Search

Efficacious strategies for early detection of lung cancer metastasis are of significance for improving the survival of lung cancer patients. Here we show the marker genes and serum secretome foreshadowing the lung cancer site-specific metastasis through dynamic network biomarker (DNB) algorithm, utilizing two clinical cohorts of four major types of lung cancer distant metastases, with single-cell RNA sequencing (scRNA-seq) of primary lesions and liquid chromatography-mass spectrometry data of sera. Also, we locate the intermediate status of cancer cells, along with its gene signatures, in each metastatic state trajectory that cancer cells at this stage still have no specific organotropism. Furthermore, an integrated neural network model based on the filtered scRNA-seq data is successfully constructed and validated to predict the metastatic state trajectory of cancer cells. Overall, our study provides an insight to locate the pre-metastasis status of lung cancer and primarily examines its clinical application value, contributing to the early detection of lung cancer metastasis in a more feasible and efficacious way., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: The objective of this study was to evaluate the feasibility of using Artificial Intelligence (AI) to measure the long-diameter of tumors for evaluating treatment response., Methods: Our study included 48 patients with lung-specific target lesions and conducted 277 measurements. The radiologists recorded the long-diameter in axial imaging plane of the target lesions for each measurement. Meanwhile, AI software was utilized to measure the long-diameter in both the axial imaging plane and in three dimensions (3D). Statistical analyses including the Bland-Altman plot, Spearman correlation analysis, and paired t-test to ascertain the accuracy and reliability of our findings., Results: The Bland-Altman plot showed that the AI measurements had a bias of -0.28 mm and had limits of agreement ranging from - 13.78 to 13.22 mm (P = 0.497), indicating agreement with the manual measurements. However, there was no agreement between the 3D measurements and the manual measurements, with P < 0.001. The paired t-test revealed no statistically significant difference between the manual measurements and AI measurements (P = 0.497), whereas a statistically significant difference was observed between the manual measurements and 3D measurements (P < 0.001)., Conclusions: The application of AI in measuring the long-diameter of tumors had significantly improved efficiency and reduced the incidence of subjective measurement errors. This advancement facilitated more convenient and accurate tumor response evaluation., (© 2024. The Author(s).)

Aerobic glycolysis is critical for tumor growth and metastasis. Previously, we have found that the overexpression of the inhibitor of growth 5 (ING5) inhibits lung cancer aggressiveness and epithelial-mesenchymal transition (EMT). However, whether ING5 regulates lung cancer metabolism reprogramming remains unknown. Here, by quantitative proteomics, we showed that ING5 differentially regulates protein phosphorylation and identified a new site (Y163) of the key glycolytic enzyme PDK1 whose phosphorylation was upregulated 13.847-fold. By clinical study, decreased p-PDK1Y163 was observed in lung cancer tissues and correlated with poor survival. p-PDK1Y163 represents the negative regulatory mechanism of PDK1 by causing PDHA1 dephosphorylation and activation, leading to switching from glycolysis to oxidative phosphorylation, with increasing oxygen consumption and decreasing lactate production. These effects could be impaired by PDK1Y163F mutation, which also impaired the inhibitory effects of ING5 on cancer cell EMT and invasiveness. Mouse xenograft models confirmed the indispensable role of p-PDK1Y163 in ING5-inhibited tumor growth and metastasis. By siRNA screening, ING5-upregulated TIE1 was identified as the upstream tyrosine protein kinase targeting PDK1Y163. TIE1 knockdown induced the dephosphorylation of PDK1Y163 and increased the migration and invasion of lung cancer cells. Collectively, ING5 overexpression-upregulated TIE1 phosphorylates PDK1Y163, which is critical for the inhibition of aerobic glycolysis and invasiveness of lung cancer cells., (© 2024. Higher Education Press.)

Background:  The best surgical treatment strategy for coexisting coronary artery disease (CAD) and lung cancer (LC) remains controversial. This study analyzed the safety and efficacy of a simultaneous minimally invasive procedure for patients with CAD and LC., Methods:  Patients who underwent simultaneous minimally invasive off-pump coronary artery bypass grafting and lung resection from January 2016 to December 2021 were retrospectively analyzed. The procedure was performed in the fourth intercostal space through a small left anterolateral minithoracotomy. Harvesting of the left internal mammary artery (LIMA) and sewing of the anastomoses were performed under direct vision. Lung resections were performed with or without the assistance of a thoracoscope., Results:  Sixteen patients were included with a mean age of 67.13 ± 10.61 years. Procedural success occurred in all patients with a mean operative time of 366.88 ± 94.48 minutes. All patients received at least one coronary artery bypass LIMA graft. Pneumonectomy, lobectomy, segment resection, and wedge resection were performed in one (6.25%), eight (50%), two (12.5%), and five (31.25%) patients, respectively. There were no perioperative deaths or new myocardial infarctions. Complications included one case of postoperative bleeding, two lung infections, two cases of atelectasis, one case of pleural effusion, and one case of cardiac arrhythmia. All the patients were followed up for 1 to 57 months, cancer recurrence occurred in two patients, and one patient died. The remaining patients showed no evidence of tumor recurrence or myocardial infarction., Conclusion:  This simultaneous minimally invasive procedure is safe and effective for selected patients with CAD and LC., Competing Interests: None declared., (Thieme. All rights reserved.)

Macrophage-to-osteoclast differentiation (osteoclastogenesis) plays an essential role in tumor osteolytic bone metastasis (BM), while its specific mechanisms remain largely uncertain in lung adenocarcinoma BM. In this study, we demonstrate that integrin-binding sialoprotein (IBSP), which is highly expressed in the cancer cells from bone metastatic and primary lesions of patients with lung adenocarcinoma, can facilitate BM and directly promote macrophage-to-osteoclast differentiation independent of RANKL/M-CSF. In vivo results further suggest that osteolytic BM in lung cancer specifically relies on IBSP-induced macrophage-to-osteoclast differentiation. Mechanistically, IBSP regulates the Rac family small GTPase 1 (Rac1)-NFAT signaling pathway and mediates the forward shift of macrophage-to-osteoclast differentiation, thereby leading to early osteolysis. Moreover, inhibition of Rac1 by EHT-1864 or azathioprine in mice models can remarkably alleviate IBSP-induced BM of lung cancer. Overall, our study suggests that tumor-secreted IBSP promotes BM by inducing macrophage-to-osteoclast differentiation, with potential as an early diagnostic maker for BM, and Rac1 can be the therapeutic target for IBSP-promoted BM in lung cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements is a molecular subset that exhibits favorable responses to tyrosine kinase inhibitor (TKI) treatment than chemotherapy. This study investigated real-world treatment patterns and survival outcomes among patients with ROS1-rearranged advanced NSCLC., Methods: We conducted a retrospective analysis of patients with ROS1-rearranged advanced NSCLC treated in four different hospitals in China from August 2018 to March 2022. The study analyzed gene fusion distribution, resistance patterns, and survival outcomes., Results: ROS1 rearrangement occurs in 1.8 % (550/31,225) of our study cohort. CD74 was the most common ROS1 fusion partner, accounting for 45.8 %. Crizotinib was used in 73.9 % of patients in the first-line treatment, and an increased use of chemotherapy, ceritinib, and lorlatinib was seen in the second-line setting. Lung (43.2 %) and brain (27.6 %) were the most common sites of progression in first-line setting, while brain progression (39.2 %) was the most common site of progression in second-line. Median overall survival was 46 months (95 % confidence intervals: 39.6-52.4). First-line crizotinib use yielded significantly superior survival outcomes over chemotherapy in terms of progression-free (18.5 vs. 6.0; p < 0.001) and overall survival (49.8 vs. 37; p = 0.024). The choice of treatment in the latter line also had survival implications, wherein survival outcomes were better when first-line crizotinib was followed by sequential TKI therapy than first-line chemotherapy followed by TKI therapy., Conclusions: Our study provided insights into the real-world treatment, drug resistance patterns, and survival outcomes among patients with ROS1-rearranged NSCLC. This information serves as a valuable reference for guiding the treatment of this molecular subset of NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to determine the potential profiles of self-psychological adjustment in patients with lung cancer undergoing chemotherapy, including sense of coherence (SOC) and positive cognitive emotion regulation (PCER). The relationship between these profiles with post-traumatic growth (PTG) and the relevant factors of self-psychological adjustment in different profiles was analysed., Design: Cross-sectional study., Setting: Patients with lung cancer undergoing chemotherapy in China., Participants: A total of 330 patients with lung cancer undergoing chemotherapy were recruited out of which 321 completed the questionnaires effectively., Methods: Latent profile analysis was used to identify self-psychological adjustment classes based on the two subscales of the Sense of Coherence Scale and Cognitive Emotion Regulation Questionnaire. One-way analysis of variance and multinomial logistic regression were performed to examine the subgroup association with characteristics and PTG., Results: Three latent profiles of self-psychological adjustment were identified: low level (54.5%), high SOC-low PCER (15.6%) and high PCER (29.9%). The results of univariate analysis showed a significant difference in PTG scores among different self-psychological adjustment subgroups ( F =11.55, p<0.001). Patients in the high-PCER group were more likely living in urban areas (OR=2.41, 95% CI 1.17 to 4.97, p=0.02), and time since cancer diagnosis was ≥6 months and <1 year (OR=3.54, 95% CI 1.3 to 9.64, p<0.001)., Conclusion: This study revealed that most patients with lung cancer undergoing chemotherapy belonged to the low-level group. Three profiles are associated with PTG. There were differences in characteristics between patients treated with chemotherapy for lung cancer in the high-PCER and low-PCER groups. Thus, these profiles provide useful information for developing targeted individualised interventions based on demographic characteristics that would assist PTG in patients with lung cancer undergoing chemotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It is reported that the incidence rate and mortality of lung cancer are very high. Therefore, early diagnosis and identification of specific biomarkers are crucial for the clinical treatment of lung cancer. This study aims to comprehensively investigate the prognostic significance of KRT6A in human lung cancer., Methods: The GEO2R online tool was utilized to analyze the differential expression of mRNA between lung carcinoma tissues and radioresistant tissues in the GSE73095 and GSE197236 datasets. DAVID database was used to perform GO and KEGG enrichment analyses on target genes. The Kaplan-Meier plotter tool was used to analyze the impact of key messenger ribonucleic acid on the survival status of lung cancer. In addition, quantitative real-time polymerase chain reaction (qPCR) was used to investigate the impact of key genes on the phenotype of lung cancer cells. After the knockout, we conducted cell migration and CCK-8 experiments to detect their effects on cell proliferation and invasion., Results: 40 differentially expressed genes (DEGs) were chosen from GSE73095 and 118 DEGs were chosen from GSE197236. Kaplan-Meier map analysis showed that the overall cancer survival rate of the high-expression KRT6A group was higher than that of the low-expression group ( P < 0.05). Besides, cell experiments have shown that when the KRT6A gene is downregulated, the proliferation and invasion ability of lung cancer cells is weakened., Conclusions: Our research concluded that KRT6A may take part in the radioresistance and progression of lung cancer and can be a potential biomarker for lung cancer patients.

Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8 + T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8 + T cells, driven by specific stromal cells such as CTHCR1 + fibroblasts. This study also highlights EGFR(L858R) neoantigens in GGO samples, suggesting potential CD8 + T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The effective therapeutic approach is still an unmet need for patients diagnosed with both lung cancer and interstitial lung disease (ILD). This is primarily due to the possible risk of ILD exacerbation caused by surgery or radiotherapy. The current study aimed to investigate the efficacy and safety of local ablative therapy (LAT) for this specific population., Methods: Consecutive patients with non-small cell lung cancer (NSCLC) and ILD who received LAT between January 2018 and August 2022 were enrolled, and propensity score matching (PSM) was utilized to match the non-ILD group. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS), adverse events (AEs) and hospital length of stay (HLOS)., Results: The PSM algorithm yielded matched pairs in the ILD group (n = 25) and non-ILD group (n = 72) at a ratio of 1:3. There were no statistically significant differences in RFS (median 16.4 vs. 18 months; HR = 1.452, p = 0.259) and OS (median: not reached vs. 47.9 months; HR = 1.096, p = 0.884) between the two groups. Meanwhile, no acute exacerbation of ILD was observed in the ILD group. However, the incidence of pneumothorax, especially pneumothorax requiring chest tube drainage, was significantly higher (36.0% vs. 11.2%, p = 0.005) among patients with NSCLC and co-existing ILD, which resulted in longer HLOS (p = 0.045)., Conclusion: Although ILD was associated with a higher incidence of pneumothorax, the efficacy of LAT for NSCLC patients with ILD was comparable to those without ILD, suggesting that LAT might be a reliable and effective treatment option for this population, particularly in the early stage., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Podoplanin (PDPN) expressed on tumour cells interacts with platelet C-type lectin-like receptor 2 (CLEC-2). This study aimed to investigate the role of the PDPN-platelet CLEC-2 interaction in melanoma pulmonary metastasis., Methods: Murine melanoma B16-F0 cells, which have two populations that express podoplanin, were sorted by FACS with anti-podoplanin staining to obtain purified PDPN + and PDPN- B16-F0 cells. C57BL/6J mice transplanted with CLEC-2-deficient bone marrow cells were used for in vivo experiments., Results: The in vivo data showed that the number of metastatic lung nodules in WT mice injected with PDPN + cells was significantly higher than that in WT mice injected with PDPN- cells and in WT or CLEC-2 KO mice injected with PDPN- cells. In addition, our results revealed that the platelet Syk-dependent signalling pathway contributed to platelet aggregation and melanoma metastasis., Conclusions: Our study indicates that the PDPN-CLEC-2 interaction promotes experimental pulmonary metastasis in a mouse melanoma model. Tumour cell-induced platelet aggregation mediated by the interaction between PDPN and CLEC-2 is a key factor in melanoma pulmonary metastasis., (© 2024. The Author(s).)

The gut microbiota plays a significant role in tumor pathogenesis by regulating the host metabolism and immune response, and there are few studies focused on tracking changes in the gut microbiota from the onset of lung cancer. Therefore, the aim of our study is combining preclinical and clinical research to thoroughly analyze the signatures of fecal microbiota in lung cancer, which will be useful for early diagnosis and predicting the therapeutic efficacy of lung cancer. The first part of this study analyzed the fecal metagenomic differences between patients with non-small cell lung cancer and healthy subjects, and the second part of this work constructed a murine lung cancer model to monitor changes in mouse fecal metagenomics and T cell immunology during lung cancer progression. We found that the fecal microbiota was altered in both humans and mice with lung cancer, characterized by a significantly reduced microbial diversity and number of beneficial microbes, with increases in potential pathogens. The fecal level of Akkermansia muciniphila and the gut metabolic module of the secondary bile acid metabolism were diminished in both humans and mice with lung cancer compared with healthy subjects. Splenomegaly was observed in the lung cancer mice. Flow cytometer analysis of the splenocytes revealed substantial alterations in the proportions of T cell subsets in the lung cancer mice, characterized by significant increases in CD4 + Foxp3 + CD25 + T regulatory cells ( p < 0.05) while significant decreases in CD3 + T cells ( p < 0.001), CD4 + T cells ( p < 0.001), and the CD4 + /CD8 + ratio ( p < 0.01). Vertical and longitudinal analyses of the fecal microbiota of the two mouse groups identified some lung cancer biomarkers (including Acutalibacter timonensis , Lachnospiraceae bacterium NSJ-38 sp014337195, etc.). The fecal microbiota of the lung cancer mice had a reduced metagenomic potential for neurotransmitters (melatonin, γ-aminobutyric acid, and histamine) compared with healthy mice. In summary, this study found that the diversity, structure, and composition of gut microbiota vary between cancer and healthy conditions, ultimately leading to changes in the potential for functional metagenomics.

A Au-Se bond-based nanoprobe using 3',3-diselenopropionic acid to simultaneously link response chains for Pro-GRP protein and Cyfra21-1 was developed. Early diagnosis and subtyping of lung cancer can be achieved based on the nanoprobes' differential response of the probes to the two targets in lung cancer patients' serum.

Computer-aided diagnosis (CAD) systems play vital roles in the early detection of pulmonary nodules for reducing lung cancer mortality rates. To provide better services for professional doctors, this paper proposes an efficient open-source CAD platform with flexible equipments, user-friendly interfaces, and completed functions for 3D CT pulmonary nodule analysis. For the platform's design and implementation, we fully consider application scenarios and system requirements. The platform supplies core functions for (1) Basic Image Processing, (2) Intelligent Image Analysis, (3) Multi-View Image Visualization, (4) Report Editing and Generation, (5) User Information Management, and (6) Inference Service Monitoring. Specifically, other state-of-the-art or user-defined algorithms can be integrated as plugin modules with no interference for system architecture. System evaluation with use-case testing demonstrates the effectiveness and universality of the proposed platform., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: It is challenging to diagnose and manage incidentally detected pulmonary subsolid nodules due to their indolent nature and heterogeneity. The objective of this study is to construct a decision tree-based model to predict malignancy of a subsolid nodule based on radiomics features and evolution over time., Materials and Methods: We derived a training set (2947 subsolid nodules), a test set (280 subsolid nodules) from a cohort of outpatient CT scans, and a second test set (5171 subsolid nodules) from the National Lung Cancer Screening Trial (NLST). A Computer-Aided Diagnosis system (CADs) automatically extracted 28 preselected radiomics features, and we calculated the feature change rates as the change of the quantitative measure per time unit between the prior and current CT scans. We built classification models based on XGBoost and employed 5-fold cross validation to optimize the parameters., Results: The model that combined radiomics features with their change rates performed the best. The Areas Under Curve (AUCs) on the outpatient test set and on the NLST test set were 0.977 (95% CI, 0.958-0.996) and 0.955 (95% CI, 0.930-0.980), respectively. The model performed consistently well on subgroups stratified by nodule diameters, solid components, and CT scan intervals., Conclusion: This decision tree-based model trained with the outpatient dataset gives promising predictive performance on the malignancy of pulmonary subsolid nodules. Additionally, it can assist clinicians to deliver more accurate diagnoses and formulate more in-depth follow-up strategies., Competing Interests: Disclosure We have read and understand the policy on declaration of interests and declare that we have no conflicts of interests., (Copyright © 2023. Published by Elsevier Inc.)

Aims: The use of non-steroid anti-inflammatory drugs (NSAIDs) is conventional in management of postoperative pain in cancer patients, and further investigations have reported that some of these drugs correlated with the outcome in cancers. However, the prognostic value of the use of NSAIDs during surgery in non-small cell lung cancer (NSCLC) patients has been less addressed., Methods: NSCLC patients staged I-III are retrospectively enrolled, and the data of the use of NSAIDs during surgery are collected. Patients are divided into two subgroups according to the use intensity (UI) (low or high) of the NSAIDs, which was calculated by the accumulate dosage of all the NSAIDs divided by the length of hospitalization. The differences of the clinical features among these groups were checked. And the disease-free survival (DFS) and overall survival (OS) differences in these groups were compared by Kaplan-Meier analysis; risk factors for survival were validated by using a Cox proportional hazards model., Results: The UI was significant in predicting the DFS (AUC = 0.65, 95% CI: 0.57-0.73, P = 0.001) and OS (AUC = 0.70, 95% CI: 0.59-0.81, P = 0.001). Clinical features including type of resection (P = 0.001), N stages (P < 0.001), and TNM stages (P = 0.004) were significantly different in UI low (< 74.55 mg/day) or high (≥ 74.55 mg/day) subgroups. Patients in UI-high subgroups displayed significant superior DFS (log rank = 11.46, P = 0.001) and OS (log rank = 7.63, P = 0.006) than the UI-low ones. At last, the UI was found to be an independent risk factor for DFS (HR: 0.52, 95% CI: 0.28-0.95, P = 0.034)., Conclusions: The use of NSAIDs during radical resection in NSCLC patients correlated with the outcome and patients with a relative high UI has better outcome., (© 2023. The Author(s).)

Rationale: Autoimmunity targeting glutamic acid decarboxylase 65 (GAD65) is associated with type 1 diabetes mellitus as well as various neurological diseases. In the central nervous system, GAD65 autoimmunity usually presents with limbic encephalitis, whereas extralimbic encephalitis (ELE) has only been reported in a few cases. Moreover, anti-GAD65 ELE in the paraneoplastic context has not yet been reported., Patient Concerns: A 60-year-old man presented with intermittent cough and sputum for 10 years, with no other diseases. The patient presented with recurrent seizures that were resistant to antiepileptic drugs (AEDs). Chest computed tomography and pathological results confirmed the diagnosis of small cell lung cancer. Paraneoplastic testing found a high level of GAD65 antibodies in his serum, and cerebrospinal fluid analysis revealed lymphocytic pleocytosis, indicating autoimmune encephalitis. Brain magnetic resonance imaging showed multifocal T2 fluid-attenuated inversion recovery hyperintensities in the extralimbic areas including the subcortex and deep white matter of the bilateral frontal lobe, parietal lobe, and insula lobes., Diagnoses: Finally, a diagnosis of anti-GAD65 autoimmune ELE with a paraneoplastic etiology from the small cell lung cancer was suspected., Interventions: The patient refused any tumor-suppressive treatment or immunotherapy for potential side effects and only received AEDs levetiracetam, sodium valproate, and diazepam., Outcomes: The epilepsy of the patient was resistant to AEDs, and the patient died a week after discharge due to disease progression., Lessons: Anti-GAD65 autoimmune encephalitis can be extralimbic, can present with isolated epilepsy, and extralimbic anti-GAD65 encephalitis can occur with an underlying malignancy., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 ., (© 2023. The Author(s).)

Background: Small pulmonary nodules (<3 cm) can sometimes be unrecognizable and nonpalpable in video-assisted thoracoscopic surgery (VATS). Near-infrared fluorescence (NIF) VATS after indocyanine green (ICG) inhalation may effectively guide surgeons to locate the nodules., Objective: This study aimed to investigate the safety, feasibility, and efficacy of ICG inhalation-based NIF imaging for guiding small pulmonary nodule resections., Methods: Between February and May 2021, the first-stage, non-randomized trial enrolled 21 patients with different nodule depth, ICG inhalation doses, post-inhalation surgery times, and nodule types at a tertiary referral hospital. Between May 2021 and May 2022, the second-stage randomized trial enrolled 56 patients, who were randomly assigned to the fluorescence VATS (FLVATS) or the white-light VATS (WLVATS) group. The ratio of effective guidance and the time consumption for nodule localization were compared., Results: The first-stage trial proved this new method is safe and feasible, and established a standardized protocol with optimized nodule depth (≤1 cm), ICG dose (0.20-0.25 mg/kg), and surgery window (50-90 min after ICG inhalation). In the second-stage trial, the FLVATS achieved 87.1% helpful nodule localization guidance, which was significantly higher than the WLVATS (59.1%, p < 0.05). The mean nodule locating time (standard deviation) was 1.8 [0.9] and 3.3 [2.3] min, respectively. Surgeons adopting FLVATS were significantly faster (p < 0.01), especially when locating small ground-glass opacities (1.3 [0.6] min vs. 7.0 [3.5] min, p < 0.05). Five of 31 nodules (16.1%) were only detectable by FLVATS, whereas both white light and palpation failed., Conclusions: This new method is safe and feasible for small pulmonary nodule resection. It significantly improves nodule localization rates with less time consumption, and hence is highly worthy for clinical promotion. Clinical Trial Registration Chinese Clinical Trial Registry Identifier: ChiCTR2100047326., (© 2023. Society of Surgical Oncology.)

Objectives: Mesothelioma is a lethal disease that arises from the serosal lining of organ cavities. Several recurrent alterations have been observed in pleural and peritoneal -mesotheliomas, including in BAP1, NF2, and CDKN2A. Although specific histopathologic parameters have been correlated with prognosis, it is not as well known whether genetic alterations correlate with histologic findings., Methods: We reviewed 131 mesotheliomas that had undergone next-generation sequencing (NGS) at our institutions after pathologic diagnosis. There were 109 epithelioid mesotheliomas, 18 biphasic mesotheliomas, and 4 sarcomatoid mesotheliomas. All our biphasic and sarcomatoid cases arose in the pleura. Of the epithelioid mesotheliomas, 73 were from the pleura and 36 were from the peritoneum. On average, patients were 66 years of age (range, 26-90 years) and predominantly male (92 men, 39 women)., Results: The most common alterations identified were in BAP1, CDKN2A, NF2, and TP53. Twelve mesotheliomas did not show a pathogenic alteration on NGS. For epithelioid mesotheliomas in the pleura, the presence of an alteration in BAP1 correlated with low nuclear grade (P = .04), but no correlation was found in the peritoneum (P = .62). Similarly, there was no correlation between the amount of solid architecture in epithelioid mesotheliomas and any alterations in the pleura (P = .55) or peritoneum (P = .13). For biphasic mesotheliomas, cases with either no alteration detected or with an alteration in BAP1 were more likely to be epithelioid predominant (>50% of the tumor, P = .0001), and biphasic mesotheliomas with other alterations detected and no alteration in BAP1 were more likely to be sarcomatoid predominant (>50% of the tumor, P = .0001)., Conclusions: This study demonstrates a significant association between morphologic features associated with a better prognosis and an alteration in BAP1., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: This study aimed to explore the correlations among heavy metals concentration, histologic subtypes and molecular characteristics in patients with non-small cell lung cancer (NSCLC)., Methods: In this study, an NGS panel of 82 tumor-associated genes was used to identify genomic alternations in 180 newly diagnosed patients with NSCLC. The concentrations of 18 heavy metals in the serum samples were detected by inductively coupled plasma emission spectrometry (ICP-MS)., Results: A total of 243 somatic mutations of 25 mutant genes were identified in 115 of 148 patients with LUAD and 45 somatic mutations of 15 mutant genes were found in 24 of 32 patients with LUSC. The genomic alternations, somatic interactions, traditional serum biomarkers, and heavy metals were markedly different between patients with LUAD and LUSC. Moreover, patients with LUSC were significantly positively correlated with Ba, but not LUAD. Lastly, patients with EGFR mutations presented significant negative correlations with Cd and Sr, whereas patients with TP53 mutations showed a significant positive correlation with Pb., Conclusion: The genomic alternations, somatic interactions, traditional serum biomarkers, and heavy metals were different between patients with LUAC and LUSC, and heavy metals (e.g., Ba, Pb, and Cd) may contribute to the tumorigenesis of NSCLC with different histological and molecular subtypes., (© 2023. The Author(s).)

The rs2736100 (A > C) polymorphism of the second intron of Telomerase reverse transcriptase (TERT) has been confirmed to be closely associated with the risk of Lung cancer (LC), but there is still no unified conclusion on the results of its association with LC. This study included Genome-wide association studies (GWAS) and case-control studies reported so far on this association between TERT rs2736100 polymorphism and LC to clarify such a correlation with LC and the differences in it between different ethnicities and different types of LC. Relevant literatures published before May 7, 2022 on 'TERT rs2736100 polymorphism and LC susceptibility' in PubMed, EMbase, CENTRAL, MEDLINE databases were searched through the Internet, and data were extracted. Statistical analysis of data was performed in Revman5.3 software, including drawing forest diagrams, drawing funnel diagrams and so on. Sensitivity and publication bias analysis were performed in Stata 12.0 software. The C allele of TERT rs2736100 was associated with the risk of LC (Overall population: [OR] = 1.21, 95%CI [1.17, 1.25]; Caucasians: [OR] = 1.11, 95%CI [1.06, 1.17]; Asians: [OR] = 1.26, 95%CI [1.21, 1.30]), and Asians had a higher risk of LC than Caucasians (C vs. A: Caucasians: [OR] = 1.11 /Asians: [OR]) = 1.26). The other gene models also showed similar results. The results of stratified analysis of LC patients showed that the C allele was associated with the risk of Non-small-cell lung carcinoma (NSCLC) and Lung adenocarcinoma (LUAD), and the risk of NSCLC and LUAD in Asians was higher than that in Caucasians. The C allele was associated with the risk of Lung squamous cell carcinoma (LUSC) and Small cell lung carcinoma(SCLC) in Asians but not in Caucasians. NSCLC patients ([OR] = 1.27) had a stronger correlation than SCLC patients ([OR] = 1.03), and LUAD patients ([OR] = 1.32) had a stronger correlation than LUSC patients ([OR] = 1.09).In addition, the C allele of TERT rs2736100 was associated with the risk of LC, NSCLC and LUAD in both smoking groups and non-smoking groups, and the risk of LC in non-smokers of different ethnic groups was higher than that in smokers. In the Asians, non-smoking women were more at risk of developing LUAD. The C allele of TERT rs2736100 is a risk factor for LC, NSCLC, and LUAD in different ethnic groups, and the Asian population is at a more common risk. The C allele is a risk factor for LUSC and SCLC in Asians but not in Caucasians. And smoking is not the most critical factor that causes variation in TERT rs2736100 to increase the risk of most LC (NSCLC, LUAD). Therefore, LC is a multi-etiological disease caused by a combination of genetic, environmental and lifestyle factors., (© 2023. Springer Nature Limited.)

Objective: Immune checkpoint inhibitors (ICIs) or combined with chemotherapy exhibit substantial efficacy for the treatment of advanced non-small cell lung cancer (NSCLC). However, reliable biomarkers that can monitor response to first-line ICIs ± chemotherapy remain unclear., Methods: A total of 16 tumor tissues and 46 matched peripheral blood samples at baseline and during treatment were retrospectively collected from 19 locally advanced or metastatic NSCLC patients. The circulating tumor DNA (ctDNA) burden by tumor-informed assay was detected to monitor and predict the therapeutic response and survival of NSCLC patients treated with first-line ICIs or plus chemotherapy., Results: We found that ctDNA was only positively detected in one patient by tumor-agnostic assay with a mean variant allele fraction (VAF) of 6.40%, whereas it was positively detected in three patients by tumor-informed assay with a mean VAF of 8.83%, 0.154%, and 0.176%, respectively. Tumor-informed assays could sensitively detect ctDNA in 93.75% (15/16) of patients. Trends in the level of ctDNA from baseline to first evaluation was consistent with the radiographic changes. There was a greater decrease in ctDNA after treatment compared with baseline in patients with partial response compared to patients with stable disease/progressive disease. Patients with over a 50% reduction in ctDNA had a significant progression-free survival and overall survival benefit., Conclusion: The tumor-informed assay was favorable for ctDNA detection, and early dynamic changes in plasma ctDNA may be a valuable biomarker for monitoring the efficacy and predicting the outcome in advanced NSCLC patients treated with first-line ICIs ± chemotherapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Programmed cell death-ligand 1 (PD-L1) expression was found to be a biomarker of inferior efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC). However, whether PD-L1 expression could also serve as a similar biomarker in anaplastic lymphoma kinase (ALK)-positive patients, especially for those treated with front-line alectinib, remains unclear. The aim of the study is to investigate the association of PD-L1 expression and efficacy of alectinib in this setting., Methods: From January 2018 to March 2020, 225 patients with ALK-rearranged lung cancer were consecutively collected at Shanghai Pulmonary Hospital, Tongji University. Baseline PD-L1 expression was detected using immunohistochemistry (IHC) in 56 patients of advanced ALK-rearranged lung cancer who received front-line alectinib., Results: Among the 56 eligible patients, 30 (53.6%) were PD-L1 expression negative, 19 (33.9%) patients had TPS 1%-49% and 7 (12.5%) had TPS ≥ 50%.We found no statistically significant associations between PD-L1 positivity and objective response rate (ORR, 90.0% vs. 80.8%, p = 0.274) or progression-free survival (PFS, not reached vs. not reached, HR: 0.98, 95 %CI: 0.37-2.61, p = 0.97) in patients treated with alectinib. Meanwhile, patients with PD-L1 high expression (TPS ≥ 50%) had a trend of longer PFS (not reached vs. not reached, p = 0.61)., Conclusions: PD-L1 expression might not serve as a predict biomarker for the efficacy of front-line alectinib in ALK-positive NSCLC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ferroptosis, an iron-dependent cell death process, is a potential therapeutic strategy for Lung squamous cell carcinoma (LUSC). Resveratrol (RES) is an anti-tumor polyphenol. However, whether and how RES treats LUSC is not yet known. This study aimed to investigate the effect of RES on LUSC and to explore its potential mechanism. This study used a combination of proteomics, bioinformatics, clinical samples, and cell experiments to study the interaction between HMMR and the ferroptosis signaling pathway and investigate the role of RES in regulating tumor immune microenvironment and anti-tumor by cytotoxic CD8 +T cells in LUSC. Ferroptosis signaling pathway and HMMR were involved in the LUSC tumor immune microenvironment and correlated with worse prognosis of LUSC patients. RES+H520 cells induced a higher level of ferroptosis and MDA, mainly by reducing the expression of GPX4 and SLC7A11, inducing the expression of ACSL4 and TFRC. HMMR, GSH, and SOD contents were lower observed than in H520 cells. When HMMR was expressed, SLC7A11 was also highly expressed in LUSC, and there was an interaction between HMMR expression and SLC7A11. In addition, RES increased the TNF-α, IFN-γ, IL-12, and IL-2 expression and increased the cytotoxic effects of CD8 +T cells expressions in LUSC. Resveratrol regulates SLC7A11-HMMR interaction, activates ferroptosis, enhances the cytotoxic effect of CD8 +T cells, and regulates the tumor immune microenvironment. Based on the pathogenesis of LUSC and the clinical efficacy of RES, this study explored the influence of RES on LUSC, clarified its biological effects, and further provided cell biological basis for the clinical application of RES, which could guide clinical combination and personalized medicine, improve the response rate of immunotherapy and benefit more patients with LUSC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate-limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome-wide CRISPR-Cas9 screening revealed that loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia-activating complement component 3 and enhance the cytolytic activity of CD8 + T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8 + T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon-gamma and inducing phagocytosis and T-cell-mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD-1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD-1 blockade may be a promising strategy to reduce metastasis., (© 2023 The Authors.)

Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers, which has the highest cancer-related mortality worldwide. Regardless of the therapeutic effects of chemotherapy or targeted therapy, drug resistance will occur after 1 year. Heat shock proteins (HSPs) are a class of molecular chaperones participated in protein stability and multiple intracellular signaling pathways. It has been widely reported that HSPs family is over expressed in non-small cell lung cancer, and these molecules are also associated with protein stability and multiple intracellular signaling pathways. The effect of chemotherapy drugs or targeted drugs on cancer cells is usually to induce apoptosis. It is necessary to explore the interaction between heat shock protein family and apoptosis pathway in NSCLC. Here we provide a brief review of how HSPs affect the apoptotic pathway in NSCLC., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Objective: Non-small cell lung cancer (NSCLC) holds high metabolic tumor burden and circulating cell-free DNA (cfDNA) levels, and the relationship between metabolic tumor burden and cfDNA in NSCLC and the underlying mechanism of their interaction therein remain poorly characterized. Our aim was to evaluate the clinical value of cfDNA and metabolic tumor burden by positron emission tomography-computed tomography (PET/CT) for NSCLC differential diagnosis from tuberculosis in patients with solitary pulmonary nodules., Methods: Metabolic tumor burden values in humans (subjects with NSCLC, subjects with tuberculosis, and healthy control subjects) and relevant mouse models were detected by preoperative 18F-fluorodeoxyglucose PET (18F-FDG PET/CT) and [3H]-2-deoxy-DG uptake, respectively. The cfDNA levels were detected by quantifying serum cfDNA fragments from the ALU (115 bp) gene using reverse transcription-polymerase chain reaction. RNA sequence was performed to determine the underlying target genes and knocked down or inhibited the target genes in vivo and in vitro to determine the mechanism therein., Results: Metabolic tumor burden correlated with serum cfDNA levels in NSCLC subjects but not in tuberculosis subjects or healthy controls. Mouse models showed a similar phenomenon. In addition, the RNA sequence showed that glucose transporter 1 (GLU1), factor-related apoptosis ligand (FasL), caspase 8, and caspase 3 were significantly increased in NSCLC mouse tumors compared with those in tuberculosis mouse masses. Inhibiting the metabolic tumor burden by blocking or knocking down GLU1 markedly reduced the expression of FasL, the phosphorylation of caspase 8/caspase 3, and serum cfDNA levels/apoptosis percentage in vivo and in vitro. Furthermore, the use of a combination of cfDNA and metabolic tumor burden allowed better ability to distinguish NSCLC subjects from those with tuberculosis or healthy controls than either method used alone., Conclusion: Metabolic tumor burden promotes the formation of circulating cfDNA through GLU1-mediated apoptosis in NSCLC, and the combination of cfDNA and metabolic tumor burden could be valuable for distinguishing NSCLC from tuberculosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We aimed to explore the mechanism of microRNA-936 (miR-936) targeting G protein coupled receptor 78 (GPR78) regulating chemoresistance of non-small cell lung cancer (NSCLC) by activating the Galphaq Rho GTPase pathway., Methods: We added cisplatin to DMEM medium of HCC827/cisplatin cells and adjusted the final concentration to 1 μg/mL. Cells were divided into the control group and the miR-936 transfection group. Tissue samples were divided into the normal tissue group and the NSCLC tissue group. The mRNA expression of miR-936 in tissue samples was analyzed via reverse transcription polymerase chain reaction (RT-PCR). Cell migration and invasion were detected by wound healing assay. Cell counting kit 8 (CCK-8) was used to detect the cell viability 1, 2 and 3 days after cisplatin induction. The toxicity of cisplatin was analyzed by flow cytometry. The targeting relationship between miR-936 and GPR78 was detected by luciferase reporter gene assay. The regulation of miR-936 on GPR78/Rho GTPase was analyzed by Western blot., Results: The expression of miR-936 in NSCLC was lower than in normal tissues (P < .05). The number of cell migrations and invasions in the miR-936 transfection group was lower than in the control group (P < .05). The cell viability in the miR-936 transfection group was lower than in the control group on the 1st, 2nd and 3rd day (P < .05). With the increase in cisplatin concentration, the apoptosis rate of cells increased in a dependent manner (P < .05). Compared with GPR78 Mut, overexpression of miR-936 inhibited the luciferase activity of GPR78 WT 3'- UTR (P < .05). The expression of GPR78, RhoA, Rac1 and ABCB1 protein in the miR-936 transfection group was lower than in the control group (P < .05). The expression of GPR78 protein in the inhibitor+miR-936 transfection group was lower than in the inhibitor+control group (P < .05)., Conclusion: miR-936 targets GPR78 and improves the sensitivity of NSCLC cells to cisplatin via the Galphaq Rho GTPase pathway.

Background: Tumor-initiating cells (TIC) often elude conventional cancer treatment, which results in metastasis and cancer relapse. Recently, studies have begun to focus on the TIC population in tumors to provide better therapeutic options. Previously, we have reported the successful development of a TIC-specific probe TiY with the binding target as vimentin. While a low concentration of TiY showed a TIC visualization, at a high concentration, TiY induced selective toxicity onto TIC in vitro. In this study, we aim to assess TiY's applicability in theranostics purposes, from in vivo visualization to therapeutic effect toward TIC, in cancer mouse models. Methods : We performed cell experiments with the TIC line model derived from resected primary non-small cell lung cancer (NSCLC) patient tumor. The animal model studies were conducted in mice of NSCLC patient-derived xenograft (PDX). TiY was intravenously delivered into the mice models at different concentrations to assess its in vivo TIC-selective staining and therapeutic effect. Results: We demonstrated the TIC-selective identification and therapeutic effect of TiY in animal models. TiY treatment induced a significant ablation of the TIC population in the tumor, and further molecular study elucidated that the mechanism of TiY is through vimentin dynamics in TIC. Conclusion: The results underscore the applicability of TiY for cancer treatment by selectively targeting soluble vimentin in TIC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The coactivator associated arginine methyltransferase (CARM1) promotes transcription, as its name implies. It does so by modifying histones and chromatin bound proteins. We identified nuclear factor I B (NFIB) as a CARM1 substrate and show that this transcription factor utilizes CARM1 as a coactivator. Biochemical studies reveal that tripartite motif 29 (TRIM29) is an effector molecule for methylated NFIB. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Here, we explore the possibility that CARM1 methylation of NFIB is important for its transforming activity. Using a SCLC mouse model, we show that both CARM1 and the CARM1 methylation site on NFIB are critical for the rapid onset of SCLC. Furthermore, CARM1 and methylated NFIB are responsible for maintaining similar open chromatin states in tumors. Together, these findings suggest that CARM1 might be a therapeutic target for SCLC., (© 2023. The Author(s).)

It is of great significance to find new effective drugs for an adjuvant therapy targeting lung cancer to improve the survival rate and prognosis of patients with the disease. Previous studies have confirmed that certain Chinese herbal extracts have clear anti-tumor effects, and in our preliminary study, betulinaldehyde was screened for its potential anti-tumor effects. The current study thus aimed to confirm the anti-tumor effect of betulinaldehyde, using in vitro experiments to explore its underlying molecular mechanism. It was found that betulinaldehyde treatment significantly inhibited the viability, proliferation, and migration of A549 cells in a dose-dependent manner. In addition, betulinaldehyde inhibited the activation of Akt, MAPK, and STAT3 signaling pathways in A549 cells in a time-dependent manner. More importantly, betulinaldehyde also decreased the expression level of SQSTM1 protein, increased the expression level of LC3 II, and increased the autophagy flux in A549 cells. The pretreatment of A549 cells with the autophagy inhibitor, 3-methyladenine, could partially negate the anti-tumor effects of betulinaldehyde. These findings suggest that betulinaldehyde could significantly inhibit the oncological activity of A549 cells by regulating the intracellular autophagy level, making it a potentially effective option for the adjuvant therapy used to treat lung cancer in the future., (© 2023. The Author(s).)

Immune checkpoint inhibitors (ICIs), which represent the new standard of care for advanced nonsmall cell lung cancer (NCSLC), are not effective in many patients. Biomarkers are needed to guide treatment. Sequencing data of an ICI-treated cohort were analyzed to identify genomic signatures predicting ICI efficacy, followed by validation using multiple independent cohorts. Their predictive mechanism was explored by evaluating the tumor immune microenvironment and tumor mutational burden (TMB). In the discovery cohort, patients carrying FGFR4 alterations (FGFR4 altered ) had a better objective response rate (ORR) (50.0% vs 19.4%; P = .057) and improved median progression-free survival (mPFS) (13.17 vs 3.17 months; HR 0.37; 95% CI 0.14-1; P = .04) than wild-type patients (FGFR4 wt ). In the publicly available validation cohorts, FGFR4 alterations correlated with higher ORR (100% vs 31%; P = .028), longer median overall survival (mOS) (not reached [NR] vs 11 months; HR 0.28, 95% CI 0.09-0.89, P = .02), and mPFS (NR vs 6.07 months; HR 0.05, 95% CI 0-3.94, P = .039). FGFR4 alterations were confirmed as an independent predictor of superior PFS (P = .014) and OS (P = .005). FGFR4 altered patients also exhibited a significantly improved disease control rate (100% vs 60%, P = .045) and prolonged mPFS (9.70 vs 3.16 months; P = .095) compared to FGFR4 wt patients in our Shanghai Pulmonary Hospital cohort. FGFR4 alterations associated with a higher TMB levels, more CD8 + T cells in the tumor stroma, and a higher M1/M2 ratio for tumor-associated macrophages in the tumor center and stroma. Thus, FGFR4 alterations may serve as a potential independent predictor of ICI efficacy in NSCLC., (© 2022 UICC.)

Context: Lung cancer is one of the most common forms of cancer. Autophagy and apoptosis play an important role in the development of lung cancer. Researchers have found upregulation of GRP78 expression in cancer cells of various types., Objective: The study intended to explore the mechanism of G protein-coupled receptor 78(GPR78) in regulating autophagy and drug resistance in non-small cell lung cancer (NSCLC)., Design: The research team performed a laboratory study., Setting: The study took place in the Department of Thoracic Surgery at Hainan General Hospital of the Hainan Affiliated Hospital of Hainan Medical University in Haikou, Hainan, China., Intervention: The research team cultured immortalized, normal, human bronchial epithelial cells C3 (HBEC3) lines and HBEC4 lines in a serum medium without keratinocytes and infected the expression of GPR78 in knockdown A549 cells using lentiviral agents. The team divided the cells into a control group and a shRNA-GPR78 group, the intervention group. The lentiviral silencing vector expressing shRNA targets human GPR78#1 and GPR78 #2aadam10., Outcome Measures: The research team analyzed the mRNA expression of GPR78 in the NSCLC cell lines H1975, H1299, and A549 and in HBEC3 and HBEC4 using a real time-polymerase chain reaction (RT-PCR) and measured the proliferation of A549 cells at 0h, 24h, 48h, 72h, and 96h using yellow tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The team also analyzed the migration and invasion ability of cells using wound healing and Transwell tests as well as measured the protein expression of the autophagy-related factors Beclin-1, microtubule-associated protein light chain 3-I/II (LC3-I/LC3-II), ubiquitin-binding protein p62 and c-Jun N-terminal kinase (JNK) using a Western blot test. The team also analyzed the protein expressions of caspase-9, caspase-3, and caspase-12 related to apoptosis using a Western blot. To detect the cell viability induced by cisplatin, the team used a Cell Counting Kit 8 (CCK-8) at the concentrations of 1μM, 3μM and 10μM., Results: The mRNA expression of GPR78 in the H1975, H1299, and A549 cell lines was significantly higher than that in the HBEC3 and HBEC4 cell lines (P < .05). At 48h, 72h, and 96h, the A549 cell proliferation in the shRNA-GPR78 group was significantly lower than that of the control group (P < .05). The cell migration and invasion of cells in the shRNA-GPR78 group was significantly lower than that in the control group (P < .05), and the cell viability of the shRNA-GPR78 group was significantly lower than that of control group (P < .05). The expression of Beclin-1 and JNK protein in shRNA-GPR78 group was significantly higher than that in the control group (P < .05), and the expression of LC3-I/LC3-II and p62 protein in shRNA-GPR78 group was significantly lower than that in the control group (P < .05). The protein expressions of caspase-9, caspase-3, and caspase-12 in the shRNA-GPR78 group were significantly higher than those of the control group (P < .05), and the protein activities of RhoA and Rac1 in the shRNA-GPR78 group were significantly lower than those in the control group (P < .05)., Conclusion: NSCLC upregulated GPR78. The knockdown of GPR78 can attenuate the proliferation, migration, and invasion of NSCLC cells and increase the apoptosis and autophagy of NSCLC cells that cisplatin has induced. Therefore, targeting GPR78 may be a promising treatment strategy for NSCLC patients.

Background: Osteosarcoma (OS) is a heterogeneous malignant spindle cell tumor in children under the age of 20. This study aims to research the association between Solute Carrier Family 7 Member 8 (SLC7A8) as well as related genes and OS., Method: OS and normal samples (GSE38698 and GSE85537) were downloaded from Gene Expression Omnibus dataset. The bioinformatics analysis was performed to distinguish 2 differentially expressed genes, prognostic candidate genes and functional enrichment pathway. Immunohistochemistry and quantitative real-time PCR were utilized for further study., Results: There were 5 DEMs and 10 differentially expressed genes in cancer tissues compared to normal tissues. According to the km-plot software, ARHGEF3, BSN, PQLC3, and SLC7A8 were significantly related to the overall survival of patients with OS. Furthermore, Multivariate analysis included that SLC7A8 was independent risk factors for OS patients. Furthermore, immunohistochemistry and quantitative real-time PCR outcomes indicated that the expression level of SLC7A8 and hsa-miR-506 was differentially expressed in lung metastasis OS tissues and non-metastasis tissues., Conclusion: The prognostic model based on the miRNA-mRNA network could provide predictive significance for prognosis of OS patients, which would be worthy of clinical application. Our results concluded that SLC7A8 may play a key role in the development of OS., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study is aimed at investigating the clinical intervention effect of afatinib targeted therapy in patients with non-small-cell lung cancer., Methods: The research object was a retrospective analysis of 86 patients with non-small-cell lung cancer who were admitted to our hospital from 1 st January 2019 to 31 st December 2021. The patients were divided into two groups. The patients in the two groups received conventional chemotherapy intervention, and the patients in group B received afatinib targeted therapy intervention on the basis of the treatment in group A. The clinical intervention effect, immune function, serum EGFR level, serum pro-GRP level, and incidence of adverse reactions were compared between the two groups of patients., Results: After afatinib targeted therapy intervention, the total intervention effective rate of patients in treatment group B was significantly higher than that in patients in treatment group A. Compared with the treatment group A, the CD3+, CD4+, CD8+, and CD4+/CD8+ of the treatment group were significantly upregulated. After the intervention, the serum EGFR levels of patients in treatment groups A and B were significantly decreased, and the serum EGFR levels in patients in treatment group B were significantly lower than those in patients in treatment group A. The serum pro-GRP level in group B patients was significantly decreased. The overall incidence of adverse reactions in treatment group B was significantly lower than that in treatment group A., Conclusion: Afatinib targeted therapy has a significant clinical intervention effect on patients with non-small-cell lung cancer, which not only helps to improve the immune function of patients but also effectively improves the serum EGFR and pro-GRP levels of patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Wei Cao et al.)

Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has been the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with driver-gene negative. However, efficacy biomarkers for ICIs-based combination therapy are lacking. We aimed to identify potential factors associated with outcomes of ICIs plus chemotherapy at baseline and dynamic changes in peripheral blood., Methods: We collected plasma samples of 51 advanced NSCLC patients without EGFR/ALK/ROS1 alteration at baseline and/or after two treatment cycles of ICIs plus chemotherapy. A blood-based intratumor heterogeneity (bITH) score was calculated based on the allele frequencies of somatic mutations using a 520-gene panel. bITH-up was defined as a ≥ 10% increase in bITH score from baseline, with a second confirmatory measurement after treatment., Results: At baseline, the number of metastatic organs and lung immune prognostic index (LIPI) were significantly associated with shorter progression-free survival (PFS) of ICIs plus chemotherapy, while bITH and other common molecular biomarkers, including ctDNA level, blood-based tumor mutational burden (bTMB), and PD-L1 expression, had no effect on PFS. LRP1B mutation at baseline was significantly associated with favorable outcomes to ICIs plus chemotherapy. There were 37 patients who had paired samples at baseline and after two cycles of treatment, with the median interval of 53 days. Intriguingly, patients with bITH-up had significant shorter PFS (HR, 4.92; 95% CI, 1.72-14.07; P = 0.001) and a lower durable clinical benefit rate (0 vs 41.38%, P = 0.036) than those with bITH-stable or down. Case studies indicated that bITH was promising to predict disease progression., Conclusions: The present study is the first to report that increased bITH is associated with unfavorable outcomes of ICIs plus chemotherapy in advanced NSCLC patients., (© 2022. The Author(s).)

Background: Lung cancer is the leading cause of cancer-related deaths. Immunotherapy is a promising therapeutic approach, but the population best suited to immunotherapy is yet to be determined., Materials and Methods: Lung squamous cell carcinoma (LUSC) was chosen as the object for the present study. Four gene expression profiles were retrieved from the GEO database. 141 differentially expressed genes (DEGs) were detected in LUSC tissues and normal tissues by the GEO2R tool and Venn diagram software., Results: 34 candidate genes were selected for further analysis. A Kaplan-Meier survival plot further isolated 29 of 34 genes and after re-validation using gene expression profiling interactive analysis and pathway enrichment, Bonferroni correction was used to adjust P values, results showed that two genes (CD168 and OPN) were markedly enriched in the extracellular matrix (ECM)-receptor interaction pathway. We believe this pathway and genes may be tightly involved in the LUSC tumor immune microenvironment. We conducted a further cellular study to knock-down OPN in H520 cells using siRNA. The expression of CD168 was reduced in siRNA-OPN H520 cells (P < 0.05). Our results indicate that the arrest of CD168 occurs after the downregulation of the OPN protein, suggesting that OPN participates in ECM-receptor interactions., Conclusions: By using integrated bioinformatics, we have identified CD168 and OPN as DEGs with poor prognosis in LUSC and have validated their interaction in the ECM receptor pathway. These genes could be potential diagnostic and therapeutic targets for LUSC patients undergoing immunotherapy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Epimedium is a traditional Chinese medicine that is most commonly prescribed by practitioners of Chinese medicine for the clinical treatment of malignant tumor bone metastasis. The main component of Epimedium is icariin (ICA). Studies have shown that ICA inhibits bone resorption of osteoclasts through the OPG/RANKL/RANK signaling pathway. Osteoclasts are the only cells in the body that have a bone-destroying capability. The OPG/RANKL/RANK system consists of cytokines that play major roles in osteoclast formation. Therefore, our study selected the OPG/RANKL/RANK system as the research target to investigate the effect of ICA on nude mice with lung cancer bone metastasis. We established the model of bone metastasis in nude mice, intervened the model with icariin and zoledronic acid, and detected the levels of OPG and RANKL by ELISA and western blot. The results showed that ICA had a significant inhibitory effect on bone metastases in nude mice. ICA achieved its antibone metastasis effect in nude mice with lung cancer via inhibiting RANKL expression and simultaneously increasing OPG expression. ICA not only alleviated osteolytic bone destruction caused by bone metastases, but it also reduced weight loss in tumor-bearing nude mice at the late stage of the experiment. The role of ICA in preventing bone metastasis of lung cancer merits further investigation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Zhao Ruilian et al.)

Objective: To investigate the value of monochromatic dual-energy CT (DECT) images based on radiomics in differentiating benign from malignant solitary pulmonary nodules., Materials and Methods: This retrospective study was approved by the institutional review board, and informed consent was waived. Pathologically confirmed lung nodules smaller than 3 cm with integrated arterial phase and venous phase (AP and VP) gemstone spectral imaging were retrospectively identified. After extracting the radiomic features of each case, principal component analysis (PCA) was used for feature selection, and after training with the logistic regression method, three classification models (Model AP , Model VP and Model Combination ) were constructed. The performance was assessed by the area under the receiver operating curve (AUC), and the efficacy of the models was validated using an independent cohort., Results: A total of 153 patients were included and divided into a training cohort (n = 107) and a validation cohort (n = 46). A total of 1130 radiomic features were extracted from each case. The PCA method selected 22, 25 and 35 principal components to construct the three models. The diagnostic accuracy of Model AP , Model VP and Model Combination was 0.8043, 0.6739, and 0.7826 in the validation set, with AUCs of 0.8148 (95% CI 0.682-0.948), 0.7485 (95% CI 0.602-0.895), and 0.8772 (95% CI 0.780-0.974), respectively. The DeLong test showed that there were significant differences in the AUCs between Model AP and Model Combination (P = 0.0396) and between Model VP and Model Combination (P = 0.0465). However, the difference in AUCs between Model AP and Model VP was not significant (P = 0.5061). These results demonstrate that Model Combination shows a better performance than the other models. Decision curve analysis proved the clinical utility of this model., Conclusions: We developed a radiomics model based on monochromatic DECT images to identify solitary pulmonary nodules. This model could serve as an effective tool for discriminating benign from malignant pulmonary nodules in patients. The combination of arterial phase and venous phase imaging could significantly improve the model performance., (© 2022. The Author(s).)

Objectives: To explore the characteristics of Notch pathway in small cell lung cancer (SCLC), clarify the expression of delta-like protein 3 (DLL3) in SCLC patients undergoing surgical treatment, and explore the correlation between DLL3 expression and clinicopathological features, prognosis, and immune microenvironment., Methods: A total of 134 patients who received surgical treatment and were diagnosed as SCLC by postoperative histopathology were enrolled. All exon gene sequencing was performed in tumor tissues and adjacent normal tissues of 28 patients to clarify the genomic characteristics of SCLC. The expressions of DLL3 and programmed cell death 1 ligand 1 (PDL1) were detected by immunohistochemistry (IHC) in 101 postoperative pathological specimens., Results: Notch receptor mutations are common, but the overall mutation rate of Notch ligand family is not high and mutually exclusive. The mutation status of Notch and Notch1 gene were not related to the prognosis. Notch1 gene mutation was significantly negatively correlated with the expression of PD-L1. DLL3 was highly expressed in SCLC and had no significant correlation with prognosis. There was a positive correlation between DLL3 expression and PD-L1 expression. Patients with positive DLL3 expression and no NOTCH 1 gene mutation had higher PD-L1 expression. SCLC patients with such characteristics may be more likely to benefit from immunotherapy., Conclusion: This study preliminarily explored the genomic characteristics and immune microenvironment of surgical resection of SCLC in China, and found the correlation between Notch gene mutation, DLL3 expression and PD-L1 expression, which provided a new idea for selecting appropriate treatment strategies for SCLC in the future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Immune-associated biomarkers can predict lung metastases from colorectal cancer. Differentially expressed genes (DEGs) were screened from sample data extracted from gene expression omnibus (GEO) database. The DEGs were screened from the lung metastasis (LM) and primary cancer (PC) groups of the Moffitt Cancer Center cohort dataset. Then, the tumor immune microenvironment and abundance of immune cell infiltration analyses were performed, and the immune-related DEGs were retrieved. In addition, the transcription factor (TF)-miRNA-mRNA network was constructed and enrichment analyses of the immune-related DEGs and upregulated and downregulated DEGs were carried out. Then, the protein-protein interaction (PPI) network was conducted and the drug-gene interaction was predicted. A total of 268 DEGs were screened. The Immune&#95;Score of samples in the LM group was significantly higher compared with the PC group. The infiltration ratio of M0 macrophages and M2 macrophages of samples was higher than others. A total of 54 immune-related DEGs in M0 macrophages were screened. Moreover, the TF-miRNA-mRNA network was constructed among 8 miRNA-mRNA and 50 TF-mRNA, and the secreted phosphoprotein 1 was regulated by 12 TFs, and the oxidized low-density lipoprotein receptor 1 was regulated by 3 miRNAs and 3 TFs. The TF SAM pointed domain containing ETS TF was also a downregulated DEG. The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the DEGs in the TF-miRNA-mRNA network were mainly involved in the interleukin-7 signaling pathway and cell adhesion molecules. In total, 23 protein interactions in this PPI network of M0 macrophage cells were involved in 27 mRNAs. There were 38 drug-gene interactions of immune-related DEGs of M0 macrophage cells predicted to contain 34 small molecule drugs and 8 mRNAs. Finally, the CON cohort dataset verified that the infiltration ratio of M0 and M2 macrophages of the samples was higher.

Angiopoietin-like protein (ANGPTL) 4 is a key factor in the regulation of lipid and glucose metabolism in metabolic diseases. ANGPTL4 is highly expressed in various cancers, but the regulation of energy metabolism in tumours remains to be determined. This study explored the role of ANGPTL4 in aerobic glycolysis, glutamine consumption and fatty acid oxidation in nonsmall cell lung cancer (NSCLC) cells. Two NSCLC cell lines (A549 and H1299) were used to investigate the role of ANGPTL4 in energy metabolism by tracer techniques and with Seahorse XF technology in ANGPTLs4 knockdown cells. RNA microarrays and specific inhibitors were used to identify targets in ANGPTLs4-overexpressing cells. The results showed that knockdown of ANGPTLs4 could inhibit energy metabolism and proliferation in NSCLC. ANGPTLs4 had no significant effect on glycolysis but affected glutamine consumption and fatty acid oxidation. Knockdown of ANGPTLs4 also significantly inhibited tumour metastasis and energy metabolism in mice and had a weak effect on glycolysis. RNA microarray analysis showed that ANGPTLs4 significantly affected glutaminase (GLS) and carnitine palmitoyl transferase 1 (CPT1). ANGPTLs4-overexpressing cells were exposed to a glutamine deprivation environment, and cell proliferation and energy metabolism were significantly decreased but still differed from normal NSCLC cells. Treatment of ANGPTLs4-overexpressing cells with GLS and CPT1 inhibitors simultaneously prevented the regulatory effects on cell proliferation and energy metabolism. ANGPTLs4 could promote glutamine consumption and fatty acid oxidation but not glycolysis or accelerate energy metabolism in NSCLC., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Bevacizumab (BV) has an inhibitory effect on tumor growth including lung adenocarcinoma. However, its efficacy is greatly affected by drug resistance. Astragaloside IV (AST-IV) is effective in combination with other drugs is effective to treat cancer. This study aimed to investigate the effect of AST-IV on enhancing the sensibility of lung adenocarcinoma cells to BV. A549 cells were treated by different concentrations of BV and AST-IV. Cell viability, cell cycle, and apoptosis were detected by thiazolyl blue tetrazolium bromide (MTT) and flow cytometry, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were performed to detect the expression levels of autophagy- and apoptosis-related proteins, protein kinase B (AKT), and mammalian target of rapamycin (mTOR). The results showed that BV or AST-IV could inhibit the viability and promote the apoptosis of A549 cells in a concentration-dependent manner. Moreover, BV or AST-IV inhibited Bcl-2 expression and increased the expressions of Bax and Cleaved caspase-3, and promoted apoptosis. BV and AST-IV in combination acted synergistically on viability and apoptosis of A549 cells. However, BV alone down-regulated P62 expression, LC3I/LC3II level, the number of cells arrested at S phase and the phosphorylation levels of AKT and mTOR, but upregulated the number of cells arrested at G0/G1 phase and Beclin1 expression, whereas AST-IV alone could reverse the effect of BV on autophagy-related proteins, the phosphorylation levels of AKT and mTOR. This paper demonstrates that AST-IV enhances the effect of BV on inhibiting proliferation and promoting apoptosis of lung adenocarcinoma cells through inhibiting autophagy pathway., (© 2021 Wiley Periodicals, LLC.)

Lung cancer is one of the most common malignancy worldwide and causes estimated 1.6 million deaths each year. Cancer immunosurveillance has been found to play an important role in lung cancer and may be related with its prognosis. KLRK1, encoding NKG2D, is a homodimeric lectin-like receptor. However, there has not been one research of KLRK1 as a biomarker in lung cancer. Data including patients` clinical characteristics and RNAseq information of KLRK1 from TCGA were downloaded. A total of 1019 patients with lung cancer were included in this study, among which 407 patients were female and 611 patients were male. Evaluations of mRNA expression, diagnostic value by ROC (receiver operating characteristic) curves and prognostic value by survival curve, Cox model and subgroup analysis were performed. The level of KLRK1 expression in lung adenocarcinoma cancer tissues and normal lung tissues was detected by qRT-PCR. The CCK-8 assay investigated the proliferation rate and the wound healing assay assessed the migratory ability in vitro. The expression of KLRK1 in tumor was lower than that in normal tissue. KLRK1 expression was associated with gender, histologic grade, stage, T classification and vital status. Patients with high KLRK1 expression presented an improved overall survival (P = 0.0036) and relapse free survival (P = 0.0031). KLRK1 was found to have significant prognostic value in lung adenocarcinoma (P = 0.015), stage I/II (P = 0.03), older patients (P = 0.0052), and male (P = 0.0047) by subgroup overall survival analysis, and in lung adenocarcinoma (P = 0.0094), stage I/II (P = 0.0076), older patients (P = 0.0072), and male (P = 0.0033) by subgroup relapse free survival analysis. Lung adenocarcinoma cancer patients with high KLRK1 expression presented an improved overall survival (P = 0.015) and relapse free survival (P = 0.0094). In vitro studies indicated that KLRK1 inhibited tumor cell proliferation and migration. KLRK1 was an independent prognostic factor and high KLRK1 expression indicated a better overall and relapse free survival. KLRK1 may be a prognostic biomarker for lung adenocarcinoma cancer., (© 2022. The Author(s).)

Lung infection seriously affects the effect of chemotherapy in patients with lung cancer and increases pain. The study is aimed at establishing the prediction model of infection in patients with lung cancer during chemotherapy by an artificial neural network (ANN). Based on the data of historical cases in our hospital, the variables were screened, and the prediction model was established. A logistic regression (LR) model was used to screen the data. The indexes with statistical significance were selected, and the LR model and back propagation neural network model were established. A total of 80 cases of advanced lung cancer patients with palliative chemotherapy were predicted, and the prediction performance of different model was evaluated by the receiver operating characteristic curve (ROC). It was found that age≧60 years, length of stay≧14 d, surgery history, combined chemotherapy, myelosuppression, diabetes, and hormone application were risk factors of infection in lung cancer patients during chemotherapy. The area under the ROC curve of the LR model for prediction lung infection was 0.729 ± 0.084, which was less than that of the ANN model (0.897 ± 0.045). The results concluded that the neural network model is better than the LR model in predicting lung infection of lung cancer patients during chemotherapy., Competing Interests: The authors declare that there was no conflict of interests., (Copyright © 2022 Wei Guo et al.)

Objectives: Immune checkpoint inhibitors (ICI) monotherapy was standard of care in second-line treatment of patients with advance non-small cell lung cancer (NSCLC). This study aims to investigate the efficacy of ICI plus chemotherapy in patients with previously treated advanced NSCLC., Patients and Methods: An investigator-initiated trial (IIT) aiming to evaluate the efficacy and safety of ICI in combination with chemotherapy as second line and beyond for patients with advanced NSCLC was undergone at Shanghai Pulmonary Hospital (ChiCTR1900026203). Patients who received ICI monotherapy as second or later line setting during the same period were also collected as a comparator., Results: From April 2018 to June 2019, 31 patients were included into this IIT study, simultaneously 51 patients treated with ICI monotherapy were selected as a comparator. ICI plus chemotherapy showed a significantly higher ORR (35.5% vs. 15.7%, p=0.039), prolonged PFS (median: 5.6 vs. 2.5 months, p = 0.013) and OS (median: NE vs. 12.6 months, p = 0.038) compared with ICI alone. In the subgroup of negative PD-L1 expression (9 patients in combination group and 12 patients in monotherapy group), ICI plus chemotherapy also had a favorable ORR (44.4% vs. 8.3%, p = 0.119), longer PFS (median: 6.5 vs 3.0 months, p < 0.05) and OS (median: NE vs. 8.2 months, p = 0.117). Meanwhile, the addition of chemotherapy did not increase immune-related adverse events., Conclusions: ICI plus chemotherapy showed superior ORR, PFS and OS than ICI alone patients with previous treated advanced NSCLC. These findings warrant further investigation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Resistance to radiotherapy is frequently observed in the clinic and leads to poor prognosis of non-small cell lung cancer (NSCLC). How to overcome resistance to radiotherapy is a challenge in the treatment of NSCLC. In this study, PPDPF was found to be upregulated in NSCLC tissues and cell lines, and its expression negatively correlated with the overall survival of patients with NSCLC. PPDPF promoted the growth, colony formation and invasion of lung cancer cells. Moreover, knockout of PPDPF inhibited tumorigenesis in the KL (Kras G12D ; LKB1 f/f ) mouse model of lung cancer. Additionally, overexpression of PPDPF led to radioresistance in lung cancer cells, and knockdown of PPDPF sensitized lung cancer cells to radiotherapy. Mechanistically, PPDPF interacted with BABAM2 (an antiapoptotic protein) and blocked its ubiquitination by MDM2, thus stabilizing BABAM2 and promoting the radioresistance of lung cancer cells. Our present study suggested PPDPF as a therapeutic target in NSCLC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)