ErbB receptor tyrosine kinase inhibitors (EGFR-TKI), gefitinib, erlotinib, icotinib and aftinib, which are approved as a frontline treatment for patients with non-small cell lung cancer (NSCLC) who have tumors harboring EGFR mutations in China. And osimertinib was approved in second line setting for patients with EGFRT 790M-positive NSCLC. Rash, paronychia, diarrhea, stomatitis, liver dysfunction and (interstitial lung disease, ILD) are frequently observed in patients treated with EGFR-TKI. Chinese Society of Lung Cancer, Chinese Anti-Cancer Association, organized Chinese experts to develop the Chinese expert consensus on EGFR-TKI adverse event (AE) management based on domestic diagnosis and treatment of ADR and also incorporating international updated theory and recommendations.
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Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; China ; Diarrhea ; etiology ; ErbB Receptors ; antagonists & inhibitors ; genetics ; metabolism ; Humans ; Liver Diseases ; etiology ; Lung Diseases ; etiology ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Stomatitis ; etiology

With the development of sequencing technology, the detection rate of de novo T790M mutation is increasing. The emergence of the third generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide treatment opportunities. Secondary T790M mutation is often emphasized in clinic, but de novo T790M mutation is neglected. This review found that the incidence of de novo T790M mutation fluctuated greatly, which was mainly affected by sequencing techniques. The de novo T790M mutation is mainly low in mutation abundance, easy to combine with other gene changes, a poor predictor and prognostic factor and the efficacy of the first and second generation EGFR-TKIs is limited. The therapeutic value of osimertinib needs to be studied.
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Carcinoma, Non-Small-Cell Lung ; diagnosis ; drug therapy ; enzymology ; genetics ; ErbB Receptors ; antagonists & inhibitors ; genetics ; Humans ; Lung Neoplasms ; diagnosis ; drug therapy ; enzymology ; genetics ; Mutation ; Prognosis ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated some dramatic efficacy in advanced non-small-cell lung cancer (NSCLC) patients with activating EGFR mutation. However, progression-free survivals (PFS) among those patients who were treated with first line EGFR TKIs were inconsistent. The aim of this study is to explore the association of clinical prognostic factors with EGFR-TKI efficacy in advanced NSCLC patients. METHODS: The demographic and clinical characteristics of 203 patients with activating EGFR mutation treated with first generation TKI as a first-line therapy were retrospectively reviewed. RESULTS: Of the 203 patients enrolled in this study, 139 patients had progression of disease and 63 patients died. The subjects had a median follow up duration of 21.1months and a median PFS of 14.3 months. Partial response (PR) was achieved in 127 (66.1%) patients and stable disease (SD) rate was achieved in 55 (28.6%) patients. In univariate analysis, patients with 2 or higher ECOG score (5.1 vs 16 months, P=0.033), SD as best overall response (9.5 vs 17.9 months, P=0.030), extrathoracic metastasis (11.7 vs 27.5 months, P=0.004), liver metastasis (4.1 vs 16.0 months, P=0.000), bone metastasis (13.3 vs 21.5months, P=0.027) and pulmonary embolism (5.5 vs 16.6 months, P=0.005) had shorter PFS than those without the listed factors. Multivariable Cox regression analysis showed best overall response (HR=1.825, 95%CI: 1.107-3.008, P=0.018) and liver metastasis (HR=1.694, 95%CI: 1.146-5.756, P=0.022) were independent predictive factors of shorter PFS. CONCLUSIONS Despite the high efficacy of EGFR-TKI, SD as best overall response and liver metastasis predicts poorer PFS in advanced NSCLC patients with EGFR gene mutations receiving first-line therapy treatment.
Adult ; Aged ; Antineoplastic Agents ; administration & dosage ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; mortality ; ErbB Receptors ; genetics ; metabolism ; Female ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; Middle Aged ; Mutation ; Protein Kinase Inhibitors ; administration & dosage ; Retrospective Studies ; Treatment Outcome ; Young Adult

OBJECTIVEEscape from the body's immune response is a basic characteristic of lung cancer, and indoleamine-2,3-dioxygenase (IDO) plays a key role in mediating immune escape of non-small-cell lung cancer, which leads to recurrence and metastasis. Feiji Recipe, a compound Chinese herbal medicine, has the effect of stabilizing lesions and prolonging survival in patients with lung cancer. The purpose of this study was to investigate the mechanisms underlying the anticancer properties of Feiji Recipe.

METHODSAn orthotopic transplant model of mouse Lewis lung cancer, with stable expression of IDO gene, was established in C57BL/6 mice. Optical imaging was used to observe the effects of Feiji Recipe in the treatment of lung cancer in vivo. The effects of Feiji Recipe on the proliferation of mouse Lewis lung cancer cell line 2LL, 2LL-enhanced green fluorescent protein (2LL-EGFP) and 2LL-EGFP-IDO were investigated, and the apoptosis of T-cells was examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide using flow cytometry. Chemical composition of Feiji Recipe was validated by high-performance liquid chromatography.

RESULTSCompared to the control group, the survival of animals treated with Feiji Recipe was significantly prolonged (P = 0.0074), and the IDO protein level decreased (P = 0.0072); moreover, the percentages of CD4CD25 T-cells and Foxp3 T-cells were significantly decreased (P < 0.05). The molecular mechanism of Feiji Recipe against lung cancer may relate to the regulation of immune cells, such as T-cells and regulatory T-cells.

CONCLUSIONThe molecular mechanism of Feiji Recipe in treatment of lung cancer is to restore the function of T-cells in the cancer microenvironment through interfering with the IDO pathway.

Animals ; Apoptosis ; drug effects ; Carcinoma, Lewis Lung ; drug therapy ; enzymology ; immunology ; physiopathology ; Cell Proliferation ; drug effects ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Growth Inhibitors ; administration & dosage ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; genetics ; immunology ; Lung Neoplasms ; drug therapy ; enzymology ; immunology ; physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes, Regulatory ; drug effects ; immunology

OBJECTIVETo investigate the effect of combined application of Xuebijing Injection ( , XBJ) and resolvin D1 (RvD1) on survival rate and the underlying mechanisms in mice with sepsisinduced lung injury.

METHODSThe cecal ligation and puncture (CLP) method was used to develop a mouse sepsis model. Specific pathogen free male C57BL/6 mice were randomly divided into 5 groups (n=20 each): sham, CLP, CLP+XBJ, CLP+RvD1 and CLP+XBJ+RvD1. After surgery, mice in the CLP+XBJ, CLP+RvD1 and CLP+XBJ+RvD1 groups were given XBJ (25 μL/g body weight), RvD1 (10 ng/g body weight), and their combination (the same dose of XBJ and RvD1), respectively. In each group, 12 mice were used to observe 1-week survival rate, while the rest were executed at 12 h. Whole blood was collected for flow cytometric analysis of leukocyte adhesion molecules CD18, lung tissues were harvested for observing pathological changes, and testing the activity of myeloperoxidase (MPO) and the expression of intercellular cell adhesion molecule 1 (ICAM-1).

RESULTSCompared with the CLP group, the histopathological damage of the lung tissues was mitigated, MPO activity was decreased in the CLP+XBJ and CLP+RvD1 groups (P<0.05). In addition, the 1-week survival rate was improved, proportion of CD18-expressing cells in whole blood and ICAM-1 protein expression in lung tissue were decreased in the CLP+XBJ+RvD1 group (P<0.05 or P<0.01).

CONCLUSIONSXBJ together with RvD1 could effectively inhibit leukocyte adhesion, reduce lung injury, and improve the survival rate of mice with sepsis.

Animals ; CD18 Antigens ; metabolism ; Cell Adhesion ; drug effects ; Docosahexaenoic Acids ; administration & dosage ; pharmacology ; therapeutic use ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; therapeutic use ; Injections ; Intercellular Adhesion Molecule-1 ; metabolism ; Leukocytes ; drug effects ; metabolism ; pathology ; Lung ; drug effects ; enzymology ; pathology ; Lung Injury ; blood ; complications ; drug therapy ; Male ; Mice, Inbred C57BL ; Peroxidase ; metabolism ; Sepsis ; blood ; complications ; drug therapy ; Survival Analysis

PURPOSE: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. MATERIALS AND METHODS: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. RESULTS: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p < 0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p < 0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03–1.42; p=0.106). CONCLUSION: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC.
Adult ; Aged ; Antineoplastic Agents/*therapeutic use ; Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/mortality ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms/*drug therapy/enzymology/mortality ; Male ; Middle Aged ; Mutation ; Pemetrexed/*therapeutic use ; Receptor Protein-Tyrosine Kinases/genetics ; Retrospective Studies ; Survival Rate ; Treatment Outcome

To establish rat model of lung ischemia/reperfusion (IR) in vivo, and to explore the effects of acidification pretreatment for respiratory acidosis on the expression of matrix metalloproteinase-9 (MMP-9) and the possible mechanisms.
 Methods: A total of 36 male Sprague-Dawley rats were divided into a sham group (S group), a IR group, and an experiment group (RA group) (n=12 in each group). The rat left lung hilum in the S group was dissociated, followed by perfusion without ischemia. After the left lung hilum in the IR group was blocked for 45 min, the rats were followed by reperfusion for 180 min. After left lung hilum in the RA group was dissociated, the respiratory parameters were adjusted so that pressure of end tidal carbon dioxide (PETCO2) reached 56-65 mmHg (1 mmHg=0.133 kPa) for 5 min, then the rats was subjected to IR. Lung tissue wet/dry (W/D) and lung permeability index (LPI) were calculated, while the lung histopathology was observed and the MMP-9 protein expression were measured.
 Results: Compared with the control group, the W/D and LPI in the IR group and the RA group increased after reperfusion (both P<0.05), and the levels of W/D and LPI in the group RA were lower than that in the IR group (P<0.05). LPI and pathology scores were significantly lower in the RA group than those in the IR group (both P<0.01). After IR, the expression of MMP9 in the lung tissues in the IR group and the RA group increased significantly (both P<0.01). The expression of MMP-9 protein in the RA group was significantly lower than that in the IR group (P<0.01).
 Conclusion: After lung IR injury, the expression of MMP-9 protein, vascular permeability and inflammatory exudation is increased. The acidification pretreatment for respiratory acidosis can inhibit the expression of MMP-9 protein and reduce inflammatory exudation after lung IR, showing a protective effect on lung IR injury.
Acidosis, Respiratory ; drug therapy ; prevention & control ; Animals ; Gene Expression Regulation, Enzymologic ; drug effects ; Lung ; enzymology ; Lung Injury ; enzymology ; Male ; Matrix Metalloproteinase 9 ; genetics ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; drug therapy ; prevention & control

BACKGROUND: Epidermal growth factor receptor (EGFR)-based targeted therapy improves the survival of patients with advanced lung adenocarcinoma harboring EGFR mutations. However, factors including treatment or heterogeneity partly contribute to EGFR genetic status alteration between baseline and disease progresses (PD). The aim of this study is to compare difference of EGFR mutations between biopsy and rebiopsy in real world. METHODS: Data from 61 paired specimens performed EGFR testing in Jilin Provincial Cancer Hospital between January 2015 and December 2017 were collected and analyzed. The specimens were collected at baseline and PD, confirmed by histology or cytology and categorized as tumor tissue, malignant pleural effusion or plasma. All patients were naive and received chemotherapy or targeted therapy as first-line treatment. Amplification Refractory Mutation System (ARMS) was used to detect EGFR mutations. RESULTS: EGFR mutation rate in tumor tissue, pleural effusion or blood was 90.2% vs 88.5%, 6.6% vs 6.6% and 3.2% vs 4.9% at baseline or PD respectively and discrepancy was 72% and 36.3% for the same (n=50) or different (n=11) type of specimens. The EGFR mutation rate was 95.1% and 91.8% in patients before and after treatment, and the discrepancy was 63.9%, among which, 69.2% and 92.3% in chemotherapy-treated patients (n=13) with discrepancy to 46.1% (6/13), and 100.0% and 91.7% in EGFR-TKI-treated patients (n=48) with discrepancy to 70.8%. There were four types of alterations in terms of EGFR mutations: wild type turned into mutation (4.9%), mutation disappeared (8.2%), sensitive mutations transformed (1.6%), and new mutations appeared (49.1%). CONCLUSIONS In real world, the EGFR mutation status in advanced non-small cell lung cancer (NSCLC) patients altered significantly, due to tissue resources and therapeutic approaches, implying the importance of rebiopsy and real-time detection of EGFR mutation, in order to provide data to guide precise strategy in the following treatment.
Adult ; Aged ; Biopsy ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; pathology ; ErbB Receptors ; antagonists & inhibitors ; genetics ; Female ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; pathology ; Male ; Middle Aged ; Mutation ; Protein Kinase Inhibitors ; therapeutic use ; Retrospective Studies ; Treatment Outcome

The incidence of ALK gene rearrangement in non-small cell lung cancer (NSCLC) was about 3% to 5%. ALK gene inhibitors have made great breakthrough in recent years, significantly extending the survival period of patients with ALK(+) advanced NSCLC. But the majority of patients will be acquired drug resistance after treatment. This article has been explained separately from the ALK genetic background, the detection method, the treatment of the three generations of ALK inhibitors and the strategy after drug resistance. It is desire to have reference value and reference meaning for clinical work.
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Anaplastic Lymphoma Kinase ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; Drug Resistance, Neoplasm ; genetics ; Gene Fusion ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Receptor Protein-Tyrosine Kinases ; antagonists & inhibitors ; genetics

Molecular target therapy is one of the most popular field of non-small cell lung cancer (NSCLC) treatmnet. Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearragement are the most important two oncogenic drivers in NSCLC, early studies suggested that EGFR mutations and ALK rearrangements are mutually exclusive, but isolated cases or small sample research with concomitant EGFR and ALK alterations have been constantly reported. The co-occurrence of EGFR mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular, the frequency of EGFR/ALK co-alterations was about 1%, however, little has been known about clinicopathologic feature and treatment. This review summarized published case report, EGFR and ALK alterations are common in female, Asian origin, never smoker, IV stage, and denocarcinomas. First-line treatment can choose EGFR or ALK tyrosine kinase inhibitors (TKIs). However, studies about the origin and resistance mechanism in EGFR/ALK co-alterations are little, require more experimental and clinical research.
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Anaplastic Lymphoma Kinase ; Carcinoma, Non-Small-Cell Lung ; diagnosis ; enzymology ; genetics ; ErbB Receptors ; genetics ; Humans ; Lung Neoplasms ; diagnosis ; enzymology ; genetics ; Mutation ; Prognosis ; Receptor Protein-Tyrosine Kinases ; genetics