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Previous studies have shown that metabolites play important roles in phenotypic regulation, but the causal link between metabolites and tumors has not been examined adequately. Herein, we investigate the causality between metabolites and various cancers through a Mendelian randomization (MR) study.We carried out a two-sample MR analysis based on genetic instrumental variables as proxies for 486 selected human serum metabolites to evaluate the causal effects of genetically determined metabotypes (GDMs) on cancers. Summary data from various cancer types obtained from large consortia. Inverse variance weighted (IVW), MR-Egger and weighted-median methods were implemented to infer the causal effects, moreover, we particularly explored the presentence of horizontal pleiotropy through MR-Egger regression and MR-PRESSO Global test. Metabolic pathways analysis and subgroup analyses were further explored using available data. Statistical analyses were all performed in R.In MR analysis, 202 significant causative relationship features were identified. 7-alpha-hydroxy-3-oxo-4-cholestenoate (OROur study integrated metabolomics and genomics to explore the risk factors involved in the development of cancers. It is worth exploring whether metabolites with causality can be used as biomarkers to distinguish patients at high risk of cancer in clinical practice. More detailed studies are needed to clarify the mechanistic pathways.

BACKGROUND: The aim of this study was to investigate the clinical features, immunohistochemistry (IHC), compound mutation, and prognosis of patients with non-small cell lung cancer (NSCLC) harboring exon 19 deletion-insertion mutations. METHODS: This retrospective analysis included 4,666 NSCLC patients harboring epidermal growth factor receptor (EGFR) mutations in a multi-center study from January 2017 to December 2020, and 69 patients with EGFR exon 19 deletion-insertions were taken to account. Next-generation sequencing (NGS) was used to detect the subtype of EGFR exon 19 deletion-insertions. These mutations were correlated with clinical features, immunophenotype and molecular characteristics of tumors and outcomes of patients. RESULTS: Sixty-nine patients with EGFR exon 19 deletion-insertions were analyzed in this study, comprising 24 cases (34.8%) with L747_P753delinsS, 9 cases (13.1%) with L747_A750delinsP, both 5 cases (7.2%) in E746_A750delinsQP, E746_S752delinsV and both 4 cases (5.8%) in E746_T751delinsA and L747_T751delinsP. Twenty-nine males (42%) and 40 females (58%), with a median age of 59.7 years; 12 (21.7%) participants were smokers and 54 (78.3%) were nonsmokers. The compound mutations were tumor protein 53 (TP53) (45.83%), phosphoinositide-3-kinase (PIK3CA) (11.59%), and almost 16.67% in retinoblastoma 1 (RB1), melanocyte stimulating hormone (MSH), and myelocytomatosis (MYC). The best overall response was complete response (CR) in 47.8% of patients, partial response (PR) in 33.3% and stable disease (SD) in 13.1% of patients. Correlation between immunoreactivity of Napsin A, thyroid transcription factor (TTF), cytokeratin (CK7), surfactant proteins B (SPB), and the subtypes of EGFR exon 19 deletion-insertion was significantly statistically different (P

Lung cancer is one of the most prevalent and lethal cancers worldwide (1). The traditional treatments include surgery, chemotherapy, radiotherapy and interventional therapy. The survival of lung cancer patients has dramatically been prolonged in recent years with the availability of targeted therapies, antiangiogenic agents and immune checkpoint inhibitors (ICIs). Meanwhile, technologies for the molecular detection of lung cancer have also advanced rapidly: the detection of single driver genes has evolved to cover combined multi-gene analysis, and whole exome sequencing (WES) has increasingly been applied in the clinical setting. In addition, life support technologies, including ventilators, artificial liver, and artificial kidney as well as extracorporeal membrane oxygenation (ECMO), have further matured, providing powerful forms of life support for patients with various acute and critical diseases. However, most clinical studies have only enrolled patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores from 0 to 1, with few patients having PS scores of 2; patients with a PS score of 3 or 4 have been typically excluded. Therefore, due to the lack of high-quality evidence, supportive care is recommended for patients with a PS score of 3 to 4 in the current guidelines. In the real-world, however, approximately 25% of lung cancer patients present with PS score of 3 or 4 (2) or attain scores between 3 and 4 during the course of treatment. Certain patients with high PS scores can benefit from individualized anti-tumor treatment plus appropriate life-support techniques. In 2017, the Lung Cancer Research Team at the First Affiliated Hospital of Guangzhou Medical College & Institute of Respiratory Diseases for the first time pioneered the concept of “advanced severe lung cancer” (3) and argued that standardized therapy for chronic obstructive pulmonary disease (COPD) plus anti-tumor therapy can improve both quality of life and prognosis in patients with lung cancer combined with COPD. The authors also found that the early detection of lung cancer driver genes and timely targeted therapy can be successful in treating patients with advanced severe lung adenocarcinoma with a PS score of 4 (4). In 2019, the concept of advanced severe lung cancer was further developed in a featured article (5) that indicated “Advanced severe lung cancer: does not refer to end-stage lung cancer but rather to stage IIIB, IIIC and IV lung cancers with a PS score of 2–4, which can result from a variety of factors related to the disease itself or anti-tumor drugs and which are highly likely to benefit from the currently available systemic anti-tumor therapies”. In recent years, with the advances in lung cancer diagnosis and treatment techniques and life support technologies, more clinical studies have enrolled patients with a PS score of 2, and some real-world studies have enrolled patients with PS scores of 3–4. Even for patients with early-stage lung cancer, studies have shown that patients with poor PS scores and co-morbidities have a reduced chance of undergoing surgery and an increased mortality rate (6); nevertheless, survival benefit may still be obtained through surgical modifications combined with individualized and multidisciplinary treatment (7). Therefore, the concept of severe lung cancer should not be limited to advanced lung cancer, but applied to all lung cancer patients. In particular, due to the increase in treatment options as well as substantially prolonged survival, the majority of patients may have a PS score between 2 and 4 for a certain period of time due to a variety of reasons. How to provide timely and reasonable treatment for these lung cancer patients has become a critically important real-world research topic. Therefore, we invited lung cancer experts at home and abroad to consider this issue, and this group has reached the following consensus.

BACKGROUND: As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. METHODS: To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. RESULTS: In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. CONCLUSIONS: LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.

Background The generation of subclonal (low-frequency) mutations is driven by tumor mutations and the relationship between the heterogeneity of tumor mutation abundance and non-small cell lung cancer (NSCLC) remains unknown. We investigate the role of allele frequency heterogeneity (AFH) defined by circulating tumor DNA (ctDNA) profiling in predicting prognosis in advanced NSCLC patients. Methods Publicly available data set of POPLAR (N=211) and OAK (N=642) trials were used for analyzing. A low ratio of allele frequency (AF) of a mutation to the maximum-somatic-allele-frequency (MSAF) was used to define the presence of AFH. The prognostic value of AF/MSAF ratio that was below a defined cutoff point in overall survival (OS) was evaluated using Cox-proportional hazards regression; and the structural break point was determined by LOESS regression and Chow test. The derived AFH was also explored in an independent cohort (N=259) of advanced NSCLC receiving first-line EGFR-TKIs from the First Affiliated Hospital of Guangzhou Medical University. Results In the POPLAR and OAK cohort, low AF/MSAF ratio was found to be significantly associated with unfavorable OS in univariate and multivariate analysis. The structural break point analysis demonstrated that AF/MSAF

BACKGROUND: Several randomized controlled trials have suggested that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were associated with prolonged disease-free survival (DFS) in EGFR-mutated NSCLC patients after radical resection, comparing with chemotherapy or placebo. We aimed to compare the effectiveness of different first-generation EGFR-TKIs as adjuvant treatment in real-world setting. METHODS: Early-stage EGFR mutated NSCLC patients who underwent radical resection and treated with first-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) as adjuvant therapy between Feb 2010 and Jan 2019 were retrieved from a prospectively-maintained database in our center. The primary endpoint was DFS in stage II/III (TNM 8th) patients with exploratory endpoint regarding DFS in stage I patients. Sensitivity analyses were based on propensity score matched (PSM) cohorts. Treatment failure patterns among different TKIs were also compared. RESULTS: Of 588 eligible patients, 198 patients (33.7%) received gefitinib, 106 patients (17.9%) received erlotinib, and 284 patients (48.2%) received icotinib. The median DFS of stage II/III patients in the gefitinib, erlotinib and icotinib group were 36.1 months (95% CI, 23.9–49.4), 42.8 months (95% CI, 29.6–97.8), and 32.5 months (95% CI, 23.9–49.4), respectively, with no significant difference (log-rank test P=0.22). There was also no significant difference in DFS among stage I patients receiving different TKIs (P=0.12). PSM adjustments and multivariate analyses adjusting for other confounders revealed similar results. In addition, there were no significant differences in treatment failure pattens in different EGFR-TKI arms, especially in terms of brain metastases (6.1% in gefitinb, 7.5% in erlotinib, 3.9% in icotinib) and bone metastases (8.6% in gefitinb, 9.4% in erlotinib, 7.0% in icotinib). CONCLUSIONS: This first and largest real-world study showed that gefitinib, erlotinib, and icotinib demonstrated comparable clinical effectiveness as adjuvant therapy for patients with early-stage EGFR mutated NSCLC.

Background: The etiology of non-small cell lung cancer (NSCLC) in non-smoker patients remains largely unknown. It has been widely proved that human papillomavirus (HPV) participates in the development of various cancers. Epidermal growth factor receptor (EGFR) mutation patients represent a large portion of non-smokers with NSCLC. We performed this meta-analysis to determine whether HPV infection in NSCLC tissue is associated with EGFR mutations compared with HPV negative controls. Methods: Online databases were searched up to June 30th 2017. We included studies in which HPV detection was based on polymerase chain reaction (PCR) methods. Random effects model was used in data synthesis and the relative effects were presented as odds ratio (OR) with 95% confidence intervals (CIs). Results: Finally, four eligible studies with a total of 498 patients from Asian countries were identified and included. The general EFGR mutation positive rate was 38.2% among all patients, and the HPV DNA detection rate (HPV subtype being involved: 16, 18, 33 and 58) was 35.3%. The presence of EGFR mutation was significantly higher in HPV-positive patients compared with HPV-negative controls (52% vs . 31%; OR =2.41, 95% CI: 1.21 to 4.77; P=0.012), with moderate heterogeneity among studies (I 2 =59%; P=0.062). Conclusions: Our results suggest that HPV infection is associated with EGFR mutations in NSCLC, at least in Asian populations. Further efforts should be made on exploring the potential mechanism and the prognostic character of HPV/EGFR positive NSCLC patient.