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RESUMEN Objetivo: Los pacientes con cáncer de pulmón de células no pequeñas positivas a la mutación del gen linfoma anaplásico quinasa (ALK+) que, además, presentan mutaciones en el gen Kirsten rat sarcoma (KRAS), como KRASG12C, están mostrando resistencia tanto a inhibidores del gen linfoma anaplásico quinasa (ALK) como de KRAS. Por ello, se analizó la interacción de los inhibidores de ALK con KRAS, para sugerir una sinergia entre ambos. Materiales y métodos: En el estudio se realizó un modelado por homología de las estructuras KRASwt, KRASG12C y ALKwt. Posteriormente, se realizaron acoplamientos moleculares para determinar la energía de unión de los inhibidores de ALK y de KRAS, y evaluar la posible interacción entre los inhibidores de ALK con KRAS y la estructura KRASG12C. Finalmente, se analizó la expresión en la vía de proliferación celular de las proteínas rat sarcoma/quinasa regulada por señales extracelulares (vía RAS/MEK) mediante la técnica de Western blot. Resultados: Los valores de energía de unión muestran la posibilidad de interacción de los inhibidores de ALKwt, como crizotinib y alectinib, con las estructuras de KRASwt y KRASG12C. Los acoplamientos entre crizotinib con KRASwt y KRASG12C, respectivamente, muestran valores de energía de interacción (42,77 kcal/mol y 46,20 kcal/mol) muy similares a los obtenidos entre crizotinib y ALK (42,37 kcal/mol). A su vez, alectinib se acopló en el mismo sitio que los fármacos específicos de KRAS y KRASG12C, y presentaron valores de energía de interacción (51,74 kcal/mol y 54,69 kcal/mol, respectivamente) superiores a los obtenidos con ALK (44,94 kcal/mol). Finalmente, la expresión de la vía RAS/MEK nos mostró una disminución significativa de la expresión de RAS en líneas celulares de cáncer de pulmón ALK+ y ALKL1196M tratadas con crizotinib y alectinib. Conclusiones: Las técnicas in silico de este estudio muestran la posibilidad de acoplamiento entre los inhibidores de ALK (crizotinib y alectinib) con la estructura de KRAS. Esto permite sugerir una posible terapia combinada entre inhibidores de KRAS y ALK para los casos de coexistencia de ambas mutaciones, que puede evaluarse en posteriores ensayos con líneas celulares.
ABSTRACT Objective: Patients with non-small cell lung cancer positive for the anaplastic lymphoma kinase (ALK+) gene mutation who also have mutations in the Kirsten rat sarcoma (KRAS) gene, such as KRAS G12C, are showing resistance to both anaplastic lymphoma kinase (ALK) gene and KRAS inhibitors. Therefore, the interaction between ALK inhibitors and KRAS was analyzed to suggest a synergy between them. Materials and methods: The study performed homology modeling of the KRASwt, KRAS G12C and ALKwt structures. Subsequently, molecular dockings were carried out to determine the binding energy of ALK and KRAS inhibitors and to evaluate the possible interaction of ALK inhibitors with KRAS and the KRAS G12C structure. Finally, the expression in the RAS/MEK pathway was analyzed using the Western Blot technique. Results: The binding energy values show the potential interaction of ALKwt inhibitors, such as crizotinib and alectinib, with the KRASwt and KRAS G12C structures. The binding of crizotinib to KRASwt and KRAS G12C, respectively, indicates interaction energy values (42.77 kcal/mol and 46.20 kcal/mol) which are very similar to those obtained between crizotinib and ALK (42.37 kcal/mol). In turn, alectinib bound to the same site as drugs targeting KRAS and KRAS G12C, and showed interaction energy values (51.74 kcal/mol and 54.69 kcal/mol, respectively) higher than those obtained with ALK (44.94 kcal/mol). Finally, a significant decrease in RAS expression within the RAS/MEK pathway was observed in ALK+ and ALK 1196M lung cancer cell lines treated with crizotinib and alectinib. Conclusions: In silico techniques of this study demonstrate the potential binding of ALK inhibitors (crizotinib and alectinib) to the KRAS structure. In addition, this allows suggesting a possible combined therapy between KRAS and ALK inhibitors for cases of coexistence of both mutations that can be assessed in subsequent trials with cell lines.
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RESUMEN Los inhibidores de la tirosina quinasa han cambiado drásticamente la perspectiva clínica de los pacientes con cáncer de pulmón de células no pequeñas avanzado con mutaciones del receptor del factor de crecimiento epidérmico. Sin embargo, existen aún retos en el manejo de los pacientes con esta mutación en un escenario metastásico, como es la resistencia intrínseca y adquirida a inhibidores de tirosina quinasa. Se discutirán los últimos avances y nuevas estrategias en primera línea de tratamiento, resistencia a osimertinib y tratamiento en mutación, en el exón 20.
ABSTRACT Tyrosine kinase inhibitors have dramatically changed the clinical outcomes for patients with advanced non-small cell lung cancer with epidermal growth factor receptor mutations. However, there are still challenges in the management of patients with this mutation in a metastatic setting, such as intrinsic and acquired resistance to tyrosine kinase inhibitors. We will discuss the latest advances and new strategies in first-line treatment, osimertinib resistance, and exon 20 mutation treatment.
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Objective To investigate the effects of indirubatin derivative E804 on proliferation and migration of non-small cell lung cancer(NSCLC)A549 cells,and to elucidate the possible mechanism of Nrf2-HO-1/GPX4 pathway.Methods Lung cancer A549 cells were used as the cell model.The proliferation and migration of differ-ent specific inhibitors(Nec-1,CQ,Z-VAD,DFO,Fer-1 and Lip-1)in 0,10 μmol/L E804 and 10 μmol/L E804+groups were observed by MTT and cell scratch assay.The contents of reactive oxygen species(ROS)were de-tected by DCFH-DA fluorescence probe method,the contents of Fe2+were detected by colorimetric method,the contents of reduced glutathione(GSH)were detected by spectrophotometry,and the contents of malondialdehyde(MDA)were detected by micromethod.The expression levels of SLC7A11,Transferrin,GPX4,SLC40A1,Nrf2 and HO-1 were detected by Western blot in cells of 0,2.5,5 and 10 μmol/L E804 groups.Results Compared with the control group(0 μmol/L E804),2.5,5 and 10 μmol/L E804 significantly increased intracellular ROS,Fe2+and MDA levels,and decreased intracellular GSH content(P＜0.01).Meanwhile,the expression levels of SLC7A11,GPX4,SLC40A1,Nrf2 and HO-1 significantly decreased(P＜0.01),and the expression level of Transferrin increased(P＜0.05).Compared with the 10 μmol/L E804 group alone,the apoptosis inhibitor(Z-VAD)group and the ferroptosis inhibitor(DFO,Fer-1 and Lip-1)group could significantly reverse the inhibition of proliferation and migration of A549 cells by 10 μmol/L E804(P＜0.01).Conclution E804 can induce ferrop-tosis and inhibit the proliferation and migration of A549 cells,which may be related to the inhibition of Nrf2-HO-1/GPX4 pathway.
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Lung cancer is the malignant tumor with the highest incidence and death in the world,among which non-small cell lung cancer(NSCLC)accounts for the largest proportion.The BRAF gene is a proto-on-cogene associated with poor prognosis in NSCLC,represented by BRAF V600E mutations.In recent years,the diagnosis and treatment of NSCLC patients with BRAF V600E mutation has become the focus of accurate di-agnosis and treatment of lung cancer,especially its whole-course management.There are many related studies on targeting,immunotherapy and chemotherapy for patients with BRAF V600E mutation.This paper reviewed the relevant research progress at home and abroad.
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Objective To observe the levels of serum thymidine kinase 1(TK1)and secreted protein Dikkopf-1(DKK1)in patients with advanced non-small cell lung cancer(NSCLC),and analyze the relation-ship between serum TK1,DKK1 and the prognosis of NSCLC.Methods This study adopted a prospective co-hort study method,a total of 91 chemotherapy patients with advanced NSCLC admitted in Jinshan Branch of Shanghai Sixth People's Hospital from January 2020 to June 2021 were enrolled as the research objects.All patients received the detection of serum TK1 and DKK1 on admission,completed 4 chemotherapy cycles in Jinshan Branch of Shanghai Sixth People's Hospital and were followed up for 3 months.The disease remission rate was evaluated according to the relevant standards.The patients with complete remission and partial re-mission were included in the good prognosis group,and those with the stable and progressive lesions were in-cluded in the poor prognosis group.The levels of serum TK1 and DKK1 were compared between the two groups.Logistic regression was used to analyze the relationship between the levels of serum TK1 and DKK1 and the prognosis of patients with advanced NSCLC.Results Among 91 patients with advanced NSCLC who received chemotherapy,threre were 58 cases(63.74％)in the good prognosis group,and 33 cases(36.26％)in the poor prognosis group.The levels of serum carcinoembryonic antigen(CEA),TK1 and DKK1 in the poor prognosis group were higher than those in the good prognosis group(P＜0.05).Logistic regression anal-ysis showed that the high levels of serum TK1 and DKK1 were the influencing factors of poor prognosis in pa-tients with advanced NSCLC(OR＞1,P＜0.05).The receiver operating characteristic curve was drawn,and the results showed that the area under the curve of serum TK1,DKK1 alone and combined for predicting the poor prognosis in patients with advanced NSCLC was＞0.700,all of which had certain predictive value,and the predictive value of the combined detection was the highest.Conclusion The abnormal increase of serum TK1 and DKK1 levels may indicate a high risk of poor prognosis in patients with advanced NSCLC.Early monito-ring of serum TK1 and DKK1 levels in patients has certain positive significance for predicting and evaluating the prognosis of patients.
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Objective To investigate the correlation between the expression of long non-coding ribonucleic acid growth arrest specific 5(lncRNA GAS5),phospholysine phosphohistidine inorganic pyrophosphate phos-phatase(LHPP)and epithelial-mesenchymal transition(EMT)in cancer tissues of patients with non-small cell lung cancer(NSCLC)and its clinical significance.Methods Cancer tissues and adjacent tissues of 90 patients with NSCLC who underwent surgical resection in the First Hospital Affiliated to Hebei North College from June 2018 to January 2020 were collected.The expressions of lncRNA GAS5,LHPP and EMT-associated pro-teins[E-calmodulin(E-Cad),N-calmodulin(N-Cad),and vimentin(VIM)]were detected by real-time fluores-cence quantitative polymerase chain reaction.The relationship between lncRNA GAS5 and LHPP mRNA and clinicopathological features in cancer tissues of NSCLC patients was analyzed,and the correlation between ln-cRNA GAS5 and LHPP mRNA and EMT-associated proteins expression in cancer tissues of NSCLC patients was analyzed by Pearson correlation.Kaplan-Meier method was used to plot the survival curves of NSCLC pa-tients with different lncRNA GAS5 and LHPP mRNA expressions,and multivariate Cox regression was used to analyze the prognostic factors of NSCLC patients.Results The expressions of lncRNA GAS5,LHPP mR-NA and E-Cad mRNA in cancer tissues of NSCLC patients were lower than those in adjacent tissues,while the expressions of N-Cad mRNA and VIM mRNA were higher than those in adjacent tissues,with statistical sig-nificance(P＜0.05).Pearson correlation analysis showed that lncRNA GAS5 in cancer tissues of NSCLC pa-tients was positively correlated with E-Cad mRNA expression(r=0.724,P＜0.001),and negatively correla-ted with N-Cad mRNA and VIM mRNA expression(r=-0.699,-0.689).P＜0.001);lncRNA GAS5 was positively correlated with LHPP mRNA expression(r=0.651,P＜0.001).The mRNA expressions of ln-cRNA GAS5 and LHPP in cancer tissues of NSCLC patients with different degrees of differentiation,tumor TNM stage and lymph node metastasis were significantly different(P＜0.05).Kaplan-Meier survival curve a-nalysis showed that the 3-year overall survival rate in the lncRNA GAS5 high expression group[68.18％(30/44)]was higher than that in the lncRNA GAS5 low expression group[36.96％(17/46)].The 3-year overall survival rate in the high LHPP mRNA expression group[67.39％(31/46)]was higher than that in the lowLHPP mRNA expression group[36.36％(16/44)],and the difference was statistically significant(x2=10.274,10.322,P＜0.05).Low differentiation,TNM stage Ⅲ and lymph node metastasis were independent risk factors for death in NSCLC patients,and lncRNA GAS5≥1.32 and LHPP mRNA≥1.12 were independ-ent protective factors(P＜0.05).Conclusion The low expression of lncRNA GAS5 and LHPP mRNA in cancer tissues of patients with NSCLC is related to EMT-associated proteins expression,differentiation de-gree,tumor TNM stage,lymph node metastasis and prognosis,and may become a new target for the diagnosis and treatment of NSCLC.
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Objective To investigate the role of microRNA(miR)-567 in the proliferation,migration and cell cycle of non-small cell lung cancer(NSCLC)through regulation of cyclin dependent kinase 8(CDK8)and its clinical relevance.Methods Tumor tissues and adjacent tissues of 40 NSCLC patients were collected,and the expressions of miR-567 and CDK8 were detected by real-time quantitative fluorescent PCR(qRT-PCR).miR-NC mimic,miR-567 mimic,oe-NC,and oe-CDK8 were transfected into A549 and H1975 cells.The ex-pressions of miR-567 and CDK8 were detected using qRT-PCR.Cell proliferation was detected by CCK-8 method,and cell migration was detected by Transwell assay.Cell cycle changes were detected by flow cytome-try.The targeting of miR-567 and CDK8 was detected by luciferase reporter gene assay.Results In the tumor tissues of NSCLC patients,the expression of miR-567 was decreased,while the expression of CDK8 was in-creased,and the two were negatively correlated(P＜0.05).In A549 and H1975 cells,miR-567 mimic group was compared with miR-NC mimic group,the expression of miR-567 was increased,the expression of CDK8 was decreased,the proliferation and migration levels of cells were decreased,the proportion of G1 phase was increased,and the proportion of S phase was decreased.The fluorescence intensity of miR-567 mimic group was lower than that of miR-NC mimic group in normal CDK8.miR-567 mimic+oe-CDK8 group was compared with miR-567 mimic+oe-NC group,the expression of CDK8 was increased,the proliferation and migration levels of cells were increased,the proportion of cells in G1 phase was decreased,and the proportion of cells in S phase was increased.Conclusion miR-567 can inhibit NSCLC proliferation and migration by targeting CDK8 expression and controlling tumor cell arrest in the S phase.
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Objective To analyze the therapeutic effect of anti-programmed death receptor 1(PD-1)/pro-grammed death ligand 1(PD-L1)and the characteristics of intestinal flora in patients with non-small cell lung cancer(NSCLC).Methods A total of 81 NSCLC patients admitted to the People's Hospital of Xinjiang Uygur Autonomous Region from January 2020 to January 2022 were taken as the research object.According to the patients'immunotherapy response,the patients were divided into non-response group and response group.The differences in clinical data and intestinal flora distribution between the two groups were compared,and the correlation between PFS and intestinal flora a diversity index was analyzed by Spearman correlation.Results The proportion of smoking patients in response group was significantly lower than that in non-re-sponse group,and the difference was statistically significant(x2=4.648,P=0.031).Chao1 index,ACE index and shannon wiener index patients in non-response group were lower than those in response group,while Simpson diversity index was higher than that in response group,with statistical significance(P＜0.05).Chao1 index,ACE index and shannon wiener index were positively correlated with PFS(r=0.526,0.579 and 0.539,all P＜0.05),while Simpson diversity index was negatively correlated with PFS(r=-0.867,P＜0.001).The principal coordinate analysis was used to analyze the β diversity structure of intestinal flora.The first principal component contribution rate was 70.36％,and the second principal component contribution rate was 16.63％.Conclusion The diversity and distribution of intestinal flora in NSCLC patients are related to anti-PD-1/PD-L1 therapy.The higher the diversity of intestinal flora,the more sensitive the anti-PD-1/PD-L1 therapy.
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Objective To screen for ferroptosis-related differentially expressed genes(DEGs)of epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)resistance in non-small cell lung cancer(NSCLC).Methods The gene sequencing dataset GSE117846 of NSCLC EGFR-TKIs resistant cells was se-lected from the Gene Expression Omnibus data base(GEO)and screened for DEGs with P＜0.05 and | log2 FC |1.Ferroptosis-related genes were collected using the FerrDb database and jvenn was used to intersected the DEGs screened from GSE117846 dataset with the ferroptosis-related genes obtained from FerrDb database.GO function and KEGG pathway enrichment analysis of intersection genes were performed,and protein-pro-tein interaction(PPI)network was drawn.The score of intersection genes was calculated by using Cytohubba plug-in in Cytoscape software,and the top 10 genes were used for Hub genes screening.ULCAN and GEPIA2 databases were used to analyze the expression of Hub genes in NSCLC and its effect on the survival prognosis of patients.Real-time fluorescence quantitative PCR(qPCR)was used to detect the relative expression levels of Hub gene mRNA in NSCLC patients'cancer tissues,adjacent tissues and in vitro cells to verify the results of bioinformatics analysis.Results A total of 60 ferroptosis-related DEGs of EGFR-TKIs resistance in NSCLC were screened out,including 30 up-regulated genes and 30 down-regulated genes.The 60 genes were mainly enriched in P53 signaling pathway,ferroptosis pathway and FoxO signaling pathway.There were 57 nodes and 99 edges in the PPI network,with an average clustering coefficient of 0.377 and PPI enrichment P＜0.01.The Hub gene screened out by Cytohubba plug-in was tumor protein P63(TP63).ULCAN and GE-PIA2 database analysis showed that the expression of TP63 in lung adenocarcinoma tissue was significantly lower than that in normal tissue,while the expression of TP63 in lung squamous cell carcinoma tissue was sig-nificantly higher than that in normal tissue,and the differences were statistically significant(P＜0.05).In pa-tients with lung adenocarcinoma,there was no significant difference in the survival prognosis between TP63 high and low expression groups(P＞0.05),while in patients with lung squamous cell carcinoma,the survival prognosis of TP63 low expression group was better,and the difference was statistically significant(P＜0.05).QPCR showed that TP63 mRNA highly expressed in lung squamous cell carcinoma tissue and lowly expressed in lung adenocarcinoma tissue compared with adjacent tissues(P＜0.05).The expression of TP63 mRNA was down-regulated in gefitinib-resistant PC9/GR cells(P＜0.05),which was consistent with the re-sults of bioinformatics analysis.Conclusion TP63 may be an important gene linking NSCLC EGFR-TKIs re-sistance to ferroptosis.
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Objective:To investigate whether chlorogenic acid can inhibit the proliferation, migration, invasion and promote apoptosis of lung cancer A549 cells by causing mitochondrial dysfunction through PI3K-Akt pathway.Methods:A549 cells were treated with chlorogenic acid at concentrations of 0, 25, 50, 100, 150, and 200 μg/ml for 48 h. CCK-8 assay was used to detect the cell proliferation rate and calculate the half maximal inhibitory concentration (IC 50). A549 cells were divided into three groups: control group, chlorogenic acid group (IC 50) and chlorogenic acid + 740-YP group (IC 50 chlorogenic acid +50 μg/ml 740YP). After 48 h of intervention, the cell migration distance was detected by cell scratch assay. Cell invasion assay was used to detect cell invasion ability. Cell cycle, apoptosis and mitochondrial membrane potential were detected by flow cytometry. The content of malondialdehyde (MDA) in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to detect the protein expression of p-PI3K, p-Akt and Caspase3. Results:The IC 50 of chlorogenic acid to A549 cells was 57.45 μg/ml. The results of cell scratch assay showed that the 48 h migration distances of the control group, chlorogenic acid group and chlorogenic acid + 740YP group were (424.80±14.43), (289.67±18.93) and (402.22±17.99) μm, respectively. The results of cell invasion assay showed that the numbers of invasive cells after 48 h were 96.00±6.24, 35.33±7.64 and 83.00±2.00, and the results of flow cytometry showed that the 48 h apoptosis rates were (6.15±0.17) %, (54.63±0.72) % and (17.27±0.39) %, respectively, among the three groups with statistically significant differences ( F=105.98, P<0.001; F=90.62, P<0.001; F=8 321.99, P<0.001). Compared with the control group, the cell migration distances and invasive numbers of chlorogenic acid group and chlorogenic acid + 740YP group were decreased (all P<0.05), while the apoptosis rates were significantly increased (both P<0.001). Compared with chlorogenic acid group, the cell migration distance of chlorogenic acid + 740YP group increased ( P<0.001), the number of cell invasion increased ( P<0.001), and the apoptosis rate decreased ( P<0.001). The results of flow cytometry showed that the proportions of cells in G 0/G 1 phase in the control group, chlorogenic acid group and chlorogenic acid + 740YP group were (65.75±0.58) %, (55.84±0.78) % and (55.24±1.37) %, respectively. The proportions of G 2/M phase were (11.21±1.03) %, (20.23±0.62) % and (9.96±0.33) %, and the proportions of S phase were (23.04±0.49) %, (23.92±1.36) % and (34.80±1.15) %, respectively, with statistically significant differences ( F=111.02, P<0.001; F=181.26, P<0.001; F=113.05, P<0.001). Compared with the control group, the proportions of G 0/G 1 phase cells in chlorogenic acid group and chlorogenic acid + 740YP group decreased (both P<0.001), and the proportion of G 2/M phase in chlorogenic acid group increased ( P<0.001), and the proportion of S phase cells in chlorogenic acid + 740YP group increased ( P<0.001). Compared with chlorogenic acid group, the proportion of G 2/M phase cells decreased and the proportion of S phase cells increased in chlorogenic acid + 740YP group (both P<0.001). The results of mitochondrial membrane potential detection showed that the JC-1 fluorescence intensity of mitochondria in the control group, chlorogenic acid group and chlorogenic acid + 740YP group were 39.51±1.32, 10.05±0.19 and 21.85±1.45, respectively, with a statistically significant difference ( F=508.82, P<0.001). Compared with the control group, the fluorescence intensity of chlorogenic acid group and chlorogenic acid + 740YP group decreased (both P<0.001). Compared with chlorogenic acid group, the fluorescence intensity of chlorogenic acid + 740YP group increased ( P<0.001). ELISA results showed that the MDA contents of the control group, chlorogenic acid group and chlorogenic acid + 740YP group were (0.47±0.01), (0.61±0.01) and (0.56±0.01) nmol/ml, respectively, with a statistically significant difference ( F=162.30, P<0.001). Compared with the control group, MDA contents in chlorogenic acid group and chlorogenic acid + 740YP group increased (both P<0.001). Compared with chlorogenic acid group, MDA content in chlorogenic acid + 740YP group decreased ( P=0.001). Western blotting results showed that the relative protein expression levels of p-PI3K in the control group, chlorogenic acid group and chlorogenic acid + 740YP group were 1.01±0.33, 0.28±0.14 and 0.34±0.20, respectively. The relative protein expression levels of p-Akt were 1.00±0.16, 0.43±0.05 and 0.95±0.14, and the relative protein expression levels of Caspase3 were 1.00±0.04, 1.41±0.05 and 0.70±0.13, respectively, and there were statistically significant differences ( F=8.48, P=0.018; F=19.11, P=0.002; F=57.50, P<0.001). Compared with the control group, the expressions of p-PI3K and p-Akt protein in chlorogenic acid group decreased, and the expression of Caspase3 protein increased (all P<0.05). The expressions of p-PI3K and Caspase3 protein in chlorogenic acid + 740YP group decreased (both P<0.05). Compared with chlorogenic acid group, the expression of p-Akt protein in chlorogenic acid + 740YP group increased, and the expression of Caspase3 protein decreased (both P<0.05) . Conclusion:Chlorogenic acid may inhibit the PI3K-Akt pathway by reducing the phosphorylation of PI3K and Akt proteins, resulting in the damage of mitochondrial function and the accumulation of MDA, which eventually leads to the damage of lung cancer A549 cells function and the reduction of cells activity, and then promotes cells apoptosis.
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Objective:To investigate the serum levels of miR-19b and miR-744-5p in patients with non-small cell lung cancer (NSCLC), and to analyze the clinical value of miR-19b and miR-744-5p in the diagnosis of NSCLC.Methods:A total of 226 NSCLC patients (NSCLC group) and 100 healthy people (control group) admitted to Jilin Cancer Hospital from August 2019 to August 2022 were selected as research objects. Quantitative real-time PCR was used to measure and compare the serum levels of miR-19b and miR-744-5p between the NSCLC group and the control group, and the relationships between the two indicators and different clinical and pathological characteristics of NSCLC patients were analyzed. The receiver operating characteristic curve was used to analyze the clinical value of miR-19b, miR-744-5p and their joint detection in the diagnosis of NSCLC.Results:Compared with the control group, the serum miR-19b level (3.86±1.25 vs. 1.06±0.41) in the NSCLC group significantly increased ( t=21.87, P<0.001), while the miR-744-5p level (1.80±0.48 vs. 5.75±1.69) significantly decreased ( t=32.36, P<0.001). The serum miR-19b levels in NSCLC patients with pathological types of adenocarcinoma, maximum tumor diameter ≥3 cm, medium to low differentiation, stage Ⅲ-Ⅳ, and with lymph node metastasis were higher than those in squamous cell carcinoma ( t=5.94, P<0.001), maximum tumor diameter <3 cm ( t=2.65, P=0.009), well differentiation ( t=4.33, P<0.001), stageⅠ-Ⅱ ( t=12.32, P<0.001), patients without lymph node metastasis ( t=8.13, P<0.001), while miR-744-5p levels were lower than those in squamous cell carcinoma ( t=8.27, P<0.001), tumor maximum diameter <3 cm ( t=5.34, P<0.001), well differentiation ( t=6.95, P<0.001), stageⅠ-Ⅱ ( t=11.40, P<0.001), patients without lymph node metastasis ( t=10.36, P<0.001). The area under the curve (AUC) of serum miR-19b combined with miR-744-5p in the diagnosis of NSCLC was 0.914 (95% CI: 0.841-0.959), with sensitivity and specificity of 90.9% and 84.0%, respectively. AUC was significantly than that of the single indicator detection of miR-19b (AUC=0.824, 95% CI: 0.770-0.869) and miR-744-5p (AUC=0.783, 95% CI: 0.709-0.838) ( Z=2.28, P=0.021; Z=2.36, P=0.017) . Conclusion:Serum miR-19b level of NSCLC patients is increased, miR-744-5p levels is decreased, and joint detection of serum miR-19b and miR-744-5p has high clinical value in the diagnosis of NSCLC.
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Objective:To explore the impact of pembrolizumab combined with chemotherapy on angiogenesis and circulating endothelial cells in patients with advanced non-small cell lung cancer (NSCLC) .Methods:The retrospective analysis of clinical data from 121 patients diagnosed with advanced NSCLC who were admitted to the Second Affiliated Hospital of Xingtai Medical College from August 2021 to January 2023 was conducted. These patients were divided into a control group ( n=57) and an observation group ( n=64) based on the designated treatment protocol. Specifically, individuals in the control group received standard chemotherapy (cisplatin+paclitaxel), while those in the observation group underwent penpilimab therapy in conjunction with conventional chemotherapy. The comparative assessment encompassed short-term clinical efficacy, quality of life, immune function parameters, angiogenic factors [including endostatin, insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) ], circulating endothelial cells, and adverse reactions within the two groups. Results:After 6 courses of treatment, the objective response rate [67.19% (43/64) vs. 49.12% (28/57) ] and disease control rate [87.50% (56/64) vs. 70.18% (40/57) ] in observation group were higher than those in control group, with statistically significant differences ( χ2=4.06, P=0.044; χ2=5.52, P=0.019). The quality of life score of observation group [ (56.77±6.81) points] was significantly higher than that of control group [ (47.73±8.23) points], with a statistically significant difference ( t=6.61, P<0.001) ; The T cell subgroup CD3 + levels [ (63.59±9.00) % vs. (53.06±8.80%), t=6.49, P<0.001], CD4 + levels [ (46.54±8.20) % vs. (30.74±7.32) %, t=11.13, P<0.001] and CD4 +/CD8 + ratio (1.90±0.36 vs. 1.21±0.28, t=11.66, P<0.001) in observation group were significantly higher than those in control group, with statistically significant differences; Endostatin in observation group [ (48.99±3.43) μmol/L] was significantly higher than that in control group [ (31.35±3.87) μmol/L], with a statistically significant difference ( t=26.58, P<0.001), IGF-1 [ (102.31±20.35) μg/L vs. (134.98±19.02) μg/L] and VEGF [ (31.70±4.32) pg/ml vs. (58.71±5.99) pg/ml] were significantly lower in observation group than those in control group, with statistically significant differences ( t=18.73, P<0.001; t=28.14, P<0.001). The number of circulating endothelial cells in observation group [ (58.77±10.03) /ml] was significantly lower than that in control group [ (87.01±8.01) /ml], with a statistically significant difference ( t=17.20, P<0.001). During treatment, there were no statistically significant differences in the incidence of gastrointestinal reaction ( χ2=0.01, P=0.908), leukopenia ( χ2=0.64, P=0.424), thrombocytopenia ( χ2=0.28, P=0.597), anemia ( χ2=1.66, P=0.197), nephrotoxicity ( χ2=0.64, P=0.424), skin rash ( χ2=1.33, P=0.249) between the two groups. Conclusion:The combination therapy of pembrolizumab and chemotherapy for the treatment of advanced NSCLC has demonstrated noteworthy effectiveness. This regimen has the potential to enhance patients' immune functionality, ameliorate their overall quality of life, suppress angiogenesis, and exhibits a commendable profile of safety and reliability.
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With the continuous in-depth research on the mechanism of KRAS G12C mutations in targeted therapy of non-small cell lung cancer, KRAS G12C has evolved from non producible to an important targeted therapy site. The KRAS G12C mutation inhibitor has achieved dual progress in efficiency and survival in targeted therapy of non-small cell lung cancer. Although drug resistance is inevitable with treatment, research on drug resistance mechanisms has found that combination medication is one of the ways to overcome or reduce drug resistance.
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Objective:To compare the clinical efficacy of camrelizumab and sintilimab in the treatment of advanced non-small cell lung cancer (NSCLC) , and to explore its impact on tumor marker levels and immune function index, as well as to perform safety analysis.Methods:A total of 87 patients with advanced NSCLC who were treated in Hai'an People's Hospital of Jiangsu Province from May 2019 to May 2021 were selected as the research objects. According to the treatment scheme, the patients were divided into camrelizumab group ( n=41) and sintilimab group ( n=46) . The clinical efficacy, prognosis, tumor marker levels, immune function index and immune related adverse reactions of the two groups were compared. Results:There were no statistically significant differences in objective response rate [48.78% (20/41) vs. 39.13% (18/46) , χ2=0.82, P=0.365] or disease control rate [78.05% (32/41) vs. 71.74% (33/46) , χ2=0.46, P=0.499] in both camrelizumab and sintilimab group. The median progression-free survival (PFS) in the camrelizumab group was 9.1 months, and the median overall survival (OS) was 15.4 months. The median PFS in the sintilimab group was 9.7 months, and the median OS was 15.7 months. There were no statistically significant differences in median PFS and median OS between the two groups ( χ2=0.18, P=0.633; χ2=0.15, P=0.697) . Before treatment, there were no statistically significant differences in carcinoembryonic antigen (CEA) [ (47.68±8.12) ng/ml vs. (49.03±8.70) ng/ml, t=0.75, P=0.458], cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) [ (18.06±3.41) ng/ml vs. (17.25±3.78) ng/ml, t=1.05, P=0.299], and carbohydrate antigen 125 (CA125) [ (72.26±21.06) U/ml vs. (74.03±22.10) U/ml, t=0.38, P=0.704] levels between the camrelizumab group and sintilimab group. After treatment, there were no statistically significant differences in CEA [ (28.11±7.68) ng/ml vs. (27.63±5.71) ng/ml, t=0.33, P=0.740], CYFRA21-1 [ (9.29±1.88) ng/ml vs. (9.06±1.80) ng/ml, t=0.15, P=0.814], and CA125 [ (61.39±21.22) U/ml vs. (60.51±11.03) U/ml, t=0.25, P=0.806] levels between the two groups, but CEA, CYFRA21-1, and CA125 levels decreased after treatment compared with those before treatment in both groups (all P<0.05) . Before treatment, there were no statistically significant differences in T cells CD4 + [ (41.15±3.24) % vs. (41.17±2.90) %, t=0.03, P=0.976], CD8 + [ (68.82±3.94) % vs. (70.06±4.08) %, t=1.44, P=0.154], and CD4 +/CD8 + (1.88±0.33 vs. 1.76±0.25, t=1.92, P=0.058) between the two groups. After treatment, there were no statistically significant differences in T cells CD4 + [ (47.08±3.22) % vs. (48.53±5.07) %, t=1.57, P=0.120], CD8 + [ (61.22±1.67) % vs. (61.45±1.66) %, t=0.64, P=0.522], and CD4 +/CD8 + (2.31±0.17 vs. 2.36±0.12, t=1.60, P=0.114) between the two groups, while T cells CD8 + was lower than that before treatment, and CD4 + as well as CD4 +/CD8 + were higher than those before treatment in both groups (all P<0.05) . The overall incidence of adverse reactions in the sintilimab group [10.87% (5/46) ] was lower than that in the camrelizumab group [31.71% (13/41) ], and with a statistically significance ( χ2=5.74, P=0.016) . Conclusion:The clinical efficacy of camrelizumab and sintilimab in NSCLC patients is basically the same, the impacts of which on tumor markers and immune function are comparable, but the safety of sintilimab is better than that of camrelizumab.
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Objective:To explore influencing factors affecting the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy based on hematologic indexes, thus to construct and evaluate a nomogram prediction model.Methods:The clinical data of 80 patients with advanced NSCLC treated with programmed death-1 inhibitor monotherapy or combination regimen from January 2018 to June 2020 at the Affiliated Hospital of North China University of Science and Technology and Tangshan People's Hospital were retrospectively analyzed. Hematologic indexes at the baseline, the optimal remission and the progressive disease (PD) were collected separately, and independent influencing factors for patient prognosis were analyzed using Cox proportional hazards regression model. A nomogram prediction model was constructed based on the results of the multifactorial analysis, and the predictive performance of the model was evaluated by receiver operating characteristic (ROC) curve, concordance index (C-index) and calibration curves.Results:As of the follow-up cut-off date, of the 80 patients, 63 had PD, with a median overall survival (OS) of 16.9 months. Univariate analysis showed that, age ( HR=2.09, 95% CI: 1.17-3.74, P=0.013) , number of treatment lines ( HR=2.23, 95% CI: 1.21-4.12, P=0.010) , lymphocyte to monocyte ratio (LMR) at the baseline ( HR=0.75, 95% CI: 0.57-0.97, P=0.028) , D-dimer ( HR=1.00, 95% CI: 1.00-1.00, P=0.002) and lactate dehydrogenase (LDH) ( HR=1.01, 95% CI: 1.00-1.01, P=0.006) at the optimal remission, haemoglobin ( HR=0.97, 95% CI: 0.96-0.99, P<0.001) , D-dimer ( HR=1.00, 95% CI: 1.00-1.00, P=0.002) , C-reactive protein ( HR=1.01, 95% CI: 1.00-1.01, P=0.011) , albumin (ALB) ( HR=0.91, 95% CI: 0.87-0.96, P=0.001) , neutrophil to lymphocyte ratio (NLR) ( HR=1.16, 95% CI: 1.05-1.27, P=0.002) and LMR ( HR=0.62, 95% CI: 0.42-0.90, P=0.012) at the PD were all influencing factors for the prognosis of advanced NSCLC patients receiving immunotherapy. Least absolute shrinkage and selection operator regression were used to screen the variables for P<0.10 in the univariate analysis, and nine possible influencing factors were obtained, which were age, fibrinogen and LDH at the optimal remission, haemoglobin, D-dimer, C-reactive protein, LDH, ALB and LMR at the PD. Multivariate analysis of the above variables showed that, age ( HR=0.91, 95% CI: 0.86-0.97, P=0.004) , LDH ( HR=1.01, 95% CI: 1.00-1.01, P=0.013) and ALB ( HR=0.82, 95% CI: 0.67-0.99, P=0.041) at the PD were independent influencing factors for the prognosis of patients with advanced NSCLC who received immunotherapy. The area under curve of the nomogram predicting model based on the above indexes, 1- and 2-year OS rates of patients were 0.77 (95% CI: 0.65-0.89) and 0.75 (95% CI: 0.66-0.88) , respectively, and C-index was 0.71 (95% CI: 0.64-0.78) , the calibration curves showed good consistency between predicted and actual probability of occurrence. Patients in the low-risk group ( n=40) had a median OS of 29.9 months (95% CI: 22.5 months-NA) , which was significantly better than that of the high-risk group ( n=40) [13.4 months (95% CI: 11.4-23.5 months) , χ2=11.30, P<0.001]. Conclusion:Age, LDH and ALB at the PD are independent influencing factors affecting the prognosis of patients with advanced NSCLC receiving immunotherapy, and the nomogram model constructed based on the above indexes has good differentiation and calibration for predicting 1- and 2-year OS rates in advanced NSCLC patients receiving immunotherapy.
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The effective local management of oligometastatic non-small cell lung cancer (NSCLC) has the potential to prolong patients' survival. The role of radiotherapy as a local treatment modality in patients with oligometastatic NSCLC, whether as first-line therapy or consolidation therapy, remains uncertain. Several studies have demonstrated that stereotactic ablative radiotherapy can offer clinical benefits for patients with oligometastatic NSCLC without increasing adverse reactions. Furthermore, the exploration of the potential synergistic effects of combining radiotherapy and immunotherapy on extending progression-free survival and overall survival in patients with oligometastatic NSCLC is also a topic worthy of attention.
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Objective:To investigate the clinical efficacy and safety of programmed death protein 1 (PD-1) inhibitos combined with Fuzheng Kang'ai Decoction in patients with stage Ⅲ or Ⅳ non-small cell lung cancer (NSCLC) and identify factors that influence progression and prognosis in real world.Methods:Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), total survival time (OS) and adverse events of patients with advanced or metastatic NSCLC who received PD-1 inhibitors for the first time in the Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine from August 2018 to March 2021 were retrospectively analyzed, and was prospectively followed up until September 2022. Kaplan-Meier method was used to plot survival curves and evaluate median PFS and median OS, while Cox proportional hazards regression model was used for multivariate analysis.Results:The final 66 patients were included in the study, with an ORR of 33.3% (22/66), a DCR of 86.4% (57/66), a median PFS of 9.90 months, and a median OS of 31.83 months. Univariate analysis showed that median PFS was associated with TNM stage, liver metastasis, PD-L1 expression level, lung immune prognostic index (LIPI), and traditional Chinese medicine syndrome types ( P values were 0.004, 0.033, 0.040, 0.004, and 0.001, respectively). Multivariate Cox regression analysis showed that TNM stage [ HR (95% CI)=4.179 (1.781, 9.804)], PD-L1 expression level 1%-49% [ HR (95% CI)=0.346 (0.127, 0.940)] or ≥ 50% [ HR (95% CI)=0.074 (0.019, 0.288)], LIPI [ HR (95% CI)=14.515 (2.939, 71.681)], and TCM characteristics of deficiency of yang qi [ HR (95% CI)=5.954 (2.093, 16.940)] were independent influencing factors for PFS. The overall and grade 3-5 treatment-related adverse events were 68.2% (45/66) and 9.1% (6/66), respectively. Conclusions:Fuzheng Kang'ai Decoction combined with PD-1 inhibitors is an effective and tolerable therapy for patients with advanced or metastatic NSCLC. TNM stage, liver metastasis, PD-L1 expression, LIPI and TCM characteristics are early predictors of clinical efficacy for patients with stage Ⅲ/Ⅳ NSCLC that receive traditional Chinese medicine combined with immunotherapy .
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Objective To investigate the clinical characteristics of stasis-toxin pathogenesis in patients with non-small cell lung cancer(NSCLC)of blood stasis and qi stagnation type,and to explore the interventional mechanism of adjuvant therapy with Bufei Huayu Decoction.Methods Seventy-eight patients with NSCLC of blood stasis and qi stagnation type admitted to the Department of Respiratory Medicine of Liu'an Hospital of Traditional Chinese Medicine from January 2021 to September 2022 were selected as the NSCLC group,and 71 volunteers who underwent physical examination during the same period served as the healthy control group.The clinical characteristics of stasis-toxin pathogenesis in the NSCLC group were observed,and the differences in the indicators of coagulation function were compared between NSCLC group and the healthy control group.According to the therapy,the NSCLC patients were divided into Bufei Huayu Decoction group(40 cases)and conventional treatment group(38 cases).The conventional treatment group was treated with conventional chemotherapy,while Bufei Huayu Decoction group was treated with Bufei Huayu Decoction together with conventional chemotherapy.Three weeks constituted one course of treatment,and the treatment lasted for 2 courses.The changes of traditional Chinese medicine(TCM)syndrome scores,Karnofsky Performance Status(KPS)score,coagulation function,immune function,serum nitric oxide(NO),vascular endothelial growth factor(VEGF)level in Bufei Huayu Decoction group and conventional treatment group were observed before and after treatment.Moreover,the clinical efficacy of the two groups and the occurrence of adverse reactions were compared during the treatment period.Results(1)NSCLC patients were classified into the clinical stages Ⅲ and Ⅳ and the pathological types of squamous carcinoma and adenocarcinoma,had the high proportion of KPS scores lower than 70,and were scored with high TCM syndrome scores,suggesting that the illness condition of patients with NSCLC was serious.Compared with the healthy control group,plasminogen time(PT)and thrombin time(TT)in NSCLC patients were significantly shortened,and levels of fibrinogen(FIB)and D-dimer(D-D)were significantly increased,and the differences were statistically significant(P＜0.01).(2)After 6 weeks of treatment,the total effective rate and total stability rate of Bufei Huayu Decoction group were 32.50%(13/40)and 85.00%(34/40),which were significantly superior to those of the conventional treatment group[versus 13.16%(5/38)and 60.53%(23/38)],and the differences were statistically significant(P＜0.05).(3)After 3 weeks of treatment,obvious improvement was presented in the scores of all the TCM symptoms of fatigue,chest distress and shortness of breath,stabbing pain in the chest,and blood stasis in the vessels and collaterals of Bufei Huayu Decoction group and in the scores of the fatigue,chest distress and shortness of breath of the conventional treatment group when compared with those before treatment(P＜0.05).After 6 weeks of treatment,all of the TCM syndrome scores of the two groups were improved compared with those before treatment and after three weeks of treatment(P＜0.05).The intergroup comparison showed that except for the scores of chest distress and shortness of breath after 3 weeks of treatment,the effect on improving all of the TCM syndrome scores in Bufei Huayu Decoction group was significantly superior to that in the conventional treatment group after 3 and 6 weeks of treatment(P＜0.05 or P＜0.01).(4)After 6 weeks of treatment,the levels of coagulation function indicators of PT,TT,FIB and D-D in the Bufei Huayu Decoction group were significantly improved compared with those before treatment(P＜0.05),while only FIB and D-D in the conventional treatment group were improved compared with those before treatment(P＜0.05).The intergroup comparison showed that Bufei Huayu Decoction group had stronger effect on improving the levels of PT,FIB and D-D than the conventional treatment group(P＜0.05).(5)After 6 weeks of treatment,the serum NO and VEGF levels in both groups were significantly lower than those before treatment(P＜0.05),and the effect on lowering serum NO and VEGF levels of the Bufei Huayu Decoction group was significantly superior to that of the conventional treatment group(P＜0.01).(6)After 6 weeks of treatment,the immune function parameters of CD3+,CD4+ levels and CD4+/CD8+ ratio in the Bufei Huayu Decoction group were increased(P＜0.05)and CD8+level was decreased(P＜0.05)as compared with those before treatment,whereas CD3+,CD4+ levels and CD4+/CD8+ ratio in the conventional treatment group were decreased(P＜0.05)and CD8+ level was increased(P＜0.05).The intergroup comparison showed that the effect of Bufei Huayu Decoction group on the increase of CD3+,CD4+ levels and CD4+/CD8+ ratio and the effect on the decrease of CD8+ level were significantly superior to those of the conventional treatment group(P＜0.01).(7)In terms of the quality of life,the KPS scores of patients in the two groups after 6 weeks of treatment were significantly higher than those before treatment(P＜0.05),and the effect of Bufei Huayu Decoction group on the increase of KPS scores was significantly superior to that of the conventional treatment group(P＜0.01).(8)During the course of treatment,the incidence of adverse reactions such as gastrointestinal reactions and alopecia in the two groups was not statistically significant(P＞0.05),while the incidence of hepatic and renal impairment,bone marrow suppression,and toxicity of oral mucosa in Bufei Huayu Decoction group was significantly lower than that of the conventional treatment group(P＜0.05 or P＜0.01),suggesting that Bufei Huayu Decoction group reduced the adverse reactions induced by chemotherapy to a certain extent.Conclusion Patients with NSCLC of blood stasis and qi stagnation type generally have advanced disease progression and high blood coagulation,which is consistent with the stasis-toxin pathogenesis in TCM.The use of Bufei Huayu Decoction against the stasis-toxin pathogenesis can significantly improve patients'TCM syndrome scores and coagulation function,down-regulate the levels of serum NO and VEGF,and improve the immune function,which brings about the enhancement of clinical efficacy and quality of life,and the reduction of adverse reactions caused by chemotherapy,with a high safety.
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Objective To investigate the influence of modified Shashen Maidong Decoction combined with Camrelizumab immunotherapy plus chemotherapy on the efficacy,survival status and serum cytokeratin 19 fragment(CYFRA21-1)and neuron-specific enolase(NSE)levels in patients with advanced non-small cell lung cancer(NSCLC).Methods Forty patients with advanced NSCLC of lung-stomach yin deficiency with intense heat-toxin type were randomly divided into a control group and a study group,with 20 patients in each group.The patients in the control group were given Camrelizumab immunotherapy plus chemotherapy,and the patients in the study group were given modified Shashen Maidong Decoction combined with Camrelizumab immunotherapy plus chemotherapy,with 21 days as a course of treatment and for a total of 4 courses of treatment.The changes of serum NSE and CYFRA21-1 levels in the two groups before and after treatment were observed,and the clinical efficacy,survival status and the incidence of toxic and side effects were compared between the two groups.Results(1)After 4 courses of treatment,the total effective rate of the study group was 70.00%(14/20),which was significantly higher than that of the control group(9/20,45.00%),but the intergroup comparison(tested by chi-square test)showed that the difference was not statistically significant(P＞0.05).(2)After 2 years of follow-up,the overall survival(OS),time to progression(TTP),and progression-free survival(PFS)of the patients in the study group were significantly prolonged compared with those in the control group(P＜0.01).(3)After treatment,the serum NSE and CYFRA21-1 levels of the patients in the two groups were decreased compared with those before treatment(P＜0.05),and the decrease of serum NSE and CYFRA21-1 levels in the study group was significantly superior to that in the control group(P＜0.01).(4)The incidence of toxic and side effects in the study group was 25.00%(5/20),which was significantly lower than that of 65.00%(13/20)in the control group,and the intergroup comparison showed that the difference was statistically significant(P＜0.05).Conclusion Modified Shashen Maidong Decoction combined with Camrelizumab immunotherapy plus chemotherapy has satisfactory therapeutic effect on patients with advanced NSCLC,which can reduce the toxic and side effects of chemotherapy,lower the level of serum tumor markers,and prolong the survival period and time to progression(TTP)of the patients.
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Objective To exploring the correlation between the expression level of serum carbohydrate antigen 211(CA211)and the number of natural killer(NK)cells and prognosis in non-small cell lung cancer(NSCLC)pa-tients.Methods 132 NSCLC patients admitted to the Affiliated Hospital of Hangzhou Normal University from June 2019 to July 2022 were selected as the test group,and 132 patients with benign lung lesions during the same period were selected as the control group.Data were collected from the laboratory to analyze the relationship between serum CA211 expression and NK cell count in NSCLC with clinical prognosis,as well as the related factors affecting the prognosis of NSCLC patients.Results The neutrophil to lymphocyte ratio(NLR)and serum CA211 expression in the test group were higher than those in the control group(P＜0.05),while the count of NK cells was less than that in the control group(P＜0.05);The expression level of serum CA211 in the test group was negatively cor-related with the count of NK cells(r=-0.405,P＜0.001);There were significant differences in lymph node metastasis and TNM staging among patients with different levels of serum CA211 expression and NK cell count(P＜0.05);The one-year survival rate of patients with low expression of CA211 was significantly higher than that of patients with high expression of CA211(P＜0.05),and the one-year survival rate of patients with high count of NK cells was higher than that of patients with low count of NK cells(P＜0.05);Lymph node metasta-sis,TNM staging and CA211 level were all risk factors affecting the prognosis of NSCLC patients(P＜0.05),while counting of NK cells was protective factor for the prognosis of NSCLC patients(P＜0.05).Conclusions The level of serum CA211 and the number of NK cells in NSCLC patients are closely related to pathological characteristics and clinical prognosis.