• Gastric cancer screening
• Helicobacter pylori
• Multiple combined serologic testing
• Noninvasive diagnostic markers
• Serum biomarkers

• IGF signaling
• fibroblasts
• glycosylation
• lung adenocarcinoma
• prognosis
• tumor dormancy

• Humans
• Glycosylation
• Machine Learning
• Adenocarcinoma of Lung/genetics
• Adenocarcinoma of Lung/pathology
• Adenocarcinoma of Lung/metabolism
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Lung Neoplasms/metabolism
• Prognosis
• Gene Expression Regulation, Neoplastic
• Tumor Microenvironment/genetics
• Biomarkers, Tumor/genetics
• Gene Regulatory Networks

• EGFR TKIs
• Osimertinib
• circulating tumor cells
• ctDNA
• liquid biopsy
• resistance

• Humans
• Acrylamides/therapeutic use
• Aniline Compounds/therapeutic use
• Aniline Compounds/pharmacology
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Non-Small-Cell Lung/genetics
• Lung Neoplasms/drug therapy
• Lung Neoplasms/pathology
• Liquid Biopsy/methods
• Antineoplastic Agents/therapeutic use
• ErbB Receptors/genetics
• Mutation
• Protein Kinase Inhibitors/therapeutic use
• Indoles
• Pyrimidines

• FCGBP
• Immune checkpoint
• Immune microenvironment
• NSCLC
• Prognostic signature

• KYCX21-3108 Postgraduate Research & Practice Innovation Program of Jiangsu Province
• LGY2016037 "Six-one" Project for High-level Health Talents
• 82370253 Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Nantong Clinical Medical Research Center of Cardiothoracic Disease, and Institution of Translational Medicine in Cardiothoracic Diseases in Affiliated Hospital of Nantong University. National Natural Science Foundation of China
• YJXYY202204 Jiangsu Provincial Research Hospital
• XNBHCX31773 Innovation Team Project of Affiliated Hospital of Nantong University
• Postgraduate Research & Practice Innovation Program of Jiangsu Province
• “Six-one” Project for High-level Health Talents

• EGFR T790M mutation
• Osimertinib
• drug resistance
• meta‐analysis
• non‐small cell lung cancer

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• ErbB Receptors/genetics
• Mutation
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Acrylamides
• Aniline Compounds
• Indoles
• Pyrimidines

• 2018A030313138 Natural Science Foundation of Guangdong Province
• 2021A1515220165 Guang Dong Basic and Applied Basic Research Foundation
• 2022JZ33 Hospital Pharmaceutical Research Fund of Guangdong Province
• 320.6750.2022-20-12 Wu Jieping Medical Foundation
• Natural Science Foundation of Guangdong Province
• Wu Jieping Medical Foundation

• CDC6
• cell cycle
• lung adenocarcinoma
• prognostic model

• Humans
• Animals
• Mice
• Prognosis
• Adenocarcinoma of Lung/genetics
• Cell Cycle
• Data Mining
• Lung Neoplasms/genetics
• Nuclear Proteins
• Cell Cycle Proteins/genetics

• DNA damage repair (DDR)
• lung adenocarcinoma (LUAD)
• prognosis
• risk score model
• tumor

• Bronchial washing fluid
• Droplet digital polymerase chain reaction
• EGFR T790M
• Epidermal growth factor receptor mutation
• Non-small cell lung cancer

• Humans
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/genetics
• Lung Neoplasms/diagnosis
• Lung Neoplasms/genetics
• Mutation/genetics
• ErbB Receptors/genetics
• Drug Resistance, Neoplasm/genetics
• Protein Kinase Inhibitors/pharmacology

• FAM66C
• Lung cancer
• long non-coding RNAs
• neutrophil extracellular traps
• prognosis signature

• Humans
• RNA, Long Noncoding/genetics
• Extracellular Traps/genetics
• Prognosis
• Adenocarcinoma
• Lung

• adjuvant therapy
• early diagnosis
• liquid biopsy
• non-small cell lung cancer
• prognosis
• recurrence

• EGFR
• NSCLC
• ctDNA/cfDNA
• liquid biopsy

• CD39
• Lung adenocarcinoma
• bioinformatics analysis
• immune checkpoint therapy
• prognosis

• NSCLC
• ctDNA
• liquid biopsy
• minimal residual disease (MRD)
• therapy monitoring

• cancer
• biomarkers

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/genetics
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/genetics
• Cell-Free Nucleic Acids/genetics
• Circulating Tumor DNA/analysis
• Circulating Tumor DNA/genetics
• Humans
• Liquid Biopsy
• Lung Neoplasms/diagnosis
• Lung Neoplasms/genetics

Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy.

Non-small-cell lung cancer (NSCLC) is a major component of lung cancer and is significantly correlated with poor prognosis. N6-methyladenosine (m6A) RNA methylation is closely related to the occurrence, progression, and prognosis of cancer. The potential biological functions and mechanisms of m6A RNA methylation in the immune microenvironment are still unclear.

We assessed m6A RNA methylation modification patterns in 1326 NSCLC patient samples based on 20 m6A regulators, linking these clusters to the tumor microenvironment and immune cell infiltration. The m6Ascore was created to quantify the m6A modification patterns of individual tumors. We then assessed the value of NSCLC patients in terms of clinical prognosis and immunotherapy response.

According to different mRNA expression levels, two different m6A clusters were identified. m6A aggregation was significantly associated with clinical prognostic characteristics, the tumor microenvironment, and immune-related biological processes. Fifteen differential genes were screened based on these two m6A clusters, and to further investigate the mechanisms of action of these differential genes, they were subjected to unsupervised clustering analysis, which classified them into four different genomic isoforms. Prognostic analysis indicated that the survival advantage of the m6A gene cluster A modification mode was significantly prominent. We continued to construct the m6Ascore, which was used as a scoring tool to evaluate tumor typing, immunity, and prognosis. Patients with a low m6Ascore showed a significant survival advantage, and the group with a low m6Ascore had a better prognosis predicted by immunotherapy. The anti-PD-1/L1 immunotherapy cohort showed that a lower m6Ascore was associated with higher efficacy of immunotherapy.

The results suggest that m6A RNA methylation regulators make an important difference in the tumor immune microenvironment of patients with NSCLC. m6A gene characterization and the construction of the m6Ascore provide us with a richer understanding of m6A RNA methylation modification patterns in NSCLC patients and help to predict clinical prognosis and immunotherapeutic response.

Accurately evaluating minimal residual disease (MRD) could facilitate early intervention and personalized adjuvant therapies. Here, using ultradeep targeted next-generation sequencing (NGS), we evaluate the clinical utility of circulating tumor DNA (ctDNA) for dynamic recurrence risk and adjuvant chemotherapy (ACT) benefit prediction in resected non-small cell lung cancer (NSCLC). Both postsurgical and post-ACT ctDNA positivity are significantly associated with worse recurrence-free survival. In stage II-III patients, the postsurgical ctDNA positive group benefit from ACT, while ctDNA negative patients have a low risk of relapse regardless of whether or not ACT is administered. During disease surveillance, ctDNA positivity precedes radiological recurrence by a median of 88 days. Using joint modeling of longitudinal ctDNA analysis and time-to-recurrence, we accurately predict patients’ postsurgical 12-month and 15-month recurrence status. Our findings reveal longitudinal ctDNA analysis as a promising tool to detect MRD in NSCLC, and we show pioneering work of using postsurgical ctDNA status to guide ACT and applying joint modeling to dynamically predict recurrence risk, although the results need to be further confirmed in future studies.

ctDNA has been shown to identify minimal residual disease (MRD) and is thus dynamically monitored in different types of tumours. Here, the authors show that serial longitudinal ctDNA analysis can be used as a tool to detect MRD, inform the use of adjuvant therapy, and predict recurrence risk in lung cancer.

• Ferroptosis
• immunotherapy
• lung adenocarcinoma
• molecular subtypes
• tumor microenvironment

• PIWI-interacting RNAs
• biomarker
• diagnosis
• lung adenocarcinoma
• serum exosome

• Adenocarcinoma of Lung/genetics
• Biomarkers, Tumor/genetics
• Exosomes/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Lung Neoplasms/genetics
• RNA, Small Interfering/genetics

• Natural Science Foundation of Shandong Province

• Immune microenvironment
• Lung adenocarcinoma
• Prognostic model
• m6A RNA methylation

Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. At present, most patients with LUAD are diagnosed at an advanced stage, and the prognosis of advanced LUAD is poor. Hence, we aimed to identify novel biomarkers for the diagnosis and treatment of early stage LUAD and to explore their predictive value.

The microarray datasets GSE63459, GSE27262, and GSE33532 were searched, and the differentially expressed genes (DEGs) were obtained using GEO2R. The DEGs were subjected to gene ontology (GO) and pathway enrichment analyses using METASCAPE. A protein–protein interaction (PPI) network was plotted with STRING and visualized by Cytoscape. Module analysis of the PPI network was performed using MCODE. Overall survival (OS) analysis and analysis of the mRNA expression levels of genes identified by MCODE were performed with UALCAN. Western blot analysis of hub genes in LUAD patients, MTS assays, and clonogenic assays were performed to test the effects of the hub genes on cell proliferation in vitro.

A total of 341 DEGs were obtained, which were mainly enriched in terms related to blood vessel development, growth factor binding, and extracellular matrix organization. A PPI network consisting of 300 nodes and 1140 edges was constructed, and a significant module including 15 genes was identified. Elevated expression of ASPM, CCNB2, CDCA5, PRC1, KIAA0101, and UBE2T was associated with poor OS in LUAD patients. In the protein level, the hub gene was overexpressed in LUAD patients. In vitro experiments showed that knockdown of the hub genes in the LUAD cell lines could promote cell proliferation.

DEGs are potential biomarkers for early stage lung adenocarcinoma and could have utility for the diagnosis and predicting treatment efficacy.

• bioinformatics
• biomarker
• early stage
• lung adenocarcinoma
• prognosis

• Afatinib
• EGFR mutation
• circulating tumor DNA
• non-small cell lung carcinoma

• Afatinib/pharmacology
• Afatinib/therapeutic use
• Aged
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Circulating Tumor DNA/genetics
• ErbB Receptors/pharmacology
• ErbB Receptors/therapeutic use
• Female
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/pathology
• Male
• Mutation
• Prospective Studies

• 1200.271 Boehringer Ingelheim
• Boehringer Ingelheim

• 6-methyladenine regulators
• Cox regression analysis
• copy number variation
• female lung adenocarcinoma
• prognostic risk scoring system

• bioinformatics
• data mining
• lung adenocarcinoma
• predictor
• prognosis

As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne^®Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.

Osimertinib is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for both EGFR-activating and T790M resistant mutation. The treatment efficacy of osimertinib was assessed in previously untreated patients with metastatic non–small cell lung carcinoma (NSCLC) harboring activating EGFR mutations in circulating tumor DNA (ctDNA) as well as tumor DNA.

Patients with activating EGFR mutations in their tumor DNA underwent screening with ctDNA analysis using Mutyper and Cobas v2 assays. Enrolled subjects received osimertinib 80 mg, once daily. Primary endpoint was objective response rate (ORR) and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety.

Among 39 screened patients, 29 were ctDNA positive for activating EGFR mutations and 19 were enrolled (ex19del, n=11; L858R/L861Q, n=7; G719A, n=1). Median age was 70 and most patients had brain metastases (15/19, 79%). ctDNA test sensitivity for activating EGFR mutations was 74% using both methods and 62% (Mutyper) or 64% (Cobas v2) for individual methods. ORR was 68% (13/19), median PFS was 11.1 months (95% confidence interval [CI], 0.0 to 26.7), and median DoR was 17.6 months (95% CI, 3.5 to 31.7). ORR and median PFS were significantly superior with ex19del (91%; 21.9 months; 95% CI, 5.5 to 38.3) than with L858R/L861Q (43%; 5.1 months; 95% CI, 2.3 to 7.9). One patient discontinued the drug because of drug-related interstitial pneumonitis.

Osimertinib had favorable efficacy in the first-line treatment of metastatic NSCLC harboring activating EGFR mutations in ctDNA as well as tumor DNA.

• Circulating tumor DNA
• EGFR mutation
• Non–small cell lung carcinoma
• Osimertinib

• capillary
• cell-free DNA
• circulating DNA
• electrochromatography
• plasma
• serum

• egfr-tki
• nonsmall cell lung cancer
• osimertinib
• toxicity

• Acrylamides/adverse effects
• Acrylamides/therapeutic use
• Aniline Compounds/adverse effects
• Aniline Compounds/therapeutic use
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Cigarette Smoking
• ErbB Receptors/genetics
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Mutation
• Pneumonia/chemically induced
• Progression-Free Survival
• Survival Rate

EGFR T790M testing is the standard of care for activating EGFR mutation (EGFRm) non-small cell lung cancer (NSCLC) progressing on 1st/2nd generation TKIs to select patients for osimertinib. Despite sensitive assays, detection of circulating tumour deoxyribonucleic acid (ctDNA) is variable and influenced by clinical factors. The number and location of sites of progressive disease at time of testing were reviewed to explore the effect on EGFR ctDNA detection. The prognostic value of EGFR ctDNA detection on survival outcomes was assessed.

Following extraction of cell-free DNA from plasma using the QIAamp Circulating Nucleic Acid Kit, custom droplet digital polymerase chair reaction (ddPCR) assays were used to assess EGFR ctDNA using the Bio-Rad QX200 system. The ddPCR assay has a limit of detection of ≤0.15% variant allele fraction. Baseline characteristics and imaging reports at time of EGFR ctDNA testing were reviewed retrospectively for a 1 year period.

The study included 177 patients who had an EGFR ctDNA test. Liver (aOR 3.13) or bone (aOR 2.76) progression or 3–5 sites of progression (aOR 2.22) were predictive of EGFR ctDNA detection. The median OS from first ctDNA test after multiple testing iterations was 12.3 m undetectable EGFR ctDNA, 7.6 m for original EGFR mutation only and 24.1 m with T790M (P=0.001).

Patients with liver or bone progression and 3–5 progressing sites are more likely to have informative EGFR ctDNA testing. Detection of EGFR ctDNA is a negative prognostic indicator in the absence of a T790M resistance mutation, potentially reflecting the disease burden in the absence of targeted therapy options.

• Epidermal growth factor receptor (EGFR)
• circulating tumour deoxyribonucleic acid (ctDNA)
• droplet digital polymerase chair reaction (ddPCR)
• predictive
• prognostic

• NGS
• cell-free DNA
• liquid biopsy
• precision medicine
• targeted therapy

• Circulating tumour DNA
• Epidermal growth factor receptor tyrosine kinase inhibitors
• Liquid biopsy
• Non-small cell lung cancer
• Resistance

Background and Purpose: Pervious studies have demonstrated that the loss of EGFR T790M after Osimertinib treatment may be the cause of Osimertinib resistance. Here, we conducted a meta-analysis to evaluate the association between the persistence of EGFR T790M and the clinical benefits of Osimertinib in non-small cell lung cancer (NSCLC) patients with baseline EGFR T790M mutation.

Experimental design and Methods: PUBMED, EMBASE, and Cochrane databases were searched for eligible studies that provided the survival outcomes including overall survival (OS), progression-free survival (PFS) or time to discontinuation (TTD) data for each patient treated with Osimertinib with the status of the T790M mutation tested after Osimertinib resistance. The hazard ratios (HRs) and their 95% confidence intervals (CI) were calculated for each study.

Results: In total, eight eligible studies were included in the analysis, among which six studies provided the data on PFS, and the other two studies provided the TTD data. Overall, 312 patients (151 patients with the persistence of T790M) were identified. The persistence of T790M was associated with longer PFS (HR, 0.40; 95% CI, 0.19-0.84; P=0.01) and TTD (HR, 0.54; 95% CI, 0.39-0.76; P=0.0004). Furthermore, overall analysis the survival outcomes including PFS and TTD subgroups also showed preferable clinical benefits for patients with the T790M persistence (HR, 0.57; 95%CI, 0.45-0.73; P<0.00001).

Conclusions: Our findings confirm the persistence of T790M is associated with the clinical benefits of Osimertinib in NSCLC patients with baseline EGFR T790M mutation treated with Osimertinib.

• EGFR T790M mutation
• Osimertinib
• meta-analysis
• non-small cell lung cancer
• resistance

Lung adenocarcinoma is one of the most common malignant tumors worldwide. Although efforts have been made to clarify its pathology, the underlying molecular mechanisms of lung adenocarcinoma are still not clear. The microarray datasets GSE75037, GSE63459 and GSE32863 were downloaded from the Gene Expression Omnibus (GEO) database to identify biomarkers for effective lung adenocarcinoma diagnosis and therapy. The differentially expressed genes (DEGs) were identified by GEO2R, and function enrichment analyses were conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The STRING database and Cytoscape software were used to construct and analyze the protein-protein interaction network (PPI). We identified 376 DEGs, consisting of 83 upregulated genes and 293 downregulated genes. Functional and pathway enrichment showed that the DEGs were mainly focused on regulation of cell proliferation, the transforming growth factor β receptor signaling pathway, cell adhesion, biological adhesion, and responses to hormone stimulus. Sixteen hub genes were identified and biological process analysis showed that these 16 hub genes were mainly involved in the M phase, cell cycle phases, the mitotic cell cycle, and nuclear division. We further confirmed the two genes with the highest node degree, DNA topoisomerase IIα (TOP2A) and aurora kinase A (AURKA), in lung adenocarcinoma cell lines and human samples. Both these genes were upregulated and associated with larger tumor size. Upregulation of AURKA in particular, was associated with lymphatic metastasis. In summary, identification of the DEGs and hub genes in our research enables us to elaborate the molecular mechanisms underlying the genesis and progression of lung adenocarcinoma and identify potential targets for the diagnosis and treatment of lung adenocarcinoma.

• cancer
• drug resistance
• heterogeneity
• sequencing technologies
• targeted therapies

• chemotherapy
• epidermal growth factor receptor
• mutation
• nonsmall cell lung cancer
• osimertinib

• Acrylamides/therapeutic use
• Aniline Compounds/therapeutic use
• Antineoplastic Agents/therapeutic use
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• ErbB Receptors/genetics
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Mutation
• Protein Kinase Inhibitors/therapeutic use

• KLK5
• L1CAM
• anlotinib
• non-small cell lung cancer
• transcriptome

Circulating tumor DNA (ctDNA) has emerged as a candidate biomarker for cancer screening. However, studies on the usefulness of ctDNA for postoperative recurrence monitoring are limited. The present study monitored ctDNA in postoperative blood by employing cancer-specific rearrangements. Personalized cancer-specific rearrangements in 25 gastric cancers were analyzed by whole-genome sequencing (WGS) and were employed for ctDNA monitoring with blood up to 12 months after surgery. Personalized cancer-specific rearrangements were identified in 19 samples. The median lead time, which is the median duration between a positive ctDNA detection and recurrence, was 4.05 months. The presence of postoperative ctDNA prior to clinical recurrence was significantly correlated with cancer recurrence within 12 months of surgery (P = 0.029); in contrast, no correlation was found between cancer recurrence and the presence of preoperative ctDNA, suggesting the clinical usefulness of postoperative ctDNA monitoring for cancer recurrence in gastric cancer patients. However, the clinical application of ctDNA can be limited by the presence of ctDNA non-shedders (42.1%, 8/19) and by inconsistent postoperative ctDNA positivity.

Fragments of tumor DNA, or circulating tumor DNA (ctDNA), in blood can help predict stomach cancer recurrence within 12 months of surgery. Kyeong-Man Hong at the National Cancer Center, in Goyang-si, South Korea, and colleagues, carried out whole genome sequencing of stomach tumor samples from 25 patients to identify personalized cancer-specific rearranged DNA sequences. When they used this information to monitor ctDNA in blood samples obtained after surgical removal of the tumor, they found a significant correlation between the presence of ctDNA and cancer recurrence. In most cases, ctDNA was detected around four months prior to clinical recurrence, highlighting the potential usefulness of ctDNA monitoring. The lack of correlation between ctDNA levels and tumor size suggests that further research into the factors determining ctDNA levels is needed.