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Pneumatosis intestinalis and portal venous gas secondary to Gefitinib therapy for lung adenocarcinoma
Joo Lee, Hye-Suk Han, Sung-Nam Lim, Young Shim, Yong Choi, Ok-Jun Lee, Ki Hyeong Lee, Seung Kim
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-87
Abstract: The present report describes a case of PI and PVG secondary to treatment with an EGFR tyrosine kinase inhibitor. A 66-year-old woman who had been diagnosed with metastatic lung adenocarcinoma presented with nausea, vomiting and abdominal distension after commencing gefitinib. A computed tomography (CT) scan of the abdomen revealed PI extending from the ascending colon to the rectum, hepatic PVG, and infarction of the liver. Gefitinib therapy was discontinued immediately and the patient was managed conservatively. A follow-up CT scan 2 weeks later revealed that the PI and hepatic PVG had completely resolved.This is the first report of PI and PVG caused by EGFR tyrosine kinase inhibitor. Although these complications are extremely rare, clinicians should be aware of the risk of PI and PVG in patients undergoing targeted molecular therapy.Recent advances in our understanding of the biology and molecular mechanisms of cancer have led to the introduction of molecular-targeted agents for the treatment of non-small cell lung cancer (NSCLC). Gefitinib is an orally active selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, an enzyme that regulates the intracellular signaling pathways implicated in the proliferation and survival of cancer cells [1]. Somatic mutations in the region of EGFR that encodes the tyrosine kinase domain of the receptor have been identified in patients with NSCLC and many studies report that NSCLC patients who carry these mutations are highly responsive to gefitinib [2,3].In general, targeted molecular therapies such as gefitinib have good toxicity profiles. However, some patients develop specific and severe toxicities, since these molecular targets are also expressed in normal cells. Although gefitinib is generally well tolerated, its most commonly reported side effects are of the gastrointestinal tract (diarrhea, nausea and vomiting) and skin (rash, acne, dry skin and pruritus). Severe gastrointestinal toxicity secondar
Successful Erlotinib Treatment for a Patient with Gefitinib-Related Hepatotoxicity and Lung Adenocarcinoma Refractory to Intermittently Administered Gefitinib
Tatsuya Nagano,Yoshikazu Kotani,Kazuyuki Kobayashi,Masahiro Katsurada,Yukihisa Hatakeyama,Suya Hori,Daisuke Tamura,Daisuke Kasai,Yasuhiro Funada,Yoshihiro Nishimura
Case Reports in Pulmonology , 2011, DOI: 10.1155/2011/812972
Abstract: A 73-year-old Japanese man was histologically diagnosed with lung adenocarcinoma harboring an exon 19 deletion in the epidermal growth factor receptor. The patient was treated with gefitinib for 6 weeks until he developed substantially elevated hepatic enzyme levels that resulted in the discontinuation of gefitinib. Gefitinib was reintroduced with an intermittent treatment schedule after the transaminase levels normalized, but the patient's enzyme levels rose again, and the cancer progressed. Gefitinib was eventually replaced with erlotinib. There was stable disease for 7 weeks without any signs of liver toxicity. Thus, erlotinib may be a beneficial and well-tolerated treatment option for patients with gefitinib-related hepatotoxicity.
Clinic outcome of gefitinib in sixty-nine elderly patients with lung adenocarcinoma  [cached]
Yan WANG,Xiangru ZHANG,Bin WANG,Ziping WANG
Chinese Journal of Lung Cancer , 2008,
Abstract: Background and Objective To evaluate the efficacy and safety of gefitinib, an orally active epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI), in elderly patients with other types of adenocarcinoma. Methods The clinical characteristics, response of treatment and survival were retrospectively reviewed in sixty-nine elderly patients (?65 years). All these patients received gefitinib 250mg/d in Cancer Institute ( Hospital ), Chinese Aacademy of Medical Sciences until disease progression or toxicities not tolerated by patient. Results Overall response rate and disease controlled rate (DCR) of gefitinib were 24.6% and 88.4% respectively. The median survival time was 15 months. One year survival was 62.2%. The response rate of gefitinib were significantly higher in patients less than 75-year-old, non-smoker and first-line treatment group than in patients above 75-year-old, smoker and second-line or third-line treatment. Furthermore, the overall survival times were significantly longer in patients of Bronchioloalveolar carcinoma, female and nonsmokers than patients with adenocarcinoma, and male and smokers. Rash and diarrhea were the most common adverse events (AEs) , but usually were mild. Conclusion Gefitinib is effective and safe in elderly patients with advanced adenocarcinomas of the lung.
Clinical Experience of Gefitinib in the Treatment of 32 Lung Adenocarcinoma Patients with Brain Metastases  [PDF]
Jianping XU, Xiaoyan LIU, Sheng YANG, Xiangru ZHANG, Yuankai SHI
- , 2015, DOI: : 10.3779/j.issn.1009-3419.2015.09.05
Abstract: Background and objective Brain metastasis was frequent in non-small cell lung cancer (NSCLC) patients with poor prognosis. Gefitinib was an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor which has been used in the treatment of NSCLC. Our study was to evaluate the efficacy and toxicities of gefitinib in lung adenocarcinoma patients with brain metastases. Methods We retrospectively reviewed clinical records of 32 lung adenocarcinoma patients with brain metastases, who had received gefitinib 250 mg Qd until disease progression or intolerable toxicities. Results The median overall survival (mOS) and median progression-free survival (mPFS) were 24.7 months and 11.2 months, respectively. Response rate (RR) and disease control rate (DCR) were 62.5% and 93.8%, respectively. The mOS and mPFS of gefitinib-naive patients were 35.6 months and 11.3 months, respectively, and RR and DCR were 75.0% and 100.0%, respectively. The mOS and mPFS of gefitinib treatment patients were 18.6 months and 6.7 months, respectively, and RR and DCR were 50.0% and 83.3%, respectively. The mOS and mPFS of patients with sensitive EGFR mutation were 24.8 months and 10.8 months, respectively, and RR and DCR were 75.0% and 100.0%, respectively. The mOS and mPFS of patients with unknown EGFR status were 35.6 months and 12.3 months, respectively, and RR and DCR were 53.3% and 86.7%, respectively. Treatment was well tolerated and no severe toxicities were observed. Common toxicities include: rash in 15 patients (46.9%), diarrhea in 7 cases (21.9%) and oral ulcer in 1 case (3.1%). Conclusion Gefitinib was highly effective and well tolerated in lung adenocarcinoma patients with brain metastases, and could be recommended as a treatment choice for this population.
Screening and Identification of MicroRNAs Related to Acquired Gefitinib-resistance in Lung Adenocarcinoma Cell Lines  [cached]
Xuebo QIN,Bin LIU,Yang LI,Jiacong YOU
Chinese Journal of Lung Cancer , 2011, DOI: 10.3779/j.issn.1009-3419.2011.06.18
Abstract: Background and objective Acquired gefitinib-resistance was closely related to inefficiency of EGFR-TKI treatment in lung adenocarcinoma. However, it was not clear that how microRNAs influenced the acquired gefitinib-resistance in lung adenocarcinoma. The aim of this study is to screen and identify the microRNAs correlated with the acquired gefitinib -resistance in lung adenocarcinoma. Methods Morphological difference was observed in gefitinib-sensitive lung adenocarcinoma cell line PC9 cell line and gefitinib-resistance lung adenocarcinoma cell line PC9/AB11 cell line derived from PC9 cell line. Cell cycles and doubling time were detected by flow cytometry, IC50 of gefitinib was evaluated by MTT assay. The differential microRNAs related to acquired gefitinib-resistance were screened and identified by microRNA array and real-time PCR. Results There were obvious morphological differences between PC9 and PC9/AB11 cells. The doubling time, distribution of cell cycle, and the IC50 between PC9 and PC9/AB11 were significantly different. In microarray analysis, compared with PC9 cell line, 4 up-regulated microRNAs were found in PC9/AB11 cells, 9 down-regulated microRNAs were found in PC9/AB11 cells. Real-time PCR revealed that miR-138 was significantly down-regulated in PC9/AB11 cells, accord with the microarray. Conclusion MicroRNAs are involved in acquired Gefitinib-resistance of lung adenocarcinoma. Our data presented here to provide an experimental basis and theory thereunder for further study of effect and molecule mechanism underlying the acquired gefitinib-resistance of lung cancer.
Effects of paclitaxel and gefitinib on the proliferation and cell cycle of human lung adenocarcinoma cell SPC-A1  [cached]
Gang JIA,Weimin ZHANG,Juan ZHOU,Zhixia ZHOU
Chinese Journal of Lung Cancer , 2008,
Abstract: Background and objective Previous clinical trials showed that there was no clinical benefit in the treatment of advanced non-small cell lung cancer when chemotherapy combined with gefitinib. The present study aims to assess the sequential administration of paclitaxel and gefitinib on the cell proliferation of lung adenocarcinoma cell SPC-A1 and to explore its mechanism by observing their effects on the cell cycle. Methods The expression of EGFR mRNA and EGFR protein were examined by RT-PCR and western blotting respectively. MTT was used to measure the cell proliferation of SPC-A1 cells. Cell cycle was detected by flow cytometry. Results Both EGFR mRNA and EGFR protein were overexpressed in SPC-A1 cells. From 1×10-14 M to 1×10-6 M, both paclitaxel and gefitinib inhibited the cell proliferation of SPC-A1 cells in a dose-dependent and time-dependent manner in vitro. The effects of paclitaxel in combination with gefitinib on cell proliferation depended on the sequence. No significant additive effects on cell proliferation was found when they were used simultaneously or gefitinib was added before paclitaxel. However, sequential administration of gefitinib following paclitaxel can remarkably enhanced the effect of paclitaxel on the cell proliferation of SPC-A1 cells. Cell cycle studies showed that paclitaxel and gefitinib induced G2/M and G0/G1 arrest respectively. The G0/G1 arrest was observed when paclitaxel and gefitinib was used simultaneously or gefitinib was added before paclitaxel. In contrast, sequential administration of gefitinib following paclitaxel induced G2/M arrest. Conclusion Both paclitaxel and gefitinib inhibits the cell proliferation of SPC-A1 cells. The additive effects on cell proliferation are sequential-dependent. The concomitant and the sequential treatment of gefitinib followed by paclitaxel exert no significant additive effects on the cell proliferation and resulted in the accumulation of cells in G0/G1 phase, which may decrease the effectiveness of paclitaxel in subsequent cycles. The additive effected on the cell proliferation are observed only when gefitinib is sequentially administrated following paclitaxel, which results in the G2/M arrest. The increase in G2/M phase suggests that cell cycle effects might not explain the observed additive effects.
Sequence-dependent Effect of Docetaxel with Gefitinib on the Proliferation and Apoptosis of Lung Adenocarcinoma Cell H1975  [cached]
Xinyu ZHANG,Guiyang LIU,Xiaoguang ZHU,Weilan WANG
Chinese Journal of Lung Cancer , 2012, DOI: 10.3779/j.issn.1009-3419.2012.03.01
Abstract: Background and objective Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib show promising therapeutic effects in patients with advanced non-small cell lung cancer (NSCLC). However, despite an initial response to EGFR-TKIs treatment among responsive patients, most inevitably acquire resistance after a progression-free period of about 10 months. The percentage of T790M in TKI acquired-resistant patients in most studies is around 50%. The aim of this study is to assess the effects of the sequential administration of docetaxel and gefitinib on cell proliferation and apoptosis of lung adenocarcinoma cell H1975. Methods An MTT assay was used to measure cell proliferation. The potency of the sequential administration of docetaxel and gefitinib were determined by isobolograms and combination index (CI). Cell apoptosis and cycle distribution were determined by flow cytometry. The Hoechst 33258 method was used to observe the apoptotic morphology. Chemical colorimetric luminescence was used to measure the caspase activity. Results The isobolograms and CI showed that the sequential administration of docetaxel following gefitinib remarkably inhibits cell proliferation and cell apoptosis compared with other sequential administration models. The cycle distribution results indicate that sequential docetaxel administration following gefitinib blocked the cells in the G2/M phase but not in the G0/G1. The activation of the Caspase-8/Caspase-3 cascade is mainly involved in the apoptotic pathway of lung adenocarcinoma cell H1975 in all sequential administration models. Conclusion The docetaxel administration following gefitinib might be a new stratagy for lung cancer with T790M mutation after having EGFR-TKIs resistance.
Skin rash by gefitinib is a sign of favorable outcomes for patients of advanced lung adenocarcinoma in Japanese patients
Yasoo Sugiura, Etsuo Nemoto, Osamu Kawai, Yasuyuki Ohkubo, Hisae Fusegawa and Shizuka Kaseda
SpringerPlus , 2013, DOI: 10.1186/2193-1801-2-22
Abstract: Skin rash is one of the notorious adverse events of gefitinib as well as other epidermal growth factor receptor tyrosine kinase inhibitors. The differences of response rate and frequency of adverse events between ethnic groups are well known. Some reports demonstrated the correlation between development of rash and efficacy in Caucasian patients treated with erlotinib, gefitinib or cetuximab. We analyzed clinical course of Japanese patients of lung adenocarcinoma in order to assess the relation between adverse events and efficacy of gefitinib. Between January 2008 and June 2012, 24 Japanese patients administered gefitinib 250 mg daily. The adverse events were evaluated in accordance with Common Terminology Criteria For Adverse Events v4.0 (CTCAE). Objective response to gefitinib was evaluated with using computed tomography every 1–2 months. The relationship between each adverse event and objective response was examined by chi-square test. The Log-rank Test was used to assess the relationship between the presence of skin rash and overall survival. Twenty four patients with a median age of 67 years (range 55–89) entered were 16 female and 8 male patients; the pathological diagnosis of all patients was adenocarcinoma. Skin rash in CTCAE occurred in 10. The objective response and overall survival among the patients with skin rash was significantly superior to the patients without skin rash. Skin rash by gefitinib correlates with improved clinical outcomes among advanced lung adenocarcinoma patients.
Expression of Acetaldehyde Dehydrogenase in Gefitinib-resistant Human Lung Adenocarcinoma HCC-827/GR Cells  [PDF]
Tingting YANG, Jingjing GU, Ting LIU, Haibin MA, Xiaona MA, Jin TAO, Yiran JIN, Xueyun LIANG
- , 2018, DOI: : 10.3779/j.issn.1009-3419.2018.06.01
Abstract: Background and objective Tumor recurrence and drug resistance are the main causes of death in tumor patients. The family of acetaldehyde dehydrogenase (ALDH) is closely related to the proliferation, migration, invasion and resistance of tumor cells, and different ALDH subtypes are expressed in different tumor cells. The aim of this study is to elucidate the ALDH subtype in human lung adenocarcinoma HCC-827/GR cells, which resistant to the gefitinib. Methods The human lung adenocarcinoma HCC-827 cells were used to generate the gefitinib-resistant HCC-827/GR cells; the expression of ALDH subtype in either HCC-827 or HCC-827/GR was detected by flow cytometry; The proliferative capacity and sensitivity to gefitinib of hcc-827/GR cells were analyzed by MTT assay before and after treatment with 100 μmol/L diethyllaminaldehyde (DEAB); Real-time quantitative PCR was used to detect the expression of ALDH subtypes at mRNA levels in hcc-827 cells and hcc-827/GR cells. Results Compared with HCC-827 cells, the positive rate of ALDH in HCC-827/GR cells increased. The proliferation ability of HCC-827/GR cells decreased after treatment with 100 μmol/L DEAB. Compared with HCC-827 cells, the expression of ALDH1A1 and ALDH1L1 mRNA was increased in hcc-827/GR cells, but the ALDH3B2 expression was decreased. Conclusion ALDH might be used as a molecular biomarker to test the gefitinib-resistant to lung adenocarcinoma cancer cells, and the ALDH1A1 may play a role in gefitinib resistance in lung cancer. ?
Dramatic responses to gefitinib when used as front line therapy in two cases of metastatic lung adenocarcinoma with poor performance status  [cached]
Gupta Ajay,Raina Vinod,Garg Priyam,Kumar Rakesh
Journal of Cancer Research and Therapeutics , 2010,
Abstract: A 54-year-old man, a non-smoker, suffering from metastatic lung adenocarcinoma presented with extensive bilateral pulmonary infiltrates. He was dyspneic at rest. Performance status (PS) was 4. Institution of gefitinib resulted in relief from dyspnea within two weeks. Positron emission tomography done after 10 months revealed only a 2 cm residual lesion. However, the patient stopped therapy on his own and died two months later. An 80-year-old female, a non smoker, presented with metastatic lung adenocarcinoma and right sided pleural effusion. Her PS was 4. She was started on gefitinib. Within four weeks, she showed marked improvement. At six months, she was radiologically documented to be in partial remission. She continues to be asymptomatic at one year follow-up. These are the first reports of dramatic responses to gefitinib when used as front-line therapy in patients with poor performance status from India.
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