EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway.

DNA methylation is important for lung cancer prognosis. In this work, it is aimed to seek novel biomarkers with DNA methylation-expression-pathway pattern and explore its underlying mechanism. Prognostic DNA methylation sites and mRNAs were screened in NSCLC data set from TCGA, and further validated using the samples retrospectively collected, and EXT1 was identified as a potential target. Gene body methylation of three CpG sites (cg03276982, cg11592677, cg16286281) on EXT1 was significantly associated with clinical outcome, and the EXT1 gene expression also predicted prognosis. The expression level of EXT1 was also correlated with its DNA methylation level. This observation was further validated in a new data set consist of 170 samples. Knocking down of EXT1 resulted in decreased proliferation and migration. EXT1 targets were analysed using GSEA. It is found that the WNT signalling is the potential downstream target of EXT1. Further analyses revealed that the EXT1 targets the beta-catenin and effect migration rate of NSCLC cell lines. The WNT signalling inhibitor, XAV-939, effectively disrupted the migration promotion effect induced by EXT1. In summary, EXT1 methylation regulates the gene expression, effects the proliferation and migration via WNT pathway and predicted a poor prognosis for NSCLC.

The deep learning model combining CT image and clinicopathological information for predicting ALK fusion status and response to ALK-TKI therapy in non-small cell lung cancer patients.

PURPOSE: This study aimed to investigate the deep learning model (DLM) combining computed tomography (CT) images and clinicopathological information for predicting anaplastic lymphoma kinase (ALK) fusion status in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Preoperative CT images, clinicopathological information as well as the ALK fusion status from 937 patients in three hospitals were retrospectively collected to train and validate the DLM for the prediction of ALK fusion status in tumors. Another cohort of patients (n = 91) received ALK tyrosine kinase inhibitor (TKI) treatment was also included to evaluate the value of the DLM in predicting the clinical outcomes of the patients. RESULTS: The performances of the DLM trained only by CT images in the primary and validation cohorts were AUC = 0.8046 (95% CI 0.7715-0.8378) and AUC = 0.7754 (95% CI 0.7199-0.8310), respectively, while the DLM trained by both CT images and clinicopathological information exhibited better performance for the prediction of ALK fusion status (AUC = 0.8540, 95% CI 0.8257-0.8823 in the primary cohort, p < 0.001; AUC = 0.8481, 95% CI 0.8036-0.8926 in the validation cohort, p < 0.001). In addition, the deep learning scores of the DLMs showed significant differences between the wild-type and ALK infusion tumors. In the ALK-target therapy cohort (n = 91), the patients predicted as ALK-positive by the DLM showed better performance of progression-free survival than the patients predicted as ALK-negative (16.8 vs. 7.5 months, p = 0.010). CONCLUSION: Our findings showed that the DLM trained by both CT images and clinicopathological information could effectively predict the ALK fusion status and treatment responses of patients. For the small size of the ALK-target therapy cohort, larger data sets would be collected to further validate the performance of the model for predicting the response to ALK-TKI treatment.

Apatinib plus Chemotherapy as a Second-Line Treatment in Unresectable Non-Small Cell Lung Carcinoma: A Randomized, Controlled, Multicenter Clinical Trial.

LESSONS LEARNED: The efficacy of second-line treatment for advanced non-small cell lung carcinoma (NSCLC) without a sensitizing driver gene mutation is still unsatisfactory. The combination of apatinib and chemotherapy improved progression-free survival in the second-line therapy of advanced NSCLC without a sensitizing mutation. This study offers a new treatment strategy for second-line treatment of such patients but requires confirmation in a larger multi-institutional trial. BACKGROUND: This study explored the efficacy and safety of apatinib combined with single-agent chemotherapy versus single-agent chemotherapy in the second-line treatment of advanced non-small-cell lung carcinoma (NSCLC) without driver mutations. METHODS: In this double-arm, open label, exploratory clinical study, we enrolled patients with unresectable locally advanced or advanced NSCLC without driver mutations that had progressed following first-line chemotherapy. The subjects were allocated into an experimental group and a control group by 2:1. The experimental group received apatinib combined with four cycles of docetaxel or pemetrexed until disease progression, intolerable toxicity, or discontinuation at the patient' request. The control group only received four cycles of docetaxel or pemetrexed. The primary endpoints were progression-free survival (PFS), and the secondary endpoints were overall survival (OS), disease control rate (DCR), and safety. RESULTS: Thirty-seven patients were enrolled. The efficacy of 33 patients was evaluated. The median PFS was 5.47 versus 2.97 months, the DCR was 95% versus 73%, and the objective response rate (ORR) was 27% versus 9% in the experimental versus control group. The OS was still under follow-up. The most common adverse effects included hypertension, hand-foot skin reaction (HFSR), and fatigue. CONCLUSION: Apatinib combined with single-agent chemotherapy may be a novel option for second-line treatment of advanced NSCLC.

Crizotinib with or without an EGFR-TKI in treating EGFR-mutant NSCLC patients with acquired MET amplification after failure of EGFR-TKI therapy: a multicenter retrospective study.

BACKGROUND: MET amplification is associated with acquired resistance to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in treating non-small-cell lung cancer (NSCLC); however, the therapeutic strategy in these patients is undefined. Herein we report the clinical outcomes of patients with c-MET amplification resistance to EGFR-TKIs treated with crizotinib. METHODS: We retrospectively analyzed advanced NSCLC patients from five sites who were diagnosed with EGFR-mutant NSCLC and received EGFR-TKI treatment. After disease progression, these patients were confirmed to have a MET-to-centromere ratio (MET:CEN) ≥ 1.8 based on fluorescence in situ hybridization (FISH) examination and without a T790M mutation. We assessed the efficacy and safety of crizotinib to overcome EGFR-TKI resistance in EGFR-activating mutations NSCLC with acquired MET amplification. RESULTS: Amplification of the acquired MET gene was identified in 18 patients with EGFR-mutant NSCLC. Fourteen patients received crizotinib treatment after acquired resistance to EGFR-TKIs. Among the 14 patients, 6 (42.9%) received crizotinib plus EGFR-TKI and 8 (57.1%) received crizotinib monotherapy. The overall objective response rate (ORR) and disease control rate (DCR) were 50.0% (7/14) and 85.7% (12/14), respectively. The median PFS (mPFS) of patients receiving crizotinib monotherapy and crizotinib plus EGFR-TKI was 6.0 and 12.6 months, respectively (P = 0.315). Notably, treatment efficacy was more pronounced in patients with crizotinib than patients with chemotherapy (24.0 months vs. 12.0 months, P = 0.046). The mOS for 8 of 14 patients receiving crizotinib monotherapy and 6 of 14 patients receiving crizotinib plus EGFR-TKI was 17.2 and 24.0 months, respectively (P = 0.862). Among the 14 patients, 1 who received crizotinib monotherapy (grade 3 nausea) and 2 who received crizotinib plus EGFR-TKI (grade 3 elevated liver aminotransferase levels) received reduced doses of crizotinib (200 mg twice daily) to better tolerate the dose. CONCLUSIONS: We observed the clinical evidence of efficacy generated by combination of crizotinib and previous EGFR-TKIs after the resistance to first-generation EGFR-TKIs. These results might increase evidence of more effective therapeutic strategies for NSCLC treatment. Combination therapy did not increase the frequency of adverse reactions.

Advances in traditional Chinese herbal medicine and their pharmacodynamic mechanisms in cancer immunoregulation: a narrative review.

Background and Objective: The cancer-immunity cycle (CIC) is defined as a series of progressive events that cause an anticancer immune response leading to the killing of the cancer cell. The concept of CIC has important guiding significance for the clinical and basic tumor immunotherapy research. As one of the methods of traditional Chinese medicine (TCM), Chinese herbal medicine (CHM) has shown unique advantages in multitarget and multipathway immune regulation. However, the tumor immune circulation targeted by CHM is generally unclear at present. To provide reference for future clinical and basic research, we systematically reviewed the existing literature on CHM (including CHM monomers, CHM compounds, and CHM patent medicines) and the mechanisms related to its efficacy. Methods: We searched the PubMed and China National Knowledge Infrastructure (CNKI) databases for relevant Chinese-language and English-language literature published from January 1988 to October 2022. The literature was screened manually at three levels: title, abstract, and full text, to identify articles related to CHM and their mechanism of regulating tumor immunity. Key Content and Findings: By further classifying the CIC, it was confirmed that CHM can regulate the activation of dendritic cells (DCs) and macrophages and promote the presentation of tumor antigens. Meanwhile, CHM can also reverse tumor-immune escape by enhancing T-cell proliferation and infiltration. In addition, CHM can also enhance the antitumor ability of the body by regulating the killing process of tumor cells. Conclusions: The theory of a CIC is of guiding significance to regulating tumor immunity via CHM.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

CacyBP/SIP enhances multidrug resistance of pancreatic cancer cells by regulation of P-gp and Bcl-2.

Our former report indicates that calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) is over-expressed in the SGC7901/ADR cell line. However, the potential role of CacyBP/SIP in the development of multidrug resistance (MDR) of pancreatic cancer is still uncertain. In this paper, we investigated the role of CacyBP/SIP in MDR of pancreatic cancer cells and its possible underlying mechanisms, and found that CacyBP/SIP was over-expressed in the Gemcitabine induced MDR pancreatic cancer cell PC-3/Gem compared with its parental cell PC-3. Up-regulation of CacyBP/SIP expression could enhance resistance of chemotherapy drugs on PC-3 cells and inhibit Adriamycin-induced apoptosis accompanied by decreased accumulation of intracellular Adriamycin. Furthermore, CacyBP/SIP could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene. In addition, the decrease of CacyBP/SIP expression using RNA interference or P-gp inhibitor could partially reverse CacyBP/SIP-mediated MDR. In brief, our study demonstrated that CacyBP/SIP could enhance the MDR phenotype of pancreatic cancer cells by increasing the expression of P-gp and Bcl-2, thus inhibiting apoptosis of pancreatic cancer cell.

Aggressive progression to EGFR tyrosine kinase inhibitors in advanced NSCLC patients: concomitant mutations, prognostic indicator and subsequent management.

BACKGROUND: EGFR tyrosine kinase (TKIs) are recommend as the first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, some patients experience aggressive progression with a progression-free survival (PFS) less than 6 months on the first-line EGFR TKI therapy. Therefore, our study is to analyze the potential influencing factors including clinical features, biomarkers, concomitant mutations et al. METHODS: A total of 1073 NSCLC patients with EGFR mutation in a multi-center study from January 2019 to December 2021. The datum pathological and molecular characteristics were collected. The area under the receiver operating characteristic (ROC) curve was used to evaluate the predictive effect of Ki-67 on the first-line TKI. The curve of PFS was conducted by Kaplan-Meier method and tested by bilateral log-rank. Cox regression model was used to predict and evaluate PFS of different variables. Chi-square or Fisher analysis was used for correlation between groups. RESULTS: 55 patients who show aggressive progression (PFS ≤ 6 months) on the first-line TKI therapy were analyzed in this study, while 71 with slow progression (PFS > 6 months). Concomitant mutations including AXIN2, P2CG and RAD51C mutations occurred only in the aggressively progressive group (P = 0.029). Correlation between Ki-67 index and the aggressive progression of the first-line TKI therapy was significant statistically different (P < 0.05). In the second-line therapy, the PFS of chemotherapy in combination with other treatments was better than single TKIs in the first ten months. CONCLUSION: NSCLC harbored EGFR and concomitant mutations (such as AXIN2, PLCG2 and RAD51C), and/or Ki-67 high expression may indicate the aggressive progression to the first-line EGFR-TKI.

Comparison of different therapeutic approaches for pulmonary cryptococcosis in kidney transplant recipients: a 15-year retrospective analysis.

Introduction: Organ transplant recipients are at increased risk of developing pulmonary cryptococcosis (PC) due to weakened cell-mediated immunity caused by immunosuppressors. However, the nonspecific symptoms associated with PC can often lead to misdiagnosis and inappropriate treatment. Methods: We conducted a retrospective analysis of data from 23 kidney transplant recipients with PC between April 2006 to January 2021. Results: The median time from transplantation to the diagnosis of pathology-proven PC 4.09 years. Seventeen patients presented respiratory symptoms, including sputum-producing cough and dyspnea. Additionally, three patients also developed central nervous system (CNS) infections. Chest CT scans frequently revealed nodule-shaped lesions, which can mimic lung carcinoma. Serological tests did not demonstrate any specific changes. Nine patients received surgical resection as treatment. Fourteen patients were treated with antifungal medication only. No recurrence was observed in all 23 patients. Conclusion: Our study suggests that fever and sputum-producing cough are common symptoms of PC, and cryptococcal meningitis should not be excluded if corresponding symptoms occur. Fluconazole is a common and effective antifungal agent. Surgical resection should be considered for patients who do not respond well to antifungal therapy. Clinicians should be aware of these findings when evaluating transplant recipients with respiratory symptoms.

Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1.

Chronic obstructive pulmonary disease (COPD) is commonly caused by smoking. FUN14 domain-containing protein 1 (FUNDC1) plays a fundamental role in mitochondrial autophagy and apoptosis in cigarette smoke extract (CSE)-treated BEAS-2B cells. The present study investigated the mechanism of action of FUNDC1 in mitochondrial dysfunction and apoptosis in CSE-treated BEAS-2B cells. The interaction between ubiquitin-specific peptidase 19 (USP19) and FUNDC1 was analyzed using co-immunoprecipitation. Effects of USP19 knockdown and/or FUNDC1 overexpression on the survival, apoptosis, mitochondrial membrane potential, and oxygen consumption rate (OCR) of BEAS-2B cells treated with 15% CSE were determined. In BEAS-2B cells, CSE inhibited cell survival, promoted apoptosis, increased the expression of USP19 and FUNDC1, increased the ratio of LC3 II to LC3 I (LC3 II/I), and decreased mitochondrial membrane potential and TOM20 levels. In CSE-treated BEAS-2B cells, USP19 knockdown reduced FUNDC1 and LC3 II/I, increased the levels of TOM20, improved cell survival, mitochondrial membrane potential, and OCR, and inhibited apoptosis. USP19 deubiquitinates FUNDC1. FUNDC1 overexpression inhibited the effect of USP19 knockdown in CSE-treated BEAS-2B cells. Overall, decreasing USP19 expression alleviates CSE-induced mitochondrial dysfunction in BEAS-2B cells by downregulating FUNDC1, providing novel insights into the molecular mechanism of FUNDC1 regulation in COPD.

A multicenter-retrospective cohort study of chromosome instability in lung cancer: clinical characteristics and prognosis of patients harboring chromosomal instability detected by metagenomic next-generation sequencing.

Background: The usefulness of metagenomic next-generation sequencing (mNGS) in identifying the prognosis of lung cancer with chromosomal instability (CIN) remains unclear. We aimed to analyze clinical characteristics and prognosis of patients in patients harboring CIN. Methods: This retrospective cohort study included 668 patients diagnosed with suspected pulmonary infection or lung cancer whose samples underwent mNGS detection from January 2021 to January 2022. Difference between clinical characteristics were calculated by the Student's t-test and the chi-square test. The subjects were followed-up from registered to September 2022. Survival curves were analyzed by the Kaplan-Meier method. Results: Of 619 bronchoalveolar lavage fluid (BALF) samples collected by bronchoscopy, 30 CIN-positive samples were confirmed as malignant on histopathology, with a sensitivity of 61.22%, a specificity of 99.65%, and an 83.17% accuracy [cut-off values were established by the receiver operating characteristic (ROC) area under the curve (AUC) =0.804]. In 42 patients with lung cancer, mNGS detected 24 patients as CIN-positive and 18 as CIN-negative. There were no differences between two groups including ages, pathologic types, stage and metastases. In 25 cases, we detected 523 chromosomal copy number variants (CNVs) with forms including duplication (dup), deletion (del), mosaic (mos), and whole chromosome amplification or loss. A total of 243 duplication variants and 192 deletion variants occurred in all chromosomes. Duplications occurred in most chromosomes except for Chr9 and Chr13, in which CNV tended to delete. The median overall survival (OS) in patients with Chr5p15 duplication was 32.4 months [95% confidence interval (CI), 10.35-54.45 months]. The median OS differed significantly between the 5p15dup+ group and the combined group (32.4 vs. 8.63 months, P=0.049). In 29 patients with unresected lung cancer, the median OS of 18 cases in the CIN-positive group was 32.4 months (95% CI, 14.2-50.6 months) and the median OS of 11 cases in the CIN-negative group was 35.63 months (95% CI, 21.64-49.62 months; Wilcoxon, P=0.227). Conclusions: Various forms of CIN detected by mNGS may predict prognosis of patients with lung cancer differentially. CIN with duplication or deletion deserves further study to guide clinical treatment.

C-reactive protein and lactate dehydrogenase serum levels potentially predict the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer.

Background: Programmed cell death-ligand 1 (PD-L1) expression and other biomarkers are not completely reliable predictors of the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC). We investigated the value of peripheral serological inflammatory indicators and their combination in predicting the prognosis of patients with advanced NSCLC treated with checkpoint inhibitors. Methods: This study retrospectively analyzed 116 NSCLC patients treated with anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies. Clinical data of the patients were collected before treatment. X-tile plots determined the optimal cut-point for C-reactive protein (CRP) and lactate dehydrogenase (LDH). A survival analysis was performed using the Kaplan-Meier method. Multi-factor Cox regression analysis was used to evaluate the statistically significant factors identified in the univariate analysis. Results: The X-tile plots show the cut-points of CRP and LDH were 8 mg/L and 312 U/L, respectively. Univariate analyses showed high baseline serum LDH and low CRP levels were associated with adverse progression-free survival (PFS). Multivariate analyses indicated that CRP (HR, 0.214, 95% CI: 0.053-0.857, P=0.029) could be a predictive indicator for PFS. In addition, we evaluated the combination of CRP and LDH, and univariate analyses showed that patients with high CRP and low LDH exhibited significantly better PFS than those in the other groups. Conclusions: Baseline levels of serum CRP and LDH have the potential to become a convenient clinical tool to predict response to immunotherapy in advanced non-small cell lung cancer.

Chinese expert consensus on the diagnosis and treatment of HER2-altered non-small cell lung cancer.

Human epidermal growth factor receptor 2 (HER2) possesses tyrosine kinase activity and participates in cell growth, differentiation and migration, and survival. Its alterations, mainly including mutations, amplifications, and overexpression are associated with poor prognosis and are one of the major drivers in non-small cell lung cancer (NSCLC). Several clinical trials had been investigating on the treatments of HER2-altered NSCLC, including conventional chemotherapy, programmed death 1 (PD-1) inhibitors, tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), however, the results were either disappointing or encouraging, but inconsistent. Trastuzumab deruxtecan (T-DXd) was recently approved by the Food and Drug Administration as the first targeted agent for treating HER2-mutant NSCLC. Effective screening of patients is the key to the clinical application of HER2-targeted agents such as TKIs and ADCs. Various testing methods are nowadays available, including polymerase chain reaction (PCR), next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), etc. Each method has its pros and cons and should be reasonably assigned to appropriate patients for diagnosis and guiding treatment decisions. To help standardize the clinical workflow, our expert group reached a consensus on the clinical management of HER2-altered NSCLC, focusing on the diagnosis and treatment strategies.

Chinese expert consensus on the diagnosis and treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, and its incidence has been increasing in recent years. Due to the insidious onset and strong local invasiveness of MPM, most patients are diagnosed in the late stage and early screening and treatment for high-risk populations are crucial. The treatment of MPM mainly includes surgery, chemotherapy, and radiotherapy. Immunotherapy and electric field therapy have also been applied, leading to further improvements in patient survival. The Mesothelioma Group of the Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) developed a national consensus on the clinical diagnosis and treatment of MPM based on existing clinical research evidence and the opinions of national experts. This consensus aims to promote the homogenization and standardization of MPM diagnosis and treatment in China, covering epidemiology, diagnosis, treatment, and follow-up.

Chinese expert consensus on the diagnosis and treatment of thymic epithelial tumors.

Thymic epithelial tumors (TETs) are a relatively rare type of thoracic tumor, accounting for less than 1% of all tumors. The incidence of TETs is about 3.93/10000 in China, slightly higher than that of European and American countries. For resectable TETs, complete surgical resection is recommended. Radiotherapy or chemotherapy may be used as postoperative adjuvant treatment. Treatment for advanced, unresectable TETs consist mainly of radiotherapy and chemotherapy, but there is a lack of standard first- and second-line treatment regimens. Recently, targeted therapies and immune checkpoint inhibitors have shown promising outcomes in TETs. Based on the currently available clinical evidences and the opinions of the national experts, the Thymic Oncology Group of Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) established this Chinese expert consensus on the clinical diagnosis and treatment of TETs, covering the epidemiology, diagnosis, treatment, prognosis and follow-up of TETs.

Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.

The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.

Applied research on serum protein fingerprints for prediction of Qi deficiency syndrome and phlegm and blood stasis in patients with non-small cell lung cancer.

OBJECTIVE: This study screened serum tumor biomarkers by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to establish a subset which could be used for the prediction of Qi deficiency syndrome and phlegm and blood stasis in patients with non-small cell lung cancer; and as diagnostic model of Chinese medicine. METHODS: Serum samples from 63 lung cancer patients with Qi deficiency syndrome and phlegm and blood stasis, and 28 lung cancer patients with non-Qi deficiency syndrome and phlegm and blood stasis were analyzed using SELDI-TOF-MS with a PBS II-C protein chip reader. Protein profiles were generated using immobilized metal affinity capture (IMAC3) protein chips. Differentially-expressed proteins were screened. Protein peak clustering and classification analyses were performed using Biomarker Wizard and Biomarker Pattern software packages, respectively. RESULTS: A total of 268 effective protein peaks were detected in the 1,000-10,000 Da molecular range for the 15 serum proteins screened (P<0.05). The decision tree model was M 2284.97, with a sensitivity of 96.2% and a specificity of 66.7%. CONCLUSION: SELDI-TOF-MS techniques, combined with a decision tree model, can help identify serum proteomic biomarkers related to Qi deficiency syndrome and phlegm and blood stasis in lung cancer patients; and the predictive model can be used to discriminate between Chinese medicine diagnostic models of disease.

[Influence of Chinese herbal medicine Feitai Capsule on completion or delay of chemotherapy in patients with stage IIIB/IV non-small-cell lung cancer: a randomized controlled trial].

BACKGROUND: Chemotherapy completion rate can reflect the tolerance and compliance of patients to chemotherapy. Poor tolerance may result in delay or suspension of the comprehensive treatment plan, thus affect the efficacy of cancer treatment. Evaluating methods to improve the completion rate of chemotherapy and reduce the occurrence of delayed chemotherapy has gained increasing attention and is the significant area of study in the field of cancer treatment. Studies have shown that Chinese medicine combined with chemotherapy could improve the quality of life in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). OBJECTIVE: To observe the effects of Feitai Capsule, a Chinese patent herbal drug, combined with chemotherapy in patients with stage IIIB/IV NSCLC. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 60 diagnosed stage IIIB/IV NSCLC patients from the Department of Oncology, Fuzhou General Hosipital of Najing Military Region were randomly divided into treatment group (30 cases) and control group (30 cases). Patients in the treatment group were treated with chemotherapy plus Feitai Capsule and patients in the control group only received chemotherapy. Both groups of patients were treated for 4 therapeutic cycles. MAIN OUTCOME MEASURES: The chemotherapy completion rate and the chemotherapy delay rate were observed in each cycle of treatment. The therapeutic efficacy was evaluated after 4 cycles. RESULTS: The chemotherapy completion rate was 96.42% in the treatment group, while that of the control group was 74.07%. The chemotherapy delay rate was 3.57% in the treatment group, while that of the control group was 14.8% (P=0.007 0). The disease control rate was 78.6% in the treatment group, while that of the control group was 59.3% (P=0.173 9). CONCLUSION: Feitai Capsule can increase the chemotherapy completion rate in patients with stage IIIB/IV NSCLC.

Genetic alteration and PD-L1 expression profiles of Chinese patients with lung squamous cell carcinoma.

BACKGROUNDS: Despite the achievements made in treating lung cancer during the past decades, lung cancer still leads in cancer incidence and mortality worldwide. Compared to lung adenocarcinoma, the gene mutation profiles of Chinese lung squamous cell carcinoma (SQCC) have not been well established yet. METHODS: 488 Chinese SQCC patients were enrolled from 2017 to 2020, and 289 of them provided archived tumor specimens for genetic testing, 199 provided plasma instead. All samples were subjected to next-generation sequencing assay (295 took testing of 14 lung cancer-related genes, and the rest took the expanded panel). 120 patients provided blood samples applying for germline mutation testing using expanded panel. Moreover, 144 cases with enough tissue samples underwent PD-L1 immunohistochemical assay. RESULTS: Of the 488 patients with SQCC, 444 (90.98%) were proved to have at least one alteration in the 14 lung cancer-related genes. Compared with SQCC patients in The Cancer Genome Atlas (TCGA) database, a significant higher mutated frequency of EGFR (16.03% vs. 3.35%), ERBB2 (9.06% vs. 1.68%), KRAS (7.76% vs. 1.22%), and ALK (5.92% vs. 2.23%) was found in our cohort. Totally, 37.50% of patients were identified with actionable alterations, and most of them were detected in the testing using expanded panel than only the driver gene panel (49.22% vs. 29.83%, p < 0.01). Meanwhile, TP53, PIK3CA and actionable alterations were more identified in the genotyping on the tissue samples than the blood circulating tumor DNA (ctDNA). However, genes associated with clonal hematopoiesis, including KMT2D and RB1, were more prevalent in the plasma ctDNA samples. Of 120 patients undertook germline genetic testing, 5 (4.17%) patients were identified with six pathogenic/ likely pathogenic (P/LP) germline variants in DNA damage repair genes. Positive PD-L1 expression was identified in 61.27% of patients, presenting with a significantly positive correlation with KRAS alterations (58.33% vs. 16.67%). CONCLUSION: Our study identified unique genomic profiles of Chinese SQCC patients and provided novel insights into the detection of additional actionable genes and ctDNA in further genotyping. Genetic testing on expanded panel merits further study to comprehensive understanding the therapeutic value of targetable alterations in Chinses SQCC patients.

Cancer cell-derived exosomal LINC00313 induces M2 macrophage differentiation in non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, which is the leading cause of cancer death worldwide. Tumor-associated macrophages (TAMs) are one of the main non-tumor cells in the tumor microenvironment. Here, we investigated the effect of cancer cell-derived exosomal LINC00313 on the M2 macrophage differentiation in NSCLC and clarified its underlying mechanism. METHODS: Flow cytometry, Western blotting, ELISA and immunohistochemical staining were performed to identify the macrophage phenotype by detecting the expression of M2 markers. The expression levels of LINC00313 and miR-135a-3p were measured by qRT-PCR, and luciferase reporter assay was used to validate the binding of lncRNA to miRNA, and miRNA to the target gene STAT6. The mouse-xenograft models were established by subcutaneous injection of the NCl-H1299 cells with stable overexpression or knockdown of LINC00313. GW4869 was injected intra-tumorally after tumor implantation. RESULTS: It was found that the cancer cells promoted M2 macrophage differentiation by secreting exosomes. LINC00313 was overexpressed in H1299-derived exosomes, and its knockdown abolished the effect of H1299-induced M2 macrophage differentiation. LINC00313 sponged miR-135a-3p to increase the STAT6 expression, resulting in the M2 macrophage differentiation. LINC00313 promoted tumor progression and promoted the expression of M2 markers in isolated tumor macrophages. A novel regulatory mechanism of M2 macrophage differentiation in NSCLC was revealed. It was found that cancer cell-derived exosomal LINC00313 promoted M2 macrophage differentiation in NSCLC by up-regulating STAT6 as miR-135a-3p sponge. CONCLUSIONS: This study provides a new mechanism and direction to prevent the M2 macrophage differentiation in NSCLC.