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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.

Background Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small‐scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first‐line treatment in locally advanced or metastatic LSCC. Methods Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression‐free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45‐Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. Results The median duration of follow‐up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF‐α, IFN‐γ, IL‐6, and IL‐8, demonstrating an overlapping trend. Conclusion The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen., Cisplatin plus Lipusu (LP) regimen has comparable efficacy and more favorable toxicity profiles compared with cisplatin plus gemcitabine (GP) regimen for patients with advanced LSCC. The study also demonstrated that LP had a significant impact on the levels of plasma cytokines and a spectrum of cytokines were associated with clinical benefit in patients who received LP. Thus, our results provided a new option for patients with advanced LSCC.

Objective Small cell lung cancer (SCLC) transformation had previously been reported mainly in epidermal growth factor receptor (EGFR) mutant adenocarcinoma. However, the underlying genomic profile remains unclear. Our study aim to find the evolution and genotypic characteristic of SCLC transformation. Patients and methods Thirty-one SCLC transformation patients who were initially diagnosed as Non-Small Cell Lung Cancer (NSCLC) patients were included. Whole exome sequencing (WES) of both primary and transformed re-biopsy lesions was conducted on 12 patients. Clinical characteristics were analyzed using R software (v.3.6.1). Results Our study included 31 patients, of whom, three had lung squamous cell carcinoma. Six patients did not carry EGFR mutations. Thirty patients received chemotherapy for SCLCs. The disease control rate (DCR) was 96.7%, and the median progression-free survival (PFS) was 4.03 months. The median time to transformation was 33.07 months, and the median overall survival (OS) was 62.08 months. Somatic mutation analysis showed that besides TP53, RB1, and EGFR, there was a high occurrence of mutations to CSMD3 and ADAMTS19, especially in the EGFR-wild type (EGFR-wt) group. Concerning mutational signature, the EGFR-mutant (EFFR-mut) transformed group favored an APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like)-associated mutation pattern (P = 0.16). DNA Damage Repair (DDR)-related signatures were significantly enriched in the EGFR-wt transformed group (P = 0.034). Additionally, clonal evolution analysis revealed that all patients had the same main trunk genes in the phylogenetic tree. Transformed SCLCs are not sensitive to immunotherapy, possibly due to increased tumor heterogeneity. Conclusion Our results indicated that the EGFR-wt patients could also transform to SCLCs, but they have different genetic features with EGFR-mut patients. SCLC-transformed patients respond to classical chemotherapy and have a better prognosis than those with classical SCLCs.

Introduction Some ALK inhibitors with good inhibition of ROS1 in preclinical studies have been reported to be possibly beneficial in ROS1-positive NSCLC. In this work, we studied the efficacy and safety of ensartinib in the treatment of patients with ROS1-positive NSCLC. Methods The exploratory study was a phase 2, single-arm, multicenter design (NCT03608007). Patients with ROS1-positive NSCLC with a previous chemotherapy line number of less than or equal to 1 who received ensartinib at the dose of 225 mg once daily were enrolled. The primary end point was objective response rate evaluated by an investigator per Response Evaluation Criteria in Solid Tumors version 1.1. Results From June 2018 to July 2019, a total of 59 patients were enrolled at 23 centers in the People’s Republic of China. At the time of data cutoff, the median follow-up was 19.8 months (range: 0.8–22.5). The median objective response rate was 27.0 % (95 % confidence interval [CI]: 13.8–44.1) with 10 partial responses. Median duration of response was 4.8 months (95 % CI: 1.8–10.8). The median progression-free survival was 4.6 months (95 % CI: 4.0–6.4). The median overall survival was not estimable (95 % CI: 14.9–not estimable). Of four patients with brain metastases, intracranial disease control was reported in three (75.0 %, 95 % CI: 19.4–99.4). The most common treatment-related adverse events (TRAEs) were rash and liver enzyme abnormalities, with good prognosis after adjustment for dosage and concomitant medication. Most of the TRAEs were of grades 1 to 2, and incidence of grade greater than or equal to 3 TRAEs was 25.4 %. Conclusions Ensartinib had a modest efficacy in patients with ROS1-positive NSCLC with an acceptable safety profile.

The reverse logistics of municipal hazardous waste (RLMHW) have received close attention from researchers and practitioners alike, given the essential impact of safe transportation and effective management of hazardous waste on public health and environmental sustainability. There are a great number of studies in the extant literature on RLMHW, with many and diverse research topics; however, a concise and complete overview of the research works already conducted in this particular area is conspicuous by its absence. This paper strives to fill the gap through the conduct of rigorous systematic literature review of RLMHW in the past three decades, and then establish a framework of studies on RLMHW. The main contributions of this study are as follows: (1) to identify the trend of journals publishing research papers on RLMHW; (2) to extract the main topics in studies on RLMHW; (3) to locate the most popular research areas of RLMHW; (4) to summarize the methods adopted in studies on RLMHW; (5) to identify research deficiencies in certain categories of RLMHW; and (6) to establish the future research directions of RLMHW. The main implications of the study are to offer a better understanding of RLMHW by systematic crystallization of archival data in a systematic chronological order across central issues. This study contributes to scholarly debate in this field by serving as a snapshot paper to document the development of the field and gives input to policymakers in process design and policy making in the domain of RLMHW.

Xiaoning He,1,2 Mengqian Zhang,1,2 Jing Wu,1,2 Song Xu,3 Xiangli Jiang,4 Ziping Wang,5 Shucai Zhang,6 Feng Xie7,8 1School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, People’s Republic of China; 2Center for Social Science Survey and Data, Tianjin University, Tianjin, People’s Republic of China; 3Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 4Tianjin Medical University Cancer Institute & Hospital, Tianjin, People’s Republic of China; 5Department of Medical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 6Department of Medical Oncology, Beijing Chest Hospital, Beijing, People’s Republic of China; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 8Centre for Health Economics and Policy Analysis, McMaster University, Hamilton, ON, CanadaCorrespondence: Jing WuSchool of Pharmaceutical Science and Technology, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin, 300072, People’s Republic of ChinaTel +862227405176Fax +862287401830Email jingwu@tju.edu.cnBackground: Cancer treatment decision-making often needs to balance benefits, harms, and costs. This study sought to identify the differences in cancer treatment preference among oncologists, patients and their family members in China.Methods: A semi-structured face-to-face qualitative interview was conducted among oncologists, patients and their family members recruited in four tertiary hospitals in China. The interview guide was developed based on literature review and expert consultation. Participants were asked to indicate their preferences when making lung cancer treatment decisions. All interviews were audio-taped, transcribed verbatim, and thematic analyzed. The preferences were compared among three groups of participants.Results: A total of 17 participants (5 oncologists, 6 dyads of patients and family members) were interviewed between June and July 2019. Five themes, namely, survival benefit, adverse effect/symptom, treatment process, treatment cost, and the impact on daily life were identified. The oncologists and family members gave highest priority on survival benefit, while the patients are concerned most about treatment cost and quality of life.Conclusion: This study reveals different preferences for cancer treatment among oncologists, patients and their family members in China. Education is needed to empower patients and family members and promote share decision-making in this country.Keywords: lung cancer, preference, qualitative interview, survival benefit, cost

BACKGROUND: This study aimed to assess the different survival outcomes of stage I–IIIA non-small cell lung cancer (NSCLC) patients who received right-sided and left-sided pneumonectomy, and to further develop the most appropriate treatment strategies. METHODS: We accessed data from the Surveillance, Epidemiology, and End Results database from the United States for the present study. An innovative propensity score matching analysis was used to minimize the variance between groups. RESULTS: For 2,683 patients who received pneumonectomy, cancer-specific survival [hazard ratio (HR) =0.863, 95% confidence interval (CI): 0.771 to 0.965, P=0.010] and overall survival (OS; HR =0.875, 95% CI: 0.793 to 0.967, P=0.008) were significantly superior in left-sided pneumonectomy patients compared with right-sided pneumonectomy patients. Cancer-specific survival (HR =0.847, 95% CI: 0.745 to 0.963, P=0.011) and OS (HR =0.858, 95% CI: 0.768 to 0.959, P=0.007) were also significantly longer with left-sided compared to right-sided pneumonectomy after matching analysis of 2,050 patients. Adjuvant therapy could significantly prolong cancer-specific survival (67 versus 51 months, HR =1.314, 95% CI: 1.093 to 1.579, P=0.004) and OS (46 versus 30 months, HR =1.458, 95% CI: 1.239 to 1.715, P

Rationale: Platinum-based chemotherapy is one of treatment mainstay for patients with advanced lung squamous cell carcinoma (LUSC) but it is still a "one-size fits all" approach. Here, we aimed to investigate the predictive and monitoring role of circulating cell-free DNA (cfDNA) profiling for the outcome of first-line chemotherapy in patients with advanced LUSC. Methods: Peripheral blood samples of 155 patients from a phase IV trial and 42 cases from an external real-world cohort were prospectively collected. We generated a copy number variations-based classifier via machine learning algorithm to integrate molecular profiling of cfDNA, named RESPONSE SCORE (RS) to predict the treatment outcome. To monitor the treatment efficacy, cfDNA samples collected at different time points were subjected to an ultra-deep sequencing platform. Results: The results showed that patients with high RS showed substantially higher objective response rate than those with low RS in training set (P < 0.001), validation set (P < 0.001) and real-world cohort (P = 0.019). Furthermore, a significant difference was observed in both progression-free survival (training set, P < 0.001; validation set: P < 0.001; real-world cohort: P = 0.019) and overall survival (training set, P < 0.001; validation set: P = 0.037) between high and low RS group. Notably, variant allele frequency (VAF) calculated from an ultra-deep sequencing platform significantly reduced in patients experienced a complete or partial response after 2 cycles of chemotherapy (P < 0.001), while it significantly increased in these of non-responder (P < 0.001). Moreover, VAF undetectable after 2 cycles of chemotherapy was correlated with markedly better objective response rate (P < 0.001) and progression-free survival (P < 0.001) than those with detectable VAF. Conclusions: These findings indicated that the RS, a circulating cfDNA sequencing-based stratification index, could help to guide first-line chemotherapy in advanced LUSC. The change of VAF is valuable to monitor the treatment response.

This paper presents a procedure for damage identification and characterization on plates, based on the principal curvatures of their first mode shape. Each mode shape represents the displacement of the structure at its corresponding natural frequency. Since, variations in the geometry due to cracks or material property degradation, make changes in the mode shapes of the structure, such changes can be used for damage identification methods. The presented procedure only requires the first mode shape of the intact and damaged structure. It is shown that the principal curvatures of the surface defined by the first mode shape of the structure, are sensitive to damage and the maximum principal curvature can be used to highlight damages on the structure. The performance of the developed method is firstly evaluated using finite element analysis. To this aim, the procedure is applied to highlight both single and multi-damages in different locations of the plate with different boundary conditions. It is shown that the location of the maximum curvature variation coincides well with the location of damages and the amount of the maximum curvature change can be used as a parameter to describe damage severity. The accuracy of the proposed method is also experimentally verified by test on an aluminum plate and it is demonstrated that the proposed method remains effective even in experimental condition when only a limited number of measurements are available.

Background Although advanced non-squamous non-small cell lung cancer (NSCLC) patients have significantly better survival outcomes after pemetrexed based treatment, a subset of patients still show intrinsic resistance and progress rapidly. Therefore we aimed to use a blood-based protein signature (VeriStrat, VS) to analyze whether VS could identify the subset of patients who had poor efficacy on pemetrexed therapy. Methods This study retrospectively analysed 72 advanced lung adenocarcinoma patients who received first-line pemetrexed/platinum or combined with bevacizumab treatment. Results Plasma samples from these patients were analysed using VS and classified into the Good (VS-G) or Poor (VS-P) group. The relationship between efficacy and VS status was further investigated. Of the 72 patients included in this study, 35 (48.6%) were treated with pemetrexed plus platinum and 37 (51.4%) were treated with pemetrexed/platinum combined with bevacizumab. Among all patients, 60 (83.3%) and 12 (16.7%) patients were classified as VS-G and VS-P, respectively. VS-G patients had significantly better median progression-free survival (PFS) (Unreached vs. 4.2 months; P Conclusions Our study indicated that VS might be considered as a novel and valid method to predict the efficacy of pemetrexed-based therapy and identify a subset of advanced lung adenocarcinoma patients who had intrinsic resistance to pemetrexed based regimens. However, larger sample studies are still needed to further confirm this result.

Introduction Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of alflutinib in patients with advanced NSCLC with confirmed EGFR T790M mutation, whose status progressed after the first- or second-generation EGFR tyrosine kinase inhibitor therapy. Methods In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. The primary end points were safety, tolerability, and pharmacokinetics for the dose-escalation study and the objective response rate (assessed by an independent radiological review committee) for the dose-expansion study. Results Between November 30, 2016, and July 24, 2018, a total of 130 patients (14 in dose escalation, 116 in dose expansion) received alflutinib treatment (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily). On October 30, 2018, 79 patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40–240 mg), the overall objective response rate was 76.7% (89 of 116), and it was 70.6% in patients with central nervous system metastases (12 of 17). A total of 79% of all patients had possibly treatment-related adverse events (AEs) (103 of 130); 8% had treatment-related grade 3 or higher AEs (11 of 130). Serious AEs were reported in 15% of patients (20 of 130), and two serious AEs were related to treatment. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state. Conclusions Alflutinib was clinically effective with an acceptable toxicity profile in patients with advanced NSCLC (including those with central nervous system metastases) with EGFR T790M mutation. Further investigation is ongoing.

The delegating computation has become an irreversible trend, together comes the pressing need for fairness and efficiency issues. To solve this problem, we leverage game theory to propose a smart contract-based solution. First, according to the behavioral preferences of the participants, we design an incentive contract to describe the motivation of the participants. Next, to satisfy the fairness of the rational delegating computation, we propose a rational delegating computation protocol based on reputation and smart contract. More specifically, rational participants are to gain the maximum utility and reach the Nash equilibrium in the protocol. Besides, we design a reputation mechanism with a reputation certificate, which measures the reputation from multiple dimensions. The reputation is used to assure the client’s trust in the computing party to improve the efficiency of the protocol. Then, we conduct a comprehensive experiment to evaluate the proposed protocol. The simulation and analysis results show that the proposed protocol solves the complex traditional verification problem. We also conduct a feasibility study that involves implementing the contracts in Solidity and running them on the official Ethereum network. Meanwhile, we prove the fairness and correctness of the protocol.

Background Thymic carcinomas (TCs) are rare aggressive tumors with no standard first‐line treatment. This study was conducted to determine the optimal chemotherapy regimen for advanced TC. Methods This retrospective study included 67 patients treated for stage IV TC in 2006–2015. The primary endpoints were the objective response rate (ORR) and progression‐free survival (PFS) with different chemotherapy regimens. Multivariate Cox regression analysis was used to identify factors associated with PFS, including metastatic status, radiotherapy post‐chemotherapy, primary lesion resection before chemotherapy, and chemotherapy regimen. Results A total of 36 patients received a paclitaxel‐platinum regimen, 31 received a gemcitabine‐platinum regimen, 14 underwent primary lesion resection, and 33 underwent radiotherapy. ORR was 31% (11/36) and 29% (9/31) in the paclitaxel‐platinum and gemcitabine‐platinum groups, respectively (P = 0.890). Median PFS, one‐year PFS rate, and two‐year PFS rate were 7.0 months, 26%, and 6% with paclitaxel‐platinum treatment and 12 months, 48%, and 24% with gemcitabine‐platinum treatment (log‐rank P = 0.030). Median PFS, one‐year PFS rate, and two‐year PFS rate were 18.0 months, 57%, and 33% with surgical resection and 7.3 months, 31%, and 7% without resection (log‐rank P = 0.030). Median PFS, one‐year PFS rate, and two‐year PFS rate were 13.0 months, 52%, and 20% with radiotherapy and 4.3 months, 22%, and 7% without radiotherapy (log‐rank P = 0.001). In multivariate analysis, metastatic status (hazard ratio [HR], 0.33, P = 0.004), surgical resection (HR, 0.32; P = 0.004), and radiotherapy (HR, 0.32; P

BACKGROUND Small-cell lung cancer (SCLC) is one of the most aggressive types of lung cancer. The prognosis for SCLC patients depends on many factors. The intent of this study was to construct a nomogram model to predict mortality for extensive-stage SCLC. METHODS Original data was collected from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States. A nomogram prognostic model was constructed to predict death probability for extensive-stage SCLC. RESULTS A total of 16 554 extensive-stage SCLC patients from 2004 to 2014 in the SEER database were included in this study. Gender, race, age, TNM staging (including tumor extent, nodal status, and metastasis), and treatment (surgery, chemotherapy, and radiotherapy) were identified as independent predictors for lung cancer-specific death for extensive-stage SCLC patients. A nomogram model was constructed based on multivariate models for lung cancer related death and other cause related death. Performance of the two models was validated by calibration and discrimination, with C-index values of 0.714 and 0.638, respectively. CONCLUSION A prognostic nomogram model was established to predict death probability for extensive-stage SCLC. This validated prognostic model may be beneficial for treatment strategy choice and survival prediction.

Background High concordance has been observed between Ventana D5F3 ALK immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) in lung adenocarcinoma (LADC). However, whether a similar conclusion can be applied to lung squamous-cell carcinoma (LSCC) has remained unclear. We therefore evaluated the ALK (anaplastic lymphoma kinase) status and the therapeutic effect of an ALK tyrosine kinase inhibitor (TKI) in IHC- or FISH-positive LSCC. Materials and methods A total of 2403 LSCC patients from three institutions were screened for ALK aberration by IHC. All IHC-positive cases were subjected to FISH (with an approximately equal number of negative cases as a control group) and next-generation sequencing (NGS). Clinical efficacy was evaluated for the patients who received TKI therapy. Results In 2403 cases of LSCC, 37 cases were identified as ALK-positive by IHC. After quality control, 28 cases were succeeded by FISH (six with insufficient tissue, three with lack of signals) and 13 by NGS (24 failed due to insufficient samples or poor DNA quality); the percentage of non-diagnostic tests was 24.3% (9/37) and 64.9% (24/37), respectively. Four cases (4/2394, 0.17%) analyzed by FISH were determined as ALK-positive. For the control group (40 ALK IHC), FISH demonstrated no samples with ALK gene fusion. The concordance between ALK IHC- and ALK FISH-positive results was 14.3% (4/28). In the 13 cases studied by NGS, two cases showed ALK-EML4 fusion (consistent with two FISH-positive results), and two cases were interpreted as harboring an ALK-association gene mutation. Among four patients (two FISH-positive and two IHC-positive only cases) receiving TKI therapy, two patients had stable disease and the other two had progressive disease. Conclusions The positive concordance rate of ALK IHC and FISH in LSCC is far less than that reported for LADC. Therefore, ALK IHC detection in LSCC cannot be used as a diagnostic method for ALK rearrangement.

Currently, there are limited treatment options for patients who developed resistance to osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor. Resistance to EGFR inhibitors is frequently associated with enhanced vascular endothelial growth factor (VEGF) levels. This multicenter, retrospective study aimed to evaluate the efficacy of the combination treatment with apatinib and osimertinib in 39 patients with EGFR-mutant non-small cell lung carcinoma (NSCLC) who developed osimertinib resistance. The patients received the combination of oral apatinib 250 mg qd and osimertinib 80 mg qd. The efficacy was evaluated after the first month then every 2 months thereafter. The primary endpoint was progression-free survival (PFS). The overall response rate (ORR) and the disease control rate (DCR) of the combination of apatinib and osimertinib was 12.8% (5/39) and 79.5% (31/39), respectively. The median PFS was 4 months [95% confidence interval (CI): 3.5–4.5 months]. Fourteen patients were administered with at least 6 months of combination therapy, and 11 of them remained on treatment programs. The 6-month PFS rate was 38%. Nine patients underwent biopsies after failing osimertinib treatment, and five of six patients with TP53 mutations had PFS of less than 3 months. The spectrum of resistance to osimertinib mechanisms included c-mesenchymal-epithelial transition factor (c-Met) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gain-of-function mutation, phosphatase and tensin homolog (PTEN) loss-of-function mutation, Erb-B2 receptor tyrosine kinase 2 (ERBB2) amplification, and insulin-like growth factor 1 receptor (IGF1R) mutation. The most common adverse events were hypertension (30.7%, 12/39), diarrhea (15.4%, 6/39), and proteinuria (12.8%, 5/39). The combination of apatinib and osimertinib improved the ORR and the DCR of patients with osimertinib-refractory EGFR-positive NSCLC, thus making it a reasonable treatment choice after the development of osimertinib resistance.

Interdigital transducer (IDT), it is widely used in structural health monitoring of large-scale projects, due to its excellent designability. However, for the implementation of structural health monitoring of large-scale complex projects, the existing conventional piezoelectric transducers have some shortcomings, such as poor flexibility, poor mechanical and electrical performance, while the flexible transducer based on polyvinylidene fluoride (PVDF) is difficult to achieve efficient actuating performance. Based on the multi-physical coupling theory, the electrode width, electrode spacing, substrate size and other parameters of IDT was optimized by piezoelectric module. The orientation and the interval of IDT was determined, so as to realize the excellent electromechanical conversion efficiency. Firstly, the annular Dielectric Elastomer Interdigital Transducer (DE-IDT) model with different electrode width, electrode spacing, substrate thickness and substrate size is constructed. Under the piezoelectric plate, the strain of different electrode width, electrode spacing, substrate thickness and substrate size is analyzed. According to the strain, the piezoelectric effect is judged, and the optimal size of DE-IDT is obtained on the basis. The azimuth and distance of DE-IDT are simulated to obtain the optimal actuating distance. The circular DE-IDT has good omnidirectional characteristics and the optimal electrode width, electrode spacing, substrate thickness and substrate size are determined.

Background Pemetrexed maintenance therapy offers a survival benefit in patients with nonprogressive advanced nonsquamous non-small cell lung cancer (NSCLC) with good tolerability. This study was designed to analyze the efficacy and safety of pemetrexed maintenance chemotherapy in advanced nonsquamous NSCLC patients in a real-world setting. Methods The response rate (RR) and adverse events in 71 nonsquamous NSCLC patients treated with pemetrexed-based chemotherapy were observed until disease progression or unacceptable toxicities. Measures of survival were analyzed during follow-up. Results Of 69 efficacy-evaluable patients, the objective response rate (ORR) was 46.4% and the disease control rate (DCR) was 98.6%. ORR showed no significant difference between patients who received pemetrexed as first-line therapy and those who received pemetrexed as second-line or higher treatment. The median treatment cycle for all patients was 8. The median progression-free survival (PFS) was 9.5 months (m) and median overall survival (OS) was 30.5 m. The univariate and multivariate analyses showed that the number of chemotherapy cycles was an independent factor for PFS. The most common adverse reactions were grade 1 to 2 hematologic toxicities, gastrointestinal reactions, and liver enzyme abnormalities. Only 1 patient experienced a grade 3 gastrointestinal event. Conclusions Pemetrexed maintenance chemotherapy can improve PFS in patients with advanced nonsquamous NSCLC with good tolerability.

Background Pemetrexed/platinum chemotherapy has been the standard chemotherapy regimen for lung adenocarcinoma patients, but the efficacy varies considerably. Methods To discover new serum biomarkers to predict the efficacy of pemetrexed/platinum chemotherapy, we analyzed 20 serum samples from advanced lung adenocarcinoma patients who received pemetrexed/platinum chemotherapy with the data-independent acquisition (DIA) quantitative mass spectrometry (MS). Results The 20 patients were categorized as "good response" [12 patients achieving partial response (PR)] and "poor response" [8 patients with progressive disease (PD)] groups. Altogether 23 significantly different expressed proteins were identified, which had relative ratios higher than 1.2 or lower than -0.83, with 7 proteins having an area under the curve (AUC) above 0.8. To further validate the DIA results, we used the parallel reaction monitoring (PRM) method to examine 16 candidate serum biomarkers in the study cohort of 20 patients and another cohort of 22 advanced lung adenocarcinoma patients (16 PR and 6 PD). Quantitative validation using PRM correlated well with the DIA results, and 10 promising proteins exhibited a similar up- or downregulation. It is worth noting that glutathione peroxidase 3 (GPX3) exhibits significant upregulation in the poor response group compared with the good response group, which was validated by both DIA and PRM methods. Conclusions Our study confirmed that combined DIA MS and PRM approaches were effective in identifying serum predictive biomarkers for advanced lung adenocarcinoma patients. Further studies are needed to explore the potential biological mechanism underlying these biomarkers.

Background The five-year cumulative incidence rate in patients diagnosed with stage I small-cell lung cancer (SCLC) who were instructed to undergo surgery was from 40 to 60%.The death competition influence the accuracy of the classical survival analyses. The aim of the study is to investigate the mortality of stage I small-cell lung cancer (SCLC) patients in the presence of competing risks according to a proportional hazards model, and to establish a competing risk nomogram to predict probabilities of both cause-specific death and death resulting from other causes. Methods The study subjects were patients diagnosed with stage I SCLC according to ICD-O-3. First, the cumulative incidence functions (CIFs) of cause-specific death, as well as of death resulting from other causes, were calculated. Then, a proportional hazards model for the sub-distribution of competing risks and a monogram were constructed to evaluate the probability of mortality in stage I SCLC patients. Results 1811 patients were included in this study. The five-year probabilities of death due to specific causes and other causes were 61.5 and 13.6%, respectively. Tumor size, extent of tumor, surgery, and radiotherapy were identified as the predictors of death resulting from specific causes in stage I SCLC. The results showed that surgery could effectively reduce the cancer-specific death, and the one-year cumulative incidence dropped from 34.5 to 11.2%. Like surgery, chemotherapy and radiotherapy improved the one-year survival rate. Conclusions We constructed a predictive model for stage I SCLC using the data from the SEER database. The proportional sub-distribution models of competing risks revealed the predictors of death resulting from both specific causes and other causes. The competing risk nomogram that we built to predict the prognosis showed good reliability and could provide beneficial and individualized predictive information for stage I SCLC patients.

Purpose: Primary mediastinal germ cell tumors (PMGCTs) are rare. The natural history and optimal treatment strategies still need to be defined. The aim of the study was to summarize the clinical characteristics, treatment outcomes, and prognostic factors of PMGCTs. Methods: Twenty-four patients with PMGCTs who were treated from December 2008 to January 2019 were evaluated retrospectively. The Kaplan–Meier method and Cox regression analysis were used to evaluate factors associated with prognosis. Results: The study population consisted of 23 male patients and 1 female patient. Five patients were diagnosed with seminoma and 19 patients were diagnosed with nonseminoma. The median follow-up time for all patients was 15.8 (3.9–114.5) months. The 5-year overall survival (OS) and progression free survival (PFS) rates for all patients were 65.2 and 44.3%. For nonseminoma and seminoma, the 5-year OS rates were 54.1 and 100% (P = 0.093), respectively, and the 5-year PFS rates were 28.7 and 100%, respectively (P = 0.044). In patients with nonseminoma, first-line radiotherapy indicated superior OS and PFS (P = 0.037 and 0.027, respectively). The median survival time after recurrence was 4.3 months and the 1-year survival rate after recurrence was 23.4%. Conclusion: These results indicated that in PMGCTs, the prognosis of seminoma is superior to that of nonseminoma. Radiotherapy may be an essential treatment in patients with nonseminoma. Patients with relapse have unfavorable prognosis.

Background This study aimed to establish a novel nomogram prognostic model to predict death probability for non-small cell lung cancer (NSCLC) patients who received surgery.. Methods We collected data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute in the United States. A nomogram prognostic model was constructed to predict mortality of NSCLC patients who received surgery. Results A total of 44,880 NSCLC patients who received surgery from 2004 to 2014 were included in this study. Gender, ethnicity, tumor anatomic sites, histologic subtype, tumor differentiation, clinical stage, tumor size, tumor extent, lymph node stage, examined lymph node, positive lymph node, type of surgery showed significant associations with lung cancer related death rate (P Conclusions A prognostic nomogram model was constructed to give information about the risk of death for NSCLC patients who received surgery.

Introduction Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy. Methods This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated. Results A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42–63) and 92% (95% CI: 84–96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5–not reached) months. Conclusions Almonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.

Purpose: We aimed to assess the survival benefit of surgery for patients with stage IA–IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS).Methods: Patients who had been diagnosed with stage IA–IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram.Results: We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio [HR], 0.642; 95% confidence interval [CI], 0.557–0.740; P < 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's C-index = 0.645).Conclusion: Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.

The CAPTRA-Lung study (NCT03334864) is a prospective observational study that will capture real-world data of patients with advanced or metastatic non-small cell lung cancer (NSCLC) across China. The study aims to complement the results from current therapeutic regimens to improve the standard of diagnosis and treatment, evaluate the effectiveness and safety of systemic therapy, and determine the factors influencing the outcomes and responses to treatment. From January 2018 to December 2023, eligible patients with advanced or metastatic NSCLC who are receiving treatment and participating in follow-up at 16 institutions in China, will be enrolled. The demographic, clinical, laboratory, and treatment characteristics and responses to treatment will be recorded in a case report form and transcribed into an electronic data capture system. Overall survival, progression-free survival, overall response rate, and incidence of adverse events will be calculated from the time of initial enrolment until progression evaluated by physicians, last contact, date of death, or analysis cutoff date, respectively. Based on the disease characteristics and treatment strategies, four sub-cohorts will also be established. This study cohort could serve as a pool of patients with advanced or metastatic NSCLC to support further research.

Background We evaluated topoisomerase I (TOPO1) expression in patients with small cell lung cancer (SCLC) and identified predictive factors for the efficacy of second-line topotecan chemotherapy. Methods We retrospectively evaluated the records of SCLC patients treated in our department from January 2007 to December 2016 who received second-line topotecan chemotherapy. Patients with archived tumor samples were enrolled. TOPO1 expression levels were evaluated by immunohistochemistry, and the relationships between TOPO1 expression, clinical factors, chemotherapy efficacy, and survival were analyzed. Results Of the 78 patients enrolled, 67 showed TOPO1 expression (85.9%). Patients were divided into strong (n = 43) or weak (n = 35) expression groups based on staining intensity. Disease control rates for topotecan were 39.5% and 14.3% in the strong and weak groups, respectively (P = 0.014). Second-line median progression-free survival was 2.2 and 2.0 months (P = 0.057), and median overall survival was 8.1 and 6.0 months (P = 0.199) in the strong and weak positive groups, respectively. Patients were also divided into sensitive (n = 47) and refractory (n = 31) disease groups according to the duration from the onset of first-line therapy to relapse. Median second-line progression-free survival was 2.2 and 1.8 months in the sensitive and refractory relapse groups, respectively (P = 0.005). Conclusions TOPO1 expression was prevalent in SCLC patients. Strong expression was associated with an elevated disease control rate after second-line topotecan chemotherapy. Patients with sensitive disease that relapsed after first-line chemotherapy had better survival than refractory patients who received second-line topotecan chemotherapy.

BACKGROUND The PD-L1 antibody atezolizumab has shown promising efficacy in patients with advanced non-small cell lung cancer. But the predictive marker of clinical benefit has not been identified. OBJECTIVE This study aimed to search for potential predictive factors in circulating blood of patients receiving atezolizumab. METHODS Ten patients diagnosed with advanced non-small cell lung cancer were enrolled in this open-label observing study. Circulating immune cells and plasma tumor markers were examined in peripheral blood from these patients before and after atezolizumab treatment respectively. Relation between changes in circulating factors and anti-tumor efficacy were analyzed. RESULTS Blood routine test showed that atezolizumab therapy induced slightly elevation of white blood cells count generally. The lymphocyte ratio was increased slightly in disease controlled patients but decreased prominently in disease progressed patients in response to atezolizumab therapy. Flow cytometric analysis revealed changes in percentage of various immune cell types, including CD4+ T cell, CD8+ T cell, myeloid-derived suppressor cell, regulatory T cell and PD-1 expressing T cell after atezolizumab. Levels of plasma tumor marker CEA, CA125 and CA199 were also altered after anti-PD-L1 therapy. In comparison with baseline, the disease progressed patients showed sharp increase in tumor marker levels, while those disease controlled patients were seen with decreased regulatory T cell and myeloid-derived suppressor cell ratios. CONCLUSIONS The circulating immune cell ratios and plasma tumor marker levels were related with clinical efficacy of atezolizumab therapy. These factors could be potential predictive marker for anti-PD-L1 therapy in advanced non-small cell lung cancer.

Lubricant failure or irrational lubrication is the root cause of industrial equipment failure. By monitoring the distribution of the suspended particles in lubricants, it is possible to discover hidden lubrication problems. After taking the lubricating oil samples of industrial equipment, the oil monitoring technology is used to analyze the particle size distribution and the type and content of the abrasive particles by electrical, magnetic, and optical monitoring techniques. It is necessary to separate the suspended particles in oils with impurities by some method to eliminate potential safety hazards and ensure the reuse efficiency of the lubricant. In this paper, the principles, advantages, and disadvantages of several important oil monitoring methods are described, and new developments in various methods are analyzed. Several typical methods for separation of the suspended particles in purified oils were introduced. The advantages and disadvantages of each process were summarized. The development direction of lubricant monitoring technology was pointed out, and guidance was provided for the separation and online monitoring of the suspended particles in lubricants. Finally, compared with similar review papers, this paper specifically figured out that ultrasonic separation method has the advantages of real time, high efficiency, and no pollution and has important application value for micron-scale particle separation of large precision machines.

In this paper, a manufacturer is considered who is regulated by the cap-and-trade scheme and sells products on an e-business (EB) platform. When this manufacturer is capital-constrained, funds can be accessed via EB platform financing mode, supplier credit financing mode, and mixed financing mode, where the manufacturer accesses funds from both the supplier and the EB platform. Considering the exogenous retail price, this paper develops optimizing models under all three financing modes to investigate the manufacturer's emission reduction, production quantities, and financing strategies. The financing strategy of a slightly capital-constrained manufacturer depends on the usage fee charged by the EB platform. The manufacturer prefers non-financing support if the usage fee rate is too high; otherwise, the manufacturer prefers accessing funds from the EB platform. A moderately capital-constrained manufacturer prefers EB platform financing if the financing rate charged by the EB platform financing is slightly higher than that charged by the supplier. Also, a moderately capital-constrained manufacturer prefers EB platform financing if the usage fee rate is relatively low; otherwise, supplier credit financing is preferred. Furthermore, a heavily capital-constrained manufacturer prefers mixed financing if the financing rate charged by the EB platform is higher than that charged by the supplier; otherwise, the manufacturer prefers EB platform financing. When the usage fee is endogenous, the EB platform financing mode is better than the non-financing mode for both the capital-constrained manufacturer and the EB platform. Furthermore, the above conclusions are robust when the retail price is endogenous.

Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC).To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor.This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC.Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily.The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC.A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals.In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC.ClinicalTrials.gov Identifier: NCT02767804.

BACKGROUND Gemcitabine plus cisplatin (GP) is commonly used to treat lung squamous cell carcinoma (SCC); however, it is not clear which subgroup of lung SCC patients could benefit most from GP treatment. We explored the predictive factors in lung SCC patient cohorts. METHODS Seventy-eight lung SCC patients treated with a first-line GP regimen were enrolled in this retrospective cohort study. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Classification tree models were used to explore the risk factors for PFS and OS in these patients. RESULTS The median PFS and OS in SCC patients treated with a GP regimen were 6.0 and 13.6 months, respectively. Three terminal subgroups were formed for both PFS and OS. The subgroup with a body mass index (BMI) > 23.94 kg/m2 and aged ≤ 54.5 had the longest PFS (9.0 months); the subgroup with a BMI < 23.94 kg/m2 and aged ≤ 54.5 had the shortest PFS (4.05 months). Patients with an objective response (partial or complete response) to treatment had the longest OS (20.0 months), while patients with a BMI ≤ 26.92 kg/m2 and stable or progressive disease as the best response had the shortest OS (11.2 months). CONCLUSIONS BMI and age may be predictors of PFS in lung SCC patients who receive GP treatment. BMI and best response to GP treatment predicts OS in such patients. Patients' clinical pathological characteristics may be used to predict the therapeutic efficacy of chemotherapy and survival.

It is of great significance to grasp the ultrasonic attenuation characteristics of materials for the nondestructive testing of materials. The dynamic properties of a piezoelectric composite material (OPCM) with self-developed transverse anisotropy have been analyzed using the experiment in this work. The OPCM sensor is attached to the surface of the iron plate and concrete structures to sense the surface waves generated by acoustic emission (AE). The experiment results show that OPCM sensor elements have unique advantages compared to piezoelectric ceramic materials (PZT). Further, by comparing the signals of isotropic and anisotropic materials, the attenuation characteristics of surface waves propagating in different materials are studied, and a new method for measuring the attenuation coefficient of surface waves is demonstrated.

Introduction Pembrolizumab plus chemotherapy significantly improved survival outcomes versus placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC in the randomized, double-blind, phase 3 KEYNOTE-407 study. We present the results of Chinese patients enrolled in the KEYNOTE-407 global and China extension studies. Methods Patients enrolled from mainland China in the KEYNOTE-407 global (NCT02775435) and China extension studies (NCT03875092) were randomized 1:1 to 35 cycles of pembrolizumab or placebo plus four cycles of carboplatin and paclitaxel or nab-paclitaxel. Dual primary end points were overall survival (OS) and progression-free survival (PFS) (based on the Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review). Results A total of 125 patients were randomized (pembrolizumab–chemotherapy, n = 65; placebo–chemotherapy, n = 60). As of September 30, 2020, median (range) study follow-up was 28.1 (25.1‒40.9) months. Pembrolizumab–chemotherapy improved OS (hazard ratio [HR] = 0.44, 95% confidence interval [CI]: 0.28–0.70) and PFS (HR = 0.35, 95% CI: 0.24–0.52) versus placebo–chemotherapy. Two-year OS and PFS rates for pembrolizumab–chemotherapy versus placebo–chemotherapy were 56.9% versus 31.7% and 24.2% versus 3.3%, respectively. Treatment-related grade 3 to 5 adverse events occurred in 81.5% and 81.7%, respectively. Relative to baseline, pembrolizumab–chemotherapy improved global health status/quality of life scores at week 18 versus placebo–chemotherapy (difference in least squares means = 7.6, 95% CI: 1.5–13.7) and prolonged time to deterioration in cough, chest pain, or dyspnea (HR = 0.50, 95% CI: 0.28–0.89). Conclusions Pembrolizumab–chemotherapy prolonged survival versus placebo–chemotherapy with manageable toxicity and preserved or improved health-related quality of life in Chinese patients with metastatic squamous NSCLC. These findings support pembrolizumab–chemotherapy as first-line therapy in this population.

Over the past three decades, business managers and academic researchers have shown considerable interest in understanding how information systems (IS) can lead to competitive advantages for firms. Although in the United States researchers have found that IS competences lead to competitive advantages, it remains unknown whether firms working in emerging economies can capitalize on IS competence for competitive advantages. This article examines the moderating effect of the learning intensity of organizations on the relationship between IS competence and competitive advantages in 122 Chinese firms. Data were collected from a mailed survey of 122 information-technology (IT) managers. The results indicate that flexibility of IT infrastructure, IT business skills, and learning intensity have significant effects on competitive advantages. The learning intensity of organizations positively moderates the relationship between IS business skills and competitive advantages, but has no moderating effect on the relationship between the flexibility of IT infrastructure and competitive advantages.

With the development of cancer immunotherapy, the combination strategy is becoming prevalent. Multiple relevant clinical trials are ongoing in this field. However, immune-related adverse events (irAEs) occurred more frequently, showing a different pattern from single-agent therapy. It is necessary for clinicians to learn about the characteristics of AEs from combination immunotherapy, and master the skills to deal with them. In this article, we reviewed presently published data about AEs from combination immunotherapy of cancers. We believe a full-scale view about this new treatment strategy will facilitate oncologists to better understand tumor immune response. With cutting edge knowledge, an experienced team can minimize these AEs and help patients to achieve high-quality long-term survival.

Purpose: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens. In this study, we sought to investigate genomic subtyping using cell-free DNA (cfDNA) analysis in advanced LCNEC and assess its potential prognostic and predictive value. Experimental Design: Tumor DNA and cfDNA from 63 patients with LCNEC were analyzed by target-captured sequencing. Survival and response analyses were applied to 54 patients with advanced stage incurable disease who received first-line chemotherapy. Results: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. The 63 patients with LCNEC were classified into small-cell lung cancer (SCLC)-like and non–small cell lung cancer (NSCLC)-like LCNEC based on corresponding genomic features derived from tumor DNA and/or cfDNA. Overall, patients with SCLC-like LCNEC had a shorter overall survival than those with NSCLC-like LCNEC despite higher response rate (RR) to chemotherapy. Furthermore, treatment with etoposide-platinum was associated with superior response and survival in SCLC-like LCNEC compared with pemetrexed-platinum and gemcitabine/taxane-platinum doublets, while treatment with gemcitabine/taxane-platinum led to a shorter survival compared with etoposide-platinum or pemetrexed-platinum in patients with NSCLC-like LCNEC. Conclusions: Genomic subtyping has potential in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis may be a reliable alternative for genomic profiling of LCNEC.

Ultrasonic linear phased array actuator for electric-acoustic conversion is the key component of the ultrasonic phased array test system. Focusing on the existing deficiency of using phased array ultrasonic testing technology into complex engineering structure, using the 2D orthotropic piezoelectric composite materials (2D-OPCM) into the research of linear phased array actuator can achieve orientable exciting. The single OPCM element and its array actuator was designed and their mechanical properties of focusing were tested by experiment. The experimental results show that 2D-OPCM ultrasound phased array actuator can achieve precise phased array focusing and deflection, which might be of great promising in the nondestructive evaluation engineering application.

Background Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates from the pleura and has a poor prognosis. Eligible patients can benefit from surgery, but their survival is affected by many factors. Therefore, we created a graphic model that could predict the prognosis of surgically treated patients. Methods We retrospectively analyzed data from the Surveillance, Epidemiology, and End Results database from 2004 to 2014 to identify the key factors affecting the prognosis of surgically treated MPM patients. On this basis we built a nomogram to predict survival. We then evaluated the performance of the nomogram in a validation cohort. Results In a training cohort of 828 cases, independent prognostic factors, including age, gender, histological type, differentiation, N stage, chemotherapy, type of surgery, and lymph node dissection, were identified. We then developed a nomogram to evaluate individual patient survival. In Kaplan-Meier analysis, a higher score in the nomogram was associated with a worse prognosis. We also used a validation cohort consisting of 312 patients to evaluate the performance of the nomogram, which was well calibrated and had good discrimination ability, with concordance indices of 0.715 and 0.656 for the training and validation cohorts, respectively. Conclusion This study has improved our understanding of resected MPM and shown that key factors, including age and histological type, are associated with overall survival. The nomogram is a reliable tool that can help clinicians turn individualized prediction into reality and maximize patient benefit by identifying the most beneficial treatment approach.

Background: Patients (pts) with advanced squamous NSCLC (sqNSCLC) have very limited second-line treatment options after failure of the platinum-based doublet chemotherapy. ORIENT-3 was conducted to compare the efficacy and safety of sintilimab, an anti-PD-1 antibody, with docetaxel in second-line treatment in sqNSCLC. (NCT03150875) Method: Pts with stage IIIB/IIIC or IV (ineligible for radical chemo-radiotherapy) sqNSCLC who have disease progression during or after first-line platimum-based chemotherapy were enrolled and randomized 1:1 to receive sintilimab 200mg (Sin arm) or docetaxel 75mg/m2 (Doc arm) intravenously, Q3W until disease progression or intolerable toxicity. Stratification factor was ECOG score (0 vs. 1). The primary endpoint was overall survival (OS). Results: As of July 31, 2020, 290 pts were enrolled with 145 in each treatment group. Efficacy analysis was based on FAS (n=280), and safety analysis was based on safety set (n=274). Baseline characteristics were well balanced between treatment groups, and most pts in efficacy analysis (75.9% in Sin arm, 77.0% in Doc arm) had ECOG PS score of 1. Pts received a median of 8.0 cycles (range: 1-45) of sintilimab, and 2.0 cycles of docetaxel (range: 1-15). With a median follow-up of 23.56 months, sintilimab had a significant improvement in OS versus docetaxel (median: 11.79 m [95% CI 10.28-15.57] vs. 8.25 m [95% CI 6.47-9.82]; HR 0.74, [95%CI 0.56-0.96], P = 0.02489). The median PFS was also significantly superior in Sin arm (4.30 m, 95% CI 4.04-5.78) to that in Doc arm (2.79 m, 95% CI 1.91-3.19) (HR 0.52, 95% CI 0.39-0.68, P Citation Format: Yuankai Shi, Lin Wu, Xinmin Yu, Yan Wang, Puyuan Xing, Jianying Zhou, Airong Wang, Jianhua Shi, Yi Hu, Ziping Wang, Guangyu An, Yong Fang, Sanyuan Sun, Caicun Zhou, Changli Wang, Feng Ye, Xingya Li, Junye Wang, Mengzhao Wang, Yunpeng Liu, Yanqiu Zhao, Jifeng Feng. ORIENT-3: A randomized, open-label, phase 3 study of sintilimab versus docetaxel in previously treated advanced/metastatic squamous non-small-cell lung cancer (sqNSCLC) [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 CT041.

Results From RATIONALE 303: A Global Phase 3 Study of Tislelizumab (TIS) vs Docetaxel (TAX) as Second- or Third-Line Therapy for Patients With Locally Advanced or Metastatic NSCLC Background: Anti-PD-1/L1 therapies have improved OS by 2-4 mo vs TAX in patients (pts) with advanced NSCLC who progressed after platinum regimens. TIS is an anti-PD-1 antibody engineered to minimize FcγR binding on macrophages, a mechanism of T-cell clearance and potential anti-PD-1 resistance. Methods: RATIONALE 303 (BGB-A317-303; NCT03358875) compared efficacy and safety of TIS vs TAX as 2 or 3L therapy for pts with advanced NSCLC. Patients without oncogenic driver mutation who failed at least 1 prior systemic therapy including a platinum regimen were randomized 2:1 to receive TIS 200 mg IV Q3W (Arm A) or TAX 75 mg/m2 IV Q3W (Arm B). Dual primary endpoints were OS in the ITT analysis set and OS in the PD-L1 high (≥25% TC) analysis set. A prespecified interim analysis (IA) was conducted after ≈426 deaths (76% of planned events); in the IA, formal OS superiority testing was conducted only in the ITT. The IA results are presented. Results: Overall, 805 pts were randomized (n=535, TIS; n=270, TAX); demographics were generally balanced between arms. With a 19-mo median follow-up (441 OS events), median OSITT was significantly longer in Arm A vs B (17.2 vs 11.9 mo; HR=0.64 [95% CI: 0.53, 0.78]; P Conclusions: RATIONALE 303 demonstrated that, as 2 or 3L therapy in pts with advanced NSCLC, TIS was tolerable and prolonged OS by 5-7 mo with improved PFS and ORR vs TAX regardless of histology or PD-L1 expression. ITT Analysis Set (N=805)Arm A Tislelizumab (n=535)Arm B Docetaxel (n=270)EfficacyMedian OS, mo17.211.9OS difference, mo5.3HR (95% CI)a0.64 (0.53, 0.78)P-valuea,b Citation Format: Caicun Zhou, Dingzhi Huang, Xinmin Yu, Yunpeng Liu, Yun Fan, Yongqian Shu, Zhiyong Ma, Ziping Wang, Ying Cheng, Jie Wang, Sheng Hu, Zhihua Liu, Mikhail Dvorkin, Elena Poddubskaya, Umut Disel, Andrey Akopov, Yiyuan Ma, Yan Wang, Zhenyu Pan, Cunjing Yu, Gareth Rivalland. Results from RATIONALE 303: A global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC [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 CT039.

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

e21072 Background: Penpulimab is a human IgG1 monoclonal antibody (mAb) directed against human programmed cell death-1 (PD-1). Penpulimab, with its unique binding epitope, was engineered to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function, and to optimize receptor occupancy by improving duration of drug binding. As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib significantly improved overall survival in advanced NSCLC patients (pts) in the phase 3 trial ALTER0303. Antiangiogenesis therapy combined with PD-1/PD-L1 inhibitors has shown excellent efficacy in advanced NSCLC pts. This is the trial evaluating chemo-free combination of penpulimab plus anlotinib in treatment-naive advanced NSCLC pts regardless of PD-L1 expression (NCT03866980). Methods: Pts with previously untreated, stage IIIB/IIIC/IV non-squamous NSCLC without sensitizing mutation of the epidermal growth factor receptor (EGFR) gene or translocation of the anaplastic lymphoma kinase (ALK) gene were enrolled. Eligible pts received penpulimab 200mg Q3W in combination with anlotinib 12mg QD (2 weeks on 1 week off) until loss of clinical benefit or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included ORR, disease control rate (DCR), duration of response (DoR) and overall survival. Results: As of January 13, 2021, 26 pts had received the combination therapy of penpulimab plus anlotinib (median age 59.5yrs [range 30-71], 76.9% male, 76.9% ECOG PS 1), with a median treatment duration of 3.5 months. Of 21 pts who have had at least one tumor assessment, the ORR was 57.1% (12 PRs) and DCR was 90.5% (12 PRs, 7 SDs). Median PFS has not been reached, and eleven responders remain in response. Treatment-related adverse events (TRAEs) occurred in 53.8% of pts (≥G3 TRAEs occurred in 15.4% [4/26]). Treatment-related SAEs occurred in 15.4% [4/26], and 7.7% of pts [2/26] had drug interruption or discontinuation due to TRAEs. Most common TRAEs (≥15%) were ALT increased, AST increased, hyperthyroidism and hypertension (15.4% each). Conclusions: The combination of penpulimab plus anlotinib as first-line treatment for locally advanced/metastatic NSCLC showed the promising efficacy with a manageable safety profile, thereby suggesting that this combination therapy may be a viable chemo-free treatment strategy for locally advanced/metastatic NSCLC pts. Clinical trial information: NCT03866980.

e21053 Background: VEGF promotes an immunosuppressive microenvironment and contributes to resistance of immune checkpoint inhibitors in cancer treatment. VEGF inhibitors have been shown to enhance efficacy of checkpoint inhibitors in clinical studies. Vorolanib (CM082) is a multi-target tyrosine kinase inhibitor including VEGF, PDGF, c-kit, and Flt-3. Toripalimab (JS001) is a humanized IgG4 mAb against programmed death-1 (PD-1). This phase II study aims to evaluate efficacy and safety of the combination of vorolanib and JS001 in non-small cell lung cancer (NSCLC) patients who progressed with prior first-line standard therapy. Methods: This single-arm, single-center, phase II study (NCT03848611) enrolls NSCLC patients with measurable disease (RECIST 1.1) and Eastern Cooperative Oncology Group performance status ≤ 1, regardless of PD-L1 status. 15 patients received 150 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks while 3 patients received 100 mg oral CM082 daily plus 240 mg intravenous JS001 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint is objective response rate (ORR). Results: Between April 2019 and July 2020, 18 patients were enrolled. Median age was 64 years. 9 of 18 patients (50%) were adenocarcinoma and 9 of 18 patients (50%) were squamous. Males account for 83% (15/18) with 4 non-smokers among the male patients. At the data cutoff (January 11, 2021), we observed 2 (11%) confirmed and 1 (6%) unconfirmed partial response (PR), 6 (33%) stable disease (SD) and 9 (50%, including 2 PR of the target lesions) progression disease (PD). Tumor shrinkage was seen in 6 (33%) of the 18 patients. Two (11%) patients were still on the study drugs. Interestingly, all the patients with confirmed PR or PR of the target lesions were squamous histology. The most common treatment-related adverse events were proteinuria (67%), elevated ALT (60%), elevated AST (53%), hypertension (40%), and increased bilirubin (40%). Grade 3 adverse events include elevated ALT (20%), elevated AST (20%), liver function damage (13%), elevated GGT (7%), fatigue (7%), bellyache (7%), ruptured and infected tumor (7%), and dysphagia (7%). One Grade 4 adverse event was pulmonary embolism. Conclusions: Vorolanib with toripalimab showed a promising antitumor activity with acceptable safety profiles for patients with NSCLC. We hypothesized that the potential benefits of combination therapy for patients with squamous cell carcinoma may be better than those for patients with adenocarcinoma, and the study is ongoing. Clinical trial information: NCT03848611.

Objective Adjuvant chemotherapy (AC) after curative resection is known to improve the survival of patients with non-small cell lung cancer (NSCLC); however, few studies have reported the correlation between the time to initiation of AC (TTAC) and survival in NSCLC patients. Methods The clinical data of 925 NSCLC patients who received curative resection and post-operative AC at the Cancer Hospital of Chinese Academy of Medical Sciences between 2003 and 2013 were retrospectively analyzed. TTAC was measured from the date of surgery to the initiation of AC. Disease-free survival (DFS) was defined as the duration from surgery to the time of tumor recurrence or last follow-up evaluation. The optimal cut-off value of TTAC was determined by maximally selected log-rank statistics. The DFS curve was estimated using the Kaplan-Meier method, and the Cox proportional hazards regression model was used to identify risk factors independently associated with DFS. Propensity score matching (PSM) was performed for survival analysis using the match data. Results The optimal discriminating cut-off value of TTAC was set at d 35 after curative resection based on which the patients were assigned into two groups: group A (≤35 d) and group B (>35 d). There was no significant difference in the DFS between the two groups (P=0.246), indicating that the TTAC is not an independent prognostic factor for DFS. A further comparison continued to show no significant difference in the DFS among 258 PSM pairs (P=0.283). Conclusions There was no significant correlation between the TTAC and DFS in NSCLC patients. Studies with larger samples are needed to further verify this conclusion.

The emerging automatic data-capturing technology, radio frequency identification technology (RFID), has been extensively adopted in logistics process and retail operations. However, limited research has been conducted on how to exploit and integrate RFID-enabled timely demand information into production processes. The lack of sufficient evaluation on the financial benefits of RFID hinders the adoption of this technology in production processes. In this study, we propose a framework to integrate RFID-enabled timely demand information into a dynamic production lot-sizing problem. Our results show that manufacturers, distributors and retailers can benefit from the availability of timely demand information via RFID. Our research sheds new light on understanding the financial value of RFID in a production process, and fills a gap in the application of RFID along the supply chain.