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Xiaorong Dong



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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP07.01 - Dysbiosis of Gut Microbiota Suppress the Brain Metastasis of Non-Small Cell Lung Cancer (ID 1501)

      00:00 - 00:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Introduction

      Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC), gut microbiota have been reported involved in the development of NSCLC. However, the impact of the gut microbiota on BM of NSCLC is still vague to date. This study aimed to explore the potential mechanism of gut microbiota dysbiosis on BM of NSCLC.

      Methods

      We collected 85 fecal samples from NSCLC patients with or without BM, and performed 16S rRNA gene sequencing. Conventional C57BL/6 mice were treated with an antibiotic cocktail to deplete the gut microbiota. The effects of gut microbiota dysbiosis was investigated in vivo by using NSCLC BM mouse models.

      Results

      There are no obvious difference in the microbial diversity and composition between NSCLC patients with BM (BM+, n=25) and without BM group (BM-, n=60). However, several differentially abundant genera were identified between subject groups by LEfSe analysis and Wilcoxon rank-sum test. Blautia, the genus implicated in central nervous system disorder, significantly decreased in BM+ group comparing to BM- group. Furthermore, the tumor burden significantly reduced in antibiotics-treated BM mice model, along with increased microglia cells by flow cytometry analysis. Remarkably, fecal bacteria transplantation (FMT) reduced gut microbial dysbiosis, partially attenuate the antibiotic-mediated tumor inhibition.

      Conclusion

      These results indicate that gut microbiota dysbiosis modulate BM of NSCLC, and Blautia, was putative microbial biomarkers that exclusively associated with BM. Mice experiments suggest that gut microbial dysbiosis inhibit BM by increasing the number of microglia. FMT suggest that BM inhibition mediated by gut microbial disorder is weakened by restoring normal microbiota, and warrant further research on the function of microglia.

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    JICC01 - Joint IASLC-CAALC-CSCO Session: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 276)

    • Event: WCLC 2020
    • Type: Workshop
    • Track: N.A.
    • Presentations: 1
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      JICC01.16 - Discussant: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 4271)

      07:00 - 09:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract

      Abstract not provided

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    MA01 - Novel Systemic Treatment in NSCLC (ID 102)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
    • Presentations: 1
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      MA01.04 - A Randomized Study Comparing Cisplatin/Paclitaxel Liposome vs Cisplatin/Gemcitabine in Chemonaive, Advanced Squamous NSCLC (ID 1225)

      11:45 - 12:45  |  Author(s): Xiaorong Dong

      • Abstract

      Introduction

      Platinum-based chemotherapy is still the backbone of advanced squamous non–small-cell lung cancer (NSCLC). Paclitaxel (PTX) liposome is the only PTX liposomal formulation on the market for the treatment of lung, ovarian and breast cancer since 2006 in China. The purpose of this study was to compare the clinical efficacy and safety between PTX liposome/cisplatin and gemcitabine/cisplatin as first-line treatment of patients with staged IIIB/IV squamous NSCLC.

      Methods

      Eligible patients with chemo naive, advanced, squamous NSCLC were randomized to receive PTX liposome (175 mg/m2, on day 1) and cisplatin (75 mg/m2 on day 1, LP group) or gemcitabine (1,000 mg//m2, on day 1 and 8) and cisplatin (75 mg/m2 on day 1, GP group) intravenously, every 3 weeks for 4-6 cycles. Primary end point of the study was progression-free survival(PFS).

      Results

      A total of 540 patients from 34 centers of China were enrolled. Median age: 64.5 years; male/ female: 497(93.1%)/37(/6.9%); stage IIIB/IV: 177(33.1%)/357(66.9%) and ECOG PS 0/1: 87(16.3%)/447(83.7%). After a median follow-up of 15.4 months, PFS and overall survival were not different between LP and GP groups (median PFS 5.2 vs. 5.5 months, hazard ratio [HR] 1.03, P=0.5762; median OS 14.6 vs 12.5 months, HR 0.83, P=0.2147). Overall response rate was comparable between the 2 groups, 41.8% in LP group vs 45.9% in GP group. The most common adverse events (AEs) in the both groups were anemia, neutropenia, leukopenia and thrombocytopenia. AEs of grade 3 or higher occurred in 68.3% of the patients in the LP group and in 66.5% of the patients in the GP group. Grade 3 or higher anemia (31.2%, 84/269 vs. 14.3%, 38/265, P<0.0001) and thrombocytopenia (14.1%, 38/269 vs. 1.5%, 4/265, P<0.0001) were more frequent in the GP group, whereas grade 3 or higher neutropenia (35.5%, 94/265 vs. 28.3%, 76/269, P=0.0781) and leukopenia (23.4%, 62/265 vs. 19.0%, 51/269, P=0.2438) were more frequent in the LP group. Discontinuation of treatment due to AEs was more frequent in the GP group than in LP group (26.4% vs. 10.9%, P<0.0001).

      Conclusion

      The chemo-regimens, LP and GP produce comparable efficacy in terms of ORR, PFS and OS as 1st line therapy of advanced squamous NSCLC. But, LP is well tolerated and results in less frequent of anemia and thrombocytopenia and lower discontinuation of treatment in Chinese patients. So, LP is one of standard 1st line chemotherapy for advanced squamous NSCLC patients. (ClinicalTrials.gov number, NCT02996214)

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    P63 - Tumor Biology and Systems Biology - Basic and Translational Science - Metastases (ID 201)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 2
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P63.03 - M1 Phenotype Polarization of Microglia via MIF/CD74 Axis for Radiosensitization in NSCLC Brain Metastasis (ID 1158)

      00:00 - 00:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Introduction

      Brain metastasis is a common complication with poor prognosis in non-small cell lung cancer (NSCLC). Radiotherapy, as the main treatment, still has unsatisfactory therapeutic effects. Microglia as brain macrophage displayed M1 or M2 phenotype depending on the microenvironment. Our previous study shows macrophage migration inhibitory factor (MIF) is overexpressed in primary tissues of NSCLC brain metastasis. Studies have reported that tumors escape M1 conversion of microglia via CD74 activation through the secretion of macrophage migration inhibitory factor (MIF). The aim of this study was to explore the effects of radiosensitization by inhibiting the MIF/CD74 axis to regulate the polarization of microglia to M1 phenotype in NSCLC brain metastasis.

      Methods

      The expression of MIF was detected in 4 NSCLC patients with brain metastasis and matched peritumoral tissues. ShRNA was applied to silence CD74 and MIF in BV2 cells and Lewis cells. M1 and M2 markers were detected by Western Blot, RT-PCR, immunofluorescence staining and flow cytometry. The phagocytosis of microspheres and Lewis cells in BV2 cells was detected by immunofluorescence staining and flow cytometry. The co-culture of Lewis and BV2 cells was constructed using transwell chambers. The wound healing and transwell assays were used to detect the migration of BV2 cells. The colony formation assay, Annexin V/7-AAD staining and PI staining were utilized to determine the effects of MIF/CD74 axis and HIF-1α/MIF on Lewis cells. In vivo model of brain metastasis was established to explore the effects of HIF-1α/MIF/CD74 signaling.

      Results

      The expression of MIF was significantly higher in brain tumors than peritumoral tissues, and high MIF expression indicated poor prognosis. Silencing CD74 promoted irradiated BV2 cells to M1 phenotype transformation. Co-culture of Lewis cells and irradiated BV2 cells showed that inhibition of MIF/CD74 axis promoted M1 polarization of BV2 cells, enhanced the ability of phagocytosis and migration in BV2 cells. Co-culture supernatant added to Lewis cells inhibited the proliferation and colony formation, induced apoptosis of Lewis cells. KC7F2 (HIF-1α inhibitor) inhibited MIF secretion and the binding of HIF-1α to MIF promoter in Lewis cells. Collecting the supernatant of Lewis cells with KC7F2 under hypoxic conditions, and added to irradiated BV2 cells knockdown CD74 for 24h. The results showed that inhibiting HIF-1α/MIF axis could transform BV2 cells to M1 phenotype, promoted the phagocytosis and migration of BV2 irradiated cells. Then, we collected the medium in BV2 cells, and applied to Lewis cells. We found that inhibition of HIF-1α/MIF/CD74 axis could inhibit the colony formation, remodel cell cycle distribution of Lewis cells, resulting cell apoptosis. The in vivo experiments indicated that radiation The in vivo experiments showed that inhibition of MIF/CD74 axis could improve hypoxia state of tumors and transform macrophages to M1 phenotype, leading to the shrinkage of brain tumors caused by radiotherapy, prolong survival time. Mechanically, we identified that MIF/CD74 pathway regulated phenotypic transformation of BV2 cells may by activating PI3K/AKT signaling.

      Conclusion

      The HIF-1α/MIF/CD74 axis could be used as a target for radiation therapy, providing a new research basis and theoretical basis for the treatment of NSCLC brain metastases.

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      P63.04 - Dysbiosis of Sputum and Gut Microbiota Modulate Development and Distant Metastasis of Non-Small Cell Lung Carcinomas (ID 1584)

      00:00 - 00:00  |  Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Introduction

      Lung cancer (LC) is the leading cause of cancer-related deaths mortality worldwide, with non-small cell lung cancer (NSCLC) being the most common form of LC. Despite the recent development of therapies for NSCLC, tumor metastasis is the main cause of recurrence and mortality in patients with NSCLC. Although dysbiosis of lung and gut microbiota have been associated with NSCLC, their relative contributions are unclear. In addition, their roles in distant metastasis (DM) are still illusive.

      Methods

      We enrolled in total 121 individuals who completed our study protocol. Among which, 87 were newly diagnosed with NSCLC who had not previously received any anticancer therapy nor treated with any antibiotics, while 34 were healthy volunteers. We classified patients into distinct disease stages (i.e. from I to IV) according to the 8th American Joint Committee on Cancer guidelines. Then, we collected in total 30 sputum and 29 fecal samples from the healthy controls and 66 sputum and 85 fecal samples from the NSCLC patients, and submitted them for 16S sequencing. To further validate microbiota play important roles in the development of NSCLC, we treated C57BL/6 adult female mice (six weeks of age) with antibiotic cocktail (ABX) of vancomycin, neomycin, ampicillin and metronidazol in drinking water starting 2 weeks before tumor inoculation. Subcutaneous tumor model was established by injecting murine Lewis lung cancer cell tagged with luciferences (LLC-luc) in the subcutaneous layer of C57BL/6 mice's right back.

      Results

      We found significant perturbations of gut- and sputum- microbiota in patients with NSCLC and DM. We obtained better Machine-learning models for patient stratification using both microbiota than either dataset, with the highest area under the curve (AUC) value of 0.842; surprisingly, sputum- microbiota contributed more than the gut. Several microbial-biomarkers were shared by both microbiota, indicating their similar roles at distinct body sites. Microbial-biomarkers of distinct disease stages were mostly shared, suggesting biomarkers for distant metastasis could be acquired early. Surprisingly, Pseudomonas aeruginosa, a species previously associated with wound infections, was associated with brain metastasis, indicating distinct types of DMs could have different microbial-biomarkers. Furthermore, we found significantly larger tumors in antibiotics-treated mice, confirming that microbiota dysbiosis could indeed promote tumor growth.

      Conclusion

      Our results indicate that in addition to gut-microbiota, sputum-microbiota could contribute significantly to NSCLC and distant metastasis, and improve the performance of patient-stratification models. Mice experiments suggest that favorable clinical outcomes could be accomplished by restoring normal microbiota, and warrant further research on the underlying molecular mechanisms.

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    P71 - Tumor Biology and Systems Biology - Basic and Translational Science - RTK/VEGF (ID 212)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P71.01 - The Effects of Vascular Endothelial Cells on Regulating Post-Irradiation Microglia Phenotype in Irradiation-Induced Brain Injury         (ID 1566)

      00:00 - 00:00  |  Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Introduction

      Radiation-induced brain injury (RIBI) is a common and devastating complication associated with cancer patients receiving cranial radiation therapy (CRT). Activated microglia and vascular injury are considered to play pivotal roles in the pathogenesis of RIBI. In the current study, we discovered that in the hippocampus perivascular, microglia were activated after 10 grays CRT and started to expand cellular protrusions towards adjacent blood vessels. The findings raises the questions of the functional relevance of the association of microglia with injured blood vessels after CRT.

      Methods

      The ultrastructural blood vessels in the hippocampus were examined by transmission electron microscopy. Immunofluorescence staining (IF) was used to explore the dynamics of microglial activation and its relationship with injured blood vessels in the hippocampus. EMSA and dual luciferase assays were performed to confirm the transcriptional activation of NF-κB induced by radiation in HUVECs. Migration and co-culture assays were used to investigate the possible mechanism on the association between HUVEC and BV-2 cell after irradiation. BV-2 cell, cultured for 3h with or without fractalkine (FKN 100ng/ml), received 10 Gy irradiation. Moreover, the CX3CR1 (the receptor of FKN on microglia) wide-type (CX3CR1WT) and CX3CR1-knockdown (CX3CR1-/-) mice were employed and subjected to lateral ventricular injection (ICV) of 5 μl FKN lentivirus or vector 3 days before CRT. And then, the in vitro and in vivo phenotype transformation of microglia and its inflammatory factors release were detected by western blotting, real-time PCR, ELISA and IF at different time-points after irradiation. Morris water maze test was used to test the cognitive function in mice.

      Results

      In the hippocampus of the CRT group, we observed that the endothelial cells were not arranged as closely as open cell-cell tight junctions, which were characterized by intralumenal protrusion of endothelial cells. In vitro migration and co-culture assays demonstrated molecular signals, secreted by vascular endothelial cells (ECs) via NF-κB pathway leading to the activation of microglia and their recruitment to blood vessels. ELISA and qRT-PCR revealed that radiation promoted the secretion of FKN from the vascular ECs via activating the NF-κB pathway. Western blotting and Flow cytometry showed that treatment with exogenous FKN promoted microglia M2 phenotype transformation, diminished radiation-induced proinflammatory factors, and enhanced phagocytosis capacity after radiation. In addition, up-regulation of FKN via FKN lentivirus promoted radiation-induced microglial M2 transformation in the hippocampus, and diminished the spatial memory injury of radiated mice. Lastly, while inhibiting the CX3CR1, which is exclusively expressed on microglia in the brain, the regulatory effect of FKN on microglia and cognitive ability of mice disappeared after radiation.

      Conclusion

      Our study has unveiled an important and novel role of FKN/CX3CR1 in RIBI, the FKN mainly secreted by vascular ECs after irradiation may attenuate RIBI through the microglia polarization toward M2 phenotype by binding to CX3CR1 on microglia.

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    P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P84.15 - Alectinib in Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer as First-Line or Sequential Treatment in China (ID 2478)

      00:00 - 00:00  |  Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Introduction

      Alectinib is a highly selective inhibitor of anaplastic lymphoma kinase (ALK) with superior systemic and central nervous system (CNS) efficacy. In ALEX study,alectinib yielded confirmed objective response rate(ORR) of 72.4%.The first-time real-world study aims to evaluate the efficacy and safety profile of alectinib in ALK-positive non-small cell lung cancer (NSCLC) Chinese patients.

      Methods

      A national retrospective cohort study of patients with ALK-positive NSCLC initiating alectinib(600 mg twice daily) was conducted in 7 centers in China between 01-Dec-2017 and 01-Sept- 2019.The last follow-up was to 31st December 2019.

      Results

      One hundred and two patients were enrolled.During a median follow-up of 10.6 months, an event of disease progression or death occurred in 21 of 102 patients (20.5%) .Patient Characteristics were shown in Table 1.

      For alectinib in the first-line setting, 39 patients were eligible for tumor evaluation.The ORR was 89.7%(35/39) and 2 patients had a complete response.Among 23 patients with measurable CNS lesions at baseline, a CNS response occurred in 22 of 23 patients (95.6%);4 patients had a complete CNS response.

      For alectinib in the sequential setting, 58 patients were eligible for tumor evaluation,of whom 37 patients received crizotinib as first-line therapy.The most common progression mode of crizotinib was CNS progression(24/37,64.9%).Fourty-four patients received alectinib as second-line treatment.The ORR was 75.9%(44/58) and 2 patients had a complete response. Among 51 patients with measurable CNS lesions, a CNS response occurred in 42 of 51 patients (82.4%);4 patients had a complete CNS response.

      Data of adverse events(AEs) were available in all patients.The most common AEs were increased blood bilirubin (23.5%),constipation(23.5%) and abnormal ALT and AST levels(22.5%).Other AEs that occurred in at least 10% of the patients included myalgia (12.7%), peripheral edema(11.8%) and rash(11.8%). Grade 3 AEs occurred in 8.8% of the patients.No grade 4 or 5 AEs were observed in this study. The most common grade 3 AEs were laboratory abnormalities(6/9,66.7%),of which was increased blood bilirubin leading to dose reduction to alectinib 300 mg twice daily.

      Table 1 Baseline Patient Characteristics

      Characteristics

      N%

      Age

      Medium (Range)

      51(24-81)

      Gender

      Male

      Female

      44(43.1%)

      58(56.9%)

      ECOG

      0-1

      ≥2

      82(80.3%)

      20(19.7%)

      Smoking history

      Yes

      No

      16(15.7%)

      86(84.3%)

      Histology

      Adenocarcinoma

      Squamous -cell carcinoma

      Large-cell carcinoma

      99(97.1%)

      2(2.0%)

      1(0.9%)

      Stage

      IIIB

      IV

      6(5.9%)

      96(94.1%)

      Metastasis site

      Brain

      Bone

      Liver

      44(43.1%)

      44(43.1%)

      15(14.7%)

      Alectinib treatment line

      First-line

      Second-line

      Beyond second-line

      41(40.2%)

      44(43.1%)

      17(16.7%)

      Previous Crizotinib treatment

      Yes

      No

      37(36.3%)

      65(63.7%)

      Previous chemotherapy

      Yes

      No

      24(23.5%)

      78(76.5%)

      Conclusion

      This study confirms the efficacy and safety of alectinib in real-world advanced ALK+ NSCLC in China, which is consistent with data reported in clinical trials.

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    P85 - Targeted Therapy - Clinically Focused - MET (ID 262)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P85.06 - Clinical and Genomic Features of Middle Intensity cMET Stain of Chinese Lung Cancer Patients (ID 1661)

      00:00 - 00:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Introduction

      Background:cMET overexpression has been identified as an oncogenic driver in Non-small cell lung cancer(NSCLC). About 25% NSCLC patients was detected cMET positive by immunohistochemistry(IHC) and has been studied for clinical and genomic features. Similarly, the clinical and genomic features of cMET negetive patients are need to be better understood.

      Methods

      Methods: Protein expression of cMET of 196 Chinese NSCLC patients by IHC was determined by measuring the intensity of the stain (0, 1+, 2+, 3+) and the percent staining (0-100%). We reviewed 132 of middle intensity cMET stain (cMET 1+/2+, negetive) with paired tumor-normal samples sequenced by 1021/59 gene panel.

      Results

      Results: In this study, 67.3% (132/196) were detected middle intensity cMET stain including 50.8% (67/132) cMET 2+. All of the patients were lung adenocarcinoma and the average age at diagnosis was 61.4 (range 33-80 years). 43.8% patients had a history of smoking. All of these characteristics were not significantly different between cMET 1+ and cMET 2+ groups. Differences was found in genomic. The common mutations were TP53(76/132), EGFR (74/132) and KRAS (23/132). 5 patients were found cMET activation mutations including 2 of cMET amplification and 3 of cMET mutation(Table 1). More non-synonymous mutation were found in cMET 2+ groups than cMET 1+ (media: 6 versus 5,p=0.02). Significantly higher number of copy numbers variations(CNV) was found in cMET 2+ groups (media: 2 versus 1, p=0.04,Fig 1). However, the gene mutations and actionable mutations were no differences in two groups except that MDM2 CNV mutation was higher in cMET 2+ groups(p=0.03).

      Table1. Genetic aberrations of MET.

      Patients Age Gender Smoking IHC of cMET NGS of cMET
      P1 61 Male NA cMET(2+) MET c.3028G>C
      P2 70 Femal NA cMET(1+) MET c.3028+3A>G
      P3 71 Male No cMET(2+) MET c.2888-19_2888-13delinsAAA
      P4 64 Male Yes cMET(1+) MET CNV
      P5 68 Femal No cMET(1+) MET CNV

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      Conclusion

      Conclusion: Our data suggest that 3.8% middle intensity cMET stain patients had cMET activation which is a clearly therapeutic target to cMET inhibitors. cMET 2+ patients had more non-synonymous mutation and CNV than cMET 1+ patients which may be related to treatment and prognosis.

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