Hydroxysafflor Yellow A Promotes HaCaT Cell Proliferation and Migration by Regulating HBEGF/EGFR and PI3K/AKT Pathways and Circ_0084443 / 中国结合医学杂志

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.

Progress of Immunotherapy in EGFR-mutated Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

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.
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Network pharmacology and molecular docking reveal the mechanism of resveratrol in oral squamous cell carcinoma treatment / 口腔疾病防治

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.

Clinical application and progression of monoclonal antibodies targeting HER2 extracellular domain Ⅳ in breast cancer / 中国药房

Human epidermal growth factor receptor 2 （HER2）-positive breast cancer is aggressive and prone to metastasis，and the applications of HER2 agents have improved the prognosis of patients with HER2-positive breast cancer. Among the marketed HER2 agents，macromolecular monoclonal antibodies that target the extracellular domain Ⅳ of HER2 were the cornerstone drugs of HER2-positive breast cancer，including trastuzumab，inetetamab，and margetuximab. Trastuzumab is available for the full-line treatment of breast cancer with sufficient proof of evidence-based medicine，sufficient practical experience and controllable safety. Inetetamab and trastuzumab have similar efficacy and controllable safety in HER2-positive metastatic breast cancer and neoadjuvant/ adjuvant therapy. Margetuximab focuses on patients carrying the CD16A-158F allele，and is an option of posterior line treatment for advanced breast cancer. It is necessary to select the most suitable drugs clinically according to the specific condition of the patient.

Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2/neu in gallbladder carcinoma in North Indian population

Background: Gallbladder carcinoma (GBC) although rare is most frequent malignant neoplasm of biliary tract system and sixth most common malignancy of digestive tract. GBC is more common in females and there are studies which show expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 neu (HER2/neu) in GBC suggesting possible molecules for targeted therapy, but results are inconsistent. Aims and Objectives: The aim of this study was to find out expression of ER, PR, and HER2/neu in GBC in North Indian population and their possible association with clinicopathological features. Materials and Methods: A total 59 resected cases of GBC diagnosed by histopathological examination were included in the study. Expression of ER, PR, and HER2/neu was accessed by immunohistochemistry method and correlated with various clinicopathological features. Results: ER expression was absent in all GBC cases. PR expression was present in only one case. Positive expression of HER2/neu was present in 13 (22%) cases, in which 12 cases were of conventional adenocarcinoma and one case was of papillary adenocarcinoma. Well and moderately differentiated tumor had significantly higher HER2/neu expression as compared to poorly differentiated tumors (P = 0.001). Pre-obese patients had significantly higher HER2/neu expression as compared to non-obese patients (P = 0.008). Conclusion: In our study, there was no expression of estrogen and PR in GBC in North Indian population. Although small in number, there is a subset of patients who overexpress HER2/neu receptor that may benefit from targeted therapy.

Research Progress on the Combination Therapy of EGFR-TKIs and Metformin in Acquired Resistance to EGFR-TKIs in Non-small Cell Lung Cancer / 中国肺癌杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR are effective in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients, but drug resistance is inevitable. With the application and expansion of individualized and combined therapy, more and more studies have shown that combined administration of Metformin effectively solves the problem of acquired drug resistance to EGFR-TKIs in clinical treatment and prolongs the survival of patients with NSCLC. EGFR-TKIs combined with Metformin is expected to be the treatment method of choice for NSCLC patients with EGFR-TKIs resistance. This paper intends to summarize the research progress of EGFR-TKIs combined with Metformin in the treatment of EGFR-TKIs acquired resistance in NSCLC, in order to provide a new idea for the treatment of NSCLC patients with acquired resistance to EGFR-TKIs.
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A Rare Case of Lung Adenocarcinoma with EGFR L833V/H835L Co-mutation and Literature Review / 中国肺癌杂志

Epidermal growth factor receptor (EGFR) mutations are the most common driver genes in the development of non-small cell lung cancer (NSCLC), of which mutations in exons 18-21 are frequent, especially the loss of exon 19 and exon 21 L858R mutation are the most frequent. Other rare gene mutations are rare. Simultaneous occurrence of two or more rare EGFR mutations are extremely rare in lung cancer, and the incidence of EGFR L833V/H835L rare gene compound mutations is very low, and there is little clinical data and evidence of relevant treatment methods. Some EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are effective in treating lung cancer patients with rare gene mutations. In this article, we reported a case of NSCLC patient with a rare gene compound mutation EGFR L833V/H835L, who responded to Afatinib in combination with Anilotinib treatment well after 5 months of treatment, and computed tomography (CT) showed shrinkage of lung lesions. Meanwhile, we also compiled previously reported NSCLC patients with EGFR L833V/H835L rare gene compound mutation and summarized the characteristics of this group of patients and the effect of applying different kinds of EGFR-TKIs treatment.
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Pathological features and immune microenvironment in HER-2 intratumoral heterogeneous breast cancers / 中华肿瘤杂志

Objective: To observe the clinical pathology features, and immune microenvironment of HER-2 intratumoral heterogeneity breast cancer. Methods: Thirty cases of HER-2 intratumoral heterogeneous breast cancer were retrospectively analyzed in Tianjin Medical University Cancer Institute and Hospital from November 2017 to June 2020. HER-2 expression was detected by immunohistochemistry and verified by dual color silver-enhanced in-situ hybridization (D-SISH). HER-2 intratumoral positive and negative regions were divided. The pathological characteristics, subtype, and the level of tumor infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) were evaluated respectively. Results: The proportion of HER-2 positive cells of the breast cancer ranged from 10% to 90%. The pathological type was mainly invasive non-special typecarcinoma. Six cases presented different pathological types between HER-2 positive and negative regions. The HER-2-positive areas included 2 cases of carcinoma with apocrine differentiation, and the negative areas included 2 cases of invasive micropapillary carcinoma, 1 case of invasive papillary carcinoma, and 1 case of carcinoma with apocrine differentiation. In HER-2 positive regions, 17 cases were Luminal B and 13 cases were HER-2 overexpressed types. There were 22 cases of Luminal B and 8 cases of triple negative tumors in the HER-2 negative areas. The levels of TILs in HER-2 positive and negative areas accounted for 53.3% (16/30) and 26.7% (8/30), respectively, with a statistically significant difference (P=0.035). The positive expression of PD-L1 in HER-2 positive area and HER-2 negative area were 6 cases and 9 cases, respectively. Among 8 cases with HER-2 negative regions containing triple negative components, 4 cases were positive for PD-L1 expression. Conclusions: In the case of HER-2 intratumoral heterogeneity, it is necessary to pay attention to both HER-2 positive and negative regions, and evaluate subtype separately as far as possible. For HER-2 intratumoral heterogeneous breast cancer containing triple negative components, the treatment mode can be optimized by refining the intratumoral expression of PD-L1.

Effects of adjuvant trastuzumab on long-term survival of T1N0M0 stage human epidermal growth factor receptor 2 positive breast cancer: a real-world study / 中华肿瘤杂志

Objective: To investigate the prognosis impact of adjuvant trastuzumab treatment on human epidermal growth factor receptor 2 (HER-2) positive early breast cancer patients. Methods: A retrospective study was conducted, HER-2-positive T1N0M0 stage breast cancer patients who underwent surgery in the Affiliated Tumor Hospital of Xinjiang Medical University from January 2010 to December 2019 were divided into treatment group and control group according to whether they were treated with trastuzumab or not. Propensity score matching (PSM) was used to balance the confounding bias caused by differences in baseline characteristics between the two groups. Cox proportional hazards model was used to analyze the risk factors affecting disease-free survival (DFS). The Kaplan-Meier method was used to estimate the 3- and 5-year DFS and overall survival (OS) rates of the two groups before and after PSM. Results: There were 291 patients with HER-2 positive T1N0M0 stage breast cancer, including 21 cases in T1a (7.2%), 61 cases in T1b (21.0%), and 209 cases in T1c (71.8%). Before PSM, there were 132 cases in the treatment group and 159 cases in the control group, the 5-year DFS rate was 88.5%, and the 5-year OS rate was 91.5%. After PSM, there were 103 cases in the treatment group and 103 cases in the control group, the 5-year DFS rate was 86.0%, and the 5-year OS rate was 88.5%. Before PSM, there were significant differences in tumor size, histological grade, vascular invasion, Ki-67 index, postoperative chemotherapy or not and radiotherapy between the treatment group and the control group (P<0.05). After PSM, there were no significant difference in clinicopathological features between the treatment group and the control group (P>0.05). Multivariate analysis showed that histological grade (HR=2.927, 95 CI: 1.476, 5.805; P=0.002), vascular invasion (HR=3.410, 95 CI: 1.170, 9.940; P=0.025), menstrual status (HR=3.692, 95 CI: 1.021, 13.344, P=0.046), and chemotherapy (HR=0.238, 95 CI: 0.079, 0.720; P=0.011) were independent factors affecting DFS. After PSM, the 5-year DFS rate of the treatment group was 89.2%, while that of the control group was 83.5%(P=0.237). The 5-year OS rate of the treatment group was 96.1%, while that of the control group was 84.7%(P=0.036). Conclusion: Postoperative targeted therapy with trastuzumab can reduce the risk of recurrence and metastasis in patients with HER-2-positive T1N0M0 stage breast cancer.

Expert consensus on icotinib as adjuvant therapy for non-small cell lung cancer / 中华肿瘤杂志

Clinical studies have established the clinical application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant targeted therapy. Compared with chemotherapy, the high efficiency and low toxicity of targeted therapy increases the survival benefit of patients. Icotinib was the first EGFR-TKI with independent intellectual property rights in China and the third EGFR-TKI to be marketed in the world. In order to summarize the experience of icotinib and other EGFR-TKIs in the adjuvant treatment of non-small cell lung cancer and further standardize and guide the clinical application of icotinib, experts from the China International Exchange and Promotive Association for Medical and Health Care and the Guangdong Association of Thoracic Diseases have organized an expert consensus on the adjuvant treatment of non-small cell lung cancer with icotinib, which is expected to provide clinicians with evidence-based medical evidences for postoperative targeted drug using.

Characteristics and Research Progress of Traditional Chinese Medicine in Treatment of HER-2-Positive Breast Cancer： A Review / 中国实验方剂学杂志

Human epidermal growth factor receptor-2 （HER-2）-positive breast cancer has higher predilection to metastasize and invade other organs， leading to poor prognosis. The anti-HER-2 drugs， such as trastuzumab， pertuzumab， and trastuzumab emtansinehas， can remarkably prolong the disease free survival （DFS） of patients. However， frequent multidrug resistance， tumor recurrence and metastasis， and adverse reactions such as cardiotoxicity and gastrointestinal discomfort caused by adjuvant therapy are still challenges for the treatment of HER-2-positive breast cancer. The understanding of breast cancer in traditional Chinese medicine （TCM） has a long history. In thousands of years of inheritance and innovation， a standardized treatment system with TCM characteristics has been gradually formed， which shows unique advantages and significant curative effects in breast cancer treatment. The treatment principles of ''treatment based on syndrome differentiation''， ''treatment based on stages and types''， ''treatment according to individual conditions''， and ''treatment of different viscera and viscera based on the toxin and pathogen'' are closely related to the precise treatment concept. In view of the challenges in the treatment of HER-2-positive breast cancer， such as multidrug resistance， tumor recurrence and metastasis， cardiotoxicity， and gastrointestinal discomfort， this paper summarizes the characteristics of TCM in reversing the multidrug resistance， inhibiting tumor recurrence and metastasis， prolonging DFS， improving prognosis， reducing adverse reactions caused by adjuvant therapy， and improving the quality of life after breast cancer surgery according to the principles of reinforcing healthy Qi and eliminating pathogen， and treatment based on syndrome differentiation. This article is expected to serve as a reference for TCM treatment of HER-2 positive breast cancer.

Anti-tumor Activity of Chinese Medicine Based on EGFR Signaling Pathway： A Review / 中国实验方剂学杂志

In China， malignant tumors have become the main cause of death. In the past half century， the incidence and mortality of malignant tumors have been on the rise， posing a threat to health of patients， and the burden of cancer has been increasing. At the moment， malignant tumors are mainly treated by surgery， radiotherapy， and cytotoxic drugs， which， however， have limitations and induce great adverse reactions. As biological technology and the research on tumor microenvironment， immunology， cell biology， and molecular biology advance， high-efficiency low-toxicity targeted therapy has attracted wide attention in the treatment of tumors. Epidermal growth factor receptor （EGFR） plays an important role in many cellular processes such as cell proliferation， survival， differentiation， migration， inflammation， and stromal homeostasis. EGFR promotes tumor growth， proliferation， and metastasis in a variety of ways. Chinese medicine has unique efficacy in the comprehensive treatment of malignant tumors. Through multiple components， multiple targets， and multiple pathways， it enhances the efficacy， reduces toxicity， prolongs life， and improves life quality in the treatment of tumors. Many Chinese medicines and their active components exert anti-tumor effect by inhibiting the EGFR signal transduction pathway. Through targeted inhibition of EGFR， Chinese medicine can promote the apoptosis and autophagy of tumor cells， suppress the proliferation and metastasis of tumor cells， and delay the progression of tumors. Thus， EGFR is a potential target for suppressing tumor. This paper summarizes the relationship between EGFR signal transduction pathway and tumor occurrence and development and analyzes the anti-tumor action mode and possible mechanisms of Chinese medicine and the active components by regulating EGFR signaling pathway， which is expected to provide a reference for clinical practice.

Pathological Types,Expression of Mismatch Repair Protein,Human Epidermal Growth Factor Receptor 2,and Pan-TRK,and Eostein-Barr Virus Infection in Patients With Colorectal Cancer Resected in Tibet / 中国医学科学院学报

Objective To study the pathological types,expression of mismatch repair protein,human epidermal growth factor receptor 2(HER2),and Pan-TRK,and Epstein-Barr virus(EBV)infection in patients with colorectal cancer resected in Tibet. Methods A total of 79 patients with colorectal cancer resected in Tibet Autonomous Region People's Hospital from December 2013 to July 2021 were enrolled in this study.The clinical and pathological data of the patients were collected.The expression of mismatch repair protein,HER2,and Pan-TRK was detected by immunohistochemical(IHC)staining,and detection of HER2 gene by fluorescence in situ hybridization(FISH)in the patients with HER2 IHC results of 2+ or above.EBV was detected by in situ hybridization with EBV-encoded small RNA. Results A total of 79 colorectal cancer patients were included in this study,with the male-to-female ratio of 1.26:1 and the mean age of(57.06±12.74)years(24-83 years).Among them,4 patients received preoperative neoadjuvant therapy.Colonic cancer and rectal cancer occurred in 57(57/79,72.15%,including 31 and 26 in the right colon and left colon,respectively)and 22(22/79,27.85%)patients,respectively.The maximum diameter of tumor varied within the range of 1-20 cm,with the mean of(6.61±3.33)cm.Among the 79 colorectal cancer patients,75(75/79,94.94%)patients showed adenocarcinoma.Lymph node metastasis occurred in 12(12/21,57.14%)out of the 21 patients with severe tumor budding,13(13/23,56.52%)out of the 23 patients with moderate tumor budding,and 2(2/31,6.45%)out of the 31 patients with mild tumor budding,respectively.The lymph node metastasis rate showed differences between the patients with severe/moderate tumor budding and the patients with mild tumor budding(all P<0.001).The IHC staining showed that mismatch repair protein was negative in 10(10/65,15.38%)patients,including 5 patients with both MSH2 and MSH6 negative,4 patients with both MLH1 and PMS2 negative,and 1 patient with MSH6 negative.Pan-TRK was negative in 65 patients.The IHC results of HER2 showed 0 or 1+ in 60 patients and 2+ in 5 patients.FISH showed no positive signal in the 5 patients with HER2 IHC results of 2+.The detection with EBV-encoded small RNA showed positive result in 1(1/65,1.54%)patient. Conclusions Non-specific adenocarcinoma of the right colon is the most common in the patients with colorectal cancer resected in Tibet,and 15% of the patients showed mismatch repair protein defects.EBV-associated colorectal carcer is rare,Pan-TRK expression and HER2 gene amplification are seldom.The colorectal cancer patients with moderate and severe tumor budding are more likely to have lymph node metastasis.

Relationship Between p53， EGFR and Radiotherapy Resistance of Head and Neck Squamous Cell Carcinoma / 中山大学学报(医学科学版)

Head and neck cancers are the seventh most common type of cancer in the world， among which more than 90% are squamous cell carcinomas（HNSCC）. Radiotherapy is one of the important treatments for HNSCC， and the sensitivity of tumor cells to the therapy is a key factor influencing the efficacy of treatment. p53 is one of the most common mutated genes in HNSCC， and epidermal growth factor receptor（EGFR） is overexpressed in many HNSCC. Both of these genes could enhance cellular DNA repair， which may be related to the radiotherapy resistance of HNSCC. This review focuses on the mechanisms by which tumor cells escape radiation-mediated apoptosis through p53 and EGFR-mediated DNA repair.

Research progress of furmonertinib for EGFR-mutated non-small cell lung cancer / 中国药房

Lung cancer is mainly non-small cell lung cancer （NSCLC）. NSCLC is often associated with epidermal growth factor receptor （EGFR） gene mutations. Currently， epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKI） are the preferred first-line treatment option for EGFR-mutated NSCLC. Furmonertinib is the second third-generation EGFR-TKI marketed in China， which is developed independently by China. In this review， it is found that furmonertinib has dual activity， strong tumor suppression， high selectivity， and high safety profile， and is effective in the treatment of EGFR-sensitive mutation， EGFR exon 20 T790M resistance mutation， EGFR exon 20 insertion mutation， and central nervous system metastasis NSCLC， and its relevant clinical trials are only enrolled in Chinese patients， which is more guidance for Chinese NSCLC patients in China.

Progress in epidermal growth factor receptor-tyrosine kinase inhibitors-associated interstitial lung disease / 中国胸心血管外科临床杂志

@#The tyrosine kinase activity of epidermal growth factor receptor (EGFR) plays a key role in tumor cell proliferation, invasion, migration, and drug resistance. Studies have shown that non-small cell lung cancer patients with somatic driver gene EGFR mutations are sensitive to and can benefit from EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Nevertheless, EGFR-TKIs-related adverse events should not be ignored. Common adverse events such as diarrhea, acne-like rash and paronychia are usually manageable; although the incidence of interstitial lung disease is low, once it occurs, it is a serious threat to patients' life, and its pathogenesis is still unclear. There is very limited animal experimental and clinical research evidence on the potential mechanism of EGFR-TKIs-related interstitial lung disease in the available literature. Based on this, this article reviews the association between EGFR-TKIs and interstitial lung disease, at the same time, also discusses the research progress of EGFR-TKIs-related interstitial lung disease in combination with cytotoxic drugs or immunotherapeutic drugs and EGFR-TKIs, in order to provide a reference for the prevention and treatment of EGFR-TKIs-related interstitial lung disease in clinical practice in the future.

Clinical observation of bevacizumab versus anlotinib respectively combined with chemotherapy drug in the treatment of EGFR-TKI acquired resistant advanced lung adenocarcinoma / 中国药房

OBJECTIVE To compare the short-term therapeutic effect and safety of bevacizumab versus anlotinib respectively combined with chemotherapy drug in the treatment of epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKI） acquired resistant advanced lung adenocarcinoma. METHODS The information of 84 patients with EGFR-TKI acquired resistant advanced lung adenocarcinoma in the Third People’s Hospital of Chengdu was analyzed retrospectively during Jun. 2019-Oct. 2021. The patients were divided into chemotherapy group （32 cases）， anlotinib combined chemotherapy group （24 cases） and bevacizumab combined chemotherapy group （28 cases）. Patients in the chemotherapy group were given Pemetrexed disodium for injection and Carboplatin injection， and symptomatic treatment was given for adverse reactions. On the first day of chemotherapy， patients in the anlotinib combined chemotherapy group received Anlotinib hydrochloride capsules 10 mg orally， once a day， for 14 consecutive days and 7 days of discontinuation， based on the treatment of the chemotherapy group. Patients in the bevacizumab combined chemotherapy group were given Bevacizumab injection of 15 mg/kg intravenously 1 day before chemotherapy， based on the treatment of the chemotherapy group. Three groups of patients were treated for a total of four cycles， with one cycle every three weeks. The overall response rate （ORR）， disease control rate （DCR）， median progression-free survival （mPFS）， and the changes of serum tumor markers were compared among three groups before and after treatment； meanwhile， the occurrence of adverse drug reactions was recorded， and the 1-year survival rate was followed up. RESULTS After 4 treatment cycles， ORR and DCR of bevacizumab combined chemotherapy group and anlotinib combined chemotherapy group were higher than chemotherapy group （P＜0.05）； mPFS of the two groups were significantly longer than chemotherapy group， and DCR of anlotinib combined chemotherapy group was significantly higher than bevacizumab combined chemotherapy group （P＜0.05）. After 4 treatment cycles， the serum levels of tumor markers in three groups were significantly lower than before treatment， and both combined chemotherapy groups were significantly lower than chemotherapy group （P＜0.05）. There was no statistically significant difference in the incidence of adverse reactions such as nausea， vomiting， bone marrow suppression， and 1-year survival rate among the three groups of patients （P＞0.05）. CONCLUSIONS Bevacizumab and anlotinib combined with chemotherapy drug are effective and safe in the treatment of advanced lung adenocarcinoma with acquired EGFR-TKI resistance.

Mechanism of Stemona tuberosa Alkaloids in Inhibiting Proliferation and Inducing Apoptosis of Non-small Cell Lung Cancer NCI-H460 Cells / 中国实验方剂学杂志

ObjectiveTo study the effect and underlying mechanism of Stemona tuberosa alkaloids on the proliferation and apoptosis of human non-small cell lung cancer NCI-H460 cells. MethodNon-small cell lung cancer NCI-H460 cells were divided into a blank group and S. tuberosa alkaloids groups （50， 100， 150， 200， and 250 mg·L-1）. The effect of S. tuberosa alkaloids on the proliferation of human NCI-H460 cells was observed by thiazolyl blue tetrazolium bromide （MTT） assay and colony formation assay. Cell apoptosis was observed by Hoechst 33258 staining and flow cytometry. Real-time fluorescence-based polymerase chain reaction （Real-time PCR） was used to detect the effect of S. tuberosa alkaloids on the mRNA expression of cysteinyl aspartate-specific protease 3 （Caspase-3）， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and epidermal growth factor receptor （EGFR）. The protein expression levels of Caspase-3， Bax， Bcl-2， protein kinase B （Akt）， phosphorylated （p-）Akt， EGFR， c-Jun N-terminal kinase （JNK）， p-JNK， p38 mitogen-activated protein kinase （p38 MAPK）， and p-p38 MAPK were measured by Western blot. ResultCompared with the blank group， the S. tuberosa alkaloids groups showed increased inhibition rate on cell proliferation （P<0.01）， reduced number of cell clones formed and the rate of cell clonal formation （P<0.05， P<0.01）， and increased karyopyknosis， cytoplasmic aggregation， and cell apoptosis rate （P<0.01）. The S. tuberosa alkaloids groups at 100， 150， 200， and 250 mg·L-1 showed increased Caspase-3 mRNA expression （P<0.05）， decreased EGFR mRNA expression （P<0.05， P<0.01）， up-regulated protein expression of Caspase-3 and p-JNK （P<0.01）， and down-regulated protein expression of EGFR and p-Akt （P<0.05， P<0.01）. Additionally， compared with the blank group， the S. tuberosa alkaloids groups showed increased expression of Bax mRNA （P<0.01）， decreased expression of Bcl-2 mRNA （P<0.01）， up-regulated protein expression of Bax and p-p38 MAPK （P<0.01）， and down-regulated protein expression of Bcl-2 （P<0.01）. ConclusionsS. tuberosa alkaloids can inhibit proliferation and induce apoptosis of human non-small cell lung cancer NCI-H460 cells， and the mechanism may be related to the inhibition of EGFR protein expression and phosphorylation of Akt protein， as well as the activation of the JNK/p38 MAPK signaling pathway.

Intermittent EGFR-TKI Therapy is Associated with Durable Response in Advanced EGFR-Mutant NSCLC: A Case Report

@#Madam S, who diagnosed to have stage IV lung adenocarcinoma with exon 21 L858R point mutation (T3N2M1a) was admitted for massive pericardial effusion in April 2016. She was ECOG 4 on admission. Her ECOG improved to 1 after pericardial tapping and initiation of free sample erlotinib 100 mg daily. Repeated CT thorax post treatment showed the disease was partial responded. Due to financial constraints, she had never bought any EGFR-TKI. She was given a free sample of erlotinib intermittently for total of 12 months followed by intermittent afatinib supply for 2 years. Due to this limited supply, she took half doses of afatinib by cutting a 40 mg tablet once every few days to sustain the continuation of cancer treatment. No major side effects were observed and she remained ECOG 0 with good weight gain. Up to her last clinic visit in September 2021, her PFS was more than 5 years. Intermittent doses of EGFR-TKI may prolong PFS in patients with advanced EGFRm+ NSCLC who has limited treatment options.

Correlation of epidermal growth factor receptor expression in esophageal cancer tissues with sensitivity of radical radiotherapy and prognosis of patients / 肿瘤研究与临床

Objective:To analyze the correlation of epidermal growth factor receptor (EGFR) expression in esophageal cancer tissues with sensitivity of radical radiotherapy and prognosis of patients.Methods:A total of 98 esophageal cancer patients admitted to the Affiliated Hospital of Jiangnan University from January 2017 to July 2019 were selected, and all patients received radical radiotherapy. The efficacy was assessed after 4 weeks of radiotherapy, partial remission (PR) + complete remission (CR) was treated as the sensitive group and disease progression (PD) + stable disease (SD) was treated as the tolerated group. The expression of EGFR in cancer tissues and paraneoplastic tissues (more than 5cm from the margin of cancer tissues) was measured by using immunohistochemistry. The expression of EGFR in cancer tissues and paraneoplastic tissues and the clinicopathological characteristics of the sensitive and tolerant groups were compared. Cox proportional risk model was used to analyze the factors influencing the prognosis of esophageal cancer patients; the Kaplan-Meier method was used to analyze the relationship between EGFR expression in cancer tissues and prognosis of patients.Results:The positive expression rate of EGFR in esophageal cancer tissues (66.3%, 65/98) was higher than that in paraneoplastic tissues (29.6%, 29/98), and the difference between the two groups was statistically significant (χ 2=26.49, P < 0.001). All 98 patients successfully completed radical radiotherapy, including 4 cases of CR, 60 cases of PR, 26 cases of SD and 8 cases of PD. The proportion of patients with highly differentiated and tumor length ≤1.5 cm in the sensitive group was higher than that in the tolerant group, and the differences were statistically significant (all P < 0.05). The positive expression rate of EGFR in cancer tissues in the sensitive group (56.3%, 36/64) was lower than that in the tolerant group (85.3%, 29/34), and the difference between the two groups was statistically significant ( χ2=8.39, P < 0.001). Multifactorial Cox regression analysis showed that poor differentiation, tumor long diameter >1.5 cm, and positive EGFR expression were independent risk factors for overall survival in patients with esophageal cancer (all P < 0.05). The difference in overall survival between patients with positive and negative EGFR expression was statistically significant ( χ2=9.70, P = 0.002). Conclusions:Highly-expressed EGFR in esophageal cancer tissues may suggest low sensitivity of radical radiotherapy and poor prognosis of patients.