Publications by authors named "Jianying Zhou"

258 Publications

Nosocomial Infections in Nonsurgical Patients Undergoing Extracorporeal Membrane Oxygenation: A Retrospective Analysis in a Chinese Hospital.

Infect Drug Resist 2022 29;15:4117-4126. Epub 2022 Jul 29.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China.

Background: The effect of nosocomial infections (NIs) in adult patients undergoing ECMO has been rarely reported in China. Moreover, the effect of NIs on ECMO patients' mortality is still unclear and inconclusive according to literature data. In this study, we examined the prevalence, risk factors, causative organisms, and effects on outcomes of NIs in ECMO patients.

Methods: A total of 79 nonsurgical patients (mean age 53.3±15.2 year (yr); 66% male) who underwent ECMO between January 2011 and September 2020 were enrolled in this retrospective study. Patients' demographic and clinical data and ECMO parameters were collected from all patients.

Results: Among 79 patients who underwent ECMO for a total of 1253 ECMO days (mean time 15.9±14.1 d), 42 developed NIs. We observed 30 ventilator-associated pneumonia (VAP), 19 bloodstream infections (BSIs), and 4 urinary tract infections, corresponding to 23.9/1000 ECMO days, 15.2/1000 ECMO days, and 3.2/1000 ECMO days, respectively. ECMO duration (22.0±16.5 VS 8.9±5.3 d, P < 0.001), invasive mechanical ventilation (IMV) duration (27.4±20.5 VS 11.4±10.1 d, P < 0001), and ICU length of stay (35.9±22.9 VS 15.7±9.2 d, P < 0.001) were longer in patients with NIs. The independent risk factors for NIs were ECMO duration (Odds Ratio [OR], 1.414; 95% Confidence Interval [CI], (1.051-1.238); P = 0.002) and viral pneumonia (OR, 5.788; 95% CI, (1.551-21.596); P = 0.009). Gram-negative bacteria were the most common causative organisms of NIs; ), and were the most common bacteria. BSI (OR, 8.106; 95% CI, (1.384-47.474); P = 0.02) was an independent predictor for mortality.

Conclusion: NIs are common complications in patients during ECMO treatment, especially VAP, followed by BSI. Also, BSI can negatively affect the survival rate.
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http://dx.doi.org/10.2147/IDR.S372913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347224PMC
July 2022

Efficacy and safety of selpercatinib in Chinese patients with advanced fusion-positive non-small-cell lung cancer: a phase II clinical trial (LIBRETTO-321).

Ther Adv Med Oncol 2022 28;14:17588359221105020. Epub 2022 Jul 28.

Department of Respiratory Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Introduction: Oncogenic alterations in occur in 1-2% of non-small-cell lung cancers (NSCLCs). The efficacy and safety of the first-in-class, highly selective, and potent RET inhibitor selpercatinib in Chinese patients with fusion-positive NSCLC remains unknown.

Methods: In this open-label, multicenter, phase II study (NCT04280081), patients with advanced -altered solid tumors received selpercatinib (160 mg orally twice daily) in a 28-day cycle. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included duration of response, central nervous system (CNS) response, and safety. Efficacy against NSCLC was assessed in the primary analysis set (PAS; centrally confirmed status) and in all enrolled patients with NSCLC.

Results: Of 77 enrolled patients, 47 had fusion-positive NSCLC. After 9.7 months of median follow-up, IRC-assessed ORR in the PAS ( = 26) was 69.2% [95% confidence interval (CI), 48.2-85.7] and 94.4% of responses were ongoing; the ORR was 87.5% and 61.1% in treatment-naïve and pre-treated patients, respectively. IRC-assessed ORR in all patients with NSCLC ( = 47) was 66.0% (95% CI, 50.7-79.1). Among five patients with measurable CNS metastases at baseline, four (80%) achieved an IRC-assessed intracranial response. In the safety population ( = 77), most treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common grade ⩾3 TEAE was hypertension (19.5%). Three (3.9%) patients discontinued therapy due to treatment-related AEs; no deaths occurred due to treatment-related AEs.

Conclusion: Selpercatinib, with potent and durable antitumor activity including intracranial activity, was well tolerated in Chinese patients with fusion-positive NSCLC, consistent with LIBRETTO-001 (ClinicalTrials.gov: NCT04280081).
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http://dx.doi.org/10.1177/17588359221105020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9340421PMC
July 2022

A novel clinical dynamic stereopsis assessment based on autostereoscopic display system.

Ann Transl Med 2022 Jun;10(12):656

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China.

Background: Although it is recognized that dynamic stereopsis is vital in daily life, there is still room for improvement in assessment methods. A novel clinical dynamic stereopsis assessment method was created based on an autostereoscopic display system that did not require additional auxiliary glasses. This study evaluated the optical parameters and clinical performance of the autostereoscopic display system for clinical dynamic stereopsis assessment.

Methods: The autostereoscopic dynamic stereopsis assessment device was based on a directional backlight technology. Experiment 1 was performed under the same environmental conditions to compare luminance, crosstalk, and spectrum between the autostereoscopic dynamic stereopsis assessment device and the conventional dynamic random-dot stereopsis measuring instrument. Experiment 2 was an observational, analytic, cross-sectional study involving 135 healthy participants, each of whom was asked to complete measurements on both the autostereoscopic and conventional devices in random order. Stereo acuity, operating time, acceptance, and visual fatigue scores were recorded for clinical evaluation.

Results: The autostereoscopic device had brighter luminance (139 and 140 cd/m for 2 eyes, respectively), lower crosstalk (4.50% for both eyes), and higher color restoration degree than those of the conventional instrument. Clinically, the novel dynamic stereopsis assessment was as accurate as the traditional method [170" (0.00") and 170" (0.00") respectively; P=0.317], and with more efficiency (166±58.9 and 298±116 s, respectively; P<0.001), higher acceptance (3.36±0.93 and 2.02±0.59 points, respectively; P<0.001), lesser fatigue (0.27±0.46 and 0.73±0.66 points, respectively; P<0.001). The autostereoscopic dynamic stereopsis assessment device with brighter luminance, lower crosstalk, and higher color restoration degree was more effective than the traditional instrument at displaying dynamic clues for clinical dynamic stereopsis assessment. Furthermore, its high-quality image and user-friendly interface provided accurate assessment results in all 3 dynamic stereopsis assessment task conditions, with a higher level of acceptance and lesser visual fatigue, than the traditional assessment method.

Conclusions: The autostereoscopic device has excellent functions in both optical parameters and clinical performance, and therefore has the potential to be applied and popularized in future assessments.
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http://dx.doi.org/10.21037/atm-21-6700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279808PMC
June 2022

Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation.

Front Oncol 2022 22;12:911303. Epub 2022 Jun 22.

Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Background: Limited treatment outcome data is available for advanced non-small cell lung cancer (NSCLC) patients with BRAF V600E mutations. In this multicenter study, we describe therapeutic options and survival outcomes for patients with mutated BRAF V600E.

Method: This was a retrospective study in which BRAF V600E-mutated advanced NSCLC patients were retrospectively recruited between January 2015 and December 2021 and had their clinical characteristics, co-mutations, and treatment efficacy assessed.

Results: Fifty-three patients with BRAF V600E-mutant advanced NSCLC were included in the study, of which 64.2% were non-smokers, and the BRAF V600E mutation was more prevalent in men (52.8%). In addition, 96.2% of the patients had adenocarcinoma, and most (96.2%) received first-line therapy (23.5% anti-BRAF), with a progression-free survival (PFS) and overall survival (OS) of 10.0 [95% confidence interval (CI): 1.5-36.0 months] and 24.0 months [95% CI: 3.0-53.0 months], respectively. Twenty-three patients (43.4%) received second-line treatment (39.1% anti-BRAF), and PFS and OS were 5.0 [95% CI: 1.0-21.0 months] and 13.0 months [95% CI: 1.5-26.0 months], respectively. BRAF and MEK-targeted therapy (dabrafenib plus trametinib) produced longer PFS compared with that of chemotherapy with or without bevacizumab as a first-line (NA vs. 4.0 months, = 0.025) or second-line therapy (6.0 vs. 4.6 months, = 0.017). NSCLC patients harboring driver oncogene mutations such as BRAF V600E, EGFR, or ALK should be treated using targeted therapies. Concurrent TP53 mutations were the most common, affecting 11.3% ( = 6) of the patients, followed by EGFR 19 Del ( = 5). Patients with concurrent mutations had shorter PFS (9.0 vs. 10.0 months, = 0.875) and OS (14.0 vs. 15.0 months, = 0.555) than those without these mutations.

Conclusion: These results suggest that combined BRAF- and MEK-targeted therapy is effective in BRAF V600E-mutated advanced NSCLC patients. Dabrafenib and trametinib re-challenge is also an option for patients with BRAF V600E-mutated NSCLC.
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http://dx.doi.org/10.3389/fonc.2022.911303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257040PMC
June 2022

Far-Field and Non-Intrusive Optical Mapping of Nanoscale Structures.

Nanomaterials (Basel) 2022 Jul 1;12(13). Epub 2022 Jul 1.

State Key Laboratory of Optoelectronic Materials and Technologies, School of Physics, Sun Yat-Sen University, Guangzhou 510275, China.

Far-field high-density optics storage and readout involve the interaction of a sub-100 nm beam profile laser to store and retrieve data with nanostructure media. Hence, understanding the light-matter interaction responding in the far-field in such a small scale is essential for effective optical information processing. We present a theoretical analysis and an experimental study for far-field and non-intrusive optical mapping of nanostructures. By a comprehensive analytical derivation for interaction between the modulated light and the target in a confocal laser scanning microscopy (CLSM) configuration, it is found that the CLSM probes the local density of states (LDOSs) in the far field rather than the sample geometric morphology. With a radially polarized (RP) light for illumination, the far-field mapping of LDOS at the optical resolution down to 74 nm is obtained. In addition, it is experimentally verified that the target morphology is mapped only when the far-field mapping of LDOS coincides with the geometric morphology, while light may be blocked from entering the nanostructures medium with weak or missing LDOS, hence invalidating high-density optical information storage and retrieval. In this scenario, nanosphere gaps as small as 33 nm are clearly observed. We further discuss the characterization for far-field and non-intrusive interaction with nanostructures of different geometric morphology and compare them with those obtainable with the projection of near-field LDOS and scanning electronic microscopic results.
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http://dx.doi.org/10.3390/nano12132274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268055PMC
July 2022

Associations between comorbidities and annual incidence plus frequency of asthma exacerbation hospitalisation during the past year: data from CARN study.

BMC Pulm Med 2022 Jul 1;22(1):261. Epub 2022 Jul 1.

Department of Respiration, Hainan General Hospital, Haikou, China.

Purpose: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX.

Methods: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study.

Results: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX.

Conclusions: COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.
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http://dx.doi.org/10.1186/s12890-022-02038-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250194PMC
July 2022

Optimizing Patient Outcomes Through Sequential EGFR TKI Treatment in Asian Patients With Mutation-Positive NSCLC.

Clin Med Insights Oncol 2022 24;16:11795549221103215. Epub 2022 Jun 24.

Department of Clinical Development and Medical Affairs, Boehringer Ingelheim (China) Investment Limited, Shanghai, P.R. China.

Patients from Asia with non-small-cell lung cancer (NSCLC) often have mutations in the epidermal growth factor receptor () gene. While an increasing number of tyrosine kinase inhibitors (TKIs) are now available for patients with mutation-positive NSCLC, most patients inevitably develop resistance to the treatment. Evidence from clinical studies suggests that treatment outcomes and resistance mechanisms vary depending on the choice of TKI therapy in the first-line setting. Hence, it is important to develop optimal treatment sequencing strategies that can provide maximum survival benefit for the patient. In this review we present clinical evidence in Asian patients with NSCLC for various EGFR TKIs, with the goal of supporting the optimization of treatment sequencing.
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http://dx.doi.org/10.1177/11795549221103215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234848PMC
June 2022

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study.

J Thorac Oncol 2022 Jun 18. Epub 2022 Jun 18.

Department of Medical Oncology/Chemotherapy, The First Affiliated Hospital of University of Science and Technology of China, Anhui Provincial Hospital, Hefei, People's Republic of China.

Introduction: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy.

Methods: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156.

Results: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively.

Conclusions: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).
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http://dx.doi.org/10.1016/j.jtho.2022.06.002DOI Listing
June 2022

Th22 Cells/IL-22 Serves as a Protumor Regulator to Drive Poor Prognosis through the JAK-STAT3/MAPK/AKT Signaling Pathway in Non-Small-Cell Lung Cancer.

J Immunol Res 2022 28;2022:8071234. Epub 2022 May 28.

Department of Respiratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

The interaction of immune cells and cytokines in the tumor microenvironment affects the development and prognosis of tumors with an unclear potential regulatory mechanism. Recent studies have elucidated the protumor role of Th22 cells and its lineage-specific cytokine IL-22 in different human cancers. The present study is aimed at investigating the biological effect of Th22 cells/IL-22 and its molecular mechanism in the pathogenesis process of non-small-cell lung cancer (NSCLC). It was initially found that Th22 cells were enriched in the peripheral blood of NSCLC patients. The level of Th22 cells in peripheral blood mononuclear cells (PBMCs) was positively correlated with the TNM stage, lymph node metastasis, and clinical tumor biomarkers. Furthermore, IL-22 not only antagonized the apoptosis inducing and cell cycle arresting effect by chemotherapy and molecular targeted drugs on NSCLC cell lines but also promoted tumor cell proliferation and tumor tissue growth. Moreover, IL-22 activated the JAK-STAT3/MAPK/AKT signaling pathway, both and . Conclusively, the present results confirm that Th22 cells/IL-22 may serve as a negative immune regulator in lung cancer.
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http://dx.doi.org/10.1155/2022/8071234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167127PMC
June 2022

TROY Modulates Cancer Stem-Like Cell Properties and Gefitinib Resistance Through EMT Signaling in Non-Small Cell Lung Cancer.

Front Genet 2022 13;13:881875. Epub 2022 May 13.

Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Targeted therapy has made breakthrough progress in the treatment of advanced non-small cell lung cancer (NSCLC) in the last 20 years. Despite that, acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is an urgent clinical problem. Our study established an acquired gefitinib-resistant cell line, which exhibited epithelial-mesenchymal transition (EMT) and stem cell-like properties. Transcriptional sequencing and bioinformatics analysis revealed that TROY was significantly increased in gefitinib-resistant cells. Gene set enrichment analysis (GSEA) showed EMT was the core enriched hallmark in the resistant cells. TROY siRNA interference could overcome the gefitinib resistance with the downregulated expression of EMT and CSC markers. In addition, immunohistochemistry indicated that TROY was overexpressed in tumor samples from patients who acquired resistance to first-generation EGFR-TKI without T790M mutation and the expression of TROY was associated with poor prognosis in LUAD. Here, we provided the potential role of TROY in the resistance of targeted therapy and a new strategy to overcome the acquired resistance to EGFR-TKI in NSCLC.
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http://dx.doi.org/10.3389/fgene.2022.881875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136171PMC
May 2022

Deguelin Attenuates Non-Small-Cell Lung Cancer Cell Metastasis by Upregulating PTEN/KLF4/EMT Signaling Pathway.

Dis Markers 2022 21;2022:4090346. Epub 2022 May 21.

Department of Respiratory Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.

Non-small-cell lung cancer (NSCLC) is the most common lung cancer and a major cause of cancer mortality worldwide. Deguelin plays a vital inhibitory role in NSCLC initiation and development. However, the downstream mechanism of deguelin-suppressed metastasis of NSCLC cells is still not completely understood. Interestingly, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Krüppel-like factor 4 (KLF4) also contribute to inhibition of metastasis in NSCLC cells. Here, we demonstrated that deguelin significantly upregulated PTEN and KLF4 expressions and PTEN positively upregulated KLF4 expression in NSCLC cells including A549 and PC9 cells. Moreover, overexpressions of PTEN and KLF4 inhibited the migration and invasion of NSCLC cells, an effect similar to that of deguelin. Furthermore, overexpressions of PTEN and KLF4 could suppress the epithelial-mesenchymal transition (EMT), an effect also similar to that of deguelin. Additionally, deguelin displayed a significant antitumor ability by upregulating PTEN and KLF4 expressions in mice model with NSCLC cells. Together, these results indicated that deguelin could be a potential therapeutic agent through upregulating PTEN and KLF4 expressions for NSCLC therapy.
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http://dx.doi.org/10.1155/2022/4090346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9148257PMC
June 2022

AENEAS: A Randomized Phase III Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With Exon 19 Deletion or L858R Mutations.

J Clin Oncol 2022 May 17:JCO2102641. Epub 2022 May 17.

Respiratory Medicine, Xiangya Hospital Central South University, Changsha, China.

Purpose: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic -mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768).

Methods: Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment.

Results: A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively.

Conclusion: Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for -mutant NSCLC in the first-line setting.
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http://dx.doi.org/10.1200/JCO.21.02641DOI Listing
May 2022

Benzo[a]pyrene inhibits myoblast differentiation through downregulating the Hsp70-MK2-p38MAPK complex.

Toxicol In Vitro 2022 Aug 12;82:105356. Epub 2022 Apr 12.

Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address:

Cigarette smoking causes skeletal muscle dysfunction and worse prognosis for patients with diverse systemic diseases. Benzo[a]pyrene (BaP), one major constituent that is inhaled during smoking, is particularly known for its ability to impair neurodevelopment, impede reproductivity, or reduce birth weight. Here, we found that BaP exposure led to the inhibition of C2C12 myoblasts differentiation in a dose-dependent manner and reduced the expression of both early and late myogenic differentiation markers. BaP exposure significantly decreased the expression of p38 mitogen-activated protein kinase (p38MAPK), but not AKT, which are both critical during myogenic differentiation. Mechanistically, BaP downregulated the expression levels of MAPK-activated protein kinase 2 (MK2) and heat shock protein 70 (Hsp70), both of which stabilize p38MAPK. Interestingly, treatment of proteasome inhibitor MG132 was able to reverse BaP-induced degradation of Hsp70/ MK2 and p38MAPK in myoblasts, implying BaP-mediated p38MAPK degradation is proteasome-dependent. Overexpression of p38MAPK also rescued the defective differentiation phenotype of C2C12 induced by BaP. Taken together, we suggest that BaP exposure induces MK2/Hsp70/p38MAPK complex degradation in C2C12 myoblasts and impairs myogenic differentiation by proteasomal-dependent mechanisms. As application of the proteasome inhibitor MG132 or overexpression of p38MAPK could reverse impaired differentiation of myoblasts induced by BaP, this may suggest potential related strategies for preventing tobacco-related skeletal muscle diseases or for respiratory rehabilitation.
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http://dx.doi.org/10.1016/j.tiv.2022.105356DOI Listing
August 2022

Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

Cancer Discov 2022 Jul;12(7):1676-1689

Dana-Farber Cancer Institute, Boston, Massachusetts.

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached.

Significance: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.
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http://dx.doi.org/10.1158/2159-8290.CD-21-1615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262839PMC
July 2022

[Pneumocystis jirovecii Pneumonia in Patients with Lung Cancer: A Review].

Zhongguo Fei Ai Za Zhi 2022 Apr 28;25(4):272-277. Epub 2022 Mar 28.

Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, China.

In recent years, with the widespread use of immunodepressant agents, Pneumocystis jirovecii pneumonia (PJP) has been significantly found in non-human immunodeficiency virus (HIV) patients, such as those with malignancies, post-transplantation and autoimmune diseases. Although the risk factors and management of PJP have been extensively studied in the hematologic tumor and post-transplant populations, the research on real tumor cases is insufficient. Lung cancer has been the most common tumor with the highest number of incidence and death worldwide, and the prognosis of lung cancer patients infected with PJP is poor in clinical practice. By reviewing the previous studies, this paper summarized the epidemiology and clinical manifestations of PJP in lung cancer patients, the risk factors and possible mechanisms of PJP infection in lung cancer patients, diagnosis and prevention, and other research progresses to provide reference for clinical application.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2022.101.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9051306PMC
April 2022

IL-17A contributes to skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway.

Am J Physiol Cell Physiol 2022 05 23;322(5):C814-C824. Epub 2022 Mar 23.

Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a proinflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy. We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging were also evaluated. We found that in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify that phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss in patients with cancer.
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http://dx.doi.org/10.1152/ajpcell.00463.2021DOI Listing
May 2022

Lorlatinib for Previously Treated ALK-Positive Advanced NSCLC: Primary Efficacy and Safety From a Phase 2 Study in People's Republic of China.

J Thorac Oncol 2022 06 17;17(6):816-826. Epub 2022 Mar 17.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. Electronic address:

Introduction: Lorlatinib was found to have activity in ALK-positive NSCLC in a global phase 1 and 2 study. We report an ongoing phase 2 study in Chinese patients with ALK-positive advanced or metastatic NSCLC.

Methods: Open-label, dual-cohort study (NCT03909971); patients had progressive disease after ALK tyrosine kinase inhibitor treatment (cohort 1: previous crizotinib; cohort 2: one ALK tyrosine kinase inhibitor other than crizotinib [±prior crizotinib]), more than or equal to one unirradiated extracranial target lesion, and Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received oral lorlatinib 100 mg once daily in continuous 21-day cycles. Primary end point: objective response in cohort 1 by independent central radiology (ICR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were based on patients receiving more than or equal to one dose.

Results: At data cutoff (August 10, 2020), 109 patients were enrolled (cohort 1: n = 67; cohort 2: n = 42). A total of 47 patients in cohort 1 (70.1%, 95% confidence interval [CI]: 57.7-80.7, p < 0.0001; primary end point) and 20 patients in cohort 2 (47.6%, 95% CI: 32.0-63.6, secondary end point) achieved objective response by ICR. Median progression-free survival was not reached in cohort 1 and was 5.6 months in cohort 2. In patients with brain lesions at baseline, 29 of 36 patients in cohort 1 (80.6%, 95% CI: 64.0-91.8) and 10 of 21 patients in cohort 2 (47.6%, 95% CI: 25.7-70.2) achieved objective intracranial response by ICR. Hypercholesterolemia (92.7%) and hypertriglyceridemia (90.8%) (cluster terms) were common treatment-related adverse events (TRAEs). Nine patients (8.3%) had serious TRAEs; one permanently discontinued from treatment because of TRAEs.

Conclusions: Lorlatinib was found to have a robust and durable response and high intracranial objective response in previously treated Chinese patients with ALK-positive NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2022.02.014DOI Listing
June 2022

Allergic Bronchopulmonary Mycosis Caused by Mucor Overlapping With Invasive Pulmonary Mucormycosis: A Case Report.

Front Med (Lausanne) 2022 24;9:831213. Epub 2022 Feb 24.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Mucormycosis is a rare and invasive fungal infection with high mortality. Cases of invasive pulmonary mucormycosis that involve allergic reactions such as allergic bronchopulmonary mycosis are rarely reported. Herein, we describe a case of invasive pulmonary mucormycosis overlapping with allergic diseases in a patient who presented with eosinophilia and high total plasma immunoglobulin E (IgE). The patient was successfully treated with systemic corticosteroids (initial dose of prednisolone approximately 0.5 mg/kg per day, total duration less than 3 months) combined with posaconazole antifungal therapy. The treatment resulted in recovery of peripheral-blood eosinophil count and total plasma IgE, and significant reduction in lung lesions. A subsequent lobectomy was performed. The findings in this case indicate that systemic corticosteroid therapy may contribute to the treatment of pulmonary mucormycosis combined with allergic factors.
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http://dx.doi.org/10.3389/fmed.2022.831213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907707PMC
February 2022

Tocilizumab overcomes chemotherapy resistance in mesenchymal stem-like breast cancer by negating autocrine IL-1A induction of IL-6.

NPJ Breast Cancer 2022 Mar 8;8(1):30. Epub 2022 Mar 8.

Houston Methodist Research Institute, Houston, TX, 77030, USA.

Triple-negative breast cancer (TNBC) patients with mesenchymal stem-like (MSL) subtype have responded poorly to chemotherapy whereas patients with basal-like 1 (BL1) subtype achieved the best clinical response. In order to gain insight into pathways that may contribute to the divergent sensitivity to chemotherapy, we compared the inflammatory profile of the two TNBC subtypes treated with docetaxel. Cellular signaling analysis determined that docetaxel activated MAPK pathway in MSL TNBCs but not BL1 TNBCs. The subsequent MAPK pathway activation in MSL TNBCs led to an IL-1A mediated cascade of autocrine inflammatory mediators including IL-6. Utilizing the humanized IL-6R antibody, tocilizumab, our in vitro and in vivo data show that MSL TNBCs treated with tocilizumab together with chemotherapy results in delayed tumor progression compared to MSL TNBCs treated with docetaxel alone. Our study highlights a molecular subset of TNBC that may be responsive to tocilizumab therapy for potential translational impact.
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http://dx.doi.org/10.1038/s41523-021-00371-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904846PMC
March 2022

Safety, Efficacy, and Pharmacokinetics of Rezivertinib (BPI-7711) in Patients With Advanced NSCLC With EGFR T790M Mutation: A Phase 1 Dose-Escalation and Dose-Expansion Study.

J Thorac Oncol 2022 05 15;17(5):708-717. Epub 2022 Feb 15.

Beta Pharma (Shanghai) Co., Ltd., Shanghai, People's Republic of China.

Introduction: Rezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M mutations. This study was designed to evaluate the safety, efficacy, and pharmacokinetics of rezivertinib for patients having advanced NSCLC with EGFR T790M mutation.

Methods: This phase 1 study (NCT03386955) was conducted across 20 sites in the People's Republic of China. Patients received rezivertinib at six oral dose levels (30 mg, 60 mg, 120 mg, 180 mg, 240 mg, 300 mg) once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary end points were safety for the dose-escalation phase and objective response rate by the blinded independent central review for the total study population.

Results: A total of 19 patients in dose-escalation phase using the standard 3 + 3 design principle and 153 patients in dose-expansion phase were enrolled from September 11, 2017, to August 23, 2019. The data cutoff date was on June 15, 2020. No dose-limiting toxicity occurred in the dose-escalation phase. The treatment-related adverse events were observed in 82.0% (141 of 172) of patients, and 17.4% (30 of 172) had grade greater than or equal to 3, among which decreased neutrophil count (2.9%), leukopenia (2.9%), and pneumonia (2.9%) were the most common. The overall blinded independent central review-evaluated objective response rate was 59.3% (102 of 172, 95% confidence interval: 51.6-66.7), and the median progression-free survival was 9.7 (95% confidence interval: 8.3-11.1) months.

Conclusions: Rezivertinib was found to have promising efficacy with a manageable safety profile in patients with EGFR T790M-mutated advanced NSCLC. Further study is warranted.
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http://dx.doi.org/10.1016/j.jtho.2022.01.015DOI Listing
May 2022

Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events.

Front Oncol 2021 23;11:757069. Epub 2021 Dec 23.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). Here, we first report a case of sintilimab-related cystitis/ureteritis. A 53-year-old man with driver gene-negative pulmonary adenocarcinoma (cTNM, Stage IVB) was being treated with sintilimab in combination of paclitaxel-albumin and bevacizumab as second-line treatment. He was hospitalized for haematuria, pollakiuria, painful micturition and low back pain after three courses. Urinalysis showed red blood cells (RBCs) and white blood cells (WBCs) were obviously increased, and serum creatinine (sCr) level was also significantly elevated. Urine culture and cytology were both negative, and cystoscopy revealed diffused redness of bladder mucosa. Urinary ultrasonography showed mild hydronephrosis and dilated ureter. The patient was diagnosed as immunotherapy-related cystitis/ureteritis after a multidisciplinary team (MDT) meeting. Once the diagnosis was made, corticosteroid therapy was given, which rapidly resolved the patient's symptoms and signs. Computer tomography angiography (CTA) and CT urography (CTU) was conducted after sCr level was back to normal and demonstrated ureter dilation and hydroureter. Once symptoms relieved, bladder biopsy was performed and confirmed the bladder inflammation. The patient was subsequently switched to maintenance dose of methylprednisolone and tapered gradually. Since sintilimab has been used in advanced malignancies, we first reported a rare case of sintilimab-induced cystitis/ureteritis and summarized sintilimab-related adverse events to improve the assessment and management of irAEs.
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http://dx.doi.org/10.3389/fonc.2021.757069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733470PMC
December 2021

The association between serum interleukin-1 beta and heparin sulphate in diabetic nephropathy patients.

Glycoconj J 2021 12 8;38(6):697-707. Epub 2022 Jan 8.

Department of Hemodialysis Center, the First Affiliated Hospital of Soochow University, Suzhou, China.

Inflammation is considered an important mechanism in the development of diabetes mellitus (DM) and persists for a long time before the occurrence of diabetic nephropathy (DN). Many studies have demonstrated that a decrease in the endothelial glycocalyx (EG) is negatively correlated with proteinuria. To elucidate whether EG damage induced by inflammasomes in DM patients leads to the occurrence of microalbuminuria (MA) and accelerates the progression of DN, this study screened 300 diagnosed DM patients. Finally, 70 type 2 diabetes patients were invited to participate in this study and were divided into two groups: the T2DM group (patients with normal MA and without diabetic retinopathy, n = 35) and the T2DN group (patients with increased MA and diabetic retinopathy, n = 35). Circulating heparin sulphate (HS, EG biomarkers) and interleukin-1 beta (IL-1β, inflammasome biomarkers) of the patients were measured by ELISA. Laboratory data were measured using routine laboratory methods. Patients in the T2DN group had increased serum HS, increased IL-1β, increased CRP, decreased haemoglobin, and increased neutrophils compared to patients in the T2DM group (all P < 0.05). Increased HS and decreased haemoglobin were independently associated with T2DN patients. ROC curves showed that the AUC of HS for the prediction of T2DN was 0.67 (P < 0.05). The combination of HS and haemoglobin yielded a significant increasement in the AUC (0.75, P < 0.001) with optimal sensitivity (71.2%) and specificity (79%). Furthermore, serum IL-1β was positively correlated with HS and was an independent associated factor of HS in the T2DN group. The relationship between HS and IL-1β was not significant in the T2DM group. Our findings surgessed the inflammasome may be associated with and promote damage to the EG during the disease course of DN that manifests as increased MA.
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http://dx.doi.org/10.1007/s10719-021-10035-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821487PMC
December 2021

Asthma Management Using the Mobile Asthma Evaluation and Management System in China.

Allergy Asthma Immunol Res 2022 Jan;14(1):85-98

Department of Pulmonary and Critical Care Medicine, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China.

Purpose: As stated in the Global Initiative for Asthma, there are still some asthmatic patients who have not achieved asthma control. Mobile is a useful tool for asthma management. We aimed to compare the advantages of mobile management with traditional management in improving adherence and control of asthma.

Methods: In this prospective, multicentre, randomized, controlled and parallel-group study, we enrolled patients with poor adherence and uncontrolled asthma at 32 hospitals in 28 provinces in China. Patients were randomly assigned to the mobile management or traditional management groups for 12 months. The primary endpoint was the proportion of patients with good adherence (Medication Adherence Report Scale for Asthma [MARS-A] score ≥ 45) for 6 months. This study is registered at ClinicalTrials.gov (NCT02917174).

Results: Between April 2017 and April 2018, 923 patients were eligible for randomization (mobile group, n = 461; traditional group, n = 462). Dropout was 84 (18.2%) in the mobile management group and 113 (24.4%) patients in the traditional management group. The proportion of patients with good adherence was significantly higher in the mobile management group than in the traditional management group (66.0% vs. 58.99%, = 0.048). The mobile management group showed higher mean MARS-A score (at 1, 6, 9, and 12 months) and asthma control test scores (at 6 and 9 months), and lower total lost rate to follow-up within 12 months than the traditional management group.

Conclusions: Mobile asthma management can improve adherence and asthma control compared to traditional management.

Trial Registration: ClinicalTrials.gov Identifier: NCT02917174.
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http://dx.doi.org/10.4168/aair.2022.14.1.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724822PMC
January 2022

Case Report: Dacomitinib Overcomes Osimertinib Resistance in NSCLC Patient Harboring L718Q Mutation: A Case Report.

Front Oncol 2021 2;11:760097. Epub 2021 Dec 2.

Department of Respiratory Disease, Thoracic Disease Centre, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Background: Advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations has been successfully treated with tyrosine kinase inhibitors (TKIs). However, resistance to osimertinib, a third-generation TKI, can be difficult to overcome in this small subset of patients and is attributed to secondary resistant mutations. Here, we report a case of acquired EGFR L858R/L718Q mutation with advanced NSCLC that resistant to osimertinib, which was successfully overcome using dacomitinib.

Case Presentation: A 64-year-old non-smoker woman was diagnosed with stage IV non-small cell lung adenocarcinoma with EGFR L858R mutation and brain metastasis in November 2018. Treatment with gefitinib and gamma knife radiosurgery was started as the first-line treatment. After 7 months, she experienced disease progression with increased primary lung lesions and switched to osimertinib based on an acquired EGFR T790M mutation. After another 4 months, the disease progressed, and she was switched to chemotherapy. During chemotherapy, brain MRI showed an increasing number of parietal lobe metastases. Hence, gamma knife radiosurgery was performed again. After 12 months, the disease progression resumed, and an EGFR L718Q mutation was found on biopsy. The patient was then challenged with dacomitinib, and the disease was partially responsive and under control for 6 months.

Conclusion: Currently, there are no established guidelines for overcoming osimertinib resistance caused by the L718Q mutation. The acquired EGFR L718Q mutation in subsequent resistance to osimertinib could be overcome using dacomitinib, indicating a promising treatment option in the clinic.
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http://dx.doi.org/10.3389/fonc.2021.760097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674200PMC
December 2021

ETV4 mediated lncRNA C2CD4D-AS1 overexpression contributes to the malignant phenotype of lung adenocarcinoma cells via miR-3681-3p/NEK2 axis.

Cell Cycle 2021 12 1;20(24):2607-2618. Epub 2021 Dec 1.

Department of Respiratory Disease, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

Lung adenocarcinoma (LUAD) is originated from the mucus-producing glands of the lungs. The involvement of long noncoding RNAs (lncRNAs) has been discovered in multiple diseases. In the present research, we aimed to unmask the role of C2CD4D and THEM5 antisense RNA 1 (C2CD4D-AS1) in LUAD. RT-qPCR or western blot analysis was respectively applied in the detection of RNA or protein expressions. The function of C2CD4D-AS1 in LUAD was assessed by functional assays. Through ChIP, RNA pull down, DNA pull down, RIP and luciferase reporter assays, the in-depth regulatory mechanism of C2CD4D-AS1 in LUAD was explored. C2CD4D-AS1 was dramatically overexpressed in LUAD tissues and cell lines. As a result, depletion of C2CD4D-AS1 significantly repressed cell proliferation, migration, invasion and stimulated cell apoptosis in LUAD. Mechanistically, ETS variant transcription factor 4 (ETV4) activated the transcription of C2CD4D-AS1 and stimulated its up-regulation in LUAD cells, thus affecting LUAD cell biological functions. Furthermore, C2CD4D-AS1 sponged microRNA-3681-3p (miR-3681-3p) and regulated NIMA-related kinase 2 (NEK2), thus participating in modulating LUAD cell biological behaviors. To conclude, C2CD4D-AS1 up-regulation induced by ETV4 enhanced NEK2 expression by sequestering miR-3681-3p to contribute to the malignant behaviors of LUAD cells.
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http://dx.doi.org/10.1080/15384101.2021.2005273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726644PMC
December 2021

Efficacy of Aumolertinib (HS-10296) in Patients With Advanced EGFR T790M+ NSCLC: Updated Post-National Medical Products Administration Approval Results From the APOLLO Registrational Trial.

J Thorac Oncol 2022 03 19;17(3):411-422. Epub 2021 Nov 19.

Department of Oncology, Binzhou Medical University Hospital, Binzhou, People's Republic of China.

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jtho.2021.10.024DOI Listing
March 2022

A Novel Third-generation EGFR Tyrosine Kinase Inhibitor Abivertinib for EGFR T790M-mutant Non-Small Cell Lung Cancer: a Multicenter Phase I/II Study.

Clin Cancer Res 2022 03;28(6):1127-1135

Department of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Purpose: To establish recommended phase II dose (RP2D) in phase I and evaluate safety and efficacy of abivertinib in patients with EGFR Thr790Met point mutation (T790M)-positive(+) non-small cell lung cancer (NSCLC) with disease progression from prior EGFR inhibitors in phase II.

Patients And Methods: This multicenter, open-label study included 367 adult Chinese patients. Abivertinib at doses of 50 mg twice a day to 350 mg twice a day was evaluated in phase I in continual 28-day cycles, and the RP2D of 300 mg twice a day was used in phase II in continual 21-day cycles. Primary endpoints include RP2D in phase I and objective response rate (ORR) at RP2D in phase II.

Results: The RP2D of 300 mg twice a day for abivertinib was established based on pharmacokinetics, efficacy, and safety profiles across doses in phase I. In phase II, 227 patients received RP2D for a median treatment duration of 24.6 weeks (0.43-129). Among 209 response-evaluable patients, confirmed ORR was 52.2% [109/209; 95% confidence interval (CI): 45.2-59.1]. Disease control rate (DCR) was 88.0% (184/209; 95% CI: 82.9-92.1). The median duration of response (DoR) and progression-free survival (PFS) was 8.5 months (95% CI: 6.1-9.2) and 7.5 months (95% CI: 6.0-8.8), respectively. The median overall survival (OS) was 24.9 months [95% CI: 22.4-not reachable (NR)]. All (227/227) patients reported at least 1 adverse event (AE), with 96.9% (220/227) of treatment-related AEs. Treatment-related serious AEs were reported in 13.7% (31/227) of patients. Death was reported in 4.4% (10/227) of patients, and none was deemed as treatment-related.

Conclusions: Abivertinib of 300 mg twice a day demonstrated favorable clinical efficacy with manageable side effects in patients with EGFR T790M+ NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2595DOI Listing
March 2022

Mefatinib as first-line treatment of patients with advanced EGFR-mutant non-small-cell lung cancer: a phase Ib/II efficacy and biomarker study.

Signal Transduct Target Ther 2021 11 1;6(1):374. Epub 2021 Nov 1.

Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Mefatinib is a novel, bioavailable, second-generation, irreversible pan-EGFR inhibitor. This phase Ib/II open-label, single-arm, multi-center study investigated the efficacy, safety, biomarker, and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC. This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg (n = 51) or 80 mg (n = 55). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The cohort achieved an ORR of 84.9% and DCR of 97.2%. The median PFS was 15.4 months and the median OS was 31.6 months. Brain metastasis was detected in 29% of patients (n = 31) at diagnosis and demonstrated an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months. Adverse events primarily involved skin and gastrointestinal toxicities, which were well-tolerated and manageable. Analyses of mutation profiles were performed using targeted sequencing of plasma samples at baseline, first follow-up 6 weeks from starting mefatinib therapy (F1), and at progression. Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53 (14.0 vs 15.4 months; p = 0.315). Furthermore, circulating tumor DNA clearance was associated with longer PFS (p = 0.040) and OS (p = 0.002). EGFR T790M was the predominant molecular mechanism of mefatinib resistance (42.1%, 16/38). First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC.
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http://dx.doi.org/10.1038/s41392-021-00773-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558340PMC
November 2021

A novel stilbene derivative (GMQ3) suppressed proliferation and induced apoptosis in lung cancer via the p38-MAPK/SIRT1 pathway.

Biochem Pharmacol 2021 11 19;193:114808. Epub 2021 Oct 19.

Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address:

Background: Lung cancer is the primary cause of cancer-related mortality worldwide. The anticancer effect of stilbene has been noted in various tumor types. GMQ3, which has a stilbene-mimicking skeleton, is a novel small-molecule compound with promising antitumor activity. Our results revealed that GMQ3 not only suppressed cell proliferation and cell migration of lung cancer cells but also led to G1 phase cell cycle arrest and triggered caspase-dependent apoptosis. Furthermore, investigation of the molecular mechanism showed that GMQ3 could inhibited proliferation and induced apoptosis via the p38-MAPK/SIRT1 pathway both in vitro and in vivo. Xenograft tumor mouse models showed that GMQ3 significantly inhibited tumor growth in vivo without affecting body weight. Our findings indicated that GMQ3 exerts a strong anticancer action by suppressing cell proliferation, inhibiting cell migration and inducing cell apoptosis. Moreover, the efficacy of GMQ3 was enhanced in the presence of CDK4/6 inhibitor Abemaciclib. We conclude that GMQ3 is a promising agent with potential for lung cancer.
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http://dx.doi.org/10.1016/j.bcp.2021.114808DOI Listing
November 2021

Pembrolizumab Plus Chemotherapy for Chinese Patients With Metastatic Squamous NSCLC in KEYNOTE-407.

JTO Clin Res Rep 2021 Oct 25;2(10):100225. Epub 2021 Sep 25.

Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.

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.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503629PMC
October 2021
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