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Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation.Patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review.A total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6-74.6). The disease control rate was 93.4% (95% CI: 89.6-96.2). The median duration of response was 15.1 months (95% CI: 12.5-16.6). The median progression-free survival was 12.4 months (95% CI: 9.7-15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5-80.3) and 91.3% (95% CI: 72.0-98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6-not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study.Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People's Republic of China for patients positive for EGFR T790M NSCLC.

Shukui Qin,1 Rui-Hua Xu,2 Lin Shen,3 Jianming Xu,4 Yuxian Bai,5 Lei Yang,6 Yanhong Deng,7 Zhen-dong Chen,8 Haijun Zhong,9 Hongming Pan,10 Weijian Guo,11 Yongqian Shu,12 Ying Yuan,13 Jianfeng Zhou,14 Nong Xu,15 Tianshu Liu,16 Dong Ma,17 Changping Wu,18 Ying Cheng,19 Donghui Chen,20 Wei Li,21 Sanyuan Sun,22 Zhuang Yu,23 Peiguo Cao,24 Haihui Chen,25 Jiejun Wang,26 Shubin Wang,27 Hongbing Wang,28 Ning Wang,29 Bin Zhang,29 Qiang Zhang,29 Weiguo Su,30 Xiaojun Guo,30 Jin Li31 1Cancer Center, Jinling Hospital, Nanjing, People’s Republic of China; 2Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 3Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 4Department of Medical Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 6Department of Medical Oncology, Nantong Cancer Hospital, Nantong, People’s Republic of China; 7Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 8Department of Medical Oncology, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China; 9Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China; 10Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 11Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 12Department of Medical Oncology, Jiangsu Provincial Hospital, Nanjing, People’s Republic of China; 13Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 14Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 15Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People’s Republic of China; 16Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, People’s Republic of China; 17Department of Medical Oncology, Guangdong Provincial People’s Hospital, Guangzhou, People’s Republic of China; 18Department of Medical Oncology, The First People’s Hospital of Changzhou, Changzhou, People’s Republic of China; 19Department of Medical Oncology, Jilin Province Cancer Hospital, Changchun, People’s Republic of China; 20Department of Medical Oncology, Shanghai Jiaotong University Affiliated First People’s Hospital, Shanghai, People’s Republic of China; 21Department of Medical Oncology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 22Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, People’s Republic of China; 23Department of Medical Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao, People’s Republic of China; 24Department of Medical Oncology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 25Department of Medical Oncology, Liuzhou Worker’s Hospital, Liuzhou, People’s Republic of China; 26Department of Medical Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, People’s Republic of China; 27Department of Medical Oncology, Peking University Shenzhen Hospital, Beijing University, Shenzhen, People’s Republic of China; 28Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou Medical College, Xuzhou, People’s Republic of China; 29Eli Lilly and Company, Shanghai, People’s Republic of China; 30Hutchison MediPharma Limited, Shanghai, People’s Republic of China; 31Department of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Jin LiDepartment of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaTel +8613761222111Email lijin@csco.org.cnObjective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45– 0.77, P< 0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17– 0.30; P< 0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.ClinicalTrials.gov Identifier: NCT02314819.Keywords: colorectal cancer, FRESCO trial, fruquintinib, liver metastasis

Summary Background Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma. Methods AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov , NCT02329860 . Findings Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in the placebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand–foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators. Interpretation Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile. Funding Jiangsu Hengrui Medicine.

To explore a better treatment strategy for patients with advanced non‐small cell lung cancer harboring sensitive epidermal growth factor receptor mutations, a total of 271 patients were retrospectively analyzed. The patients were divided into two groups: the combination group (58 cases), which received concurrent icotinib, pemetrexed, and platinum treatment, and the sequential group (213 cases), which received the sequential pemetrexed and platinum therapy, followed by icotinib treatment. The primary end points were progression‐free survival (PFS) and PFS on the subsequent line of therapy (PFS2). PFS in the combination group was significantly higher compared with that in the sequential group (16.89 months vs. 9.90 months; p

By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel.A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation.Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.

Background: FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. Materials & methods: In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. Results: In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression-free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Conclusion: Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. Clinical trial registration: NCT02314819 ( ClinicalTrials.gov )

In order to solve the problem of serious attenuation of the performance of heat pump air conditioning system for pure electric bus at high temperature in summer and at low temperature in winter, a heat pump air conditioning system for medium-pressure air-supply pure electric bus with economizer is developed. The performance of the system working at from +50? to ?20? ambient temperature and at different compressor speed is studied. The results show that the exhaust temperature of the compressor can be reduced greatly.

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

When the exhaust temperature of heat pump air conditioning system of pure electric bus is too high, the performance of the system is attenuated. In order to solve the problem, an alternative system with low pressure air supply is developed. The experimental platform is set up to reveal the main factors affecting the refrigeration and heating performance of the system. The results show that the low pressure air-supply technology can significantly reduce the exhaust temperature of the compressor.

In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial. In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized. A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib. The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population. Trial Registration: Clinical Trials identifier NCT02314819.

The relentless debate on postoperative adjuvant radiotherapy in gastric adenocarcinoma (GA) has been lasting for decades. In this study, a new biomarker, named promoter methylation burden of DNA repair genes (RPMB), was established to identify the subgroup of patients who might benefit from adjuvant radiotherapy. Methylation profiles of 397 GA tumor samples were downloaded from The Cancer Genome Atlas (TCGA). RPMB for a patient was defined as the ratio of methylated DNA repair genes to the number of all DNA repair genes. Subgroup analyses in term of overall survival (OS) and disease-free survival (DFS) indicated that most of the subgroups favored the high-RMPB group. Kaplan-Meier analysis showed that overall the patients with high RPMB after R0 resection had a significantly better clinical outcome regarding DFS (hazard ratio [HR] = 0.013, p = 0.042). Additionally, high-RPMB patients, who underwent adjuvant radiotherapy with both ≥T2 tumor and positive lymph nodes, showed superior DFS in comparison with the low-RPMB group (HR = 5.35 × 10−10, n = 26, p = 0.010). RPMB might be considered as a promising biomarker for decision-making with regard to postoperative adjuvant radiotherapy for GA patients., Graphical Abstract, To identify the subgroup of gastric adenocarcinoma (GA) patients who can benefit from postoperative adjuvant radiotherapy, An et al. proposed a new biomarker, named promotor methylation burden of DNA repair genes (RPMB), closely associated with patient prognosis, hopefully to provide guidance for treating GA patients after radical resection.

Supplemental Digital Content is available in the text., Objective: We aim to develop and validate an effective nomogram prognostic model for patients with typical lung carcinoid tumors using a large patient cohort from the Surveillance, Epidemiology, and End Results (SEER) database. Materials and Methods: Data from patients with typical lung carcinoid tumors between 2010 and 2015 were selected from the SEER database for retrospective analysis. Univariate and multivariate Cox analysis was performed to clarify independent prognostic factors. Next, a nomogram was formulated to predict the probability of 3- and 5-year overall survival (OS). Concordance indexes (c-index), receiver operating characteristic analysis and calibration curves were used to evaluate the model. Results: The selected patients were randomly divided into a training and a validation cohort. A nomogram was established based on the training cohort. Cox analysis results indicated that age, sex, T stage, N stage, surgery, and bone metastasis were independent variables for OS. All these factors, except surgery, were included in the nomogram model for predicting 3- and 5-year OS. The internally and externally validated c-indexes were 0.787 and 0.817, respectively. For the 3-year survival prediction, receiver operating characteristic analysis showed that the areas under the curve in the training and validation cohorts were 0.824 and 0.795, respectively. For the 5-year survival prediction, the area under the curve in the training and validation cohorts were 0.812 and 0.787, respectively. The calibration plots for probability of survival were in good agreement. Conclusion: The nomogram brings us closer to personalized medicine and the maximization of predictive accuracy in the prediction of OS in patients with typical lung carcinoid tumors.

Although the prognostic value of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/white blood cell ratio (LWR) has been described in advanced non-small cell lung cancer (NSCLC), the association between complete blood cell parameters prior to disease treatment and NSCLC have yet to be identified. The aim of the present study was to assess the complete blood cell parameters prior to disease treatment in patients with advanced NSCLC. A total of 268 patients with advanced NSCLC were enrolled in this study. Clinical and laboratory data of the patients were acquired through medical records. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values of the neutrophil/white blood cell ratio (NWR), NLR, platelet/white blood cell ratio (PWR), PLR, monocyte/white blood cell ratio (MWR), monocyte/lymphocyte ratio (MLR) and LWR. Kaplan-Meier univariate and multivariate Cox regression analyses were used to evaluate the effect of complete blood parameters on progression-free survival (PFS) and overall survival (OS). The optimal cut-off values were identified as 0.67 for NWR, 2.85 for NLR, 37.23 for PWR, 166.56 for PLR, 0.074 for MWR, 0.31 for MLR and 0.24 for LWR. Univariate analysis revealed that sex (P=0.038), histological type (P

Summary Background Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. Methods We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov , NCT03215693 . Findings Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43–60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53–83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]). Interpretation Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. Funding Betta Pharmaceuticals.

Background Clinical options for lung squamous carcinoma (LUSC) are still quite limited. Carcinogenesis is an exceedingly complicated process involving multi-level dysregulations. Therefore, only looking into one layer of genomic dysregulation is far from sufficient. Methods We identified differentially expressed genes with consistent upstream genetic or epigenetic dysregulations in LUSC. Random walk was adopted to identify genes significantly affected by upstream abnormalities. Expression differentiation and survival analysis were conducted for these significant genes, respectively. Prognostic power of selected gene was also tested in 102 male LUSC samples through immunohistochemistry assay. Results Twelve genes were successfully retrieved from biological network, including ERα (ESRS1), EGFR, AR, ATXN1, MAPK3, PRKACA, PRKCA, SMAD4, TP53, TRAF2, UBQLN4 and YWHAG, which were closely related to sex hormone signaling pathway. Survival analysis in public datasets indicated ERα was significantly associated with a poor overall survival (OS) in male LUSC. The result of our immunohistochemistry assay also demonstrated this correlation using R0 resected tumors (n = 102, HR: 2.152, 95% CI: 1.089–4.255, p = 0.024). Although disease-free survival (DFS) difference was non-significant (n = 102, p = 0.12), the tendency of distinction was straight-forward. Cox analysis indicated ERα was the only independent prognostic factor for male patients’ OS after R0 resection (HR = 2.152, p = 0.037). Conclusion ERα was significantly related to a poor prognosis in LUSC, especially for male patients after radical surgery, confirmed by our immunohistochemistry data.

Mechanical ventilation (MV) is frequently employed to manage respiratory failure in sepsis patients and is required for the surgical management of intra-abdominal sepsis. The impact of MV varies dramatically depending on tidal volume, with even moderate tidal volume (MTV) ventilation leading to ventilator-induced lung injury, whereas low tidal volume (LTV) ventilation protects against sepsis-induced acute respiratory distress syndrome. Interleukin (IL)-33 is known to contribute to lung injury in sepsis and its release can be induced by mechanical stress. To determine the relationship between the IL-33-suppression of tumorigenicity 2 (ST2) pathway and patterns of lung injury associated with MV in sepsis, mice were subjected to cecal ligation and puncture (CLP) followed 6 h later by either MTV (10 mL/kg) or LTV (6 mL/kg) ventilation for 4 h. MTV and LTV ventilation alone for 4 h had no impact on lung injury. MTV markedly exacerbated lung injury and inflammation, while LTV significantly suppressed these parameters in septic mice. Lung and plasma levels of IL-33 ST2 were significantly elevated by CLP alone at 10 h. MTV caused further and significant increases in IL-33 and sST2 levels, while LTV significantly suppressed levels induced by CLP. Deletion of IL-33 or ST2 prevented the increase in lung injury and inflammation induced by MTV in septic mice, while administration of recombinant IL-33 in the airway reversed the protection seen with LTV. Taken together, these findings implicate the IL-33-ST2 pathway in the pro-inflammatory changes induced by the mechanical ventilation that leads to lung injury in the setting of intra-abdominal sepsis in a tidal volume-dependent manner.

To study the clinical significance of serum epidermal growth factor receptor (EGFR) gene mutation and serum tumor markers in the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with lung adenocarcinoma. Ninety patients with pathologically diagnosed lung adenocarcinoma were enrolled. Further, 51 out of 90 patients received the EGFR-TKI therapy, oral gefitinib. The correlations among serum EGFR gene mutations in exons 18–21, serum tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 24-2 (CA24-2), carbohydrate antigen 125, carbohydrate antigen 15-3 as well as carbohydrate antigen 19-9 (CA19-9) levels, and EGFR-TKI efficacy were determined. There was a high consistency of EGFR gene mutation rate between serum and tissue samples. The serum EGFR gene mutation rate in female patients or non-smokers was significantly higher than that in male patients or smokers, respectively. Serum CA19-9, CA24-2, and CEA levels were significantly correlated with serum EGFR mutation. After receiving gefitinib, the progression-free survivals (PFSs) of patients with high serum CEA level, high serum CA19-9 level, or serum EGFR gene mutation were significantly higher than those of normal patients, respectively. The PFSs were significantly prolonged in patients with EGFR gene mutation and high serum CEA level or patients with EGFR gene mutation and high serum CA19-9 level compared with those in patients with one abnormal biomarker and normal patients. Combined detection of EGFR gene mutations as well as CA19-9 and CEA levels in peripheral blood can predict the efficacy of EGFR-TKI in the treatment of patients with lung adenocarcinoma.

Purpose: The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacologic intervention have not been systematically characterized. Experimental Design: Pyroptotic cell death was assessed by immunoblot analysis, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of patients with lung cancer were analyzed using IHC. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models. Results: We showed that diverse small-molecule inhibitors specifically targeting KRAS-, EGFR-, or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by DFNA5), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including KRAS-mutant, EGFR-altered, and ALK-rearranged adenocarcinomas. As a result, cooccurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells, succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models. Conclusions: These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics.

Lung cancer is the most commonly diagnosed type of cancer and the leading cause of cancer-associated death worldwide. MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules of ∼20–25 nucleotides in length. Single nucleotide polymorphisms are a class of genetic variation in the human genome, which when present in miRNA genes are associated with the risk of developing cancer. This study aimed to identify whether the miRNA (miR)-608 polymorphism rs4919510 influenced the incidence of lung cancer, and to explore the underlying mechanisms of miR-608 in the pathogenesis of the disease. A total of 37 patients with non-small cell lung cancer (NSCLC) were selected to determine the expression levels of miR-608; 96 NSCLC patients and 136 cancer-free healthy controls were recruited to determine the incidence of miR-608 rs4919510 in lung cancer patients. Additionally, the impact of miR-608 on the expression of predicted target genes, cell migration, viability, proliferation, and apoptosis was also assessed. We found that the presence of miR-608 rs4919510 did not affect the susceptibility of patients to NSCLC or the maturation of miR-608. miR-608 expression levels were found to be downregulated in NSCLC tissues. Furthermore, overexpression of miR-608 promoted doxorubicin-induced apoptosis in NSCLC cell lines A549 and HCC4006 by inhibiting the expression of transcription factor activating enhancer-binding protein 4 (TFAP4), and high expression levels of TFAP4 were observed in NSCLC tissues. Therefore, our results may provide valuable insights for the chemotherapeutical treatment of NSCLC.

Related studies have reported that cystatin C (Cys C), uric acid (UA) and lactate dehydrogenase (LDH) affect tumor growth and invasion; however, the correlation between them and the prognosis of patients with small-cell lung cancer (SCLC) remains unclear. The present study aimed to investigate the effects of serum Cys C, UA and LDH concentrations on the prognosis of patients with SCLC prior to initial treatment, in order to identify potential targets for determining the clinical outcome of patients with SCLC. A total of 205 patients with SCLC were enrolled in the present study, and the clinical and laboratory data were obtained from the medical records. The receiver operating characteristic curve was used to determine the optimal cut-off values of Cys C, UA and LDH, while the Kaplan-Meier method was used for survival analysis. The Cox proportional hazard model was used for univariate and multivariate analyses to identify independent prognostic factors. The optimal cut-off values for Cys C, UA and LDH were 0.775 mg/l, 296.45 µmol/l and 198.5 U/l, respectively. The survival curves demonstrated that progression-free survival (PFS) and overall survival (OS) time were shorter in patients with high levels of Cys C, UA and LDH prior to chemotherapy. Univariate and multivariate analyses indicated that LDH concentration prior to chemotherapy may be an independent prognostic factor for both PFS and OS in patients with SCLC, while Cys C concentration may be an independent prognostic factor for PFS in patients with SCLC. The concentrations of Cys C, UA and LDH prior to chemotherapy were associated with prognosis of patients with SCLC. PFS and OS time were shorter, and the prognosis was poor in patients with elevated serum levels of Cys C, UA and LDH. Taken together, the results of the present study suggest that high concentrations of LDH and Cys C prior to chemotherapy may indicate rapid disease progression, thus it is important to focus on the progression and recurrence of the disease. High LDH concentration may also indicate a shorter survival time.

Preliminary reports suggested that presepsin was a powerful biomarker for sepsis in a general population. However, presepsin levels change with age. This study aimed to investigate the diagnostic and prognostic value of presepsin among elderly patients with sepsis in the intensive care unit (ICU).A total of 142 elderly patients were enrolled and assorted into three groups: non-infection, infection, and sepsis. Blood samples were collected on days 1, 3 and 7 during the first week of ICU stay for presepsin measurement. Diagnostic and prognostic utilities were tested by receiver operating characteristic, cutoff levels, Kaplan Meier survival curves and hazard ratios.The presepsin level on days 1 and 3 were significantly higher in sepsis compared with infection (P0.01) and non-infection (P0.01). The diagnostic area under the curve (AUC) of presepsin was comparable to that of procalcitonin (P0.05) and higher than that of C-reactive protein or interleukin 6 (P0.05) on days 1 and 3. In AUC and Kaplan-Meier survival curves, presepsin on day 3 showed a significant prognostic value for 30-day mortality but was not superior to other biomarkers.The presepsin level was significantly higher in elderly patients with sepsis compared with the non-infection and infection groups. Presepsin has a reliable early diagnostic ability for sepsis comparable to that of PCT. However, it cannot be defined as a perfect biomarker for prognosis of 30-day mortality in elderly patients. An overall and continual assessment of all the clinical indexes for sepsis during the course of the disease is necessary.

Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539).A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee.As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group.In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.

In order to expand the application fields of micro-UAVs, the ability of land mark recognition and autonomous landing is one of the key technologies for UAVs flighting in complex environment. For achieving more robust and precise relative pose estimation, we propose to apply an ellipse feature-based pose estimation method instead of QR code features. Considering the poor calculating ability on-board, the land mark recognition algorithms based on deep learning are difficult to be used in micro-UAVs. Hence, we put forward a new strategy for target recognition by taking advantage of incremental learning. Concretely, we select to use broad learning system (BLS) to replace the classification layer of MobileNetV3, and design a new target recognition network that may be named as MobileNetV3-BLS. To verify the effectiveness of proposed MobileNetV3-BLS, we use PASCAL VOC2007 and data set collected in our university, and carry out a series of comparative experiments on Nvidia TX2. Results of experiments show that MobileNetV3-BLS can progressively increase the accuracy of landmark recognition online. In addition, the proposed MobileNetV3-BLS does meet the need of deployment on Nvidia TX2 and the real-time requirement of on-board calculation in mirco-UAV avionics systems.

Injurious mechanical ventilation has been shown to directly affect pulmonary and systemic immune responses. How these responses propagate or attenuate remains unknown. The goal of this study was to further determine whether toll-like receptor (TLR) 4 and WNT1-inducible signaling pathway protein 1 (WISP1) could contribute to injurious mechanical ventilation, especially focusing on the role of macrophages during experimental ventilator-induced lung injury. A prospective, randomized, and controlled animal study was designed, and male, wild-type (WT) C57BL/6 mice, TLR4 knockout (TLR4−/−), and lyzTLR4 knockout (lyzTLR4−/−) mice aging 8~12 weeks were used. Animals were anesthetized and randomized to spontaneous breathing (SB) group or to high tidal volume (VT, 20 ml/kg) mechanical ventilation (HTV) group. Histological evaluation, alveolar–capillary permeability of Evan’s blue albumin (EBA), WISP1 protein levels, macrophage inflammatory protein-2 (MIP-2), and interleukin-6 (IL-6) in plasma and bronchoalveolar lavage fluid (BALF) concentrations were analyzed. HTV group was associated with a significant increase of WISP1 and EBA ratio in C57BL/6 mice, a significant decrease of WISP1 protein levels, and a significant decrease of IL-6, MIP-2 in plasma, and BALF concentrations of pro-inflammatory cytokines in TLR4−/− and lyzTLR4−/− knockout mice. In TLR4−/− mice and lyzTLR4−/− mice, there were also significant differences between SB group and HTV group in terms of H&E score and EBA ratio and level of pro-inflammation cytokines. The entire TLR4-targeted mice could further improve various inflammatory changes and damages when compared with lyzTLR4-targeted mice. What is more, TLR4−/− mice and lyzTLR4−/− mice reacted differently to rWISP1 and/or BMMC treated. TLR4−/− mice had no response to rWISP1, while lyzTLR4−/− mice still showed drastic response to both treatments. TLR4 and WISP1, especially the former one, on macrophages could contribute to releasing of pro-inflammatory cytokines during ventilator-induced lung injury. Injurious mechanical ventilation may result in an immune response which is similar to that of infection.

B cell malignancies are classified as different types such as B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and B cell non-Hodgkin lymphoma (NHL) based on cell surface expression of various clusters of differentiation molecules. CD19 is a B cell lineage-specific antigen which is expressed on malignant B cells in patients with B-ALL, CLL and NHL. Adoptive transfer of T cells that are genetically modified to express a CD19-specific chimeric antigen receptor (CAR) represents a promising clinical strategy for patients with B cell malignancies. CD19-CAR T cell therapy has achieved high response rates and durable remissions on B cell malignancies. However, the efficacy of CAR-T therapy is still inefficient and the critical factors for better efficacy remain unclear. In this review, we summarized the critical factors for better efficacy of CD19 CAR-T cells in B-lineage malignancies including B-ALL, B-CLL and lymphoma. T cell persistence, lymphodepletion regimen, CD3/CD28 beads treatment and no IL-2 administration to T cells were positively associated with better responses. The method of enhancing the persistence of CAR-T cells need to be further optimized in order to improve the clinical efficacy in the treatment of B cell malignancies. In order to improve the therapeutic effect of CAR-T therapy, new therapeutic strategies should be developed to make factors which influence efficacy the more beneficial.

A novel method of vessel segmentation in angiocardiography image processing is studied. The process of vessel segmentation is implemented based on Hessian matrix, in which a new vascular function is employed. Subsequently, the vessel contour is extracted from the handled image by using the dual-stage region growing. Extracting vessel skeleton, searching skeleton point and measuring diameter are carried out to realize the automatic diagnosis of vascular stenosis based on vessel segmentation. The experimental results show that the stated method for vessel segmentation manages to accurately extract the main branch contour, and even most small vessels. The automatic diagnosis of vascular stenosis can get relatively accurate results, which may provide auxiliary references and quantify the judgment of vascular stenosis for doctors.

D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study (NCT03861156) Background: Despite initial response to EGFR-TKI, most patients (pts) develop resistance with the EGFR T790M mutation detectable in ~50% of patients treated with first-/second-generation EGFR-TKIs. D-0316 is a third-generation EGFR-TKI that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in pts with non-small cell lung cancer (NSCLC). We report the results of a registered, single-arm, phase II study of D-0316 in NSCLC pts with EGFR T790M who progressed on previous treatment with first-line EGFR-TKIs. Methods: In this phase II, open-label, single-arm study, eligible pts were those who had confirmed locally advanced or metastatic NSCLC, and had disease progression after first-line EGFR-TKI and with T790M mutation. Pts were initially orally given D-0316 50 mg. However, considering the benefits and risks of the pts, the dose was modified to 100 mg once daily with a 21-day lead-in at 75 mg once daily. The primary endpoint was objective response rate (ORR) based on independent review committee (IRC) according to RECIST 1.1.Results: As of October 31, 2019, 176 pts were enrolled in the 50 mg phase, in which 90 pts had partial response, achieving an ORR of 51.1% (95%CI: 43.5-58.7). Despite the immature PFS, disease progression or death occurred in 60 pts (34.1%) and the median PFS was 8.4 months (95% CI: 8.0-NE). Between September 12, 2019 and July 29, 2020, 689 pts were screened and 290 pts (median age 62.5) were enrolled in China and received 100mg D-0316 with a 21-day lead-in at 75 mg. At data cutoff (October 18, 2020), the median duration of follow-up was 5.5 months. 188 of the 290 pts achieved confirmed partial responses by IRC. The ORR was 64.8% (95% CI: 59.0-70.3) and the disease control rate (DCR) was 95.2% (95% CI: 92.0-97.3). The ORR was consistent across in most subgroups. Among 34 pts with brain metastases at baseline, 18 pts achieved confirmed partial responses and the intracranial ORR was 52.9% (95% CI: 35.1-70.2). The PFS, DoR, and OS were premature. The most common treatment-related adverse events were thrombocytopenia (57.2%), headache (27.6%), leukopenia (23.4%), anemia (22.1%) and rash (20.7%). The most common grade 3 or higher treatment-related adverse events were thrombocytopenia (11.7%). One death was due to treatment-related adverse events (interstitial lung disease). Six interstitial lung diseases (2.1%) were observed during study treatment. Conclusion: D-0316 has showed strong anti-tumor activities and tolerable toxicity in pts with EGFR T790M-positive NSCLC who have progressed after EGFR-TKI treatment. Citation Format: Shun Lu, Yiping Zhang, Guojun Zhang, Jianying Zhou, Shundong Cang, Ying Cheng, Gang Wu, Peiguo Cao, Dongqing Lv, Xiangming Jin, Hong Jian, Chengshui Chen, Guanming Jiang, Panwen Tian, Kai Wang, Hui Zhao, Gongyan Chen, Qun Chen, Cuimin Ding, Junquan Yang, Renhua Guo, Guoping Sun, Bin Wang, Liyan Jiang, Wu Zhuang, Zhe Liu, Jian Fang, Yunpeng Liu, Jian Zhang, Jun Chen, Yueyin Pan, Qitao Yu, Min Zhao, Jiuwei Cui, Dianming Li, Tienan Yi, Zhuang Yu, Yan Yang, Yan Zhang, Xiuyi Zhi, Yunchao Huang, Rong Wu, Liangan Chen, Aimin Zang, Lejie Cao, Qingshan Li, Xiaoling Li, Yong Song, Donglin Wang, Shucai Zhang. D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study (NCT03861156) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT170.

9013 Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value

A driving cycle is a speed–time profile for a vehicle driving under a specified condition. It is usually developed from vehicle driving data collected by experiments to represent the real-life diving patterns. Because of lacking corresponding sampling theory, it is difficult for engineers to determine when vehicle driving cycle experiments should be stopped. In order to obtain sufficient experimental data, engineers normally choose to prolong the time of experiments wasting time and money. How to build a synthetical sampling subset of data representing a larger one becomes a main problem of sampling experiments. This paper, based on statistical inference theory, proposed a method to solve this problem at the city zone scale. First, the information entropy of road intersections was applied to determine the reasonable zone size. Then, according to one-month driving data of Changchun taxis and one-week driving data of Beijing taxis, it was found that the traffic distribution in city zone were able to be described by Nakagami distribution. It can pass the K-S test under the 0.05 significance level. In the order to fully use driving data, the bootstrap method was employed to conduct three resampling experiments in Changchun and five in Beijing. After analyzing the confidence intervals of distribution parameters, this paper discovered that the quality of the sampling data could be indicated by the accuracy of each zone’s per car per day per square kilometers travel times. The linear relationship between the expectation of zone travel times variable coefficient and the expectation of α ab which was used to evaluate the similarity between sampling distribution and population distribution was discovered. This relationship was also proved in this paper theoretically. Since the expectation of variable coefficient can be computed by sampling data, engineers are able to estimate the quality of these data in real time. If the α ab reaches the preset threshold, experiments can be stopped.

Background In recent years, systemic chemotherapy and molecular targeted therapy have become standard first-line treatments for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). The objective of this survey was to investigate first-line anticancer treatment patterns and gene aberration test status of patients with advanced nonsquamous NSCLC in China. Methods Patients included in this study had unresectable Stage IIIB/IV nonsquamous NSCLC and were admitted during August 2015 to March 2016 into one of 12 tertiary hospitals throughout China for first-line anticancer treatment. Patient data (demographics, NSCLC histologic type, Eastern Cooperative Oncology Group [ECOG] Performance Status [PS], gene aberration test and results [if performed], and first-line anticancer treatment regimen) were extracted from medical charts and entered into Medical Record Abstraction Forms (MERAFs), which were collated for analysis. Results Overall, 1041 MERAFs were collected and data from 932 MERAFs were included for analysis. Patients with unresectable Stage IIIB/IV nonsquamous NSCLC had a median age of 59 years, 56.4% were male, 58.2% were never smokers, 95.0% had adenocarcinoma, and 92.9% had an ECOG PS ≤1. A total of 665 (71.4%) patients had gene aberration tests; 46.5% (309/665) had epidermal growth factor receptor (EGFR) gene mutations, 11.5% (48/416) had anaplastic lymphoma kinase (ALK) gene fusions, and 0.8% (1/128) had a c-ros oncogene 1 gene fusion. The most common first-line treatment regimen for unresectable Stage IIIB/IV nonsquamous NSCLC was chemotherapy (72.5%, 676/932), followed by tyrosine kinase inhibitors (TKIs; 26.1%, 243/932), and TKIs plus chemotherapy (1.4%, 13/932). Most chemotherapy regimens were platinum-doublet regimens (93.5%, 631/676) and pemetrexed was the most common nonplatinum chemotherapy-backbone agent (70.2%, 443/631) in platinum-doublet regimens. Most EGFR mutation-positive patients (66.3%, 205/309) were treated with EGFR-TKIs. Conclusions Findings from our survey of 12 tertiary hospitals throughout China showed an increased rate of gene aberration testing, compared with those rates reported in previous surveys, for patients with advanced nonsquamous NSCLC. In addition, pemetrexed/platinum-doublet chemotherapy was the predominant first-line chemotherapy regimen for this population. Most patients were treated based on their gene aberration test status and results. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3451-x) contains supplementary material, which is available to authorized users.

This study proposes a new nonlinear tracking control method with safe angular velocity constraints for a cushion robot. A fuzzy path planning algorithm is investigated and a realtime desired motion path of obstacle avoidance is obtained. The angular velocity is constrained by the controller, so the planned path guarantees the safety of users. According to Lyapunov theory, the controller is designed to maintain stability in terms of solutions of linear matrix inequalities and the controller U+02BC s performance with safe angular velocity constraints is derived. The simulation and experiment results confirm the effectiveness of the proposed method and verify that the angular velocity of the cushion robot provided safe motion with obstacle avoidance.

// Hong-Bo Yang 1 , Meng Xing 1 , Lei-Na Ma 1 , Ling-Xin Feng 1 , Zhuang Yu 1 1 Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China Correspondence to: Zhuang Yu, email: yuzhuang2002@163.com Keywords: NLR, PLR, OS, clinicopathologic parameters, lung cancers Received: April 06, 2016 Accepted: August 10, 2016 Published: October 08, 2016 ABSTRACT Setting: For now, hematological markers of inflammatory response have emerged as prognostic factors for patients with cancer. Many articles have confirm that neutrophil to lymphocyte ratio(NLR) and platelet–lymphocyte ratio (PLR) are relate with poor prognosis in various types of tumors. Objective: To investigate the association between NLR/PLR and progression free survival (PFS), overall survival (OS) and clinicopathologic parameters in lung cancer patients. Design: We performed relevant searches in PubMed database, Google Scholar, Springer Link. We included retrospective cohort studies that reported hazard ratios with 95% confidence intervals for the NLR or PLR and PFS or OS. Results: Both high NLR ( P < 0.00001) and high PLR ( P = 0.01) were significantly predictive of poorer OS. It also demonstrated that elevated NLR predicted poorer PFS ( P = 0.0002). High NLR was significantly associated with deeper Invasive of tumor, ( P = 0.006) extensive lymph nodetastasis(N2–3) ( P = 0.01), poor differentiation ( P = 0.0002) and vascular invasion( P = 0.002).There was no evidence of publication bias. Subgroup analysis indicated that little evidence of heterogeneity. However, PLR has no prognostic significance for SCLC. Conclusions: We provides further evidence in support of elevated NLR and PLR were predictors of poor OS and PFS in patients with lung cancer. Given this, NLR and PLR may be markers to report treatment outcomes.

Until recently, few cases of three or more malignant tumors in one patient have been reported. Owing to the high incidence rate of these tumors, the improvement in cancer diagnosis and treatment, and the extension of patient survival time, the incidence of reported multiple primary malignant neoplasms has gradually increased. The present study reported the case of a 57-year-old man with non-small cell lung cancer combined with B-Raf proto-oncogene serine/threonine kinase V600E mutation, gastrointestinal stromal tumors and lumbar vertebral malignant mucinous sarcoma. The pathogenesis, diagnosis and treatment of these three malignancies are discussed and previous studies are also reviewed. The aim of the study was to analyze the genetic mutations associated with multiple primary malignant tumors and to discuss whether those mutations with unknown functional significance could be used as therapeutic indicators. This case report will serve as a reference for future treatment of such patients.

In recent years, the incidence of lung cancer has been increasing, and lung cancer has become the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Platinum-containing chemotherapy is the first-line treatment for advanced patients. For patients with epidermal growth factor receptor ( EGFR ) mutation, EGFR-tyrosine kinase inhibitor (EGFR-TKI) is the best treatment choice. In studies, these patients have initially shown excellent response to EGFR-TKI treatment. However, the median progression-free survival (PFS) of NSCLC patients treated with EGFR-TKI is only 10–12 months, so the problem of drug resistance in treatment needs to be urgently solved. Clinical studies have shown that metformin and EGFR-TKI have synergistic effects in the treatment of NSCLC patients. Additionally, patients who are diagnosed with type 2 diabetes mellitus, with EGFR mutation have shown synergistic effects. This combination therapy can lead to longer PFS and overall survival (OS). This article reviews the synergistic effect of metformin and EGFR-TKI in the treatment of NSCLC.

Background Hepatic ischemia-reperfusion injury (IRI) is a common pathological phenomenon, which causes hepatic injury as well as remote organ injuries such as the lung. Several mediators, such as oxidative stress, Ca2+ overload and neutrophil infiltration, have been implied in the pathogenesis of liver and remote organ injuries following reperfusion. WNT1 inducible signaling pathway protein 1 (WISP1) is an extracellular matrix protein that has been associated with the onset of several malignant diseases. Previous work in our group has demonstrated WISP1 is upregulated and contributes to proinflammatory cascades in hepatic IRI. However, the role of WISP1 in the pathogenesis of lung injury after hepatic IRI still remains unknown. Methods Male C57BL/6 mice were used to examine the expression and role of WISP1 in the pathogenesis of lung injuries after hepatic IRI and explore its potential mechanisms in mediating lung injuries. Results We found WISP1 was upregulated in lung tissues following hepatic IRI. Treatment with anti-WISP1 antibody ameliorated lung injuries with alteration of cytokine profiles. Administration with rWISP1 aggravated lung injuries following hepatic IRI through excessive production of proinflammatory cytokines and inhibition of anti-inflammatory cytokines. Conclusions In this study, we concluded that WISP1 contributed to lung injuries following hepatic IRI through TLR4 pathway.

Background: Golgi protein 73 (GP73) is a potential serum marker for the diagnosis of hepatocellular carcinoma (HCC). However, the diagnostic value of GP73 for HCC remains controversy, and little is known about the relationship between serum GP73 concentration and clinical characteristics of HCC. This study was designed to analyze the clinical values of GP73 in diagnosing HCC and the relationship between GP73 level and clinical characteristics in HCC patients. Materials and Methods: In this study, a total of 443 serum samples including 180 patients with HCC, 61 patients with liver cirrhosis (LC), 99 chronic hepatitis patients, and 103 healthy individuals were enrolled from November 2011 to April 2013. Enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to detect the serum level of GP73 and other biomarkers. Results: GP73 level in HCC group was significantly higher than LC group, chronic hepatitis B group, and healthy control group. In HCC group, GP73 level significantly increased in patients with lymphatic metastasis; moreover, GP73 level in Child–Pugh Class B and C groups was statistically significantly higher than that in Child–Pugh Class A group (P < 0.05). The area under the receiver operating characteristic (AUROC) curve of GP73 and alpha-fetoprotein (AFP) was 0.840 and 0.718, respectively, when diagnosing HCC. Moreover, the AUROC curve by use of the combination of GP73 and AFP was 0.903. The differences among these three aspects were statistically significant (P < 0.05). Conclusion: GP73 was better than AFP for the diagnosis of HCC, and the expression of serum GP73 is related with the clinical characteristics of HCC patients.

Introduction: In the previous phase II clinical trial (NCT03215693), ensartinib, a next generation (NG) ALK TKI, showed comparable efficacy to other NG ALK TKIs in the post-crizotinib setting. In the preplanned biomarker analysis, we investigated the efficacy and the resistance mechanisms of ensartinib via longitudinal ctDNA analysis. Methods: Pts with stage IIIB/IV ALK+ NSCLC, and had progressive disease (PD) after crizotinib were eligible. Plasma samples from this trial were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1) and the end of treatment (EOT). Plasma DNA was analyzed using a 212-gene sequencing panel. ctDNA amount was defined as the sum of variant allele fraction (VAF) of ALK fusions and mutations. Cox model was applied for multivariate analysis. Results: Between 9/2017 and 7/2019, 182 pts were enrolled in the trial. In total, 178 were included in the full analysis set (FAS), with a median PFS (mPFS) of 9.8 months (95% CI, 7.5 to 11.7 months). 169 pts were evaluable by independent review committee (IRC), with an ORR of 57.7% (95% CI, 50.2% to 65.3%). A total of 431 ctDNA samples were analyzed, including 168 at BL, 165 at C3D1, and 106 at EOT (8 overlappings between C3D1 and EOT). 168 (99.4%) pts had evaluable ctDNA at BL. The median ctDNA amount was 0.00704. The higher ctDNA amount was associated with liver metastases, bone metastases, and TP53 mutations. Tumor burden, as measured by the sum of the target lesions' longest diameters, also positively correlated with ctDNA amount (Pearson correlation 0.261; p < 0.001). Multivariable Cox regression revealed that high level of ctDNA amount and TP53 mutations at BL was significantly associated with poor PFS independently (p =0.020 and p < 0.001) (Table). 106 (62.7%) pts had evaluable ctDNA at both BL and EOT. Compared to baseline, the frequency of certain ALK mutations significantly increased at EOT, such as G1269A (7.5% vs 21.7%), G1202R (3.8% vs 17.0%) and E1210K (0% vs 10.4%). TP53 statusctDNA amountTP53 Wildtype TP53 Mutations Low amountHigh amount(n = 34)(n = 134)(n = 46)(n = 47)mPFS, months (95% CI) 11.7 (9.8, 14.0) 4.2 (3.0, 5.6)9.3 (5.6, 11.7) 4.2 (2.8, 5.5)HR (95% CI); p value2.50 (1.65, 3.79) ; p < 0.0012.34 (1.52, 3.61) ; p < 0.001 Consistent with the change in frequency, the abundance of G1269A, G1202R, and E1210K also trended to increase at EOT, while the abundance of C1156Y and I1171X had a downward trend in most pts. Conclusions: Consistent with previous reports, ensartinib showed high clinical efficacy. Longitudinal ctDNA analysis could be a powerful tool in predicting treatment outcomes and revealing resistant mechanisms of ensartinib. We observed G1269A, G1202R and E1210K as the major resistant mutations to ensartinib. Additional analyses are ongoing and results will be updated and reported in the meeting. Citation Format: Yunpeng Yang, Jie Huang, Tao Wang, Jianya Zhou, Jing Zheng, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Li Mao, Giovanni Selvaggi, Larry Zhu, Shanshan Xiao, Li Zhang. Longitudinal circulating tumor DNA (ctDNA) analysis predicts response and reveals the resistance mechanisms of ensartinib in ALK+ NSCLC patients (pts) progressed on crizotinib: Updated analysis of a phase II clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2997.

Background: Almonertinib (HS-10296) is an oral, potent, high selective third generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) for sensitizing mutations and EGFR T790M mutation. The preliminary clinical data of almonertinib reported in WCLC showed favorable efficacy and safety in target populations. Here, we presented the latest efficacy data, including the subgroup analysis of central nervous system (CNS) response. Methods: Patients aged at least 18 years with centrally confirmed EGFR T790M mutation, locally advanced or metastatic non-small cell lung cancer (NSCLC) progressing on prior EGFR-TKI treatment, received almonertinib 110 mg orally once daily until disease progression. Patients with asymptomatic, stable brain metastases not requiring steroids were enrolled. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), depth of response (DepOR), overall survival (OS) and safety. Response endpoints were assessed in full analysis set (NCT02981108). Results: From May 2018 to October 2018, 244 patients entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients). Of 88 patients with CNS metastases on baseline brain scans, 23 had at least one intracranial measurable target lesion. At cutoff date (Aug 1, 2019), the median duration of follow-up for progression-free survival was 11.8 months. 168 of 244 patients achieved confirmed partial responses. The ORR was 68.9% (95% CI: 62.6, 74.6). The DCR was 93.4% (95% CI: 89.6, 96.2). The mPFS (48.0% maturity) and mDOR were 12.3 (95% CI: 9.6, 13.8) and 12.4 (95% CI: 11.3, NA) months, respectively. The confirmed CNS ORR and DCR were 60.9% (95% CI: 38.5, 80.3) and 91.3% (95% CI: 72.0, 98.9), respectively. The CNS mPFS (47.8% maturity) was 10.8 (95% CI: 5.5, 12.6) months. The safety profile was consistent with the previous report. The most common grade 3 and 4 adverse reactions were increased blood creatine phosphokinase (17 [7.0%]) and pulmonary embolism (6 [2.5%]). There was no interstitial lung disease reported. Conclusions: Almonertinib demonstrated progression-free survival benefit in EGFR T790M positive NSCLC patients who had progressed after previous EGFR-TKI treatment, especially showed clinically meaningful efficacy against CNS metastases, and the safety profile was consistent with that reported previously. A randomized, controlled, double-blinded, phase III study is ongoing comparing almonertinib with gefinitib in first-line treatment of advanced NSCLC patients. Citation Format: Shun Lu, Qiming Wang, Guojun Zhang, Xiaorong Dong, Cheng-Ta Yang, Yong Song, Gee-Chen Chang, You Lu, Hongming Pan, Chao-Hua Chiu, Zhehai Wang, Jifeng Feng, Jianying Zhou, Xingxiang Xu, Renhua Guo, Jianhua Chen, Haihua Yang, Yuan Chen, Zhuang Yu, Her-Shyong Shiah, Chin-Chou Wang, Nong Yang, Jian Fang, Ping Wang, Kai Wang, Yanping Hu, Jianxing He, Ziping Wang, Jianhua Shi, Shaoshui Chen, Qiong Wu, Changan Sun, Chuan Li, Hongying Wei, Ying Cheng, Wu-Chou Su, Te-Chun Hsia, Jiuwei Cui, Yuping Sun, James Chih-Hsin Yang. A multicenter, open-label, single-arm, phase II study: The third generation EGFR tyrosine kinase inhibitor almonertinib for pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (APOLLO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT190.

e13590 Background: Immunotherapy is becoming one of the promising treatments for cancer administration, and several studies indicated a better outcome was received in patients with high tumor mutation burden (TMB). The distribution of TMB is still unknown and this study aimed to analysis the association between TMB and age especially in East Asian populations. Methods: In our study, TMB value was measured as the numbers of synonymous, nonsynonymous mutations and InDels by next generation sequencing with 539 genes panel in tumor tissue. TMB-H was defined as highest mutation load quintile (top 20%) in each cancer type. The association between TMB and age in 874 patients was investigated including 174 patients with liver cancer, 32 patients with bile duct cancer, 54 patients with gastric cancer, 119 patients with colorectal cancer, 27 patients with pancreatic cancer, 32 patients with melanoma, 25 patients with glioma and 411 patients with lung cancer cases, respectively. Spearman rank correlation analysis, Mann-Whitney U-test and Fisher’s exact test were used for statistical analysis. Results: A significant correlation between TMB and ages was observed in patients with solid tumors (r = 0.204, p = 1.263×10−9). The median age of included patients was 60 years-old. Based on nonparametric test, the value of TMB in patients with liver cancer ( p = 2.310×10−4), gastric cancer ( p = 0.029) and lung cancer ( p = 0.001) aged ≥ 60 years-old was significantly higher than the corresponding patients aged < 60 years-old. No significant differences of TMB values were found between patients < 60 and ≥ 60 years-old in bile duct cancer ( p = 0.419), colorectal cancer ( p = 0.075), pancreatic cancer ( p = 1), melanoma ( p = 0.952) and glioma ( p = 0.720). The TMB-H ratio in patients with liver ( p = 0.049) and gastric ( p = 0.015) cancer aged < 60 years old was significantly lower than patients aged ≥ 60 years-old. Conclusions: Our study indicated the TMB value and TMB-H ratio were relatively higher with ages ≥ 60 years old in specific tumors, which might provide useful information to guide precisely the the application of PD-1 or PD-L1 inhibitors. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.

IMPORTANCE: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. OBJECTIVE: To evaluate the efficacy and safety of oral fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objective response rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stable disease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTS: Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2-10.5] vs 6.6 months [95% CI, 5.9-8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P

Objectives This study investigated factors associated with (i) the likelihood of receiving a gene aberration test and (ii) the choice of treatment between chemotherapy and targeted therapy in patients with non-small cell lung cancer (NSCLC) in China. Materials and methods This cross-sectional study analyzed data previously extracted from the medical charts of patients with unresectable Stage IIIB/IV nonsquamous NSCLC discharged from one of 12 tertiary hospitals in China between August 2015 and March 2016. Logistic regressions were applied to investigate factors associated with receiving a gene aberration test and the treatment decision. Results Data from 932 patients were analyzed. Patients were less likely to have a gene aberration test if they had a histologic subtype other than adenocarcinoma or a hospital waiting time for test results of >5 days. Patients were more likely to receive tyrosine kinase inhibitor (TKI) treatment than chemotherapy if they had a positive result for epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase gene aberration testing. EGFR positive patients were more likely to receive TKI treatment than chemotherapy if they did not have insurance for TKI or pemetrexed treatment, and more likely to receive chemotherapy than TKI treatment if they had a waiting time for test results of >5 days. EGFR wild-type/unknown patients receiving chemotherapy were more likely to receive pemetrexed if they attended a hospital in a developed area or had insurance for pemetrexed. Conclusion In this real-world setting in China, the choice of first-line treatment for advanced NSCLC was appropriately guided by gene aberration testing for most patients. However, gene aberration testing and the treatment decision were influenced by practical factors such as hospital location, the waiting time for test results, and insurance coverage, which should be addressed to ensure optimal patient care.

In the production assembly manufacturing process, a large amount of quality data has been generated by civil aircraft equipment system. With the passage of time and the accumulation of data, these massive data cannot be dealt with effectively using traditional statistical analysis of discrete manufacturing industry. To solve this problem, the method of quality data analysis for unsupervised learning presented in this paper was developed, after evaluating the generating characteristics of the civil aircraft quality data and the problems associated with the processing of the traditional quality data analysis. On this basis, in this paper, according to the disorder association, complex structure and large amount of data of the civil aircraft quality data, the data mining association analysis Apriori algorithm and the big data Splunk platform are introduced to effectively reduce the complexity of the quality data analysis through the complementary advantages of both, and put the data in an orderly, coherent state. The results show that the developed method is effective with high efficiency value.

SUMO-specific proteases 3 (SENP3) is a member of the small ubiquitin-like modifier-specific protease family and deconjugates SUMO2/3 from protein substrates. To date, the expression and function of SENP3 in traumatic brain injury (TBI) are unclear. The present study examined dynamic changes in SENP3 expression in the cerebral cortex and in its cellular localization, using an acute TBI model in adult mice. SENP3 expression was examined at 3, 6, 12, 24 h, 3, and 5 days after TBI using Western Blot analysis and quantitative real-time PCR. Immunohistochemistry and immunofluorescence were examined to detect SENP3 localization. Western Blot indicated that SENP3 protein levels gradually increased from 3 h after TBI and peaked at 24 h. Quantitative real-time PCR demonstrated a gradual increase in SENP3 expression, which peaked 12 h after TBI and declined subsequently. Immunohistochemical staining demonstrated that SENP3-positive cells were observed in both the sham and 24 h post-TBI groups. However, robust expression of SENP3 was seldom observed in the sham group, while it was notably enhanced after TBI. Furthermore, immunofluorescence results revealed that the expression of SENP3 increased more significantly in neurons at day 1 after TBI compared with sham group and less significantly in astrocytes and microglia. Moreover, the SENP3-positive cells that were co-expressed with NeuN also expressed caspase-3, indicating a potential correlation between SENP3 and apoptosis after TBI. Collectively, our results showed obvious up-regulation of SENP3 expression in the brain after TBI, especially in the neurons. However, the full role of SENP3 and its therapeutic potential in TBI needs further investigation.