Comparison of the somatic genomic landscape between central- and peripheral-type non-small cell lung cancer.

OBJECTIVE: Lung cancer is classified into central and peripheral types based on the anatomic location. The present study aimed to explore the distinct patterns of genomic alterations between central- and peripheral-type non-small cell lung cancers (NSCLCs) with negative driver genes and identify potential driver genes and biomarkers to improve therapy strategies for NSCLC. METHODS: Whole-exome sequencing (WES) was performed with 182 tumor/control pairs of samples from 145 Chinese NSCLC patients without EGFR, ALK, or ROS1 alterations. Significantly mutated genes (SMGs) and somatic copy number alterations (SCNAs) were identified. Subsequently, tumor mutation burden (TMB), weighted genome integrity index (wGII), copy number alteration (CNA) burden, Shannon diversity index (SDI), intratumor heterogeneity (ITH), neoantigen load (NAL), and clonal variations were evaluated in central- and peripheral-type NSCLCs. Furthermore, mutational signature analysis and survival analysis were performed. RESULTS: TP53 was the most frequently mutated gene in NSCLC and more frequently mutated in central-type NSCLC. Higher wGII, ITH, and SDI were found in central-type lung adenocarcinoma (LUAD) than in peripheral-type LUAD. The NAL of central-type lung squamous cell carcinoma (LUSC) with stage III/IV was significantly higher than that of peripheral-type LUSC. Mutational signature analysis revealed that SBS10b, SBS24, and ID7 were significantly different in central- and peripheral-type NSCLCs. Furthermore, central-type NSCLC was found to evolve at a higher level with fewer clones and more subclones, particularly in central-type LUSC. Survival analysis revealed that TMB, CNA burden, NAL, subclonal driver mutations, and subclonal mutations were negatively related to the overall survival (OS) and the progression-free survival (PFS) of central-type LUAD. CONCLUSIONS: Central-type NSCLC tended to evolve at a higher level and might suggest a favorable response to immunotherapy. Our study also identified several potential driver genes and promising biomarkers for the prognosis and prediction of chemotherapy responses in NSCLC.

Regulatory considerations for generic products of non-biological complex drugs.

The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.

Analysis of prognostic and therapeutic values of drug resistance-related genes in the lung cancer microenvironment.

Background: The interaction between cancer cells and stromal cells has a significant contribution in tumorigenesis and tumor development, and plays an anti-tumor immune effect under the regulation of drug resistance-related genes, which affects the outcome of patients. Coiled-coil domain-containing protein 73 (CCDC73), DLG associated protein 1 (DLGAP1), dermatan sulfate epimerase like (DSEL), estrogen receptor 1 (ESR1), and SEC14-like 5 (SEC14L5) were identified as drug resistance-related genes in lung cancer. However, these genes have no clear value in lung cancer in terms of expression and prognosis. Methods: ONCOMINE, GEPIA, UALCAN, cBioPortal, GeneMANIA, STRING, and TIMER were utilized in this study. Results: The transcriptional expression level of DLGAP1 was remarkably decreased in lung cancer tissues, while the transcriptional level of SEC14L5 was significantly increased. The pathological stage of lung adenocarcinoma (LUAD) was tightly correlated with the expression of SEC14L5. The lung cancer patients with high transcription level of CCDC73 gene tended to have a good prognosis. The function of drug resistance-related genes is mainly related to RNA polymerization. Our results showed that infiltration of six types of immune cells (dendritic cells, macrophages, neutrophils, B cells, CD4+ T cells, and CD8+ T cells) significantly correlated with the expression of these drug resistance-related genes. Conclusions: Novel screening for immunotherapy targets and prognostic biomarkers in lung cancer may draw inspiration from our results.

Microbes in lung cancer initiation, treatment, and outcome: Boon or bane?

Lung cancer is the top reason for cancer-related deaths worldwide. The 5-year overall survival rate of lung cancer is approximately 20 % due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are associated with the risk of lung cancers based on epidemiological evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.

Mechanisms of Progression and Heterogeneity in Multiple Nodules of Lung Adenocarcinoma.

Lung cancer remains the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD) is thought to be caused by precursor lesions of atypical adenoma-like hyperplasia and may have extensive in situ growth before infiltration. To explore the relevant factors in heterogeneity and evolution of lung adenocarcinoma subtypes, the authors perform single-cell RNA sequencing (scRNA-seq) on tumor and normal tissue from five multiple nodules' LUAD patients and conduct a thorough gene expression profiling of cancer cells and cells in their microenvironment at single-cell level. This study gives a deep understanding of heterogeneity and evolution in early glandular neoplasia of the lung. This dataset leads to discovery of the changes in the immune microenvironment during the development of LUAD, and the development process from adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IAC). This work sheds light on the direction of early tumor development and whether they are homologous.

Percutaneous Microwave Coagulation Therapy: A Promising Therapeutic Method for Breaking the Barrier of the Intertumor Heterogeneity.

Intertumor heterogeneity is common in various cancers and has been widely accepted as the primary cause of the diversity and variation of the effect of the same treatment on patients with the same type of tumor. Percutaneous microwave coagulation therapy (PMCT) is a minimally invasive and effective approach for destroying tumors by microwave beam under image guidance, which has been applied in lung cancer. However, no previous study has investigated the capability of PMCT solving intertumor heterogeneity. Here, we performed a component analysis of four lung cancer patients' tumor microenvironment (TME) via single-cell RNA sequencing (scRNA-seq) and treated all four cases with PMCT. One patient's TME could be classified into a hot tumor, mainly proinflammatory cytokines, and T cell infiltration. The other three patients' TMEs were cold tumors, where immunosuppressive cells occupied a large proportion, including tumor-associated macrophages and cancer cells. Despite a high level of heterogeneity among their tumor microenvironment compositions, disease type and stage, and basic physical conditions, all four patients presented a stable disease (SD) without any cancer cell detected in the TME of cancer tissues after PMCT. In conclusion, this report uniquely contributed to the knowledge of the PMCT adaptation to tumor heterogeneity. Therefore, PMCT is promising to demonstrate a stable and robust antitumor efficacy in unresectable lung cancers with various TMEs.

Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy.

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer.

DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no EGFR/ALK alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types (p < 0.001). DDR mechanisms attach great importance to the determination of patients' prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all p < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692-0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including TAP1 and TAP2 than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 (p = 0.01), CD28 (p = 0.020), HLA-DRB6 (p = 0.014) in adenocarcinoma, lower TNFRSF4 (p = 0.017), and TGFB1 expressions (p = 0.033) in squamous carcinoma, and higher CD40 (p = 0.012) and TNFRSF14 expressions (p = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma (p = 0.044) and M2 macrophage in squamous carcinoma (p = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.

A narrative review of tumor heterogeneity and challenges to tumor drug therapy.

OBJECTIVE: To accurately evaluate tumor heterogeneity, make multidimensional diagnosis according to the causes and phenotypes of tumor heterogeneity, and assist in the individualized treatment of tumors. BACKGROUND: Tumor heterogeneity is one of the most essential characteristics of malignant tumors. In tumor recurrence, development, and evolution, tumor heterogeneity can lead to the formation of different cell groups with other molecular characteristics. Tumor heterogeneity can be characterized by the uneven distribution of tumor cell subsets of other genes between and within the disease site (spatial heterogeneity) or the time change of cancer cell molecular composition (temporal heterogeneity). The discovery of tumor targeting drugs has dramatically promoted tumor therapy. However, the existence of heterogeneity seriously affects the effect of tumor treatment and the prognosis of patients. METHODS: The literature discussing tumor heterogeneity and its resistance to tumor therapy was broadly searched to analyze tumor heterogeneity as well as the challenges and solutions for gene detection and tumor drug therapy. CONCLUSIONS: Tumor heterogeneity is affected by many factors consist of internal cell factors and cell microenvironment. Tumor heterogeneity greatly hinders effective and individualized tumor treatment. Understanding the fickle of tumors in multiple dimensions and flexibly using a variety of detection methods to capture the changes of tumors can help to improve the design of diagnosis and treatment plans for cancer and benefit millions of patients.

Visible Light-Driven Jellyfish-like Miniature Swimming Soft Robot.

Soft actuators that exhibit large deformation and can move at a fast speed in response to external stimuli have been in high demand for biomimetic applications. In this paper, we propose a convenient approach to fabricate a reversible and thermal-responsive composite hydrogel. Under the irradiation of visible light, the striped hydrogel can bend at a speed of up to 65.72°/s with carbon nanotubes loaded at a concentration of 3 mg/mL. A jellyfish-like miniature soft robot is made using this hydrogel. When driven by visible light, the robot can move at a maximum speed of 3.37 mm/s. Besides swimming, other motion modes, including walking and jumping, are also achieved by the robot. In addition, the robot can perform directional transportation of tiny objects. As a new actuation approach for the research of jellyfish-like miniature soft robots, this work is of great significance to the development of flexible bionic robots. Moreover, this work also offers some important insights into the research of biomimetic robots driven by visible light.

Collection on reports of molecules linked to epithelial-mesenchymal transition in the process of treating metastasizing cancer: a narrative review.

Epithelial-mesenchymal transition (EMT) is a morphological process in which epithelial cells transform into mesenchymal cells via a specific procedure. EMT plays an important role in the cancer invasion-metastasis cascade and the current treatment of metastatic cancer, influences the migration, polarity, and adhesion of tumor cells, promotes their migration, invasiveness, anti-apoptotic ability. It contributes to the changes of the tumor microenvironment and suppresses the sensitivity of tumor cells to chemotherapy, causing cancer metastasis and worse, hindering the control and therapy of it. This paper reviews the mechanisms, detection, and treatments of cancer metastasis that have been identified and applied to date, summarizes the EMT-related biological molecules, providing a reference for EMT-targeted research and therapy. As EMT is significant in the progress of tumor metastasis, it is meaningful for the therapy and control of metastatic cancer to understand the mechanism of EMT at the molecular level. We summarized the mechanisms, detection and therapeutic implications of EMT, listed the research progress of molecules like genes, miRNAs, signaling pathways in EMT. We also discussed the prospects of EMT-targeted treatment in cancer metastasis interventions and the challenges the treatment and researches are facing. The summary is conducive to the treatment and further research of EMT and metastatic cancer.

Risk-score model to predict prognosis of malignant airway obstruction after interventional bronchoscopy.

BACKGROUND: Interventional bronchoscopy exhibits substantial effects for patients with malignant airway obstruction (MAO), while little information is available regarding the potential prognostic factors for these patients. METHODS: Between October 31, 2016, and July 31, 2019, a total of 150 patients undergoing interventional bronchoscopy and histologically-confirmed MAO were collected, in which 112 eligible participants formed the cohort for survival study. External validation cohort from another independent institution comprised 33 MAO patients with therapeutic bronchoscopy. The least absolute shrinkage and selection operator regression (LASSO) was applied to the model development dataset for selecting features correlated with MAO survival for inclusion in the Cox regression from which we elaborated the risk score system. A nomogram algorithm was also utilized. RESULTS: In our study, we observed a significant decline of stenosis rate after interventional bronchoscopy from 71.7%±2.1% to 36.6%±2.7% (P<0.001) and interventional bronchoscopy dilated airway effectively. Patients in our study undergoing interventional bronchoscopy had a median survival time of 614.000 days (95% CI: 269.876-958.124). Patients receiving distinct therapeutic methods of interventional bronchoscopy had different prognosis (P=0.022), and patients receiving treatment of electrocoagulation in combination with stenting and electrosurgical snare had worse survival than those receiving other options. Multivariate Cox analysis revealed that nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, as independent predictive factors for better overall survival (OS) of MAO patients. Then, the nomogram based on Cox regression and risk score system based on results from LASSO regression were elaborated respectively. Importantly, this risk score system was proved to have better performance than the nomogram and other single biomarkers such as traditional staging system (area under the curve 0.855 vs. 0.392-0.739). Survival curves showed that patients with the higher risk-score had poorer prognosis than those with lower risk-score (third quantile of OS: 126.000 days, 95% CI: 73.588-178.412 vs. 532.000 days, 95% CI: 0.000-1,110.372; P<0.001). CONCLUSIONS: Nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, were independent predictive factors for better OS of MAO patients. We proposed a nomogram and risk score system for survival prediction of MAO patients undergoing interventional bronchoscopy with good performance.

An immune-based risk-stratification system for predicting prognosis in pulmonary sarcomatoid carcinoma (PSC).

Pulmonary sarcomatoid carcinoma (PSC) is an uncommon subtype of lung cancer, and immune checkpoint blockade promises in clinical benefit. However, virtually nothing is known about the expression of common immune checkpoints in PSC. Here, we performed immunohistochemistry (IHC) to detect nine immune-related proteins in 97 PSC patients. Based on the univariable Cox regression, random forests were used to establish risk models for OS and DFS. Moreover, we used the GSEA, CIBERSORT, and ImmuCellAI to analyze the enriched pathways and microenvironment. Univariable analysis revealed that CD4 (P = 0.008), programmed cell death protein 1 (PD-1; P = 0.003), galectin-9 (Gal-9) on tumor cells (TCs; P = 0.021) were independent for DFS, while CD4 (P = 0.020), PD-1 (P = 0.004), Gal-9 (P = 0.033), and HLA on TILs (P = 0.031) were significant for OS. Meanwhile, the expression level of CD8 played a marginable role in DFS (P = 0.061), limited by the number of patients. The combination of Gal-9 on TC with CD4 and PD-1 on TILs demonstrated the most accurate prediction for DFS (AUC: 0.636-0.791, F1-score: 0.635-0.799), and a dramatic improvement to TNM-stage (P < 0.001 for F1-score of 1-y, 3-y, and 5-yDFS). A similar finding was also observed in the predictive ability of CD4 for OS (AUC: 0.602-0.678, F1-score: 0.635-0.679). CD4 was negatively associated with the infiltration of neutrophils (P = 0.015). PDCD1 (coding gene of PD-1) was positively correlated to the number of exhausted T cells (Texs; P = 0.020) and induced regulatory T cells (iTregs; P = 0.021), and LGALS9 (coding gene of Gal-9) was positively related to the level of dendritic cells (DCs; P = 0.021). Further, a higher combinational level of CD4, PDCD1 on TILs, and LAGLS9 on TCs were proved to be infiltrated with more M1-type macrophages (P < 0.05). We confirmed the expression status of nine immune-related proteins and established a TNM-Immune system for OS and DFS in PSC to assist clinical risk-stratification.

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC.

Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma.

INTRODUCTION: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies. METHODS: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics. RESULTS: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes. CONCLUSION: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.

FOXP3-based immune risk model for recurrence prediction in small-cell lung cancer at stages I-III.

BACKGROUND: Immunotherapies may prolong the survival of patients with small-cell lung cancer (SCLC) to some extent. The role of forkhead box protein P3 (FOXP3) in tumor microenvironment (TME) remains controversial. We aimed to examine FOXP3-related expression characteristics and prognostic values and to develop a clinically relevant predictive system for SCLC. METHODS: We enrolled 102 patients with histologically confirmed SCLC at stages I-III. Through immunohistochemistry, we determined the expression pattern of FOXP3 and its association with other immune biomarkers. By machine learning and statistical analysis, we constructed effective immune risk score models. Furthermore, we examined FOXP3-related enrichment pathways and TME traits in distinct cohorts. RESULTS: In SCLC, FOXP3 level was significantly associated with status of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), CD4, CD8, and CD3 (p=0.002, p=0.001, p=0.002, p=0.030, and p<0.001). High FOXP3 expression showed longer relapse-free survival (RFS) than the low-level group (41.200 months, 95% CI 26.937 to 55.463, vs 14.000 months, 95% CI 8.133 to 19.867; p=0.008). For tumor-infiltrating lymphocytes (TILs), subgroup analysis demonstrated FOXP3 and PD-1, PD-L1, lymphocyte activation gene-3, CD3, CD4, or CD8 double positive were significantly correlated with longer RFS. We further performed importance evaluation for immune biomarkers, constructed an immune risk score incorporating the top three important biomarkers, FOXP3, TIL PD-L1, and CD8, and found their independently prognostic role to predict SCLC relapse. Better predictive performance was achieved in this immune risk model compared with single-indicator-based or two-indicator-based prediction systems (area under the curve 0.715 vs 0.312-0.711). Then, relapse prediction system integrating clinical staging and immune risk score was established, which performed well in different cohorts. High FOXP3-related genes were enriched in several immune-related pathways, and the close relationships of interleukin-2, CD28, basic excision repair genes MUTYH, POLD1, POLD2, and oxidative phosphorylation related gene cytochrome c oxidase subunit 8A with FOXP3 expression were revealed. Moreover, we found low-immune risk score group had statistically higher activated CD4+ memory T cells (p=0.014) and plasma cells (p=0.049) than the high-risk group. The heterogeneity of tumor-infiltrating immune cells might represent a promising feature for risk prediction in SCLC. CONCLUSION: FOXP3 interacts closely with immune biomarkers on tumor-infiltrating cells in TME. This study highlighted the crucial prognostic value and promising clinical applications of FOXP3 in SCLC.

Research progress on the molecular mechanisms of hepatic metastasis in lung cancer: a narrative review.

The liver is one of the most common sites of metastatic spread of lung cancer, and the process of metastasis is regulated by many factors. A number of genes, including multiple tumor suppressor 1 (mts1), p120 catenin, and CT45A1, increase the possibility of hepatic metastasis in lung cancer, whereas Tip30/CC3, CUL5, and SOCS3 expression in lung tumors inhibit tumor metastasis. microRNAs (miRNAs), such as miRNA-126, miRNA-338, and miRNA-218, can affect the metastasis of lung cancer cells to the liver. The D114-Notch signaling pathway can inhibit liver metastasis in small cell lung cancer. Serum tumor markers cytokeratin 19 fragment antigen 21-1 and neuron-specific enolase (NSE) are closely related to the risk of hepatic metastasis in lung cancer. Based on previously published literature, we found that the metastasis and invasion of lung cancer to the liver are determined by molecular factors. Therefore, the selective identification and intervention of these erroneous signals can predict early lung cancer metastasis to the liver. In this review article, we describe the mechanisms and influencing factors (genes, signal pathways, chemicals, proteins, miRNAs) of hepatic metastasis in lung cancer. We hope to provide a summary of the evidence for the mechanisms by which related genes or proteins affect the malignancy of liver metastasis from lung cancer so that doctors and researchers can improve treatment options.

Curative efficacy might be an early predictor of prognosis in patients with small cell lung cancer treated with 2 cycles of platinum-based first-line chemotherapy.

BACKGROUND: Platinum-based chemotherapy remains the essential therapy for small cell lung cancer (SCLC). Here, we conducted a statistical analysis to explore whether the curative efficacy of 2-cycle platinum-based chemotherapy can predict the survival of patients with SCLC. METHODS: Fifty-six SCLC patients who had each received 2 cycles of platinum-based chemotherapy were enrolled. The curative efficacy of the chemotherapy was evaluated, mainly by chest computed tomography, and the treatment response was categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients were continuously followed up for progression-free survival (PFS) and overall survival. The 55 patients were separated into 2 groups by the curative efficacy of the 2-cycle first-line platinum-based chemotherapy. All statistical analyses were performed with SPSS software (version 17.0; SPSS, Inc.; Chicago, IL, USA). RESULTS: Patients who responded to 2-cycle chemotherapy (partial response, PR) had significantly better survival than others who did not (stable disease, SD or progressive disease, PD). The median progression-free survival (mPFS) in the PR group was 6.330 months, which was significantly longer than the 2.870 months seen in SD+PD group (95% CI: 4.631-8.029 vs. 0.000-5.790, P=0.022). The median overall survival (mOS) was 10.870 months in the PR group, which was remarkably longer than the 8.970 months observed in the SD+PD group (95% CI: 9.546-12.194 vs. 6.517-11.423, P=0.028). Curative efficacy had no correlation with clinical features. CONCLUSIONS: The curative efficacy of 2-cycle first-line platinum-based chemotherapy was significantly correlated with PFS and OS, and showed prognostic value in SCLC patients. Patients who were sensitive to chemotherapy had superior survival to those who were chemotherapy insensitive.

Single-Cell Sequencing, an Advanced Technology in Lung Cancer Research.

Single-cell sequencing (SCS) which has an unprecedentedly high resolution is an advanced technique for cancer research. Lung cancer still has a high mortality and morbidity. For further understanding the lung cancer, SCS is also been applied to lung cancer research to investigate its heterogeneity, metastasis, drug resistance, tumor microenvironment and many other issues. In this review, we summarized lung cancer research using SCS and their research achievements.

Aberrant methylation modifications reflect specific drug responses in small cell lung cancer.

In the study, Methylated DNA immunoprecipitation sequencing, RNA sequencing, and whole-exome sequencing were employed to clinical small cell lung cancer (SCLC) patients. Then, we verified the therapeutic predictive effects of differentially methylated genes (DMGs) in 62 SCLC cell lines. Of 4552 DMGs between chemo-sensitive and chemo-insensitive group, coding genes constituted the largest percentage (85.08%), followed by lncRNAs (10.52%) and miRNAs (3.56%). Both two groups demonstrated two methylation peaks near transcription start site and transcription end site. Two lncRNA-miRNA-mRNA networks suggested the extensive genome connection between chemotherapy efficacy-related non-coding RNAs (ncRNAs) and mRNAs. Combing miRNAs and lncRNAs could effectively predict chemotherapy response in SCLC. In addition, we also verified the predictive values of mutated genes in SCLC cell lines. This study was the first to evaluate multiple drugs efficacy-related ncRNAs and mRNAs which were modified by methylation in SCLC. DMGs identified in our research might serve as promising therapeutic targets to reverse drugs-insensitivity by complex lncRNA-miRNA-mRNA mechanisms in SCLC.