摘要
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.
摘要
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC. .
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , ErbB Receptors/metabolism , Immunotherapy , Mutation , B7-H1 Antigen/genetics , Protein Kinase Inhibitors/pharmacology , Tumor Microenvironment摘要
OBJECTIVE@#To investigate the effect and possible mechanism of hydroxysafflor yellow A (HSYA) on human immortalized keratinocyte cell proliferation and migration.@*METHODS@#HaCaT cells were treated with HSYA. Cell proliferation was detected by the cell counting kit-8 assay, and cell migration was measured using wound healing assay and Transwell migration assay. The mRNA and protein expression levels of heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF), EGF receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF-1α) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. Circ_0084443-overexpressing HaCaT cells and empty plasmid HaCaT cells were constructed using the lentiviral stable transfection and treated with HSYA. The expression of circ_0084443 was detected by qRT-PCR.@*RESULTS@#HSYA (800 µmol/L) significantly promoted HaCaT cell proliferation and migration (P<0.05 or P<0.01). It also increased the mRNA and protein expression levels of HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α, and increased the phosphorylation levels of PI3K and AKT (P<0.05 or P<0.01). Furthermore, HSYA promoted HaCaT cell proliferation and migration via the HBEGF/EGFR and PI3K/AKT/mTOR signaling pathways (P<0.01). Circ_0084443 attenuated the mRNA expression levels of HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α (P<0.05). HSYA inhibited the circ_0084443 expression, further antagonized the inhibition of circ_0084443 on HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α, and promoted the proliferation of circ_0084443-overexpressing HaCaT cells (P<0.05 or P<0.01). However, HSYA could not influence the inhibitory effect of circ_0084443 on HaCaT cell migration (P>0.05).@*CONCLUSION@#HSYA played an accelerative role in HaCaT cell proliferation and migration, which may be attributable to activating HBEGF/EGFR and PI3K/AKT signaling pathways, and had a particular inhibitory effect on the keratinocyte negative regulator circ_0084443.
Subject(s)
Humans , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinase , Phosphatidylinositol 3-Kinases/metabolism , ErbB Receptors/genetics , TOR Serine-Threonine Kinases/metabolism , Cell Proliferation , RNA, Messenger/genetics , Cell Movement , Cell Line, Tumor , Chalcone/analogs & derivatives , Quinones摘要
Objective@#To explore the molecular mechanism of resveratrol (RES) in the treatment of oral squamous cell carcinoma (OSCC) through the use of biological information methods such as network pharmacology and molecular docking and to provide a theoretical reference for the clinical application of RES in the treatment of OSCC.@*Methods@#The Swiss Target Prediction(http://www.swisstargetprediction.ch), SEA (http://sea.bkslab.org)database, and Pharm mapper database(http://lilab-ecust.cn) were used to retrieve RES-related targets, and the DISGENET (www.disgenet.org), OMIM (https://omim.org) and GeneCards (https://www.genecards.org) databases were used to screen OSCC disease targets. The intersection of drugs and disease targets was determined, and Cytoscape 3.7.2 software was used to construct a "drug-diseasetarget pathway" network. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to construct a target protein interaction network, and the DAVID database was used for enrichment analysis of key proteins. Finally, molecular docking validation of key proteins was performed using AutoDock and PyMOL. The enrichment analysis and molecular docking results were integrated to predict the possible molecular mechanisms of RES treatment in OSCC; western blot was used to determine the effect of resveratrol at different concentrations (50, 100) μmol/L on the expression of Src tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), estrogen receptor gene 1 (ESR1), and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway proteins in OSCC HSC-3 cells.@*Results@#A total of 243 targets of RES drugs and 6 094 targets of OSCC were identified. A total of 116 potential common targets were obtained by intersecting drugs with disease targets. These potential targets mainly participate in biological processes such as in vivo protein self-phosphorylation, peptide tyrosine phosphorylation, transmembrane receptor protein tyrosine kinase signaling pathway, and positive regulation of RNA polymerase Ⅱ promoter transcription, and they interfere with the PI3K/AKT signaling pathway to exert anti-OSCC effects. The docking results of resveratrol with OSCC molecules indicated that key targets, such as EGFR, ESR1, and SRC, have good binding activity. The results of cell-based experiments showed that resveratrol inhibited the protein expression of SRC, EGFR, ESR1, p-PI3K, and p-AKT in HSC-3 cells in a dose-dependent manner.@*Conclusion@#RES can inhibit the expression of its targets EGFR, ESR1, SRC, p-PI3K, and p-AKT in OSCC cells.
摘要
Objective To explore and analyze the expression and prognostic value of serum vitamin D(VitD),fer-ritin(FRT)and heparin-binding epidermal growth factor(HB-EGF)in sepsis patients.Methods 86 sepsis patients who were admitted to the intensive care unit(ICU)of a hospital from January 2021 to January 2022 were selected as the case group,and 60 non-sepsis patients in the ICU were selected as the control group.According to the prognosis of sepsis patients one month later,patients were divided into survival group and death group.Patient's serum upon admission was taken,levels of serum VitD,FRT and HB-EGF were detected,the correlation with the prognosis of sepsis patients was analyzed,and the prognostic value was evaluated by area under curve(AUC)of receiver opera-ting characteristic curve.Results Levels of white blood cell count(WBC),C-reactive protein(CRP),procalcitonin(PCT),tumor necrosis factor-α(TNF-α),interleukin(IL)-6,IL-1β and FRT of case group were all higher than those of non-sepsis patients in the control group,while the VitD and HB-EGF levels were lower than those of non-sepsis patients in the control group,differences were all statistically significant(all P＜0.05).One month follow-up on the prognosis of sepsis patients showed that 55 patients survived and 31 died.Acute physiology and chronic health evaluationⅡ(APACHE IⅡ)score,sequential organ failure assessment(SOFA)score,PCT,TNF-α,L-1βand FRT score in patients in the death group were all higher than those in patients in the survival group,while VitD and HB-EGF were lower than patients in the survival group,differences were all statistically significant(all P＜0.05).The Pearson correlation analysis results showed that VitD were negatively correlated with APACHE Ⅱ score,SOFA score,WBC,CRP,PCT and TNF-α(all P＜0.05),HB-EGF was negatively correlected with APACHE Ⅱ,score,CRP,PCT,TNF-α,IL-6 and IL-1β(all P＜0.05);while FRT was positively correlated with APACHE Ⅱscores,CRP,PCT,TNF-α,IL-6 and IL-1β(all P＜0.05).The AUC,sensitivity,and specificity of combined de-tection of serum VitD,FRT and HB-EGF in predicting the prognosis of sepsis patients were 0.82(95％CI:0.72-0.86),84.39％,and 69.35％,respectively.Conclusion Serum levels of VitD and HB-EGF are lower and FRT is higher in sepsis patients,their expression levels are closely related to patient prognosis,and have good predictive value for predicting the prognosis of sepsis patients.
摘要
Objective:To investigate the clinical efficacy of recombinant human epidermal growth factor combined with sodium hyaluronate eye drops in the treatment of cataracts after multifocal intraocular lens implantation and its effect on inflammation factors in tears and tear film stability.Methods:A total of 86 patients with cataracts who underwent multifocal intraocular lens implantation at Jinan 2 nd People's Hospital from July 2020 to January 2023 were included in this randomized controlled study. These patients were randomly divided into a control group and a combined group, with 43 patients in each group. Patients in the control group were administered sodium hyaluronate eye drops postoperatively, while patients in the combined group received a combination of recombinant human epidermal growth factor and sodium hyaluronate eye drops. All patients were treated for 1 month. Before and after treatment, the levels of inflammatory factors in tears, tear film stability-related indicators, and corneal endothelial cells were measured and compared between the two groups. Additionally, any adverse reactions experienced by the patients were recorded throughout the treatment period. Results:After treatment, the levels of interleukin-6 and tumor necrosis factor-α in the tear fluid of the combined group were (17.91 ± 2.45) μg/L and (72.14 ± 8.43) μg/L, respectively. These values were significantly lower than those in the control group, which were (24.63 ± 3.05) μg/L and (86.97 ± 9.85) μg/L, respectively ( t = 11.26, 7.50, both P < 0.001). Additionally, the fluorescein staining score for corneal damage in the combined group was (2.34 ± 0.37) points. This was significantly lower than the score of (3.42 ± 0.48) points observed in the control group ( t = 11.69, P < 0.001). Tear break-up time and Schirmer I Test in the combined group were (8.68 ± 0.96) seconds and (9.31 ± 1.04) mm/5 minutes, respectively. These values were significantly higher than those in the control group, which were (7.81 ± 0.89) seconds and (7.14 ± 0.86) mm/5 minutes, respectively ( t = -4.36, -10.54, both P < 0.001). Furthermore, the corneal endothelial cell density and the proportion of hexagonal cells in the combined group were (2 514.09 ± 259.31) counts/mm 2 and (41.67 ± 5.05)%, respectively. These values were significantly higher than those in the control group, which were (2 244.82 ± 253.37) counts/mm 2 and (36.75 ± 4.96)% in the control group ( t = -4.87, -29.45, both P < 0.001). The incidence of adverse reactions in the combined group was 11.63% (5/43), which was significantly higher than 6.98% (3/43) in the control group ( χ2 = 0.55, P > 0.05). Conclusion:The combination of recombinant human epidermal growth factor with sodium hyaluronate eye drops following multifocal intraocular lens implantation in patients with cataracts effectively decreases the levels of inflammatory factors in tear fluid. This treatment regimen also enhances tear film stability, promotes the repair of injured corneal tissue, and is highly safe.
摘要
Objective To evaluate the clinical value of free glycoprotein non-metastatic melanoma protein B(GPNMB)as a drug resis-tance and prognostic marker for non-small cell lung cancer(NSCLC)patients with epidermal growth factor receptor(EGFR)amplifica-tion accompanied by mutations.Methods Fifty-five cases of NSCLC patients with EGFR amplification associated with mutations who received treatment from March 2018 to September 2019 were included as the observation group.All patients received an EGFR-tyrosine kinase inhibitor(EGFR-TKI)as the first-line treatment;67 blood samples from the physical examination center during the same period were randomly included as healthy control.We compared the expression levels of free GPNMB between the two groups,explored the correlation between GPNMB expression and the clinicopathological information in the observation group;and combined the clinical efficacy to evaluate its value as a drug resistance marker.Through follow-up,the progress free survival(PFS)of patients was statistically analyzed,and through multivariate Cox regression analysis,independent risk factors affecting the survival in the observation group were explored.Results Compared with that in the control group,the expression level of free GPNMB in the observation group was signi-ficantly up-regulated.The expression level of free GPNMB in the observation group is significantly related to the clinical efficacy of EGFR-TKI(P = 0.016).Patients with high GPNMB expression have significantly stronger drug resistance,and patients with high GPNMB expression have significantly shorter PFS duration(P = 0.032).A high free GPNMB expression(HR = 4.029,95%CI:1.942-8.358,P＜0.001)is also an independent risk factor affecting patient survival.Conclusion The expression level of free GPNMB in patients with EGFR amplification accompanied by mutant NSCLC is significantly up-regulated,and its high expression is significantly related to the enhancement of the patient's drug resistance.High GPNMB expression is significantly related to the poor prognosis of patients and is an independent risk factor affecting patient survival.
摘要
Objective:To analyze the correlation between the expressions of human epidermal growth factor receptor 2(HER2)and carbohydrate antigen 153(CA153)and the technical parameter of acoustic palpation tissue imaging quantification(VTIQ)in patients with breast cancer.Methods:A total of 80 female patients with breast cancer admitted to The Third People's Hospital of Hefei from May 2018 to May 2020 were selected,including 14 cases at WHO stage Ⅰ,22 cases at WHO stage Ⅱ,31 cases at WHO stage Ⅲ and 13 cases at WHO stage Ⅳ.Another 53 female patients with benign breast diseases who were treated during the same period were selected as controls.At first,all patients underwent routine ultrasound examination,and then they entered the ultrasound VTIQ imaging mode to obtain the mean value of shear wave velocity(SWV).An immunohistochemistry was used to detect HER2 expressions in breast tissues,and Roche E411 electrochemiluminescence immunoassay analyzer was used to detect serum CA153 levels of them.Pearson method was used to analyze the correlation between serum CA153 levels and SWV mean values in patients with breast cancer.Results:Compared with benign patients,the SWV mean value of VTIQ technical parameter,serum CA153 level and HRR2 positive expression rate in patients with breast cancer were significantly higher,and the difference was statistically significant(F=39.107,78.353,P<0.05),respectively.Compared with patients at stages Ⅰ + Ⅱ of breast cancer,the SWV mean value of VTIQ technical parameter,serum CA153 level and HRR2 positive expression rate of patients at stages Ⅲ and Ⅳ of breast cancer significantly increased(t=2.685,3.556,8.326,10.455,P<0.05),respectively.Compared with patients at stage Ⅲ of breast cancer,the SWV mean value of VTIQ technical parameters,serum CA153 level and HRR2 positive expression rate of patients at Ⅳ stage of breast cancer were significantly higher(t=4.632,8.659,P<0.05),respectively.Compared with the SWV mean value of patients with HER2 negative expression of breast cancer,that of patients with HER2 positive expression of breast cancer was significantly higher(x2=59.751,P<0.05).There was a positive correlation between serum CA153 levels and SWV mean values in patients with breast cancer(r=0.501,P<0.05).Conclusion:The SWV mean value of VTIQ parameters is closely related to the expression levels of biomarkers HER2 and CA153 in patients with breast cancer.
摘要
Objective:To investigate the value of radiomics nomogram based on standardized pre-treatment chest enhanced CT in predicting the mutation status of epidermal growth factor receptor (EGFR) for patients with lung adenocarcinoma.Methods:A retrospective analysis was conducted on pre-treatment chest enhanced CT images and clinical data of 262 patients from the affiliated hospital of Jining Medical University with pathologically proven primary lung adenocarcinoma who received EGFR gene testing, including EGFR wild type ( n=122) and mutant type ( n=140). The patients were divided into training group ( n=183) and testing group ( n=79) according to a ratio of 7∶3 by stratified sampling method. Standardized pre-processed the images, delineated the ROI and extracted the radiomics features. Least absolute shrinkage and selection operator (LASSO) algorithm was used to reduce the dimension and select key features. The standardized radiomics model, clinical model and the combined model were established by Logistic Regression (LR) machine learning method. Calculated the Rad-score and drew the nomogram. ROC curve and Delong were used to evaluate and compare the predictive performance of different models. Results:23 standardized enhanced CT radiomics features and 4 clinical features were selected. The predictive performance of standardized radiomics model was better than that of non-standardized radiomics model [area under curve (AUC): 0.863 vs. 0.805, t=2.19, P<0.05]. The AUCs of the combined model and standardized radiomics model were higher than that of the clinical model (training group: 0.885, 0.863 vs. 0.774, t=3.57, 2.17, P<0.05; testing group: 0.873, 0.829 vs. 0.763, t=2.19, 2.02, P<0.05). The radiomics nomogram was built based on Rad-score, age, sex, smoking history and BMI. Conclusions:The combined model and standardized radiomics model could effectively predict the mutation status of EGFR gene in lung adenocarcinoma patients before treatment, providing valuable clinical insights.
摘要
Objective:To explore the reasonable timing of radiotherapy for epidermal growth factor receptor ( EGFR) mutation-positive non-small cell lung cancer patients with brain metastasis in the era of third-generation targeted drugs. Methods:Clinical data of EGFR mutation-positive non-small cell lung cancer patients with brain metastasis who received first-line treatment with third-generation targeted drugs and stereotactic radiotherapy at Shanghai Armed Police Corps Hospital from September 2019 to May 2022 were retrospectively analyzed. According to the timing of radiotherapy before / after targeted drug resistance, all patients were divided into the early and salvage radiotherapy groups. The proportion of brain metastasis, physical fitness, complete response rate, objective response rate, delaying the progression of brain metastasis and overall survival (OS) were compared between two groups. Kaplan-Meier method was used for survival analysis, log-rank test was used for univariate prognostic analysis, and factors with P <0.1 were included in Cox multivariate analysis. Results:A total of 85 patients were included, including 51 (60%) cases receiving early radiotherapy. Patients who participated in early radiotherapy had a higher proportion of symptomatic brain metastasis (82% vs. 56%, P=0.013) and poorer physical fitness (Kanofsky performance score <70: 61% vs. 26%, P=0.002) compared to patients who underwent salvage radiotherapy. Early radiotherapy significantly improved the complete response rate of intracranial lesions (35% vs. 12%, P=0.015) and objective response rate (88% vs. 71%, P=0.041), delayed the progression of brain metastasis (median intracranial progression free survival: 23.0 months vs. 16.0 months, P=0.005; median intracranial secondary progression free survival: 31.0 months vs. 22.0 months, P=0.021), and improved OS (median OS: 44.0 months vs. 35.0 months, P=0.046). In multivariate analysis, diagnosis-specific graded prognostic assessment score <2.5, mutation of EGFR exon 21, and salvage brain radiotherapy were adverse prognostic factors for OS. Conclusion:In the era of third-generation targeted drugs therapy, early involvement of stereotactic radiotherapy in non-small cell lung cancer patients with brain metastasis can bring greater clinical benefits.
摘要
Objective:Exploration of epidermal growth factor receptor (EGFR) expression and its clinical significance in pancreatic adenosquamous carcinoma (PASC).Methods:A total of 60 pancreatic cancer tissue samples and 8 normal pancreatic tissue samples were obtained from patients who were surgically treated at Beijing Chao-Yang Hospital, Capital Medical University from January 2016 to December 2021. A retrospective analysis of the clinical and pathological data of these 60 patients was conducted, including 23 males and 37 females with an age of (62.7±10.2) years. Among them, 20 cases were pathologically diagnosed as PASC, and 40 contemporaneous cases of pancreatic ductal adenocarcinoma (PDAC) were selected through propensity score matching. Immunohistochemistry (IHC) staining was used to measure the integrated optical density (IOD) of EGFR expression, and quantitative polymerase chain reaction (qPCR) was employed to detect the expression differences of EGFR mRNA. Based on the median IOD value of EGFR, the 20 PASC samples were divided into two groups, high and low expression groups. Kaplan-Meier survival analysis was performed to compare the impact of EGFR expression on the prognosis of PASC patients.Results:The IOD value of EGFR in PASC group (29.2 [25.7, 35.1]) was significantly higher than that in the PDAC group [9.5 (5.5, 13.0)] and they both exceeded the value in normal tissues [2.4 (1.7, 3.1)], with statistical significances ( all P<0.001 ). The level of EGFR mRNA expression in the PASC group was higher than that in the PDAC group [3.0 (1.8, 3.5) vs 1.2 (0.8, 1.2)], showing statistically significant difference ( P=0.0079). Patients with high EGFR expression had shorter overall survival compared with patients with low expression ( P=0.002). The incidence of vascular invasion in the PASC group [40.0% (8/20)] was higher than that in the PDAC group [17.5% (7/40)], with a significant difference ( P=0.002). The median survival time for the PASC group was 16.00 (9.25, 25.25) months, which was shorter than that of the PDAC group 21.50 (11.25, 40.75) months, showing a statistically significant difference ( P=0.033). The overall survival rate of the PASC group was lower than PDAC group ( P=0.028). Conclusion:EGFR expression is significantly elevated in PASC tissues and PASC patients have poor prognosis.
摘要
Objective:To investigate the value of traditional metabolic parameters, CT features and intratumoral heterogeneity parameters measured by 18F-FDG PET/CT in predicting the mutation status of the epidermal growth factor receptor (EGFR) gene in patients with adenocarcinoma. Methods:A total of 147 patients (73 males, 74 females, age (59.8±10.2) years) with pathological confirmed adenocarcinoma between January 2016 and June 2020 in the Affiliated Hospital of Jining Medical University were retrospectively included. The differences of clinical data (smoking history, tumor location and clinical stage), CT features (maximum diameter, ground-glass opacity content, lobulation, speculation, cavitation, air-bronchogram, pleural retraction and bronchial cut-off sign), 18F-FDG PET/CT traditional metabolic parameters (SUV max, SUV mean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG)) and intratumoral heterogeneity parameters ( CV, heterogeneity index (HI)) were analyzed between patients with EGFR mutation and patients with EGFR wild-type. Independent-sample t test, Mann-Whitney U test and χ2 test were used to analyze the data. Multivariate logistic regression was used to analyze the predictors of EGFR mutation. ROC curve analysis was used to evaluate the predictive value of clinical and PET/CT information. Results:Among 147 patients, 87 were with EGFR mutation and 60 were with EGFR wild-type. There were significant differences in gender (male/female), smoking history (with/without), location (peripheral lesion/central lesion), pleural retraction (with/without), SUV max, SUV mean, TLG, CV and HI ( χ2 values: 4.72-23.89, z values: from -2.31 to 5.74, all P<0.05). Multivariate logistic regression analysis showed that smoking history (odds ratio ( OR)=0.167, 95% CI: 0.076-0.366; P<0.001), pleural retraction ( OR=1.404, 95% CI: 1.115-3.745; P=0.012), SUV max ( OR=0.922, 95% CI: 0.855-0.995; P=0.003), TLG ( OR=0.991, 95% CI: 0.986-0.996; P=0.001) and HI ( OR=0.796, 95% CI: 0.700-0.859; P<0.001) were predictors of EGFR mutation. ROC curve analysis showed the AUC of HI was 0.779, with the sensitivity of 76.67%(46/60) and the specificity of 79.31%(69/87). The predictive model was constructed by combining smoking history, pleural retraction, TLG, SUV max and HI, and the AUC was 0.908, with the sensitivity of 88.33%(53/60) and the specificity of 68.97%(60/87). The difference of AUCs between HI and the predictive model was statistically significant ( z=3.71, P<0.001). Conclusion:HI can predict EGFR mutations better, and the predictive value for EGFR mutations can be enhanced when combining HI with smoking history, pleural retraction, TLG and SUV max.
摘要
Objective:To investigate the therapeutic effect difference between first-line treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) and chemotherapy in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) rare mutation.Methods:A retrospective case-control study was performed. Data of NSCLC patients with rare EGFR mutation who were treated in Shanxi Province Cancer Hospital from January 2013 to October 2019 were retrospectively analyzed. EGFR mutations in living tissues or blood were detected by using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) before first-line treatment. According to first-line treatment methods,they were divided into EGFR-TKI treatment group and chemotherapy group. Objective remission rate (ORR) and disease control rate (DCR) of both groups were compared. Kaplan-Meier method was used to draw progression-free survival (PFS) and the overall survival (OS) curves. Log-rank test was used for comparison among groups. Single-factor and multi-factor Cox proportional risk models were used to analyze the influencing factors of PFS and OS.Results:A total of 169 patients with EGFR rare mutations were included, and the age [ M (IQR)] was 63 years (12 years); there were 96 cases (56.8%) < 65 years and 73 cases (43.2%) ≥65 years; 70 (41.4%)males and 99 (58.6%) females; 55 cases (32.5%) had EGFR G719X mutation,45 cases (26.6%) had L861Q mutation, 17 cases (10.1%) had S768I mutation, and 52 cases (30.8%) had complex mutation; 55 cases (32.5%) received the first-line chemotherapy and 114 cases (67.5%) received the first-line EGFR-TKI treatment. In the chemotherapy group, ORR was 36.4% (20/55) and DCR was 85.5% (47/55); in EGFR-TKI treatment group, ORR was 72.8% (83/114) and DCR was 90.4% (103/114). The ORR of EGFR-TKI treatment group was higher than that of chemotherapy group ( χ2 = 20.70, P = 0.001), and there was no statistically significant difference in DCR between two groups ( χ2 = 1.76, P = 0.184). Subgroup analysis showed that ORR in EGFR-TKI treatment group with G719X, L861Q and complex mutations was higher than that of the corresponding mutations in chemotherapy group, and the differences were statistically significant (all P < 0.05), while there were no significant differences in DCR among subgroups (all P > 0.05). The median PFS time was 9.7 months (95% CI: 6.0-13.4 months) and 3.8 months (95% CI: 3.1-7.1 months), respectively in EGFR-TKI treatment group and chemotherapy group, and there was a statistically significant difference in PFS between the two groups ( P < 0.001). The median OS time was 25.6 months (95% CI: 18.0-37.9 months) and 31.7 months (95% CI: 18.0-42.8 months), respectively in EGFR-TKI treatment group and chemotherapy group, and there was no statistically significant difference in OS between the two groups ( P = 0.231). Multivariate Cox regression analysis showed that brain metastasis [with vs. without: HR = 2.306, 95% CI: 1.452-3.661, P < 0.001] and the first-line treatment methods (EGFR-TKI vs. chemotherapy: HR = 0.457, 95% CI:0.317-0.658, P < 0.001) were independent influencing factors for PFS of NSCLC patients with EGFR rare mutation; brain metastasis (with vs. without: HR = 2.087, 95% CI: 1.102-3.953, P = 0.024; unknown vs. without: HR = 2.118,95% CI: 1.274-3.520, P = 0.004) were independent influencing factors for OS of NSCLC patients with EGFR rare mutation. Conclusions:Compared with the first-line chemotherapy, EGFR-TKI first-line treatment could improve objective remission and PFS of NSCLC patients with EGFR rare mutation, while no OS benefit is observed.
摘要
Objective:To investigate the effect of trastuzumab deruxtecan (T-DXd) in the treatment of metastatic breast cancer (MBC) patients with different expression levels of human epidermal growth factor receptor 2 (HER2) and the influencing factors of prognosis.Methods:The retrospective case series analysis and cohort study were conducted. Clinical data of 20 MBC patients with different expression levels of HER2 treated with T-DXd at Xi'an International Medical Center Hospital from August 2021 to August 2023 were retrospectively collected to analyze the efficacy and safety of T-DXd. The Cox proportional hazards model was used for multivariate analysis of prognostic factors.Results:All 20 patients were female, with a median age [ M ( Q1, Q3)] of 49 years old (40 years old, 58 years old). Of the 20 cases, 12 had low expression of HER2 [immunohistochemistry HER2+, or immunohistochemistry ++ and fluorescence in situ hybridization (FISH)-negative], and 8 had overexpression of HER2 (immunohistochemistry HER2+++, or immunohistochemistry ++ and FISH-positive); median number of lines of treatment with T-DXd was 6 lines (3 lines, 7 lines); 14 patients had partial remission, 3 patients had stable disease, and 3 patients had disease progression, with an objective remission rate (ORR) of 70% (14/20) and a disease control rate of 85% (17/20). Eight patients with overexpression of HER2 had objective remission in 6 cases, and 12 patients with low expression of HER2 had objective remission in 8 cases, and the ORR difference between the two groups was not statistically significant ( P = 1.000). The main adverse reactions of the patients were nausea (14 cases), vomiting (12 cases), leukopenia (10 cases), elevated aspartate aminotransferase (10 cases), elevated alanine aminotransferase (9 cases), anemia (8 cases), fatigue (8 cases), alopecia (8 cases), neutropenia (6 cases), and thrombocytopenia (5 cases); ≥ grade 3 adverse reactions were bone marrow suppression and gastrointestinal reactions, all with an incidence of ≤10%. The median follow-up time was 7.1 months (1.9 months, 11.5 months). The median progression-free survival (PFS) time was 6.5 months (95% CI: 3.9-9.1 months), and the median PFS time of patients with overexpression of HER2 was longer than that of patients with low expression of HER2 [7.0 months (95% CI: 6.4- 7.6 months) vs. 4.0 months (95% CI: 1.7-6.3 months)], and the difference in PFS between the two groups was statistically significant ( P = 0.025). Multivariate Cox regression analysis showed that overexpression of HER2 was an independent protective factor for PFS in MBC patients treated with T-DXd ( HR = 0.265, 95% CI: 0.075-0.945, P = 0.041). Conclusions:MBC patients with overexpression or low expression of HER2 have a good therapeutic effect and safety profile when treated with T-DXd. The overexpression of HER2 may predict good PFS in MBC patients treated with T-DXd, and may serve as a biomarker for predicting PFS in such patients, but it may not affect the ORR.
摘要
Pyrotinib is a new irreversible epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) dual tyrosine kinase inhibitor, and it has shown excellent clinical efficacy in treatment of HER2-positive breast cancer patients. The combination of pyrotinib and capecitabine in the treatment of advanced breast cancer has been recognized at home and abroad. Further exploration of whether there are other antitumor agents that work well in combination with pyrotinib, and whether pyrotinib can enhance clinical benefit in patients with early-stage or middle-stage breast cancer, could develop additional potential of pyrotinib. This article reviews the progress related to pyrotinib in recent years.
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Objective@#To summarize the clinicopathological characteristics and prognostic factors of salivary duct carcinoma (SDC) patients.@*Methods@#This study was reviewed and approved by the Ethics Committee, and informed consent was obtained from the patients. The clinical data of 30 SDC patients who were admitted to the Fourth Hospital of Hebei Medical University from 2014 to 2022, including case records, pathological diagnoses, immunohistochemical indicators, treatment methods, follow-up data, and other data, were retrospectively analyzed. SPSS 26.0 software was used to process the data and construct relevant curves. The chi-square test was used to analyze the correlation between different immunohistochemical indices and the recurrence and metastasis of SDC, and a single factor was used to analyze clinical prognostic factors.@*Results@#Among the 30 SDC patients, the male-to-female ratio was 5∶1, with a median age of 61.5 years. Approximately 60% of cases occurred in the parotid gland, whereas the remainder occurred in the submaxillary gland, sublingual gland, or minor salivary gland. Among them, 19 patients were androgen receptor-positive, 23 patients were human epidermal growth factor receptor-2 positive, and 26 patients were Ki-67 positive. Postoperative follow-up was 18-94 months, with a median follow-up of 37 months. There were 13 cases of recurrence and 14 cases of distant metastasis. The 5-year overall survival rate was only 31.2%. The long-term survival of patients who underwent postoperative radiotherapy and chemoradiotherapy was better than that of patients who underwent surgery alone (P= 0.027). T stage and lymph node invasion were associated with prognosis and survival (P<0.05). There was a correlation between a Ki-67-positive cell count ≥ 40% and postoperative recurrence or metastasis (P = 0.025).@*Conclusion@#Radical surgery combined with postoperative radiotherapy and chemoradiotherapy is helpful for improving long-term overall survival, and tumor T stage and lymph node metastasis may be the main factors affecting the prognosis of patients with SDC. Patients with Ki-67-positive cell counts ≥ 40% are prone to postoperative recurrence or metastasis.
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OBJECTIVE To evaluate the cost-effectiveness of trastuzumab biosimilars （Hanquyou） versus original drug （Hesaiting） in the treatment of recurrent/metastatic human epidermal growth factor receptor-2 （HER-2） positive breast cancer. METHODS A partitional survival model was constructed based on the NCT03084237 trial data. The simulation period was 3 weeks， and the simulation time was 10 years. Using costs and quality-adjusted life year （QALY） as the output indicator， the cost- utility analysis method was used to evaluate the cost-effectiveness of the two schemes mentioned above. Univariate and probabilistic sensitivity analyses were performed to verify the robustness of the basic analysis. RESULTS The costs of the trastuzumab biosimilars group and original drug group were 111 516.72 yuan and 111 122.30 yuan respectively， with health utility values of 1.52 QALYs and 1.36 QALYs， and ICER of 2 465.12 yuan/QALY， which were less than 3 times China’s per capita gross domestic product （GDP） in 2023 as the threshold for willingness-to-pay （WTP） （268 200 yuan/QALY）. Univariate sensitivity analysis showed that the cost of the trastuzumab biosimilars and original drug had a great impact on the ICER. The probabilistic sensitivity analysis showed that the probability of trastuzumab biosimilars being cost-effective was 100% at WTP threshold of 14 902 yuan/QALY. CONCLUSIONS When WTP threshold is 3 times China’s GDP in 2023 （268 200 yuan/QALY）， compared with original drug， trastuzumab biosimilars have good cost-effectiveness in the treatment of recurrent/metastatic HER-2 positive breast cancer.
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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 find the correlation between phosphatidylinositol kinase-3 catalytic subunit A gene(PIK3CA)mutation and pathological features as well as clinical prognosis of breast cancer.Methods The patho-logical data of 181 patients diagnosed with invasive breast cancer from January 2018 to January 2020 were collected.The estrogen receptor(ER),progestogen receptor(PR),human epidermal growth factor receptor-2(HER2),Ki67 were examined by immuno-histochemistry(IHC).Mutation of exon 9 and exon 20 of PIK3CA were examined by quantitative real-time PCR(qPCR).Results Among 181 cases of invasive breast cancer,70 cases had PIK3CA mutation with 31 cases(44.28%)showed exon 9 mutations and 39 cases(55.71%)showed exon 20 mutations.The difference between PIK3CA mutation and their distribution in molecular typing of breast cancer was statistically significant(P＜0.05).The expression of PIK3CA mutation in breast cancer with different Ki67 expression was sig-nificantly different(P＜0.05).There were 34 cases(48.57%)showed PIK3CA mutations in the HR+/HER2 group and 36 cases(51.43%)of non HR+/HER2 group mutations.There was a statistically significant difference in the distribution of PIK3CA mutations between 2 groups(P＜0.05).The death rate of PIK3CA mutation cases was higher than that of PIK3CA wild type cases(P＜0.05).Conclusions PIK3CA mutation is associated with molecular typ-ing,Ki67 increment index and prognosis of breast cancer.Detection of PIK3CA mutation provides potential support to the development of precise treatment of breast cancer patients.
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Objective To evaluate the regulatory effect of the adaptor related protein complex 2 subunit μ1(AP2M1)on proliferation and invasion of diffuse large B-cell lymphoma(DLBCL).Methods Human diffuse large B-cell lymphoma cell line OCI-LY8 was aliquoted into control group,NC-shRNA group,AP2M1-shRNA group,NC-LV group,and AP2M1-LV group.Lipofectamine 2000 was used for cell transfection.Cell proliferation was detected by tetramethylazolium salt(MTT)method,apoptosis was detected by flow cytometry and cell migration and invasion were detected by Transwell assay.The protein expression of AP2M1,epidermal growth factor receptor(EGFR),p-phosphatidylinositol 3 kinase(PI3K),PI3K,p-protein kinase B(Akt)and AKT was detec-ted by Western blot.Results Compared with control group,the relative expression of AP2M1 mRNA and protein in the AP2M1-shRNA group was decreased(P＜0.05).The relative cell viability was increased(P＜0.05).The cell apoptosis rate was decreased(P＜0.05).The counting number of migrating and invading cells was in-creased(P＜0.05).The relative expression level of EGFR protein and the phosphorylation level of PI3K and AKT were increased(P＜0.05).Compared with Control group,the expression of AP2M1 mRNA and protein relative ex-pression level in AP2M1-LV group was increased(P＜0.05).The relative cell viability was decreased(P＜0.05).The cell apoptosis rate was increased(P＜0.05).The number of migrating and invading cells was decreased(P＜0.05).The relative expression level of EGFR protein and the phosphorylation level of PI3K and AKT were all decreased(P＜0.05).Conclusions The over-expression of AP2M1 partially inhibits the proliferation and invasion of DLBCL cells by inhibiting the EGFR/PI3K/AKT signaling pathway.