Concomitant Mutations in EGFR 19Del/L858R Mutation and Their Association with Response to EGFR-TKIs in NSCLC Patients.
Liang Hengrui,Li Caichen,Zhao Yi,Zhao Shen,Huang Jun,Cai Xiuyu,Cheng Bo,Xiong Shan,Li Jianfu,Wang Wei,Zhu Changbin,Li Weiwei,He Jianxing,Liang Wenhua
Cancer management and research
Objective:Differences in efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been observed between non-small cell lung cancer (NSCLC) patients with and mutation. We explored whether the total number or pattern of concomitant mutations of and may explain their different sensitivities. Patients and Methods:This study contained the mutational profiles of EGFR-mutated NSCLC patients from two cohorts: Guangzhou (G1) and database (G2). Concomitant mutation status and EGFR-TKI response information were retrieved. Results:A total of 403 patients covered 283 genes in the G1 and 803 patients with a different gene set in the G2 were included. Similar prevalence of total concomitant mutation number was observed in both G1 ( 32.48% vs 30.45%; =0.68) and G2 ( 74.9% vs 73.2%; =0.65) cohorts. Only pathway same more related to mutation. EGFR-TKI response information was recorded for 134 patients in the G2 cohort. showed a higher objective response (OR) rate compared with , regardless of concomitant mutations. Compared to patients with OR, non-OR patients had more concomitant mutations, both in (53.8% vs 83.3%; =0.021) and (51.4% vs 77.8%; =0.029). In particular, total concomitant mutations (OR=0.27; =0.03), sensitive mutations (OR=2.21; =0.04), and (OR=0.244; =0.02) significantly affected the TKI response. Conclusion:Concomitant mutations were widespread in and and were associated with poorer OR to EGFR-TKIs. However, and had similar numbers and patterns of concomitant mutations, which might not explain the different sensitivity to EGFR-TKI.
Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei (epicentre) and outside Hubei (non-epicentre): a nationwide analysis of China.
Liang Wen-Hua,Guan Wei-Jie,Li Cai-Chen,Li Yi-Min,Liang Heng-Rui,Zhao Yi,Liu Xiao-Qing,Sang Ling,Chen Ru-Chong,Tang Chun-Li,Wang Tao,Wang Wei,He Qi-Hua,Chen Zi-Sheng,Wong Sook-San,Zanin Mark,Liu Jun,Xu Xin,Huang Jun,Li Jian-Fu,Ou Li-Min,Cheng Bo,Xiong Shan,Xie Zhan-Hong,Ni Zheng-Yi,Hu Yu,Liu Lei,Shan Hong,Lei Chun-Liang,Peng Yi-Xiang,Wei Li,Liu Yong,Hu Ya-Hua,Peng Peng,Wang Jian-Ming,Liu Ji-Yang,Chen Zhong,Li Gang,Zheng Zhi-Jian,Qiu Shao-Qin,Luo Jie,Ye Chang-Jiang,Zhu Shao-Yong,Cheng Lin-Ling,Ye Feng,Li Shi-Yue,Zheng Jin-Ping,Zhang Nuo-Fu,Zhong Nan-Shan,He Jian-Xing
The European respiratory journal
BACKGROUND:During the outbreak of coronavirus disease 2019 (COVID-19), consistent and considerable differences in disease severity and mortality rate of patients treated in Hubei province compared to those in other parts of China have been observed. We sought to compare the clinical characteristics and outcomes of patients being treated inside and outside Hubei province, and explore the factors underlying these differences. METHODS:Collaborating with the National Health Commission, we established a retrospective cohort to study hospitalised COVID-19 cases in China. Clinical characteristics, the rate of severe events and deaths, and the time to critical illness (invasive ventilation or intensive care unit admission or death) were compared between patients within and outside Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicentre as well the administrative centre of Hubei province) and the duration between symptom onset and admission on prognosis were also determined. RESULTS:At the data cut-off (31 January 2020), 1590 cases from 575 hospitals in 31 provincial administrative regions were collected (core cohort). The overall rate of severe cases and mortality was 16.0% and 3.2%, respectively. Patients in Hubei (predominantly with Wuhan-related exposure, 597 (92.3%) out of 647) were older (mean age 49.7 44.9 years), had more cases with comorbidity (32.9% 19.7%), higher symptomatic burden, abnormal radiologic manifestations and, especially, a longer waiting time between symptom onset and admission (5.7 4.5 days) compared with patients outside Hubei. Patients in Hubei (severe event rate 23.0% 11.1%, death rate 7.3% 0.3%, HR (95% CI) for critical illness 1.59 (1.05-2.41)) have a poorer prognosis compared with patients outside Hubei after adjusting for age and comorbidity. However, among patients outside Hubei, the duration from symptom onset to hospitalisation (mean 4.4 4.7 days) and prognosis (HR (95%) 0.84 (0.40-1.80)) were similar between patients with or without Wuhan-related exposure. In the overall population, the waiting time, but neither treated in Hubei nor Wuhan-related exposure, remained an independent prognostic factor (HR (95%) 1.05 (1.01-1.08)). CONCLUSION:There were more severe cases and poorer outcomes for COVID-19 patients treated in Hubei, which might be attributed to the prolonged duration of symptom onset to hospitalisation in the epicentre. Future studies to determine the reason for delaying hospitalisation are warranted.
Feasibility and safety of PD-1/L1 inhibitors for non-small cell lung cancer in front-line treatment: a Bayesian network meta-analysis.
Liang Hengrui,Lin Guo,Wang Wei,Huang Jun,Yang Yilin,Lan Yuting,Wang Runchen,Cui Fei,Hao Zhexue,Deng Hongsheng,Zhao Shen,Cheng Bo,Xiong Shan,Li Jianfu,Li Caichen,Liu Jun,He Jianxing,Liang Wenhua
Translational lung cancer research
Background:This Bayesian network meta-analysis (NMA) was conducted to compare efficacy and safety of programmed death 1/ligand 1 (PD-1/L1) inhibitors in previous untreated advanced non-small cell lung cancer (NSCLC) patients. Methods:Eligible studies evaluating first-line anti-PD-1/L1 based regimens in advanced NSCLC patients were included. Overall survival (OS), progression free survival (PFS), objective response rate (ORR), as well as treatment-related severe adverse events (tr-SAE) were synthesized within the Bayesian framework. Subgroup analysis was conducted according to PD-L1 expression. Results:Twelve studies including 7,490 patients and 9 treatment strategies were enrolled in this study. For the PD-L1 expression non-selective patients, all chemo-immunotherapies were significantly better than chemotherapy for prolonging OS and PFS, except for caremlizumab plus chemotherapy (HR =0.72) failed to show advantages for OS. In addition, pembrolizumab plus chemotherapy showed better PFS than nivolumab plus ipilimumab (HR =0.66). In PD-L1 ≥50% patients, all immunotherapy was better than chemotherapy for OS, except for nivolumab (HR =0.83) and nivolumab plus ipilimumab (HR =0.70). For PFS, pembrolizumab plus chemotherapy (HR =0.39), atezolizumab plus chemotherapy (HR =0.47) and pembrolizumab (HR =0.67) were significantly better than chemotherapy. In PD-L1 1-49% patients, pembrolizumab plus chemotherapy (HR =0.52) and atezolizumab plus chemotherapy (HR =0.70) were better than chemotherapy for PFS. In the PD-L1 positive or negative group, all included corresponding regimens were equivalence according to OS and PFS. Conclusions:We conducted a systematic comparison of first line immunotherapy for advanced NSCLC. Chemo-immunotherapies were better than chemotherapy and mono-immunotherapies in most patients. Pembrolizumab might have better efficacy than other PD-1/L1 inhibitors.
Complete video-assisted thoracoscopic surgery (VATS) bronchial sleeve lobectomy.
Huang Jun,Li Shuben,Hao Zhexue,Chen Hanzhang,He Jiaxi,Xu Xin,Qiu Yuan,Dong Qinglong,Liang Lixia,Pan Hui,He Jianxing
Journal of thoracic disease
BACKGROUND:To explore the effectiveness of video-assisted thoracoscopic surgery (VATS) bronchial sleeve resection and reconstruction. METHODS:The clinical data of patients who had received VATS bronchial sleeve lobectomy in our center from January 2008 to February 2015 were retrospectively analyzed. RESULTS:Totally 118 patients (105 men and 13 women) received the VATS bronchial sleeve lobectomy. The procedures included sleeve resection of right upper lobe (n=59), right middle lobe (n=7), right lower lobe (n=8), left upper lobe (n=34), and left lower lobe (n=10). The lesions were confirmed to be squamous cell carcinoma (n=68), adenocarcinoma (n=16), mucoepidermoid carcinoma (n=8), adenosquamous carcinoma (n=7), large cell carcinoma (n=1), carcinoids (n=5), and others (n=13; including small cell carcinoma, pleomorphic carcinoma, and inflammatory myofibroblastic tumor). Operations lasted 118-223 min [mean ± standard deviations (SD): 124.00±31.75 min]. The length of removed bronchus was 1.50-2.00 cm (mean ± SD: 1.75±0.26 cm). The duration of bronchial anastomosis (from the first puncture to the completion of knotting) was 15-42 min (mean ± SD: 30.20±7.97 min). The number of dissected lymph node stations (at least three mediastinal lymph node stations, including station 7) was 5-9 stations (mean ± SD: 6.50±1.18 min). The number of dissected lymph nodes was 10-46 (mean ± SD: 26.00±10.48). The intraoperative blood loss was 20-400 mL (mean ± SD: 71.00±43.95 mL), and no blood transfusion was performed. All patients were observed in intensive care unit (ICU) for 1 day. Postoperative drainage was performed for 3-8 days (mean ± SD: 5.00±1.49 days). Postoperative hospital stay was 3-8 days (mean ± SD: 5.10±2.07 days). CONCLUSIONS:VATS bronchial sleeve resection and reconstruction is a safe and feasible technique.
Characterization of γδT cells in lung of Plasmodium yoelii-infected C57BL/6 mice.
Wei Haixia,Jin Chenxi,Peng Anping,Xie Hongyan,Xie Shihao,Feng Yuanfa,Xie Anqi,Li Jiajie,Fang Chao,Yang Quan,Qiu Huaina,Qi Yanwei,Yin Zhinan,Wang Xinhua,Huang Jun
BACKGROUND:Malaria has high morbidity and mortality rates in some parts of tropical and subtropical countries. Besides respiratory and metabolic function, lung plays a role in immune system. γδT cells have multiple functions in producing cytokines and chemokines, regulating the immune response by interacting with other cells. It remains unclear about the role of γδT cells in the lung of mice infected by malaria parasites. METHODS:Flow cytometry (FCM) was used to evaluate the frequency of γδT cells and the effects of γδT cells on the phenotype and function of B and T cells in Plasmodium yoelii-infected wild-type (WT) or γδTCR knockout (γδT KO) mice. Haematoxylin-eosin (HE) staining was used to observe the pathological changes in the lungs. RESULTS:The percentage and absolute number of γδT cells in the lung increased after Plasmodium infection (p < 0.01). More γδT cells were expressing CD80, CD11b, or PD-1 post-infection (p < 0.05), while less γδT cells were expressing CD34, CD62L, and CD127 post-infection (p < 0.05). The percentages of IL-4, IL-5, IL-6, IL-21, IL-1α, and IL-17 γδT cells were increased (p < 0.05), but the percentage of IFN-γ-expressing γδT cells decreased (p < 0.05) post-infection. The pathological changes in the lungs of the infected γδT KO mice were not obvious compared with the infected WT mice. The proportion of CD3 cells and absolute numbers of CD3 cells, CD3 CD4 cells, CD3 CD8 cells decreased in γδT KO infected mice (p < 0.05). γδT KO infected mice exhibited no significant difference in the surface molecular expression of T cells compared with the WT infected mice (p > 0.05). While, the percentage of IFN-γ-expressing CD3 and CD3 CD8 cells increased in γδT KO infected mice (p < 0.05). There was no significant difference in the absolute numbers of the total, CD69, ICOS, and CD80 B cells between the WT infected and γδT KO infected mice (p > 0.05). CONCLUSIONS:The content, phenotype, and function of γδT cells in the lung of C57BL/6 mice were changed after Plasmodium infection. γδT cells contribute to T cell immune response in the progress of Plasmodium infection.
Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity.
Leung Elaine Lai Han,Luo Lian Xiang,Liu Zhong Qiu,Wong Vincent Kam Wai,Lu Lin Lin,Xie Ying,Zhang Ni,Qu Yuan Qing,Fan Xing Xing,Li Ying,Huang Min,Xiao Dai Kai,Huang Jun,Zhou Yan Ling,He Jian Xing,Ding Jian,Yao Xiao Jun,Ward David C,Liu Liang
Cell death & disease
Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEδ and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking "tumor protective" autophagy, but inhibited if combined with an anti-oxidant.
Erlotinib intercalating pemetrexed/cisplatin versus erlotinib alone in Chinese patients with brain metastases from lung adenocarcinoma: a prospective, non-randomised, concurrent controlled trial (NCT01578668).
Yang Haihong,Deng Qiuhua,Qiu Yuan,Huang Jun,Guan Yubao,Wang Fengnan,Xu Xin,Yang Xinyun
Objective:Erlotinib has a synergistic effect with pemetrexed for treating non-squamous non-small-cell lung cancer. We investigated the efficacy and safety of erlotinib (E) in combination with pemetrexed/cisplatin (E-P) in Chinese patients with lung adenocarcinoma with brain metastases. Design:Patients who were erlotinib-naïve or pemetrexed-naïve were assigned in parallel to receive either E or E-P. The primary endpoint was the intracranial overall response rate (ORRi). Results:Sixty-nine patients with lung adenocarcinoma with brain metastases received E (n=35) or E-P (n=34) from January 2012 to November 2014. Demographics and patient characteristics were well balanced between the two groups, including epidermal growth factor receptor () status, sex, age, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, brain metastases and number of prior treatments. ORRi in the E-P arm was superior to that in the E arm (79% vs 48%, p=0.008). Compared with E as the first-line treatment, E-P was associated with better intracranial progression-free survival (PFSi, median: 9 vs 2 months, p=0.027) and systemic PFS (median: 8 vs 2 months, p=0.006). The most frequent E-related adverse events were higher in the combination arm. No new safety signals were detected. The side effects were tolerable, and there were no drug-related deaths. Conclusion:Our study suggests that the E-P combination may be effective in Chinese patients with lung adenocarcinoma with brain metastases, with improved PFS in treatment-naïve patients. Toxicities are tolerable, and there are more E-related side effects.
Identifying optimal candidates for primary tumor resection among metastatic non-small cell lung cancer patients: a population-based predictive model.
Liang Hengrui,Liu Zhichao,Huang Jun,Liu Jun,Wang Wei,Li Jianfu,Xiong Shan,Li Caichen,Cheng Bo,Zhao Yi,Cui Fei,He Jianxing,Liang Wenhua
Translational lung cancer research
Background:A survival benefit was observed in metastatic non-small cell lung cancer (NSCLC) patients that underwent surgical resection of the primary tumor. We developed a model testing the hypothesis that only certain stage IV patients would benefit from surgery and the potential benefit would vary based on primary tumor characteristics. Methods:Patients with stage IV NSCLC were identified in the Surveillance, Epidemiology and End Results (SEER) database and then divided into surgery and non-surgery groups. A 1:1 Propensity score matching (PSM) was performed to balance characters. We assumed that patients received primary tumor surgery that lived longer than median cancer specific survival (CSS) time of those who didn't underwent surgery could benefit from the operation. Multivariable Cox model was used to explore the independent factors of CSS in two groups (beneficial and non-beneficial group). Logistic regression was used to build a nomogram based on the significant predictive factors. Results:A total of 30,342 patients with stage IV NSCLC were identified; 8.03% (2,436) received primary tumor surgery. After PSM, surgical intervention was independently correlated with longer median CSS time (19 9 months, P<0.001). Among the surgery cohort, 1,374 (56.40%) patients lived longer than 9 months (beneficial group). Differentiated characters (beneficial and non-beneficial group) included age, gender, TNM stage, histologic type, tumor position and differentiation grade, which were integrated as predictors to build a nomogram. Conclusions:A practical predictive model was created and might be used to identify the optimal candidates for surgical resection of the primary tumor among stage IV NSCLC patients.
PD-L1 expression with respect to driver mutations in non-small cell lung cancer in an Asian population: a large study of 1370 cases in China.
Li Caichen,Liu Jun,Xie Zhanhong,Zhu Feng,Cheng Bo,Liang Hengrui,Li Jianfu,Xiong Shan,Chen Zisheng,Liu Zhichao,Zhao Yi,Ou Limin,Zhong Ran,Wang Wei,Huang Jun,Sun Jinyun,Zhang Chunya,Weng Landong,He Jianxing,Liang Wenhua,Pan Zhenkui
Therapeutic advances in medical oncology
Background:Programmed cell death ligand 1 (PD-L1) expression with respect to genetic alternations has not been well established in non-small cell lung cancer (NSCLC), especially in the Asian population. Methods:We reviewed 1370 NSCLC patients from a prospectively maintained database. Immunohistochemistry was performed on tumor cells and tumor-infiltrating lymphocytes (TILs) using the VENTANA (SP142) anti-PD-L1 antibody. The tumor proportion score (TPS) cutoff values were set at ⩾1% and ⩾50%, and the immune proportion score (IPS) cutoff values were set at ⩾1% and ⩾10%. Results:In tumor cells, PD-L1 positivity was observed in 405 (29.6%), 122 (8.9%), and 27 (2.0%) patients with TPS cutoff values at ⩾1% and ⩾50%. Contrastingly, TILs of 1154 (84.2%) and 346 (25.3%) patients stained positive at IPS cutoff values of ⩾1% and ⩾50%, respectively. PD-L1 expression was more common in patients who were mutation-negative irrespective of the TPS cutoff values and tumor size. PD-L1 expression in tumor cells was less frequent in patients harboring mutations (18.8% TPS ⩾ 1% and 4.6% TPS ⩾ 50%). Conversely, PD-L1 expression was high in the presence of mutations (47.3% TPS ⩾ 1% and 22.5% TPS ⩾ 50%). Overall, mutations and and translocations were more frequent, while and mutations and translocations were less frequent compared with the overall PD-L1 expression levels. Although the difference between TILs among the PD-L1-positive cases was comparatively small, PD-L1 positivity was less prevalent in -mutated tumors and more common in those with mutations, translocations, mutations, or mutations. Conclusion:Our study showed the heterogeneity in PD-L1 expression with respect to nine major oncogenic drivers in China. Future studies are warranted to further clarify the association between PD-L1 expression and driver mutations in NSCLC.
Compound Library Screening Identified Cardiac Glycoside Digitoxin as an Effective Growth Inhibitor of Gefitinib-Resistant Non-Small Cell Lung Cancer via Downregulation of α-Tubulin and Inhibition of Microtubule Formation.
Zhang Yi-Ze,Chen Xi,Fan Xing-Xing,He Jian-Xing,Huang Jun,Xiao Da-Kai,Zhou Yan-Ling,Zheng Sen-You,Xu Jia-Hui,Yao Xiao-Jun,Liu Liang,Leung Elaine Lai-Han
Molecules (Basel, Switzerland)
Non-small-cell lung cancer (NSCLC) dominates over 85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) activating mutation is a common situation in NSCLC. In the clinic, molecular-targeting with Gefitinib as a tyrosine kinase inhibitor (TKI) for EGFR downstream signaling is initially effective. However, drug resistance frequently happens due to additional mutation on EGFR, such as substitution from threonine to methionine at amino acid position 790 (T790M). In this study, we screened a traditional Chinese medicine (TCM) compound library consisting of 800 single compounds in TKI-resistance NSCLC H1975 cells, which contains substitutions from leucine to arginine at amino acid 858 (L858R) and T790M mutation on EGFR. Attractively, among these compounds there are 24 compounds CC50 of which was less than 2.5 μM were identified. We have further investigated the mechanism of the most effective one, Digitoxin. It showed a significantly cytotoxic effect in H1975 cells by causing G2 phase arrest, also remarkably activated 5' adenosine monophosphate-activated protein kinase (AMPK). Moreover, we first proved that Digitoxin suppressed microtubule formation through decreasing α-tubulin. Therefore, it confirmed that Digitoxin effectively depressed the growth of TKI-resistance NSCLC H1975 cells by inhibiting microtubule polymerization and inducing cell cycle arrest.
SCD1 is required for EGFR-targeting cancer therapy of lung cancer via re-activation of EGFR/PI3K/AKT signals.
She Kelin,Fang Shenghua,Du Wei,Fan Xingxing,He Jiaxi,Pan Hui,Huang Liyan,He Ping,Huang Jun
Cancer cell international
Background:Cancer cells are characterized by aberrant activation of lipid biosynthesis, producing saturated fatty acids and monounsaturated fatty acids via stearoyl-CoA desaturases (SCD) for regulating metabolic and signaling platforms. SCD1 overexpression functions as an oncogene in lung cancer and predicts a poor clinical outcome. This study aimed to investigate the role of SCD1 inhibition by EGFR inhibitor (Gefitinib)-based anti-tumor therapy of lung cancer both in vitro and in vivo. Methods:CCK-8 assay was performed to determine cell viability. The SCD1 mRNA level was detected by qPCR. The protein levels were assessed by Western blotting. E-cadherin and N-cadherin levels were determined by immunofluorescence. Apoptosis detection was conducted by flow cytometry. Cell migration or invasion was evaluated by transwell assay. The tumor sizes and tumor volumes were calculated in nude mice by subcutaneous injection of A549 cells transfected with vector of pcDNA3.1-SCD1 or negative control. Expression of Ki-67 was detected by immunohistochemistry. Result:SCD1 up-regulated expression was observed in lung cancer cell lines. Cells with overexpressed SCD1 had high IC50 values for Gefitinib in A549 and H1573 cell lines. Overexpression of SCD1 inhibited Gefitinib-induced apoptosis, decreased cell vitality and impaired ability of migration and invasion, while these effects were counteracted by A939572. Mechanistically, SCD1 promoted the activation of proliferation and metastasis-related EGFR/PI3K/AKT signaling, and up-regulated epithelial to mesenchymal transition (EMT) phenotype in the two cell lines, which was restored by SCD1 inhibition. Furthermore, in spite of EGFR inhibition, overexpression of SCD1 in vivo significantly promoted tumor growth by activating EGFR/PI3K/AKT signaling in tumor tissues, but A939572 treatment restricted SCD1-induced tumor progression and inhibited EMT phenotype of cancer cells in vivo. Conclusion:These findings indicated that inhibition of oncogene SCD1 is required for targeting EGFR therapy in lung cancer.