N
SO
Lung Cancer. 2004;45(1):93.
 
A high incidence of interstitial lung disease (ILD) has been reported in patients with non-small cell lung cancer (NSCLC) treated with gefitinib in Japan. We retrospectively analyzed 112 patients with advanced NSCLC who received gefitinib monotherapy. Univariate and multivariate analyses were used to identify risk factors for gefitinib-related ILD and predictive factors for tumor response to gefitinib. The incidence of ILD was 5.4%, and it was higher in the patients with pre-existing pulmonary fibrosis (33% versus 2%; P<0.001). The results of a multivariate analysis showed that pulmonary fibrosis was a significant risk factor for ILD (odds ratio: 177, 95% confidence interval: 4.53-6927, P = 0.006). The response rate was 33% in the 98 evaluable patients and higher in women (53% versus 23%; P = 0.003), patients with adenocarcinoma (38% versus 6%; P = 0.010), never-smokers (63% versus 18%; P<0.001), and the patients with no history of thoracic radiotherapy (39% versus 13%; P = 0.015). The results of a multivariate analysis showed that the predictors of tumor response were "no history of smoking" and "no history of thoracic radiotherapy". Never-smokers had a significantly longer survival time than smokers (P = 0.007). Although gefitinib therapy confers a clinical benefit on patients with advanced NSCLC, especially on women, patients with adenocarcinoma, never-smokers, and patients with no history of thoracic radiotherapy, it also poses a high risk of ILD, especially to patients with pulmonary fibrosis. The risk-benefit ratio must be carefully considered.
AD
Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. totakano@ncc.go.jp
PMID
6
TI
An ADAM family member with expression in thymic epithelial cells and related tissues.
AU
Haidl ID, Huber G, Eichmann K
SO
Gene. 2002;283(1-2):163.
 
We have analyzed the tissue-specific expression, mRNA isoforms, and genomic structure of murine ADAM28, an ADAM family member recently discovered in human and mouse. While human ADAM28 is expressed in lymphocytes (J. Biol. Chem. 274 (1999) 29251), we observe expression of murine ADAM28 in thymic epithelial cells and developmentally related tissues including the trachea, thyroid, stomach, and lung, but not in lymphocytes. The expression patterns in adult and day 15.5 embryos are similar. We have detected multiple mRNA isoforms varying in the cytoplasmic domain coding sequence and 3prime prime or minute untranslated region due to alternative polyadenylation and splicing events that occur in the final four exons and three introns. The entire ADAM28 gene spans 55 kb and contains 23 exons. The protein sequence contains all conserved residues required for metalloprotease activity, indicative of a role in ectodomain shedding and extracellular matrix modeling. Given its unique expression pattern and potential functions, murine ADAM28 may play a role in organogenesis and organ-specific functions such as thymic T cell development.
AD
Max-Planck-Institute for Immunobiology, Stübeweg 51, D-79108, Freiburg, Germany.
PMID
7
TI
Impaired lung branching morphogenesis in the absence of functional EGF receptor.
AU
Miettinen PJ, Warburton D, Bu D, Zhao JS, Berger JE, Minoo P, Koivisto T, Allen L, Dobbs L, Werb Z, Derynck R
SO
Dev Biol. 1997;186(2):224.
 
The mammalian lung develops through branching morphogenesis which is controlled by growth factors, hormones, and extracellular matrix proteins. We have evaluated the role of EGF-receptor signaling in lung morphogenesis by analyzing the developmental phenotype of lungs in mice with an inactivated the EGF-receptor gene both in vivo and in organ culture. Neonatal EGF-receptor-deficient mice often show evidence of lung immaturity which can result in visible respiratory distress. The lungs of these mutant mice had impaired branching and deficient alveolization and septation, resulting in a 50% reduction in alveolar volume and, thus, a markedly reduced surface for gas exchange. The EGF-receptor inactivation also resulted in type II pneumocyte immaturity, which was apparent from their increased glycogen content and a reduced number of lamellar bodies. The defective branching was already evident at Day 12 of embryonic development. When explants of embryonic lungs from Day 12 embryos were cultured under defined conditions, the branching defect in EGF-receptor-deficient lungs was even more pronounced, with only half as many terminal buds as normal lungs. EGF treatment stimulated the expression of surfactant protein C and thyroid transcription factor-1 in cultured normal lungs, but not in EGF-receptor-deficient lungs, suggesting that EGF-receptor signaling regulates the expression of these marker genes during type II pneumocyte maturation. Taken together, our data indicate that signal transduction through the EGF receptor plays a major role in lung development and that its inactivation leads to a respiratory distress-like syndrome.
AD
Department of Growth and Development, University of California at San Francisco, 94143, USA.
PMID
8
TI
Attenuation of acute lung injury in transgenic mice expressing human transforming growth factor-alpha.
AU
Hardie WD, Prows DR, Leikauf GD, Korfhagen TR
SO
Am J Physiol. 1999 Nov;277(5 Pt 1):L1045-50.
 
Transforming growth factor-alpha (TGF-alpha) is produced in the lung in experimental and human lung diseases; however, its physiological actions after lung injury are not understood. To determine the influence of TGF-alpha on acute lung injury, transgenic mouse lines expressing differing levels of human TGF-alpha in distal pulmonary epithelial cells under control of the surfactant protein C gene promoter were generated. TGF-alpha transgenic and nontransgenic control mice were exposed to polytetrafluoroethylene (PTFE; Teflon) fumes to induce acute lung injury. Length of survival of four separate TGF-alpha transgenic mouse lines was significantly longer than that of nontransgenic control mice, and survival correlated with the levels of TGF-alpha expression in the lung. The transgenic line expressing the highest level of TGF-alpha (line 28) and nontransgenic control mice were then compared at time intervals of 2, 4, and 6 h of PTFE exposure for differences in pulmonary function, lung histology, bronchoalveolar lavage fluid protein and cell differential, and lung homogenate proinflammatory cytokines. Line 28 TGF-alpha transgenic mice demonstrated reduced histological changes, decreased bronchoalveolar lavage fluid total protein and neutrophils, and delayed alterations in pulmonary function measures of airway obstruction compared with those in nontransgenic control mice. Both line 28 and nontransgenic control mice had similar increases in interleukin-1beta protein levels in lung homogenates. In contrast, interleukin-6 and macrophage inflammatory protein-2 levels were significantly reduced in line 28 transgenic mice compared with those in nontransgenic control mice. In the transgenic mouse model, TGF-alpha protects against PTFE-induced acute lung injury, at least in part, by attenuating the inflammatory response.
AD
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. bill.hardie@chmcc.org
PMID