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Meng Chen
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P05 - Early Stage/Localized Disease - Radiotherapy (ID 114)
- Event: WCLC 2020
- Type: Posters
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P05.03 - Circulating Lymphocyte Counts after Lung Stereotactic Body Radiation Therapy May Predict after Optimal Short-term Efficacy (ID 1547)
00:00 - 00:00 | Presenting Author(s): Meng Chen
- Abstract
Introduction
The Optimal short-term efficacy of Stereotactic Body Radiation Therapy (SBRT) is thought to be 3 months after treatment. Circulating lymphocyte (CL) has decisive effect on immune system for cancer patients. We investigated the association between circulating lymphocyte counts (CLCs) before and after lung SBRT and the short-term efficacy.
Methods
One hundred ninety-one patients treated with lung SBRT between September 2014 and December 2018 were retrospectively analyzed. The pre-treatment and post-treatment total circulating lymphocyte counts (CLCs) were obtained and analyzed. Univariate and multivariate Logistic-regression analyses were used to test the significance for the short-term efficacy prediction. Objective Response Rate (ORR) was assessed according to RECIST 1.1 criteria. Short-term efficacy was defined as within six months after SBRT.
Results
The ORR were 35.1%, 43.5%, and 37.2%, at one-, three- and six- month, respectively. The mean CLCs before and after SBRT were 1.4×109/L and 1.1×109/L, respectively. Univariate analysis results revealed that post-treatment CLC were significantly correlated with 0.56(95%CI 0.32,0.98) (p=0.042) and 0.49(95%CI 0.28,1.19) (p=0.003), and changes after treatment in CLCs≥0.45×109/L were significantly correlated with 0.38(95%CI 0.21,0.67) (p=0.001) and 0.57(95%CI 0.33,0.98) (p=0.043) at three- and six- month. Multivariate analysis revealed that post-treatment CLC were significantly correlated with 0.54(95%CI 0.30,0.96) (p=0.035) and 0.45(95%CI 0.26,0.79) (p=0.005), and changes after treatment in CLCs≥0.45×109/L were significantly correlated with 0.40(95%CI 0.22,0.73) (p=0.003) and 0.58(95%CI 034,1.01) (p=0.050) at three- and six- month.
ConclusionTABLE | Univariate and multivariate analyses of Optimal Short-term Efficacy in patients with lung cancer treated with stereotactic body radiation therapy
Variable
Patients
(N= 191) (%)
1 months after SBRT
3 months after SBRT
6 months after SBRT
Univariate analysis
Multivariate analysis
Univariate analysis
Multivariate analysis
Univariate analysis
Multivariate analysis
OR
(95%CI)
P
OR
(95%CI)
P
OR
(95%CI)
P
OR
(95%CI)
p
OR
(95%CI)
P
OR
(95%CI)
p
Age
(>65 years)
97
(50.8)
1.09
(0.98,1.03)
0.489
1.41
(0.82,2.42)
0.208
1.34
(0.80,2.25)
0.273
Sex
(female)
45
(23.6)
0.36
(0.18,0.68)
0.002
0.77
(0.30,1.94)
0.573
0.47
(0.24,0.89)
0.022
0.66
(0.29,1.51)
0.324
0.48
(0.26,0.89)
0.021
0.84
(0.38,1.86)
0.674
Smoking
(ever)
123
(64.4)
2.68
(1.50,4.76)
0.001
2.12
(0.94,4.80)
0.071
2.20
(1.24,3.91)
0.007
1.68
(0.81,3.50)
0.163
2,45
(1.40,4.28)
0.002
2.29
(1.13,4.65)
0.022
Pathology
(Adenocarcinoma)
75
(39.3)
0.87
(0.51,1.51)
0.630
0.88
(0.51,1.53)
0.659
0.66
(0.39,1.13)
0.132
Location
(Peripheral)
142
(74.3)
1.01
(0.55,1.85)
0.986
0.87
(0.47,1.61)
0.664
0.65
(0.36,1.19)
0.164
Origin
(Primarily)
118
(61.8)
0.45
(0.33,0.61)
0.001
0.005
(0.001,0.04)
<0.001
0.44
(0.25,0.78)
0.004
0.53
(0.30,0.95)
0.032
0.61
(0.35,1.04)
0.0667
0.69
(0.4,1.19)
0.185
BED
(≥100Gy)
152
(79.6)
1.93
(0.98,3.78)
0.056
1.85
(0.86,4.00)
0.117
2.24
(1.13,4.44)
0.021
1.94
(0.97,3.89)
0.062
1.56
(0.82,2.97)
0.179
Pre-treatment CLCs
(≥1.4×109/L)
106
(55.5)
1.12
(0.73,1.71)
0.614
0.98
(0.64,1.51)
0.942
0.79
(0.52,1.20)
0.276
Post-treatment CLCs
(≥1.1×109/L)
99
(51.8)
0.85
(0.49,1.46)
0.554
0.56
(0.32,0.98)
0.042
0.54
(0.30,0.96)
0.035
0.49
(0.28,1.19)
0.010
0.45
(0.26,0.79)
0.005
Changes after treatment in CLCs
(≥0.45×109/L)
70
(36.6)
0.70
(0.4,0.82)
0.200
0.38
(0.21,0.67)
0.001
0.40
(0.22,0.73)
0.003
0.57
(0.33,0.98)
0.043
0.58
(034,1.01)
0.050
The circulating lymphocyte counts (CLCs) after SBRT might be an independent prognostic factor after the optimal short-term efficacy.
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.02 - Expression and Significance of Indoleamine 2,3 Dioxygenase on Tumor Cell and Tumor Stroma Compartments of Lung Squamous Cell Carcinoma (ID 1085)
00:00 - 00:00 | Author(s): Meng Chen
- Abstract
Introduction
Indoleamine 2,3 dioxygenase (IDO), a human immune escape factor, especially in pregnant women, is a immune suppressor that protects the fetus from maternal immune rejection. IDO, the tryptophan-metabolizing enzyme, is an important regulator of tumor immune suppression through inhibiting lymphocytic functions, and is frequently increased expression in solid tumor. This aimed to expound expression and significance of indoleamine 2,3 dioxygenase(IDO) on tumor cell(TC) and tumor stroma compartments(TSC) of lung squamous cell carcinoma (LSCC).
Methods
Patients with resected specimen from 2015 to 2018 in Taizhou Hospital of Zhejiang Province were enrolled included in this study. The expressions of IDO (ab211017) in on TC and TSC of tumor tissue and adjacent tissue were evaluated by immunohistochemistry (IHC). The results of staining were scored according to the intensity of staining with Fourtier system (level 0–3: negative = 0, weakest = 1, moderate = 2, strong = 3) and staining positive rate score: 0 (negative), 1 (1-25%), 2 (26-50%), 3 (51-75%), 4 (76-100%). Total score was the product of "intensity score" and "positive rate score". And grouping was divided into that < 6 was low expression group, while ≥ 6 was divided into high expression group. Three pathologists, who were blind to all clinical and biological data, performed and analyzed IHC.
Results
A total of 86 patients with resected tissue specimen available for IHC analysis were studied. The high and low expression of IDO were identified in 37(43.02%), 49(56.98%) and 12(13.95%), 74(86.05%) on TC of tumor tissue and adjacent tissue from LSCC patients, respective. And, the high and low expression of IDO were identified in 20(23.26%), 66(76.74%) and 45(52.33%), 41(47.67%) in TSC of tumor tissue and adjacent tissue from LSCC patients, respective. Patients with high expression of IDO showed significantly poorer overall survival than those with low expression of IDO ( not reached months versus 57 months respectively) (p = 0.025) on TC of tumor tissue.In the same way, the high IDO expression were showed significantly poorer overall survival than those with low expression of IDO (not reached months versus 29 months respectively) (p = 0.025) on TSC of tumor tissue.
Conclusion
IDO expression was higher in tumor tissues than in adjacent tissues. IDO expression not only on TC but also on TSC of tumor tissue may be useful for predicting the prognosis in LSCC patients. Further studies on the correlation between IDO and PDL1 and co-expression rates need to be carried out.
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P14.06 - Dysregulation of m6a Reader IGF2BP1 in Lung Adenocarcinoma Affects the Immune Microenvironment and Indicates a Poor Recovery (ID 1638)
00:00 - 00:00 | Author(s): Meng Chen
- Abstract
Introduction
IGFII mRNA-binding protein 1 (IGF2BP1, also known as IMP1), a m6a reader gene, expressed only in a few adult human tissues, but common highly expressed in a various of malignant tumors. Previous studies have shown that IGF2BP1 overexpression may influence MAPK/ERK signaling pathway by promoting kras or pkcα expression in breast cancer or melanoma. Inhibiting IGF2BP1 expression enhances the effects of braf-inhibitor and braf-MEK inhibitors. IGF2BP1 is also required for β-actin mRNA localization, which promote cell migration. These results drivers us to the study the function role of IGF2BP1 in LUAD initiation and progression.
Methods
IGF2BP1 expression data and clinical information were abtained from RNA-sequencing datasets in TCGA. Bioinformatics analyses including differential expression analysis, and weighted gene coexpression network analysis were used to find the potential changes of gene expressions and its coexpression network. LUAD and paired tumor adjacent normal lung tisses were stained with IGF2BP1 IHC antibody to explore the protein level differences between normal and tumor tissues. Kaplan-Meier analysis, cox univariate and multivariate analyses were performed on the overall survival LUAD patients to illustrate the clinical role of IGF2BP1. Those genes coexpressed with IGF2BP1 were analyzed by Gene Ontology (GO).
Results
Transcriptome sequencing data of TCGA LUAD datasets analysis showed that IGF2BP1 transcripts was significantly highly expressed in LUAD tissues compared with normal lung tissues and was related to LUAD various clinical pathological stages. IGF2BP1 IHC analytical comparison demonstrated that LUAD tumor cells was highly stained comparable with normal cells. Kaplan-Meier analysis showed that patients with high IGF2BP1 RNA level in LUAD tissues had considerably shorter overall survival than patients low expression. Coexpression genes functional analysis were enriched with 37 GO terms. GO analysis revealed that the coexpression genes mainly participated in some immunological process including antigen processing and presentation via MHC class Ib, regulation of myeloid cell differentiation, antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, regulation of T cell mediated cytotoxicity, regulation of adaptive immune response. These genes own function,such as mRNA 5'-UTR binding, enhancer sequence-specific DNA binding, enhancer binding, translation regulator activity, mRNA 3'-UTR binding, RNA polymerase II distal enhancer sequence-specific DNA binding.
Conclusion
Our results showed that highly expressed IGF2BP1 in LUAD indicates shorter overall survival rate and poorer recovery. Its coexpression network influences the Immune microenvironment through DNA or RNA binding manner, which suggested that IGF2BP1 worked as a m6a reader might be developed as novel therapeutic targets for LUAD.
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P62 - Tumor Biology and Systems Biology - Basic and Translational Science - Metabolomics (ID 200)
- 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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P62.03 - Increased GPX4 Drives Ferroptosis Resistance by Suppressing Radiation-Induced Lipid Peroxidation Confers Acquired Radioresistance in NSCLC (ID 1028)
00:00 - 00:00 | Author(s): Meng Chen
- Abstract
Introduction
Radiotherapy (RT) is one of the major modalities for the treatment of lung cancer (NSCLC), but, the clinical efficacy is limited due to radioresistance. Ferroptosis is a recently recognized cell death modality that is morphologically, biochemically and genetically distinct from other forms of cell death and that has emerged to play an important role in ionizing radiation (IR) induced cell death response; however, the dysregulation of ferroptosis in radioresistance is poorly understood. Here we investigate whether, and how the ferroptosis resistance is involved in acquired resistance to RT in NSCLC cell line.
Methods
We established the radioresistant subline A549R from radiosensitive parental A549 cells using hypo-fractionated irradiations (a fraction of 6-Gy and repeated 10 times, a total of 60Gy of X-rays), clonogenic survival assay was used to assess radiosensitization in NSCLC cell line. Cell viability, protein alterations, and the expression of indicated mRNA were measured by MTT assay, Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) respectively, lipid peroxidation assessment by flow cytometry using the fluorescent probes C11-BODIPY staining.
Results
The radioresistant cell A549R show decreased plating efficiency (PE) without IR, increased SF2 value (survival fraction at 2Gy) compared to parental cells. The expression of glutathione peroxidase 4 (GPX4) is increased in A549R compared to parental A549 cell, and pharmacological inhibition of GPX4 using RSL3, or genetic downregulation of GPX4 using shRNA strongly increased cellular radiosensitivity. Conversely, overexpression of GPX4 decreased the responsiveness of parental A549 cells to IR. Mechanistically, increased GPX4 in radioresistance cell, resulting in reduced IR-induced lipid peroxidation and decreased IR induced ferroptosis.
Conclusion
Irradiation combined with GPX4 blockade by RSL3 may reverse the resistance to radiation in radioresistant NSCLC cell. These results suggest ferroptosis resistance is involved in NSCLC resistance to RT, and the GPX4 inhibitor may be an effective radiosensitizers. The radiosensitizing efffect of ferroptosis inducer such as GPX4 inhibitor warrants further clinical investigation.
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P82 - Immunotherapy (Phase II/III Trials) - Immunotherapy Plus Radiotherapy (ID 259)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P82.04 - Adaptive Radiation Therapy with Consolidation Sintilimab in Stage III NSCLC: Challenges in Recruiting Patients for Adjuvant Immunotherapy (ID 1542)
00:00 - 00:00 | Author(s): Meng Chen
- Abstract
Introduction
The PACIFIC reported a significantly improved overall survival for consolidative durvalumab after chemoradiotherapy in unresectable stage III non-small cell lung cancer (NSCLC) in 2018. However, the details in the exclusion of patient enrollment were not reported. It is unclear what proportion of patients after chemoradiotherapy would be eligible to receive immunotherapy. In this study, we aimed to recruit all for consolidation sintilimab, an anti-PD-1 antibody, after definitive chemoradiotherapy using adaptive radiotherapy which can target to the shrunk tumor to reduce the dose to surrounding normal tissues and decrease the toxicities.
Methods
This was a single-arm prospective phase II trial (CARTAI; NCT03732430). Patients with histologically confirmed NSCLC, unresectable stage III medically fit for concurrent chemoradiotherapy were eligible. Radiation therapy was delivered using mid-treatment CT guided adaptive IMRT. Sintilimab was given within 45 days after completion of RT, when patients had grade 1 or less acute toxicity, with ECOG PS 0 or 1, adequate hematologic, liver and kidney function. Any patients who had unresolved grade 2 or higher toxicity were excluded from enrollment. The prescription doses of radiotherapy were 64-66Gy to the GTV and 54Gy to the PTV in 30 fractions, unless exceeding the dose constraints. The patents were intravenously given sintilimab, an anti-PD-1 antibody, 200mg q3w. We initially screened potential patients before the radiotherapy and all interested patients were treated consistently with adaptive RT. Final written consent was obtained, and eligibility was confirmed after completion of radiotherapy.
Results
From November 2018 to December 2019, after the initial screening, 107 consecutive patients potentially eligible received concurrent chemoradiation received adaptive IMRT. Eight-eight patients failed for enrollment of consolidation sintilimab. In which, seventy (80%) patients refused to participate the study at the last minutes. Eighteen of 88 (20%) did not meet the inclusion criteria after the end of radiotherapy. main ineligible reasons were grade 2 or higher toxicities, including radiation-induced pneumonitis in 7 patients, unresolved esophagitis in 5, 2 developed both, and 2 with unresolved leukopenia. A total of 19 patients (17.8%) consented to participate in the adjuvant immunotherapy. Four of them (21.5%) were found ineligible, including 2 patients with grade 2 radiation pneumonitis, 1 with esophagitis, and 1 with leukopenia. There were finally 15 patients (78.9%) enrolled in this study.
Conclusion
This study found approximately twenty percent of all consented and refused patients were ineligible to receive consolidative immunotherapy after the end of concurrent chemoradiotherapy. The main barrier for eligibility was the radiation-induced acute toxicities, especially pneumonitis and esophagitis.
