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Backgrounds: Non-small cell lung carcinoma (NSCLC) is a common type of lung cancer. Prior investigations have elucidated the pivotal role of miR-29b-3p in restraining tumor growth and metastasis. Nonetheless, it remains to be determined whether miR-29b-3p can effectively suppress NSCLC progression and enhance the sensitivity of NSCLC cells to cisplatin. This investigation sought to determine the mechanism by which miR-29b-3p inhibited the advancement of NSCLC and mitigated resistance to cisplatin., Methods: We initially assessed miR-29b-3p and VEGF levels in NSCLC tissues and cell lines. Next, miR-29b-3p expression was elevated in NSCLC cell lines H1975 and A549 by overexpression plasmid transfection. Following this, a sequence of molecular biology experiments was conducted to evaluate the impact of miR-29b-3p on the biological behaviors of NSCLC cells and their resistance to cisplatin. Additionally, we predicted VEGF was a target gene of miR-29b-3p by bioinformatics analysis. We next employed western blot to evaluate the protein expression of Nrf2 and HO-1 in NSCLC cells. Finally, we elucidated the effects of VEGF and Nrf2/HO-1pathway on NSCLC progression and cisplatin resistance by in vitro assays., Results: In comparison to paracancerous tissues and human normal lung epithelial cells, the expression of miR-29b-3p was notably reduced and VEGF expression was clearly elevated in NSCLC tissues and cells. Moreover, miR-29b-3p upregulated obviously suppressed the biological activities of NSCLC cells and increased their sensitivity to cisplatin. Furthermore, in NSCLC cells, miR-29b-3p bound to VEGF and negatively regulate its transcription. Additionally, miR-29b-3p overexpression also inhibited the Nrf2/HO-1 signaling pathway. Finally, the overexpression of VEGF and the activation of the Nrf2/HO-1 pathway reversed miR-29b-3p-mediated inhibitory effect on biological behaviors of NSCLC cells and increased the cisplatin resistance., Conclusion: Our findings indicate that miR-29b-3p impedes NSCLC cells' biological behaviors and augments their sensitivity to cisplatin by targeting VEGF to modulate the Nfr2/HO-1 signaling pathway., (© 2024 Wiley Periodicals LLC.)

Smoking is a well-known risk factor for non-small-cell lung cancer (NSCLC) and bladder urothelial carcinoma (BLCA). Despite this, there has been no investigation into a prognostic marker based on smoking-related genes that could universally predict prognosis in these cancers and correlate with immune checkpoint therapy. This study aimed to identify smoking-related differential genes in NSCLC and BLCA, analyse their roles in patient prognosis and immune checkpoint therapy through subgroup analyses, and shed light on PRR11 as a crucial prognostic gene in both cancers. By examining PRR11 co-expressed genes, a prognostic model was constructed and its impact on immunotherapy for NSCLC and BLCA was evaluated. Molecular docking and tissue microarray analyses were conducted to explore the correlation between PRR11 and its reciprocal gene SPDL1. Additionally, miRNAs associated with PRR11 were analysed. The study confirmed a strong link between smoking-related genes, prognosis, and immune checkpoint therapy in NSCLC and BLCA. PRR11 was identified as a key smoking-associated gene that influences the efficacy of immune checkpoint therapy by modulating the stemness of these cancers. A prognostic model based on PRR11 co-expressed genes in BLCA was established and its prognostic value was validated in NSCLC. Furthermore, it was found that PRR11 regulates PDL1 via SPDL1, impacting immunotherapeutic efficacy in both cancers. The involvement of hsa-miR-200b-3p in the regulation of SPDL1 expression by PRR11 was also highlighted. Overall, the study elucidates that PRR11 modulates patient immunotherapy by influencing PDL1 expression through its interaction with SPDL1, with potential upstream regulation by hsa-miR-200b-3p., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Metastasis is the leading cause for the high mortality of lung cancer, however, effective anti-metastatic drugs are still limited. Here it is reported that the RNA-binding protein RBMS1 is positively associated with increased lymph node metastasis in non-small cell lung cancer (NSCLC). Depletion of RBMS1 suppresses cancer cell migration and invasion in vitro and inhibits cancer cell metastasis in vivo. Mechanistically, RBMS1 interacts with YTHDF1 to promote the translation of S100P, thereby accelerating NSCLC cell metastasis. The RRM2 motif of RBMS1 and the YTH domain of YTHDF1 are required for the binding of RBMS1 and YTHDF1. RBMS1 ablation inhibits the translation of S100P and suppresses tumor metastasis. Targeting RBMS1 with NTP, a small molecular chemical inhibitor of RBMS1, attenuates tumor metastasis in a mouse lung metastasis model. Correlation studies in lung cancer patients further validate the clinical relevance of the findings. Collectively, the study provides insight into the molecular mechanism by which RBMS1 promotes NSCLC metastasis and offers a therapeutic strategy for metastatic NSCLC., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8 + T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8 + T cells., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Orifice reduction strategies for da Vinci robotic surgery have been a hot topic of research in recent years. We retrospectively analyzed the perioperative outcomes of robotic-assisted thoracoscopic surgery (RATS) with two, three, and four-hole approaches in radical lung cancer surgery. Our results revealed that the two-hole group has advantages in terms of operative time, postoperative 3-day drainage, postoperative drainage time, postoperative hospital stay and postoperative day 3 visual analogue scale (VAS) pain scores. There were no significant differences between the three groups in terms of intraoperative bleeding, number of lymph nodes dissected, VAS pain scores on postoperative days 1 and 2, and postoperative complications. In addition, the two-hole group was superior to the three-hole and four-hole groups in terms of C-reactive protein (CRP), procalcitonin (PCT) and interleukin 10 (IL-10). In summary, the RATS two-hole approach has advantages in operation time, rapid recovery after operation and some postoperative inflammatory indicators, and is worth promoting in hospitals that are skilled in three-hole and four-hole da Vinci robot surgery and have conditions., (© 2023. Italian Society of Surgery (SIC).)

Antisense oligonucleotides hold therapeutic promise for various lung disorders, but their efficacy is limited by suboptimal delivery. To address this challenge, we explored the use of inhaled bottlebrush polymer-DNA conjugates, named pacDNA, as a delivery strategy. Inhaled pacDNA exhibits superior mucus penetration, achieving a uniform and sustained lung distribution in mice. Targeting the 5' splice site of an aberrant enhanced green fluorescence protein ( EGFP ) pre-mRNA in EGFP-654 mice, inhaled pacDNA more efficiently corrects splicing than a B-peptide conjugate and restores EGFP expression in the lung. Additionally, in an orthotopic NCI-H358 non-small-cell lung tumor mouse model, inhaled pacDNA targeting wild-type KRAS mRNA effectively suppresses KRAS expression and inhibits lung tumor growth, requiring a substantially lower dosage compared to intravenously injected pacDNA. These findings demonstrate the potential of bottlebrush polymer-DNA conjugates as a promising agent for enhanced oligonucleotide therapy in the lung and advancing the treatment landscape for lung disorders.

Background: Lung cancer is the leading cause of cancer-related death worldwide, and patients have limited survival benefits from traditional treatments such as surgery, radiotherapy and chemotherapy. As a new treatment for lung cancer, immunotherapy has significantly prolonged the overall survival (OS) of patients. However, only some patients can benefit from it. We need to explore immunotherapy biomarkers more deeply to screen for advantages., Methods: The original data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, and the immunological and prognostic genes of lung squamous cell carcinoma (LUSC) were screened using R software and TIMER database. The expression of target genes was studied in TCGA and GEO databases, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and correlation analysis with tumor immune characteristics were performed by R software and TISIDB database., Results: We screened out a gene related to immunity and prognosis, cAMP dependent protein kinase inhibitor γ (PKIG), which is significantly differentially expressed in LUSC and normal tissues, and has important reference value for the diagnosis and prognosis assessment of LUSC. PKIG differential genes are mainly concentrated in the regulation of humoral immune response and other processes. The expression of PKIG was positively correlated with the infiltration level of regulatory T cells (Tregs) (r=0.340, P<0.001). In addition, the expression level of PKIG was positively correlated with the expression of chemokines/chemokine receptors such as chemokine C-C motif ligand 2 (CCL2) (r=0.503, P<0.001), CXC chemokine ligand 12 (CXCL12) (r=0.386, P<0.001) and CXC-chemokine receptor 4 (CXCR4) (r=0.492, P<0.001), and immunoinhibitors such as programmed cell death protein 1 (PDCD1) (r=0.359, P<0.001), cytotoxic T-lymphocyte associated antigen 4 (CTLA4) (r=0.375, P<0.001) and T cell immunoglobulin and ITIM domains (TIGIT) (r=0.305, P<0.001) in LUSC., Conclusions: The immunological and prognostic gene PKIG in lung squamous cell carcinoma was screened through bioinformatics analysis. PKIG is highly correlated with LUSC prognosis and immune microenvironment, and is expected to be a potential biomolecular marker for LUSC immunotherapy.

Background: The three-dimensional (3D) can assist in planning lung segmentectomy. 3D reconstruction software based on artificial intelligence algorithm is gradually applied in clinic. The aim of this study was to evaluate the accuracy and safety of 3D reconstruction assisted planning of thoracoscopic segmentectomy., Methods: A total of 90 patients admitted to Department of Thoracic Surgery of Lanzhou University Second Hospital were evaluated for thoracoscopic segmentectomy. Before operation, artificial intelligence 3D reconstruction software was used to make 3D lung images and conduct preoperative planning. Surgical videos were saved during the operation and perioperative data were recorded. Video recordings of 38 patients were selected to explore the effectiveness of artificial intelligence 3D reconstruction for surgical planning. The results of artificial intelligence 3D reconstruction and Mimics 21 software reconstruction were compared with the actual results in the operation, and the detection and classification ability of bronchus and blood vessels of the two reconstruction methods were compared., Results: All the 90 patients underwent artificial intelligence 3D reconstruction planning, including 57 patients (63.3%) with single lung segmentectomy and 33 patients (36.7%) with combined sub-segmentectomy. The accuracy of artificial intelligence 3D reconstruction for lesion localization was 100.0%, and the accuracy of computed tomography (CT) was 94.4% (85/90). The detection accuracy of artificial intelligence 3D reconstruction and Mimics 21 software was 92.1% (35/38) and 89.5% (34/38), and the anatomic typing accuracy was 89.5% (34/38) and 84.2% (32/38), and the total accuracy was 76.3% (29/38) and 71.1% (27/38). In the comparative observation of 38 surgical videos and reconstructed images, the consistent rates of target segment planning, surgical approach, artery dissection, vein dissection and bronchial dissection for preoperative planning using artificial intelligence 3D reconstruction were 92.1% (35/38), 92.1% (35/38), 89.5% (34/38), 86.8% (33/38) and 94.7% (36/38). The overall planning operational consistency rate was 68.4% (26/38)., Conclusions: It is accurate and safe to use artificial intelligence 3D reconstruction to assist planning thoracoscopic segmentectomy.

Globally, air pollution is the fourth leading risk factor for death, while lung cancer (LC) is the leading cause of cancer-related death. The aim of this study was to explore the prognostic factors of LC and the influence of high fine particulate matter (PM 2.5 ) on LC survival. Data on LC patients were collected from 133 hospitals across 11 cities in Hebei Province from 2010 to 2015, and survival status was followed up until 2019. The personal PM 2.5 exposure concentration (μg/m 3 ) was matched according to the patient's registered address, calculated from a 5-year average for every patient, and stratified into quartiles. The Kaplan-Meier method was used to estimate overall survival (OS), and Cox's proportional hazard regression model was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The 1-, 3-, and 5-year OS rates of the 6429 patients were 62.9%, 33.2%, and 15.2%, respectively. Advanced age (75 years or older: HR = 2.34, 95% CI: 1.25-4.38), subsite at overlapping (HR = 4.35, 95% CI: 1.70-11.1), poor/undifferentiated differentiation (HR = 1.71, 95% CI: 1.13-2.58), and advanced stages (stage III: HR = 2.53, 95% CI: 1.60-4.00; stage IV: HR = 4.00, 95% CI: 2.63-6.09) were risk factors for survival, while receiving surgical treatment was a protective factor (HR = 0.60, 95% CI: 0.44-0.83). Patients exposed to light pollution had the lowest risk of death with a 26-month median survival time. The risk of death in LC patients was greatest at PM 2.5 concentrations of 98.7-108.9 μg/m 3 , especially for patients at advanced stage (HR = 1.43, 95% CI: 1.29-1.60). Our study indicates that the survival of LC is severely affected by relatively high levels of PM 2.5 pollution, especially in those with advanced-stage cancer., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale and Objectives: The research aims to investigate whether MRI radiomics on hepatic metastasis from primary nonsmall cell lung cancer (NSCLC) can be used to differentiate patients with epidermal growth factor receptor (EGFR) mutations from those with EGFR wild-type, and develop a prediction model based on combination of primary tumor and the metastasis., Materials and Methods: A total of 130 patients were enrolled between Aug. 2017 and Dec. 2021, all pathologically confirmed harboring hepatic metastasis from primary NSCLC. The pyradiomics was used to extract radiomics features from intra- and peritumoral areas of both primary tumor and metastasis. The least absolute shrinkage and selection operator (LASSO) regression was applied to identify most predictive features and to develop radiomics signatures (RSs) for prediction of the EGFR mutation status. The receiver operating characteristic (ROC) curve analysis was performed to assess the prediction capability of the developed RSs., Results: A RS-Primary and a RS-Metastasis were derived from the primary tumor and metastasis, respectively. The RS-Combine by combination of the primary tumor and metastasis achieved the highest prediction performance in the training (AUCs, RS-Primary vs. RS-Metastasis vs. RS-Combine, 0.826 vs. 0.821 vs. 0.908) and testing (AUCs, RS-Primary vs. RS-Metastasis vs. RS-Combine, 0.760 vs. 0.791 vs. 0.884) set. The smoking status showed significant difference between EGFR mutant and wild-type groups (p < 0.05) in the training set., Conclusion: The study indicates that hepatic metastasis-based radiomics can be used to detect the EGFR mutation. The developed multiorgan combined radiomics signature may be helpful to guide individual treatment strategies for patients with metastatic NSCLC., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: For North Chinese lung cancer patients, there is limited study on the distribution of air pollution and smoking related features based on analyses of large-scale, high-quality population datasets. The aim of the study was to fully analyze risk factors for 14604 Subjects., Methods: Participants and controls were recruited in 11 cities of North China. Participants' basic information (sex, age, marital status, occupation, height, and weight), blood type, smoking history, alcohol consumption, history of lung-related diseases and family history of cancer were collected. PM2.5 concentration data for each year in each city of the study area from 2005 to 2018 were extracted based on geocoding of each person's residential address at the time of diagnosis. Demographic variables and risk factors were compared between cases and matched controls using a univariate conditional logistic regression model. Multivariate conditional logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for risk factors in univariate analysis. The nomogram model and the calibration curve were developed to predict lung cancer probability for the probability of lung cancer., Results: There was a total of 14604 subjects, comprising 7124 lung cancer cases and 7480 healthy controls included in the study. Marital status of unmarried persons, people with a history of lung-related disease, corporate personnel and production /service personnel were protective factors for lung cancer. People younger than 50 years old, people who were smoking and quit smoking, people who had been drinking consistently, people with family history of cancer and PM2.5 exposure were proven to be a risk factor for lung cancer. The risk of lung cancer varied with sex, smoking status and air pollution. Consistent alcohol consumption, persistent smoking and smoking quit were risk factors for lung cancer in men. By smoking status, male was risk factor for lung cancer in never smokers. Consistent alcohol consumption added risk for lung cancer in never smokers. The combined effects of PM2.5 pollution exposure and ever smoking aggravated the incidence of lung cancer. According to air pollution, lung cancer risk factors are completely different in lightly and heavily polluted areas. In lightly polluted areas, a history of lung-related disease was a risk factor for lung cancer. In heavily polluted areas, male, consistent alcohol consumption, a family history of cancer, ever smokers and smoking quit were all risk factors for lung cancer. A nomogram was plotted and the results showed that PM2.5 was the main factor affecting the occurrence of lung cancer., Conclusions: The large-scale accurate analysis of multiple risk factors in different air quality environments and various populations, provide clear directions and guidance for lung cancer prevention and precise treatment., (© 2023. The Author(s).)

Background: The mammalian target of rapamycin (mTOR) has a crucial role in carcinogenesis, angiogenesis, cellular proliferation, and metastasis; however, its significance in non-small cell lung cancer (NSCLC) remains contentious. Consequently, this study aims to assess the clinicopathological and prognostic importance of mTOR/p-mTOR expression in NSCLC., Methods: Literature retrieval was undertaken by searching English databases PubMed, EMBASE, Web of Science, and Cochrane Library as well as Chinese databases CNKI, Wan Fang, and VIP for full-text publications that satisfied our eligibility criteria up to November 2021. STATA 12.0 was used to conduct statistical analysis (STATA Corporation, College Station, TX)., Results: This meta-analysis includes a total of 4683 patients from 28 primary publications. mTOR/p-mTOR expression was associated with sex (OR = 0.608, 95% CI: 0.442-0.836), lymph node metastasis (OR = 2.084, 95% CI: 1.437-3.182), and CEA (OR = 1.584, 95% CI: 1.135-2.209), but not with age, histological type, depth of tumor invasion, distant metastasis, TNM stage, differentiation degree, tumor size, or smoking. In addition, the expression of mTOR/p-mTOR is related to shorter overall survival in NSCLC patients (HR = 1.415, 95% CI: 1.051-1.905)., Conclusion: Positive mTOR/p-mTOR expression was substantially correlated with unfavorable conditions on the sex, lymph node metastases, and CEA levels. mTOR/p-mTOR may indicate a bad prognosis for NSCLC. The current findings must be confirmed and changed by other high-quality research employing a multivariate analysis on bigger sample size., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Liu, Wang, Zheng, Ren, Zhang and Yao.)

Background: d-Borneol has been widely used as a drug absorption enhancer, but there are few studies on the anti-resistance ability of d-borneol combined with cisplatin in cisplatin-resistant non-small cell lung cancer cells. Ferroptosis, autophagy and epithelial-mesenchymal transition (EMT) have been reported to be associated with drug resistance., Purpose: To investigate the molecular mechanisms and sensitizing effects of d-borneol combined with cisplatin to against drug cisplatin resistance from the perspective of ferroptosis, autophagy and EMT resistance., Methods: H460/CDDP xenograft tumor model was established to verify the antitumor activity and safety in vivo. RNA sequencing was used to predict target molecules and signaling pathways. Reactive oxygen species (ROS) were used as marker of ferroptosis, and its level was determined by a dichlorodihydrofluorescein diacetate fluorescent probe and flow cytometry. Levels of glutathione (GSH), malondialdehyde (MDA), and antioxidants such as superoxide dismutase (SOD) and thioredoxin (Trx) involved in the balance of oxidative stress were measured by an assay kit or enzyme-linked immunosorbent assay. Western blotting and real-time polymerase chain reaction were used to assess the regulatory mechanism of EMT markers, autophagy, and ferroptosis signaling pathways., Results: d-Borneol in combination with cisplatin reduced tumor volume and weight, enhanced tumor-inhibiting effects, and alleviated cisplatin-induced damage to the liver and kidney in vivo. RNA-sequencing showed that differentially expressed genes were enriched in ferroptosis. d-Borneol in combination with cisplatin promoted ROS accumulation, increased the content of MDA levels, and decreased GSH, SOD, Trx, and heme oxygenase-1 expression to induce oxidative damage. d-Borneol combination with cisplatin induced ferroptosis by promoting nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and regulating intracellular iron ion transport via upregulating PRNP and downregulating PCBP2. In addition, d-borneol combined with cisplatin promoted autophagy by upregulating expression of LC3II/ATG5/Beclin-1 and inhibited the EMT by increasing the expression of epithelial marker E-cadherin and decreasing mesenchymal markers (N-cadherin and vimentin) and transcription factors (Snail and ZEB1)., Conclusion: For the first time, our study implies that d-borneol enhanced cisplatin sensitivity by inducing ferroptosis, promoting autophagy and inhibiting EMT progression, thereby enhancing antitumor activity. It suggests that d-borneol could be developed as a novel chemosensitizers., Competing Interests: Declaration of Competing Interests The authors declare that there are no conflicts of interest associated with this publication., (Copyright © 2022. Published by Elsevier GmbH.)

Chemotherapy resistance limits the efficacy of cisplatin (DDP) when treating non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) confers a regulatory role in drug resistance. Innovatively, the regulatory role of circular RNA HIPK2 (circHIPK2) in DDP resistance was probed in the work. In this research, tumor tissues and matched normal tissues were obtained from 52 NSCLC patients, and the expressions of circHIPK2, miR-1249-3p and VEGFA in the tissues were detected by qPCR or Western Blot. Correlation analysis of circHIPK2 expression with survival prognosis and clinicopathological features was conducted. Parental NSCLC cell lines (A549, H460) and DDP-resistant cell lines (A549/DDP, H460/DDP) were selected, and the expression of circHIPK2, miR-1249-3p and VEGFA in the cells were detected. Cell IC50 value, proliferation, migration, invasion, apoptosis and angiogenesis were detected. Tumor xenografts were established to detect the role of circHIPK2 in vivo. The binding relationship between circHIPK2, miR-1249-3p and VEGFA was verified by dual luciferase reporter experiment, RNA pull down and RIP experiment. Our data showed that circHIPK2 and VEGFA were abnormally overexpressed and miR-1249-3p was underexpressed in DDP-resistant NSCLC tissues and cell lines. CircHIPK2 knockdown or miR-1249-3p upregulation inhibited DDP resistance, malignant behavior, and angiogenesis in NSCLC. CircHIPK2 by competitive absorption of miR-1249-3p mediated VEGFA. CircHIPK2 promoted the sensitivity of drug-resistant cells to DDP in NSCLC by regulating VEGFA. CircHIPK2 enhanced the growth of DDP-resistant NSCLC cells in vivo. In conclusion, circHIPK2 has the malignant property for angiogenesis and chemoresistance in NSCLC via the network of miR-1249-3p/VEGFA., Competing Interests: Declaration of competing interest None., (Copyright © 2022. Published by Elsevier Inc.)

Background: Cisplatin (CDDP) is commonly used to treat non-small cell lung cancer (NSCLC), but the appearance of drug resistance greatly hinders its efficacy. Borneol may promote drug absorption; however, synergism between borneol and CDDP in suppressing NSCLC is not clearly understood. Hence, we investigated borneol as a novel chemosensitizer to support chemotherapeutic efficacy and reduce side effects., Methods: We compared viability after exposure to d-borneol, l-borneol, and synthetic borneol in two NSCLC cell lines, A549 and H460, and selected the most sensitive cells. We then assessed synergy between borneol forms and CDDP in cisplatin-resistant NSCLC cells, H460/CDDP. Next, we identified effective concentrations and exposure times. Subsequently, we evaluated cell migration via wound healing and cell proliferation via clone formation assay. Then, we focused on P-glycoprotein (P-gp) function, cell cycle, apoptosis, and RNA sequencing to elucidate underlying molecular mechanisms for synergy. Finally, we used an H460/CDDP xenograft tumor model to verify antitumor activity and safety in vivo. Data were examined using one-way analysis of variance (ANOVA) for multiple datasets or t-test for comparisons between two variables., Results: d-Borneol was more effective in H460 than A549 cells. d-Borneol combined with CDDP showed greater inhibition of cell proliferation, migration, and clone formation in H460/CDDP cells than CDDP alone. RNA sequencing (RNA-seq) analysis identified differentially expressed genes enriched in cell cycle pathways. The impact of d-borneol on CDDP chemosensitivity involved arrest of the cell cycle at S phase via p27/p21-mediated cyclinA2/D3-CDK2/6 signaling and activation of intrinsic apoptosis via p21-mediated Bax/Bcl-2/caspase3 signaling. Further, d-borneol ameliorated drug resistance by suppressing levels and activity of P-gp. Cotreatment with d-borneol and CDDP inhibited tumor growth in vivo and reduced CDDP-caused liver and kidney toxicity., Conclusions: d-Borneol increased the efficacy of cisplatin and reduced its toxicity. This compound has the potential to become a useful chemosensitizer for drug-resistance NSCLC., (© 2022. The Author(s).)

The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRAS MUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS -driven human cancers and warrant further preclinical and clinical development.

Background: Artificial intelligence has far surpassed previous related technologies in image recognition and is increasingly used in medical image analysis. We aimed to explore the diagnostic accuracy of the models based on deep learning or radiomics for lung cancer staging., Methods: Studies were systematically reviewed using literature searches from PubMed, EMBASE, Web of Science, and Wanfang Database, according to PRISMA guidelines. Studies about the diagnostic accuracy of radiomics and deep learning, including the identifications of lung cancer, tumor types, malignant lung nodules and lymph node metastase, were included. After identifying the articles, the methodological quality was assessed using the QUADAS-2 checklist. We extracted the characteristic of each study; the sensitivity, specificity, and AUROC for lung cancer diagnosis were summarized for subgroup analysis., Results: The systematic review identified 19 eligible studies, of which 14 used radiomics models and 5 used deep learning models. The pooled AUROC of 7 studies to determine whether patients had lung cancer was 0.83 (95% CI 0.78-0.88). The pooled AUROC of 9 studies to determine whether patients had NSCLC was 0.78 (95% CI 0.73-0.83). The pooled AUROC of the 6 studies that determined patients had malignant lung nodules was 0.79 (95% CI 0.77-0.82). The pooled AUROC of the other 6 studies that determined whether patients had lymph node metastases was 0.74 (95% CI 0.66-0.82)., Conclusion: The models based on deep learning or radiomics have the potential to improve diagnostic accuracy for lung cancer staging., Systematic Review Registration: https://inplasy.com/inplasy-2022-3-0167/, identifier: INPLASY202230167., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, He, Hu, Ren, Chen, Zhang, Ma, Ouyang, Chu, Gao, He, Liu and Li.)

Heterogeneity is a hallmark of cancer, diabetes, cardiovascular diseases, and many other complex diseases. This study has been partly motivated by the unsupervised heterogeneity analysis for complex diseases based on molecular and imaging data, for which, network-based analysis, by accommodating the interconnections among variables, can be more informative than that limited to mean, variance, and other simple distributional properties. In the literature, there has been very limited research on network-based heterogeneity analysis, and a common limitation shared by the existing techniques is that the number of subgroups needs to be specified a priori or in an ad hoc manner. In this article, we develop a penalized fusion approach for heterogeneity analysis based on the Gaussian graphical model. It applies penalization to the mean and precision matrix parameters to generate regularized and interpretable estimates. More importantly, a fusion penalty is imposed to "automatedly" determine the number of subgroups and generate more concise, reliable, and interpretable estimation. Consistency properties are rigorously established, and an effective computational algorithm is developed. The heterogeneity analysis of non-small-cell lung cancer based on single-cell gene expression data of the Wnt pathway and that of lung adenocarcinoma based on histopathological imaging data not only demonstrate the practical applicability of the proposed approach but also lead to interesting new findings., (© 2021 The International Biometric Society.)

Background: Lung cancer is the cancer with the highest mortality at home and abroad at present. The detection of lung nodules is a key step to reducing the mortality of lung cancer. Artificial intelligence-assisted diagnosis system presents as the state of the art in the area of nodule detection, differentiation between benign and malignant and diagnosis of invasive subtypes, however, a validation with clinical data is necessary for further application. Therefore, the aim of this study is to evaluate the effectiveness of artificial intelligence-assisted diagnosis system in predicting the invasive subtypes of early‑stage lung adenocarcinoma appearing as pulmonary nodules., Methods: Clinical data of 223 patients with early-stage lung adenocarcinoma appearing as pulmonary nodules admitted to the Lanzhou University Second Hospital from January 1st, 2016 to December 31th, 2021 were retrospectively analyzed, which were divided into invasive adenocarcinoma group (n=170) and non-invasive adenocarcinoma group (n=53), and the non-invasive adenocarcinoma group was subdivided into minimally invasive adenocarcinoma group (n=31) and preinvasive lesions group (n=22). The malignant probability and imaging characteristics of each group were compared to analyze their predictive ability for the invasive subtypes of early-stage lung adenocarcinoma. The concordance between qualitative diagnostic results of artificial intelligence-assisted diagnosis of the invasive subtypes of early-stage lung adenocarcinoma and postoperative pathology was then analyzed., Results: In different invasive subtypes of early-stage lung adenocarcinoma, the mean CT value of pulmonary nodules (P<0.001), diameter (P<0.001), volume (P<0.001), malignant probability (P<0.001), pleural retraction sign (P<0.001), lobulation (P<0.001), spiculation (P<0.001) were significantly different. At the same time, it was also found that with the increased invasiveness of different invasive subtypes of early-stage lung adenocarcinoma, the proportion of dominant signs of each group gradually increased. On the issue of binary classification, the sensitivity, specificity, and area under the curve (AUC) values of the artificial intelligence-assisted diagnosis system for the qualitative diagnosis of invasive subtypes of early-stage lung adenocarcinoma were 81.76%, 92.45% and 0.871 respectively. On the issue of three classification, the accuracy, recall rate, F1 score, and AUC values of the artificial intelligence-assisted diagnosis system for the qualitative diagnosis of invasive subtypes of early-stage lung adenocarcinoma were 83.86%, 85.03%, 76.46% and 0.879 respectively., Conclusions: Artificial intelligence-assisted diagnosis system could predict the invasive subtypes of early‑stage lung adenocarcinoma appearing as pulmonary nodules, and has a certain predictive value. With the optimization of algorithms and the improvement of data, it may provide guidance for individualized treatment of patients.

Rationale and Objectives: Preoperative identifications of epidermal growth factor receptor (EGFR) mutation subtypes based on the MRI image of spinal metastases are needed to provide individualized therapy, but has not been previously investigated. This study aims to develop and evaluate an MRI-based radiomics nomogram for differentiating the exon 19 and 21 in EGFR mutation from spinal bone metastases in patients with primary lung adenocarcinoma., Materials and Methods: A total of 76 patients underwent T1-weighted and T2-weighted fat-suppressed MRI scans were enrolled in this study, 38 were positive for EGFR mutation in exon 19 and 38 were in exon 21.MRI imaging features were extracted and selected from each MRI pulse sequence, and used to form the radiomics signature. A radiomics nomogram was developed integrating the radiomics signature and important clinical factors with receiver operating characteristic, calibration and decision curve analysis to assess the nomogram. Clinical characteristics were analyzed with Mann-Whitney U and Chi-Square tests to identify the most important factors., Results: A total of 6 features were selected as the most discriminative predictors from the two MRI pulse sequences. The nomogram integrating the combined radiomics signature, age and CEA level generated good prediction performance in the training (AUCs, nomogram vs. combined radiomics signature vs. clinical model, 0.90 vs. 0.87 vs. 0.59) and validation (AUCs, nomogram vs. combined radiomics signature vs. clinical model, 0.88 vs. 0.86 vs. 0.72) cohort. DCA analysis confirmed the potential clinical utility of the nomogram., Conclusion: This study demonstrated that MRI features from spinal bone metastases can be used to prognosticate EGFR mutation subtypes in exon 19 and 21. The developed pre-treatment nomogram can potentially guide treatments for lung adenocarcinoma patients., Competing Interests: DECLARATION OF COMPETING INTEREST None., (Copyright © 2021 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aims to develop and evaluate multi-parametric MRI-based radiomics for preoperative identification of epidermal growth factor receptor (EGFR) mutation, which is important in treatment planning for patients with thoracic spinal metastases from primary lung adenocarcinoma., Methods: A total of 110 patients were enrolled between January 2016 and March 2019 as a primary cohort. A time-independent validation cohort was conducted containing 52 patients consecutively enrolled from July 2019 to April 2021. The patients were pathologically diagnosed with thoracic spinal metastases from primary lung adenocarcinoma; all underwent T1-weighted (T1W), T2-weighted (T2W), and T2-weighted fat-suppressed (T2FS) MRI scans of the thoracic spinal. Handcrafted and deep learning-based features were extracted and selected from each MRI modality, and used to build the radiomics signature. Various machine learning classifiers were developed and compared. A clinical-radiomics nomogram integrating the combined rad signature and the most important clinical factor was constructed with receiver operating characteristic (ROC), calibration, and decision curves analysis (DCA) to evaluate the prediction performance., Results: The combined radiomics signature derived from the joint of three modalities can effectively classify EGFR mutation and EGFR wild-type patients, with an area under the ROC curve (AUC) of 0.886 (95% confidence interval [CI]: 0.826-0.947, SEN =0.935, SPE =0.688) in the training group and 0.803 (95% CI: 0.682-0.924, SEN = 0.700, SPE = 0.818) in the time-independent validation group. The nomogram incorporating the combined radiomics signature and smoking status achieved the best prediction performance in the training (AUC = 0.888, 95% CI: 0.849-0.958, SEN = 0.839, SPE = 0.792) and time-independent validation (AUC = 0.821, 95% CI: 0.692-0.929, SEN = 0.667, SPE = 0.909) cohorts. The DCA confirmed potential clinical usefulness of our nomogram., Conclusion: Our study demonstrated the potential of multi-parametric MRI-based radiomics on preoperatively predicting the EGFR mutation. The proposed nomogram model can be considered as a new biomarker to guide the selection of individual treatment strategies for patients with thoracic spinal metastases from primary lung adenocarcinoma., (© 2021 American Association of Physicists in Medicine.)

Background: Preoperative prediction of epidermal growth factor receptor (EGFR) mutation status in patients with spinal bone metastases (SBM) from primary lung adenocarcinoma is potentially important for treatment decisions., Purpose: To develop and validate multiparametric magnetic resonance imaging (MRI)-based radiomics methods for preoperative prediction of EGFR mutation based on MRI of SBM., Study Type: Retrospective., Population: A total of 97 preoperative patients with lumbar SBM from lung adenocarcinoma (77 in training set and 20 in validation set)., Field Strength/sequence: T1-weighted, T2-weighted, and T2-weighted fat-suppressed fast spin echo sequences at 3.0 T., Assessment: Radiomics handcrafted and deep learning-based features were extracted and selected from each MRI sequence. The abilities of the features to predict EGFR mutation status were analyzed and compared. A radiomics nomogram was constructed integrating the selected features., Statistical Tests: The Mann-Whitney U test and χ 2 test were employed for evaluating associations between clinical characteristics and EGFR mutation status for continuous and discrete variables, respectively. Least absolute shrinkage and selection operator was used for selection of predictive features. Sensitivity (SEN), specificity (SPE), and area under the receiver operating characteristic curve (AUC) were used to evaluate the ability of radiomics models to predict the EGFR mutation. Calibration and decision curve analysis (DCA) were performed to assess and validate nomogram results., Results: The radiomics signature comprised five handcrafted and one deep learning-based features and achieved good performance for predicting EGFR mutation status, with AUCs of 0.891 (95% confidence interval [CI], 0.820-0.962, SEN = 0.913, SPE = 0.710) in the training group and 0.771 (95% CI, 0.551-0.991, SEN = 0.750, SPE = 0.875) in the validation group. DCA confirmed the potential clinical usefulness of the radiomics models., Data Conclusion: Multiparametric MRI-based radiomics is potentially clinical valuable for predicting EGFR mutation status in patients with SBM from lung adenocarcinoma., Level of Evidence: 3 TECHNICAL EFFICACY: 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: Lung cancer as a stressful event profoundly impacts the entire family, especially patients and their family caregivers. This study uses a dyadic analysis approach to explore the dyadic effects of family functioning on the quality of life (QoL), and whether resilience acts as a mediator in advanced lung cancer patient-caregiver dyads., Methods: This was a cross-sectional study, and 287 dyads of advanced lung cancer patients and their caregivers were enrolled. Family-functioning, resilience, and QoL were assessed by the General Functioning subscale of the Family Assessment Device (FAD), the 10-item Connor-Davidson Resilience Scale, and the Short Form-8 (SF-8) Health Survey, respectively. Data were analyzed using the actor-partner interdependence mediation model., Results: This study found that, for patients and caregivers, resilience mediates the actor effects of family-functioning on QoL. That is, family-functioning was positively related to their resilience, which improved QoL. Another important finding is that caregivers' family-functioning had significant indirect effects on patients' QoL through their resilience., Conclusions: Positive family functioning perceived by patients and caregivers can improve their QoL by developing their own resilience. Furthermore, family-functioning perceived by caregivers can also improve patients' QoL through their resilience. Medical staff should identify vulnerable patients and caregivers with poorer family-functioning and resilience, and make focused intervention to improve the QoL of both lung cancer patients and their family caregivers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pentraxin 3 (PTX3) has been documented to be involved in the development of chemoresistance, however, the mechanisms by which it regulates cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC) have never been elucidated. Quantitative reverse transcriptase polymerase chain reaction and Western blot were carried to determine the expression of PTX3, ATP-binding cassette sub-family B member 1 (ABCB1)/P-glycoprotein 1 (p-gp), protein kinase B (Akt), phosphorylated Akt and nuclear factor-kappa B (NF-кB) p65. The biological roles of PTX3 in NSCLC progression and NSCLC cell resistance to DDP were evaluated using enzyme-linked immunosorbent assay, cell count kit-8, colony formation assay, flow cytometry, as well as xenograft tumor assay. The expression of PTX3 was increased in the serum of NSCLC patients as well as in NSCLC cell lines. Lower PTX3 level was associated with longer overall survival in lung adenocarcinoma and lung squamous cell carcinoma patients. Furthermore, PTX3 expression was greatly higher in DDP-resistant NSCLC cells than that in NSCLC cells. Silencing of PTX3 restrained the proliferation and promoted the apoptosis of NSCLC cells, as well as sensitized DDP-resistant NSCLC cells to DDP. Additionally, knockdown of PTX3 inhibited the growth of NSCLC tumors in vivo. Upregulation of PTX3 expression was dependent on the activation of Akt/NF-κB signaling. The induction of apoptosis by PTX3 knockdown was enhanced by MK-2206 or JSH-23. In conclusion, knockdown of PTX3 restrained the progression of NSCLC and sensitized NSCLC cells towards DDP, which provides a potential target to restore DDP chemoresponse., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Lung metastases may worsen overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). We investigated (post hoc) the impact of lung metastases on survival in SELECT (a phase 3 study)., Patients and Methods: 392 patients with RR-DTC were randomised 2:1 to lenvatinib 24 mg daily (n = 261) or placebo (n = 131). Placebo-treated patients could crossover to open-label lenvatinib following progression. Patients were grouped by size of baseline lung metastases. Safety/efficacy outcomes, collated by these lung-metastases subgroups, were generated., Results: Lenvatinib-treated population distributions per baseline lung metastases subgroup were any lung metastases (target/nontarget lesions; n = 226), and by maximum size of target lung lesions ≥1.0 cm (n = 199), ≥1.5 cm (n = 150), ≥2.0 cm (n = 94) and <2.0 cm (n = 105). In patients with any lung metastases, no statistically significant difference in OS was observed between treatment arms (HR: 0.76; 95% CI: 0.57-1.01; P = 0.0549). Median OS for lung metastases of ≥1.0 cm was 44.7 months (lenvatinib) versus 33.1 months (placebo) (HR: 0.63; 95% CI: 0.47-0.85; P = 0.0025). OS was significantly prolonged with lenvatinib versus placebo among patients with lung metastases of ≥1.0 cm, ≥1.5 cm, ≥2.0 cm and <2.0 cm; median OS was shorter in the ≥2.0 cm subgroup (lenvatinib: 34.7 months) versus other subgroups (lenvatinib: 44.1-49.2 months). Multivariate analysis demonstrated lenvatinib significantly prolonged OS in patients with lung metastases of ≥1.0 cm after adjustment for baseline characteristics., Conclusions: Lenvatinib treatment resulted in longer OS in patients with lung metastases of ≥1.0 cm versus placebo (even with the 89% crossover rate). Early initiation of lenvatinib may improve outcomes in patients with RR-DTC and lung metastases of ≥1.0 cm., Source Study Registration: ClinicalTrials.Gov Identifier: NCT01321554., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MT: Honoraria from Bayer, Bristol Myers Squibb, Eisai, Merck Serono, Takeda; consulting or advisory role with Bayer, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Ono Pharmaceutical, Pfizer; research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Merck Sharp & Dohme, NanoCarrier, Novartis, Ono Pharmaceutical, Pfizer. NK: Honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Merck Serono, AstraZeneca, Eisai, Bayer; research funding from Eisai, AstraZeneca, Pfizer, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb. AOH: Research funding from Eisai, Bayer, Eli Lilly, Exelixis; consulting or advisory role with Bayer, Eli Lilly. CB: Nothing to disclose. TKO: Research funding from Novartis, Astellas, Celgene, Bayer, Stemcentrx, Regeneron, AstraZeneca/MedImmune, AbbVie, G1 Therapeutics, Bristol Myers Squibb, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck; consulting or advisory role with Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol Myers Squibb, MedImmune, BerGenBio, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Heron Pharmaceutical, ARMO BioSciences; IRC/DSMB for EMD Serono, Roche/Genentech; stock ownership with Cambium Oncology. CED: Employee of Eisai Inc. TS: Employee of Eisai Co. Ltd. MR: Employee of Eisai Inc. LW: Consulting or advisory role for Bayer, Blueprint Medicines, Cue Biopharma, Eisai, Exelixis Lilly, Loxo Oncology, Merck, and Rakuten Medical., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Combined small cell lung cancer (C-SCLC) represents a rare subtype of all small cell lung cancer cases, with limited studies investigated its prognostic factors. The aim of this study was to construct a novel nomogram to predict the overall survival (OS) of patients with C-SCLC., Methods: In this retrospective study, a total of 588 C-SCLC patients were selected from the Surveillance, Epidemiology, and End Results database. The univariate and multivariate Cox analyses were performed to identify optimal prognostic variables and construct the nomogram, with concordance index (C-index), receiver operating characteristic curves, and calibration curves being used to evaluate its discrimination and calibration abilities. Furthermore, decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) were also adopted to assess its clinical utility and predictive ability compared with the classic TNM staging system., Results: Seven independent predictive factors were identified to construct the nomogram, including T stage, N stage, M stage, brain metastasis, liver metastasis, surgery, and chemotherapy. We observed a higher C-index in both the training (.751) and validation cohorts (.736). The nomogram has higher area under the curve in predicting 6-, 12-, 18-, 24-, and 36-month survival probability of patients with C-SCLC. Meanwhile, the calibration curves also revealed high consistencies between the actual and predicted OS. DCA revealed that the nomogram could provide greater clinical net benefits to these patients. We found that the NRI for 6- and 12-month OS were .196 and .225, and the IDI for 6- and 12-month OS were .217 and .156 in the training group, suggesting that the nomogram can predict a more accurate survival probability. Similar results were also observed in the validation cohort., Conclusion: We developed and verified a novel nomogram that can help clinicians recognize high-risk patients with C-SCLC and predict their OS.

Lung cancer is the most common malignant tumor in the world. The five-year survival rate is 19.7%, which seriously threatens human health. Lung cancer screening is an effective measure to reduce lung cancer mortality. Existing studies have shown that screening with low-dose computed tomography (LDCT) can reduce lung cancer deaths by 20%. Currently, lung cancer screening is recommended internationally and nationally. Studying the development status of lung cancer screening helps us to identify the high-risk groups of lung cancer, explore reasonable screening programs, improve the cost-effectiveness of screening and reduce the economic burden. Therefore, this article summarizes the current status of lung cancer screening, the cost-effectiveness of lung cancer screening and the existing problems as follows.
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The aim of this study was to investigate the prognostic value of the prognostic nutritional index (PNI) on the long-term survival of non-small cell lung cancer (NSCLC) patients who received platinum-based chemotherapy. Data on nutritional parameters and clinicopathological characteristics [e.g., albumin, total protein, body mass index (BMI), eastern cooperative oncology group (ECOG) performance status, stage, pathology, treatment strategy] were analyzed and retrospectively correlated with overall survival (OS). The PNI was calculated based on the concentration of albumin and lymphocyte count [10 × albumin, (g/dl) + 0.005 × lymphocyte (count/mm3)]. A receiver operating characteristic curve (ROC) analysis was used to find the optimal cut-off value of PNI. Univariate and multivariate analyses were used to evaluate the prognostic value of PNI. A total of 186 patients met the inclusion criteria. The optimal cut-off value for PNI was 50.45. Compared with the parameters of the low PNI group (n=76), high PNI was significantly associated with adenocarcinoma type, stage III, better ECOG and comprehensive treatment modality. The univariate analysis demonstrated that OS was superior when PNI ≥50.45, albumin ≥35 g/l, platelet-lymphocyte ratio (PLR) ≥163 and ECOG <2, and when the patient received a comprehensive treatment modality. In the multivariate analysis, PNI, TNM stage and treatment strategy were identified as independent predictors of survival in this study. This retrospective study demonstrated that a low PNI was related to worse overall survival in patients with stage III/IV NSCLC who received platinum-based chemotherapy. These data provided a conceptual basis for further research on the clinical application of the PNI index for patients receiving chemotherapy for intermediate- and advanced-stage NSCLC.

Salidroside, a glycoside of tyrosol, is isolated from Rhodiola rosea and shows anti-cancer functions in several cancers. However, the potentials of salidroside in the migration and invasion of lung cancer cells and its underlying mechanisms remain unknown. We aimed to investigate the functions and mechanisms of salidroside in non-small cell lung cancer (NSCLC). Human NSCLC cell line A549 was treated with different doses of salidroside. Cell viability, colony formation, apoptosis, migration and invasion were detected by CCK-8, crystal violet-staining assay, flow cytometry and transwell assay, respectively. qRT-PCR and western blot analysis were performed to assess the regulatory effects of salidroside on miR-195 expression and the activation of AKT and the MEK/ERK signal pathway. We found that, salidroside remarkably reduced cell viability, colony formation and Cyclin D1 expression, but increased p21 expression and apoptosis in A549 cells. Additionally, salidroside inhibited the migration and invasion of A549 cells by regulating expressions of migration- and invasion-related proteins. Finally, salidroside inhibited phosphorylation of AKT, MEK and ERK by upregulating miR-195 expression in A549 cells. In conclusion, salidroside inhibited the survival, migration and invasion of NSCLC cells. Salidroside blocked AKT and the MEK/ERK signal pathway by upregulating miR-195 expression in A549 cells.

Objectives: Despite improved outcomes associated with immunotherapies for non-small cell lung cancer (NSCLC), many patients do not respond to treatment. Therefore, there is still an unmet need for molecularly targeted therapies in this patient population. Fusions of the RET oncogene have been identified as driver alterations in patients with NSCLC. Lenvatinib is a multityrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, RET, and other targets. This study evaluated the safety and efficacy of lenvatinib in patients with RET fusion-positive lung adenocarcinoma., Materials and Methods: In this phase 2, multicenter, open-label study (NCT01877083), patients with RET-positive lung adenocarcinoma received oral lenvatinib 24 mg/day. The primary end point was objective response rate (ORR) by investigator review per Response Evaluation Criteria In Solid Tumors v1.1 criteria. The secondary end points included safety and tolerability, progression-free survival (PFS), and overall survival (OS)., Results: Of 536 patients who screened for study inclusion and exclusion, 25 patients with RET translocations (KIF5B-RET [n = 13] and CCDC6-RET [n = 12]) were identified and received lenvatinib. The overall ORR was 16% (95% CI: 4.5%-36.1%). At data cutoff (February 3, 2016), the median PFS was 7.3 months (95% CI: 3.6-10.2) and the median OS was not reached. Duration of response was not estimable at the time of data cutoff. All patients experienced a treatment-emergent adverse event (TEAE); 23 (92%) patients experienced a TEAE of ≥ grade 3, and 6 (24%) patients discontinued lenvatinib due to a TEAE. The most common TEAEs were hypertension (68%), nausea (60%), decreased appetite (52%), diarrhea (52%), and proteinuria (48%)., Conclusions: Lenvatinib demonstrated activity in patients with RET fusion-positive lung adenocarcinomas; although the response rate was relatively low, the median PFS supports the activity of lenvatinib in these patients., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Tumors of the pineal region are rare, and metastatic carcinoma occurring in the pineal region is extremely rare. No previous reports have described pineal region metastasis with intraventricular seeding., Patient Concerns: We report a case of a 51-year-old woman presented with a 1-week history of severe headache, nausea, and vomiting. Imaging examination revealed 2 lesions in the pineal region and the right lateral ventricle., Diagnosis: Pinealocytoma or germinoma was considered as the preoperative diagnosis. The postoperative pathological diagnosis was small cell neuroendocrine carcinoma. After bronchoscopic biopsy, small cell lung cancer was confirmed., Interventions: A right frontal craniotomy and a translateral ventricle approach were performed to remove 2 lesions completely. And regular radiotherapy and chemotherapy were initiated after surgery., Outcomes: The patient was discharged from the hospital 2 weeks after operation and went to another cancer hospital for bronchoscopic biopsy, radiotherapy, and chemotherapy. Finally, the patient died 2 years after surgical treatment., Conclusion: Metastatic tumors of the pineal region are very rare. For patients with pineal lesions, a diagnosis of a metastatic tumor should be considered. Retrograde cerebrospinal fluid circulation might be the reason for a secondary metastasis.

Rationale: The standard treatment for uterine high-grade endometrial stromal sarcoma (HGESS) is chemotherapy after surgery. However, the traditional combination chemotherapy has certain limitation, for example, the cancer cells will quickly become resistant to the chemotherapy drugs. Apatinib is a small-molecule antiangiogenic agent which has shown promising therapeutic effect against diverse tumor, but it still remains unknown whether apatinib has an antitumor effect in patients with endometrial stromal sarcoma (ESS). Here, we report a case of pulmonary metastasis from uterine HGESS successfully treated with apatinib combined with chemotherapy. We also review relevant literature discussing treatment of ESS., Patients Concerns: A 54-years-old Chinese woman complained of intermittent pain in the waist and abdomen for 4 months. The patient was diagnosed as uterine fibroids before operation. The surgeon performed a total hysterectomy with bilateral salpingo-oophorectomy, resection of peritoneal disseminated lesions, and the pathological examination revealed a HGESS., Diagnosis: Uterine HGESS stage IV with lung metastases., Interventions: The patient underwent surgery, chemotherapy, chemotherapy combined with apatinib, apatinib maintenance therapy, and radioactive particle implantation for lung metastasis., Outcomes: The patient experienced the above interventions and achieved good results. And continue oral apatinib (500 mg daily) as maintenance therapy. It has been 16 months since the initial diagnosis, and the patient is still in follow-up., Lessons: Apatinib combined with chemotherapy and apatinib monotherapy as maintenance therapy could be a new therapeutic strategy for ESS.

Background and Objective: We performed this systematic review and meta-analysis to assess the efficacy and safety of antigen-specific immunotherapy (Belagenpumatucel-L, MAGE-A3, L-BLP25, and TG4010) in the treatment of patients with non-small-cell lung cancer (NSCLC)., Methods: A comprehensive literature search on PubMed, Embase, and Web of Science was conducted. Eligible studies were clinical trials of patients with NSCLC who received the antigenspecific immunotherapy. Pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated for overall survival (OS), progression-free survival (PFS). Pooled risk ratios (RRs) were calculated for overall response rate (ORR) and the incidence of adverse events., Results: In total, six randomized controlled trials (RCTs) with 4,806 patients were included. Pooled results showed that, antigen-specific immunotherapy did not significantly prolong OS (HR=0.92, 95%CI: 0.83, 1.01; P=0.087) and PFS (HR=0.93, 95%CI: 0.85, 1.01; P=0.088), but improved ORR (RR=1.72, 95%CI: 1.11, 2.68; P=0.016). Subgroup analysis based on treatment agents showed that, tecemotide was associated with a significant improvement in OS (HR=0.85, 95%CI: 0.74, 0.99; P=0.03) and PFS (HR=0.70, 95%CI: 0.49, 0.99, P=0.044); TG4010 was associated with an improvement in PFS (HR=0.87, 95%CI: 0.75, 1.00, P=0.058). In addition, NSCLC patients who were treated with antigen-specific immunotherapy exhibited a significantly higher incidence of adverse events than those treated with other treatments (RR=1.11, 95%CI: 1.00, 1.24; P=0.046)., Conclusion: Our study demonstrated the clinical survival benefits of tecemotide and TG4010 in the treatment of NSCLC. However, these evidence might be limited by potential biases. Therefore, further well-conducted, large-scale RCTs are needed to verify our findings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Bone is one of the most preferred sites of metastasis in lung cancer. Currently, bisphosphonates and denosumab are major agents for controlling tumor-associated skeletal-related events (SREs). However, both bisphosphonates and denosumab significantly increase the risk for jaw osteonecrosis. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the most frequently prescribed cholesterol-lowering agents, have been reported to inhibit tumor progression and induce autophagy in cancer cells. However, the effects of statin and role of autophagy by statin on bone metastasis are unknown. In this study, we report that fluvastatin effectively prevented lung adenocarcinoma bone metastasis in a nude mouse model. We further reveal that fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy in lung adenocarcinoma cells. Atg5 or Atg7 deletion, or 3-methyadenine (3-MA) or Bafilomycin A1 (Baf A1) treatment prevented the fluvastatin-induced suppression of bone metastasis. Furthermore, we reveal that fluvastatin stimulation increased the nuclear p53 expression, and fluvastatin-induced autophagy and anti-bone metastatic activity were mostly dependent on p53., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Understanding how sex impacts the efficacy of anticancer agents is a crucial step toward personalized and precision medicine. This review and meta-analysis evaluated sex differences in hazard ratios (HRs) of progression-free survival and overall survival in representative Phase III clinical trials of non-small-cell lung cancer (NSCLC)., Methods: Data were extracted from 24 large-scale clinical trials that included 12,000 male and 7000 female patients. The data were examined for HR differences between subgroups by sex, smoking status, and age, and for potential sex-smoking status, sex-age, and sex-drug interactions, during cancer treatment., Findings: Summarized information revealed variations in the influences of sex, smoking status, and age on the efficacy of drugs used for the treatment of NSCLC. The male and female subgroups had different HR values. Smoking status, age, and the percentage of female patients in a treatment group had no influence on the sex HR. The sex difference was supported by a set of data collected from all journals., Implications: The findings from this meta-analysis are important for assessing potential toxicity during drug treatment in both sexes. The outcomes measures of a drug in clinical application should be specified by subpopulation, such as males versus females, as a first step in personalized medicine., (Published by Elsevier Inc.)

Accumulating studies have demonstrated that long noncoding RNAs (lncRNAs) act a crucial role in the development of tumors. However, the role of lncRNAs in lung cancer remains largely unknown. In this study, we demonstrated that theexpression of RMRP was upregulated in lung adenocarcinoma tissues compared to the matched adjacent normal tissues. Moreover, of 35 lung adenocarcinoma samples, RMRP expression was upregulated in 25 cases (25/35; 71.4%) compared to the adjacent normal tissues. We also showed that RMRP expression was upregulated in lung adenocarcinoma cell lines (A549, SPC-A1, H1299 and H23) compared to the bronchial epithelial cell line (16HBE). Ectopic expression of RMRP promoted lung adenocarcinoma cell proliferation, colony formation and invasion. In addition, overexpression of RMRP inhibited the miR-206 expression in the H1299 cell and increased the KRAS, FMNL2 and SOX9 expression, which were the target genes of miR-206. Re-expression of miR-206 reversed the RMRP-induced the H1299 cell proliferation and migration. Our data proved that RMRP acted as an oncogene LncRNA to promote the expression of KRAS, FMNL2 and SOX9 by inhibiting miR-206 expression in lung cancer. These data suggested that RMRP might serve as a therapeutic target in lung adenocarcinoma., Competing Interests: The authors have declared that no competing interests exist.

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is frequently over-expressed and serves as a prognostic marker in human cancers. However, little is known about the role of MALAT1 in gastric cancer. Here, we reported that the tissue and plasma MALAT1 levels were significantly higher in gastric cancer patients with distant metastasis (P<0.01) than patients without distant metastasis and the healthy controls. In addition, high levels of plasma MALAT1 independently correlated to a poor prognosis for gastric cancer patients (hazard ratio, 0.242; 95% CI, 0.154-0.836; P=0.036; Cox regression analysis). Functional studies revealed that knockdown of MALAT1 could inhibit cell proliferation, cell cycle progression, migration and invasion, and promote apoptosis in gastric cancer cells. Furthermore, the miR-122-IGF-1R signaling correlated with the dysregulated MALAT1 expression in gastric cancer. These data suggest that MALAT1 could function as an oncogene in gastric cancer, and high MALAT1 level could serve as a potential biomarker for the distant metastasis of gastric cancer., Competing Interests: The authors declare no competing financial interests.

Amplification Refractory Mutation System (ARMS) is the most popular technology for EGFR gene mutation analysis in China. Cutoff Ct or ΔCt values were used to differentiate low mutation abundance cases from no mutation cases. In this study, all of 359 NSCLC samples were tested by ARMS. Seventeen samples with larger Ct or ΔCt than cutoff values were retested by PCR-sequencing. TKI treatment responses were monitored on the cases with ARMS negative and PCR-sequencing positive results. One exon 18 G719X case, 67 exon 19 deletion cases, 2 exon 20 insertion cases, 1 exon 20 T790M case, 60 exon 21 L858R cases, 5 exon 21 L861Q cases and 201 wild type cases were identified by ARMS. Another 22 cases were evaluated as wild type but had later amplification fluorescent curves. Seventeen out of these 22 cases were retested by PCR-sequencing. It turns out that 3 out of 3 cases with exon 19 deletion later amplifications, 2 out of 2 cases with L858R later amplifications and 4 out of 12 cases with T790M later amplifications were identified as mutation positive. Two cases with exon 19 deletion and L858R respectively were treated by TKI and got responses. Our study indicated that PCR-sequencing might be a complementary way to confirm ARMS results with later amplifications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: An increased incidence of venous thromboembolism (VTE) is associated with anti-vascular endothelial growth factor (VEGF) treatment in cancer. However, the mechanism underlying this effect remains elusive. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on VTE in a murine xenograft A549 cell tumor model., Methods: Inferior vena cava stenosis model and FeCl3-induced saphenous vein thrombosis model were performed in a mouse xenograft models of human lung adenocarcinoma., Results: We found that treatment with bevacizumab significantly increased the thrombotic response to inferior vena cava obstruction and femoral vein injury. Plasminogen activator inhibitor (PAI-1) expression in tumors, plasma, and thrombi was significantly increased by bevacizumab. However, bevacizumab did not enhance VTE in PAI-1-deficient mice, suggesting that PAI-1 is a major mediator of bevacizumab's prothrombotic effect. VEGF inhibited expression of PAI-1 by A549 cells, and this effect was neutralized by bevacizumab, suggesting that bevacizumab increases PAI-1 expression in vivo by blocking the inhibitory effect of VEGF on PAI-1 expression by tumor cells. Pharmacological inhibition of PAI-1 with PAI-039 blocked bevacizumab-induced venous thrombosis., Conclusion: Collectively, these findings indicate that PAI-1 plays a role in VTE associated with antiangiogenic therapy and the inhibition of PAI-1 shows efficacy as a therapeutic strategy for the prevention of bevacizumab-associated VTE.

Multiple lung adenocarcinomas (AC) are uncommon. We herein report a case of multiple AC. A 62-year-old Chinese woman was admitted to our hospital because of her chest enhanced computed tomography (ECT) finding. Her ECT revealed a suspected lung cancer in the left lower lung and ill-defined weak ground-glass opacity in the left upper lobe. Upon operation, however, both were pathologically diagnosed as AC, an invasive one and an in-situ one, respectively. Only the invasive AC presented epidermal growth factor receptor (EGFR) mutation, while anaplastic lymphoma kinase (ALK) rearrangement was detected in none of them. To not miss rare invasion-related mutations, the whole exome sequencing of the in-situ and invasive AC was conducted subsequently matched the adjacent normal tissue of this patient. On sequencing the invasive tumor sample was found to have 27 exclusive somatic mutations as compared with in-situ and adjacent normal tissues. Our case exemplifies the need for deep sequencing and the discovery of new potential driver mutations.

Variation of plasma free amino acids (PFAAs) is an essential feature of protein metabolic abnormalities in cancer patients. But there still little data about the cancer tissue free amino acid (TFAAs) profiles, including their patterns and correlations with PFAAs. To evaluate the variation in PFAAs and cancer TFAAs in patients with lung cancer, including their patterns and correlations, we investigated the concentrations of free amino acids in lung cancer tissues (n=27), paired lung paracarcinomous tissues (n=27) and plasma (n=27) using an automatic amino acid analyzer after pre-treatment. Within the PFAAs, the concentrations of five amino acids (tryptophan, glycine, citrulline, ornithine and proline) were significantly decreased, while that of phenylalanine was markedly increased compared with control subjects. Within the TFAAs, the concentrations of three amino acids (taurine, glutamic acid and glycine) were increased, while the concentrations of two amino acids (lysine and ornithine) were decreased significantly in lung cancer tissues compared with the paracarcinomous tissues. The amino acid patterns in PFAAs and TFAAs had similar trends, but percentage variations were diverse. Additionally, the concentrations of five amino acids (lysine, phenylalanine, threonine, serine, and alanine) in PFAAs correlated with those in lung cancer TFAAs, but no amino acids in PFAAs were correlated with those in lung paracarcinomous TFAAs. Thus, PFAA profiles may reflect the status of cancer tissues, which may provide more information about the metabolic statuses and prognoses of patients with lung cancer.

Lung cancer is still the leading cause of cancer-related deaths worldwide. Identifying new oncogenic drivers and developing efficient inhibitors through molecular targeting approaches are crucial for improving therapies. The aim of this study was to investigate whether targeting fibroblast growth factor receptor 1 (FGFR1) with ponatinib inhibits the cell growth in both established and primary lung cancer cells overexpressing FGFR1. Eighty-eight non-small cell lung cancer (NSCLC) and paired normal tissue specimens were analyzed by real-time RT-PCR for FGFR1 gene expression. We identified four cell lines and two newly established primary lung cancer cultures that showed high FGFR1 expression levels, and evaluated the effect of the novel FGFR1 inhibitor ponatinib on cell growth. Approximately 50% (30 out of 59) NSCLC specimens expressed FGFR1>2-fold compared with their adjacent normal counterparts using quantitative RT-PCR. Ponatinib treatment of established NSCLC cell lines expressing higher levels of FGFR1 resulted in marked cell growth inhibition and suppression of clonogenicity. This growth inhibition was associated with inactivation of FGFR1 and its downstream targets. FGFR1 knockdown by shRNA achieved similar results when compared to treatment with ponatinib. Furthermore, ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1.

Transforming growth factor-beta 1 (TGF-beta1) signaling in tumor cells has been implicated in tumor angiogenesis and metastasis by regulating matrix proteolysis. Although MMP-9/gelatinase-B is an important component of these TGF-beta1 responses, the mechanism of its regulation is not well understood. Here, we present evidence that TGF-beta-activated protein kinase 1 (TAK1) is critical for TGF-beta regulation of MMP-9 and the metastatic potential of breast cancer cell line MDA-MB-231. We found that suppression of TAK1 signaling by dominant-negative (dn) TAK1 or RNA interference (siRNA) reduces expression of MMP-9 and tumor cell invasion, without growth inhibition in cell culture. The orthotopic xenograft studies in SCID mice showed that suppression of TAK1 signaling by dn-TAK1 reduces tumor growth and formation of lung metastases. Dn-TAK1 reduced the proliferation Ki-67 index and neovasculature of orthotopic xenografts. TAK1-mediated regulation of MMP-9 involves NF-kappaB signaling. Dn-TAK1 reduces NF-kappaB transcriptional response and inhibition of NF-kappaB reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-beta1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-kappaB-MMP-9 pathway.