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Although immune checkpoint blockade (ICB) therapies have shifted the treatment paradigm for non-small-cell lung cancer (NSCLC), many patients remain resistant. Here we characterize the tumor cell states and spatial cellular compositions of the NSCLC tumor microenvironment (TME) by analyzing single-cell transcriptomes of 232,080 cells and spatially resolved transcriptomes of tumors from 19 patients before and after ICB-chemotherapy. We find that tumor cells and secreted phosphoprotein 1-positive macrophages interact with collagen type XI alpha 1 chain-positive cancer-associated fibroblasts to stimulate the deposition and entanglement of collagen fibers at tumor boundaries, obstructing T cell infiltration and leading to poor prognosis. We also reveal distinct states of tertiary lymphoid structures (TLSs) in the TME. Activated TLSs are associated with improved prognosis, whereas a hypoxic microenvironment appears to suppress TLS development and is associated with poor prognosis. Our study provides novel insights into different cellular and molecular components corresponding to NSCLC ICB-chemotherapeutic responsiveness, which will benefit future individualized immuno-chemotherapy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abstract: We reported a 72-year-old man who was diagnosed with squamous lung cancer and received 2 cycles of 177 Lu-FAP-2286 treatment. Radiological remission was observed on follow-up FAP imaging 7 months later with squamous cell carcinoma antigen decreased to normal level. No other abnormality monitored by routine laboratory examination was noted., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to analyze potential ethnic disparities in the dose-exposure-response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure-response (E-R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E-R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m 2 , without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose-exposure-response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m 2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Lung cancer is a highly malignant disease with limited treatment options and significant adverse effects. It is urgent to develop novel treatment strategies for lung cancer. In recent years, TMEM16A has been confirmed as a specific drug target for lung cancer. The development of TMEM16A-targeting drugs and combined administration for the treatment of lung cancer has become a research hotspot., Methods: Fluorescence screening and electrophysiological experiments were conducted to confirm the inhibitory effect of CCA on TMEM16A. Molecular dynamics simulation and site-directed mutagenesis were employed to analyze the binding mode of CCA and TMEM16A. CCK-8, colony formation, wound healing, transwell, and annexin-V experiments were conducted to explore the regulatory effects and mechanisms of CCA on the proliferation, migration, and apoptosis of lung cancer cells. Tumor model mice and pharmacokinetic experiments were used to examine the efficacy and safety of CCA and cisplatin in vivo., Results: This study firstly confirmed that CCA effectively inhibits TMEM16A to exert anticancer effects and analyzed the pharmacological mechanism. CCA bound to S517/N546/E623/E633/Q637 of TMEM16A through hydrogen bonding and electrostatic interactions. It inhibited the proliferation and migration, and induced apoptosis of lung cancer cells by targeting TMEM16A. In addition, the combined administration of CCA and cisplatin exhibited a synergistic effect, enhancing the efficacy of lung cancer treatment while reducing side effects., Conclusion: CCA is an effective novel inhibitor of TMEM16A, and it synergizes with cisplatin in anticancer treatment. These findings will provide new research ideas and lead compound for the combination therapy of lung cancer., 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 GmbH. All rights reserved.)

Purpose: The aim of this study was to evaluate the efficacy and safety of peptide-targeted radionuclide therapy (PTRT) with 177Lu-FAP-2286 in advanced lung cancer., Patients and Methods: This single-center prospective study included 9 patients diagnosed with advanced lung cancer. These patients met the inclusion criteria and received PTRT with 177Lu-FAP-2286. Short-term efficacy was assessed using RECIST 1.1 and PERCIST 1.0 criteria. Long-term efficacy was evaluated through overall survival, progression-free survival (PFS), overall response rate, EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status. Toxicity response was assessed using CTCAE v5.0., Results: The results based on RECIST 1.1 and PERCIST 1.0 criteria were comparable, with 44% of patients showing a partial metabolic response, 33.3% with stable metabolic disease, and 22.22% with progressive metabolic disease. The highest metabolic response after treatment reached 66.89%, and the overall response rate could reach 77.78%. In the long-term efficacy assessment, the median overall survival and PFS were 10 months and 6 months, respectively. The 2 patients with the lowest PFS (3 months) started PTRT relatively late. EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status scores showed that the overall health status, symptom response, and quality of life of patients improved after 177Lu-FAP-2286 treatment. The most noticeable improvements in clinical symptoms were dyspnea and cancer-related pain. No grade III/IV toxicity events were observed during follow-up period, and fibrinogen decreased significantly after treatment., Conclusions: 177Lu-FAP-2286 has the potential to be a viable PTRT option for patients with advanced lung cancer., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no competing interests. This study was supported in part by research foundation projects from Luzhou Science & Technology Department (20107) and (2022-JYJ-118)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The flare phenomenon is a transient increase in the number or intensity of lesions on bone scans after treatment, signifying curative effect. DOTA-ibandronic acid (DOTA-IBA) is a new prodrug that targets bone metastases and can be labeled with 177 Lu. Here, we report the case of a 58-year-old woman with bone metastasis, in whom the flare phenomenon was observed after 4 cycles of 177 Lu-DOTA-IBA treatment. No adverse effects were observed during the treatment and follow-up periods., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no competing interests. This study was supported in part by research foundation projects from Luzhou Science & Technology Department (20107) and (2022-JYJ-118), and The Affiliated Hospital of Southwest Medical University (20087)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: A 56-year-old man with metastatic lung adenocarcinoma received combined 177 Lu-FAP-2286 radiation therapy and targeted therapy. After 1 treatment cycle, improvement of symptoms and radiological remission was observed. Moreover, the patient did not report any adverse effects., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no competing interests. This study was supported in part by research foundation projects from Luzhou Science and Technology Department (20107 and 2022-JYJ-118), and The Affiliated Hospital of Southwest Medical University (20087)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Whether Inuit in Canada experience disparities in lung cancer survival remains unknown. When requiring investigation and treatment for lung cancer, all residents of Nunavik, the Inuit homeland in Quebec, are sent to the McGill University Health Centre (MUHC), in Montréal. We sought to compare survival among patients with lung cancer at the MUHC, who were residents of Nunavik and Montréal, Quebec, respectively., Methods: We conducted a retrospective cohort study. Using lung cancer registry data, we identified Nunavik residents with histologically confirmed lung cancer diagnosed between 2005 and 2017. We aimed to match 2 Montréal residents to each Nunavik resident on sex, age, calendar year of diagnosis, and histology (non-small cell lung cancer v. small cell lung cancer). We reviewed medical records for data on additional patient characteristics and treatment, and obtained vital status from a provincial registry. We compared survival using Kaplan-Meier analysis and Cox proportional hazards regression., Results: We included 95 residents of Nunavik and 185 residents of Montréal. For non-small cell lung cancer, median survival times were 321 (95% confidence interval [CI] 184-626) days for Nunavik ( n = 71) and 720 (95% CI 536-1208) days for Montréal residents ( n = 141). For small cell lung cancer, median survival times were 190 (95% CI 159-308) days for Nunavik ( n = 24) and 270 (95% CI 194-766) days for Montréal residents ( n = 44). Adjusting for matching variables, stage, performance status, and comorbidity, Nunavik residents had a higher hazard of death (hazard ratio 1.68, 95% CI 1.17-2.41)., Interpretation: Nunavik residents experience disparities in survival after lung cancer diagnosis. Although studies in other Inuit Nunangat regions are needed, our findings point to an urgent need to ensure that interventions aimed at improving lung cancer survival, including lung cancer screening, are accessible to Inuit Nunangat residents., Competing Interests: Competing interests: Sarah MacIsaac reports fellowship training grants from Janssen Pharmaceuticals and Boehringer Ingelheim, payment or honoraria from Boehringer Ingelheim, participation on a board for Boehringer Ingelheim, and a role on a Canadian Thoracic Society equity, diversity, and inclusion committee. Nathalie Boulanger is director of professional services, Ungava Tulattavik Health Centre. Nicole Ezer reports grants from Canadian Institutes of Health Research (CIHR), MUHC (McGill University Health Centre) Foundation, and Fonds de recherche du Québec – Santé; consulting fees from the GSK Advisory Board for chronic obstructive pulmonary disease (COPD); speaker fees for AstraZeneca family practice clinic teaching on COPD; speaker fees for GSK family practice clinic teaching on spirometry; and advisor roles on a Ministère de la Santé et des Services sociaux committee on lung cancer screening and Institut national d’excellence en santé et services sociaux committee on lung cancer screening. Anne Gonzalez reports a grant from Lung Cancer Canada, and is chair of the Lung Cancer Section, Thoracic Oncology, and Chest Procedures Network, American College of Chest Physicians. Scott Owen reports consulting fees for being on the advisory boards of AstraZeneca, Bristol Myers Squibb (BMS), Roche, Novocure, and Takeda. Carmela Pepe reports advisory board membership and speaker honoraria from AstraZeneca and Merck, speaker honoraria from BMS, and advisory board membership from Takeda. Jonathan Spicer reports grants to his institution from BMS, Merck, AstraZeneca, Roche, Protalix Biotherapeutics, and CLS Therapeutics, and payments from AstraZeneca, Merck, BMS, Roche, Amgen, Pfizer, Xenetic Biosciences, Protalix Biotherapeutics, BMS, and Eisai. Shirley White-Dupuis receives honoraria from the Research Institute of the McGill University Health Centre for expertise and guidance on lung health research projects as a member of Puvaqatsianirmut, and is chair of the board of directors of the Nunavik Regional Board of Health and Social Services. Larry Watt receives honoraria from the Research Institute of the McGill University Health Centre for expertise and guidance on lung health research as a member of Puvaqatsianirmut, and is also executive director of Ungava Tulattavik Health Centre. Minnie Grey is former executive director of Nunavik Regional Board and Health Social Services. Faiz Ahmad Khan reports grants from CIHR, World Health Organization, Fonds de recherche du Québec – Nature et technologies, National Research Council of Canada, and Observatoire international sur les impacts sociétaux de l’IA et du numérique, funded by the Fonds de recherche du Québec. No other competing interests were declared., (© 2024 CMA Impact Inc. or its licensors.)

Purpose: This article aims to compare the diagnostic performance of 18-fluorodeoxyglucose ([ 18 F]FDG) PET/CT and fibroblast activating protein inhibitor (FAPI) PET/CT in the assessment of primary tumors, lymph nodes, and distant metastases in lung cancer patients., Methods: A systematic search was conducted on the Cochrane Library, Embase, and PubMed/MEDLINE databases from inception until November 1, 2022. Included studies assessed the use of FAPI PET/CT and [ 18 F]FDG PET/CT in patients with lung cancer. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to evaluate the risk of bias. A random variable model was used to analyze the diagnostic tests of the two imaging modalities., Results: The sensitivity of FAPI PET/CT in detecting primary lung cancer lesions was 0.98 (95% CI: 0.88-1.00), while the sensitivity of [ 18 F]FDG PET/CT was 0.99 (95% CI: 0.74-1.00). For the detection of metastatic lesions (lymph node metastases and distant metastases), FAPI PET/CT had a sensitivity of 0.99 (95% CI: 0.90-1.00), while the sensitivity of [ 18 F]FDG PET/CT was 0.77 (95% CI: 0.66-0.85). However, the specificity of the two imaging modalities could not be assessed due to the lack of sufficient information on pertinent true negatives., Conclusion: In the diagnosis of metastatic lung cancer lesions, FAPI PET/CT demonstrated a higher sensitivity compared to [ 18 F]FDG PET/CT. Therefore, FAPI PET/CT may be considered an alternative imaging modality for the assessment of primary lung cancer tumors, lymph node metastases, and distant metastases., Clinical Relevance Statement: FAPI may be an alternative to [ 18 F]FDG in the assessment of primary lung cancer tumors, lymph node metastases, and distant metastases, which plays a very important role in treatment., Key Points: • This article is to compare the performance of [ 18 F]FDG PET/CT with FAPI PET/CT in the assessment of primary tumors, lymph nodes, and distant metastases in lung cancer. • However, FAPI PET/CT has a higher sensitivity for the diagnostic assessment of metastatic lung cancer lesions., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

This study aimed to investigate the relationship between complete pathological remission (PCR), tertiary lymphoid structure (TLS) maturation and expression and clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy. Totally 80 patients with resectable NSCLC (stage IB-IIIB) receiving neoadjuvant chemoimmunotherapy were analyzed. We used the Kaplan-Meier method to plot survival curves and the log-rank test to compare differences. Among all patients included, 45 patients (56.25%) achieved major pathological response (MPR), including 30 patients (37.50%) with PCR. The proportion of patients diagnosed with stage IB, II, IIIA and IIIB was 1.25%, 10.00%, 52.50% and 36.25%, respectively. We divided patients into PCR group and non-PCR group respectively according to whether they achieved PCR. We found that patients achieving PCR had significantly improved disease-free survival (DFS) (mDFS: NR vs. 20.24 months, P  = .020). TLS expression was low in 43 cases (53.75%) and high in 37 cases (46.25%). TLS maturation was low in 55 cases (68.75%) and high in 25 cases (31.25%). The DFS of patients with TLS high-maturation (34.07 vs. 22.30 months, P  = .024) and TLS high-expression (34.07 vs. 22.30 months, P  = .041) was significantly longer. In most subgroups, the PCR, TLS high-maturation and TLS high-expression group respectively achieved a better clinical outcome relative to the non-PCR, TLS low-maturation and TLS low-expression group. In patients with resectable NSCLC receiving neoadjuvant chemoimmunotherapy, the acquirement of PCR may predict better DFS. In addition, high expression and maturation of TLS may be prognostic factors.

Background: Whether patients with advanced non-small cell lung cancer (NSCLC) should choose an immune-combination therapy regimen after EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance is currently unclear., Methods: We evaluated 118 NSCLC patients treated by immune checkpoint inhibitors (ICIs) + chemotherapy (I + C), ICIs + chemotherapy + antiangiogenic therapy (I + C + A), chemotherapy + antiangiogenic therapy (C + A) after inefficacy of EGFR-TKIs. We assessed the objective remission rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of these treatments., Results: The ORR was 26.1% vs 38.2% vs 16.3% in the three groups (P = 0.093). The divergence in DCR was also statistically significant (65.2% vs 85.3% vs 74.4%, P = 0.209). The median PFS was no statistically significant difference in PFS (3.09 vs 6.31 vs 5.91 months, P = 0.809), but the Kaplan-Meier survival curve of 12-month-PFS indicated an apparent survival advantage in the I + C + A group (P = 0.001). In addition, the I + C/I + C + A group showed higher median PFS than the C + A group in patients with brain metastases (median PFS, 6.44 vs 4.21 months, P = 0.022). The divergence in ORR of patients in the brain group was also statistically significant (P = 0.045). The I + C + A group showed superior efficacy in patients with liver metastases (median PFS, 0.95 vs 6.44 vs 3.48 months, P < 0.0001). The Cox proportional hazard modeling analysis suggested that the age, brain metastases, and liver metastases were all connected with the prognosis., Conclusions: This study suggests that advanced NSCLC patients after resistance to EGFR-TKIs may achieve better outcomes from triple therapy. Patients with brain metastases favor ICIs-related combination therapies and patients with liver metastases prefer I + C + A therapy., (© 2023. The Author(s).)

This study investigated the associations between diet and frailty in lung cancer patients and the potential role of the gut microbiota involved. We assessed dietary intake and frailty status in 231 lung cancer patients by 3-day, 24-h dietary recalls and Fried frailty criteria, respectively, and collected 50 fecal samples for next-generation sequencing. A total of 75 (32.5%) patients were frail, which might be related to significantly lower intake of energy, protein, carbohydrate, dietary fiber, niacin, leucine, some minerals, and a poorer dietary quality as indicated by the Chinese Healthy Eating Index ( p < 0.05). Among these, carbohydrate (OR = 0.98; 95% CI 0.96-0.99; p = 0.010), calcium (OR = 0.99; 95% CI 0.99-1.00; p = 0.025), and selenium (OR = 1.03; 95% CI 1.00-1.06; p = 0.022) were all significantly associated with frailty. A multivariate logistic regression analysis showed that the mean risk of frailty was 0.94 times lower (95% CI 0.90-0.99; p = 0.009) among participants with higher CHEI scores. Additionally, the frail patients demonstrated significantly lower gut microbiota β diversity ( p = 0.001) and higher relative abundance of Actinobacteriota ( p = 0.033). Frailty in lung cancer patients might be associated with insufficient nutrients intake and a poor dietary quality through gut microbiota regulation.

Importance: The onset age of nonalcoholic fatty liver disease (NAFLD) is decreasing, and whether earlier ages of NAFLD onset are associated with increased cancer risk is currently unclear., Objective: To explore the association between NAFLD new-onset age and cancer risk., Design, Setting, and Participants: This cohort study was conducted among 179 328 participants included in the Kailuan Cohort Study between 2006 and 2021. In total, 46 100 incident NAFLD cases were identified. For each case, a participant matched by age (older or younger by 1 year) and sex was randomly selected to create a new matched study cohort. Data were analyzed from December 2022 through April 2023., Exposure: Onset of NAFLD., Main Outcomes and Measures: The association between the onset age of NAFLD and the risk of different cancer types was evaluated using weighted Cox regression models. Population-attributable fractions (PAFs) were used to quantify the association of NAFLD with cancer risk at different ages., Results: Among 63 696 participants (mean [SD] age, 51.37 [12.43] years; ‭10 932 females [17.2%] and ‭52 764 males [82.8%]), 31 848 individuals had NAFLD and 31 848 individuals were in the control group. During a median (IQR) follow-up of 10.16 (7.89-11.67) years, 2415 patients were diagnosed with cancer. Compared with the matched group, patients aged less than 45 years at NAFLD onset exhibited a higher risk of cancer (average hazard ratio [AHR], 1.52; 95% CI, 1.09-2.12), and as the onset age of NAFLD increased, the cancer risk decreased (ages 45-54 years: AHR, 1.50; 95% CI, 1.15-1.97; ages 55-64 years: AHR, 1.13; 95% CI, 0.97-1.33; ages >65 years: AHR, 0.75; 95% CI, 0.45-1.27; P for interaction < .001). Among patients aged less than 45 years at NAFLD onset, cancers were mainly digestive system and lung cancers, with AHR values of 2.00 (95% CI, 1.08-3.47) and 2.14 (95% CI, 1.05-4.36), respectively. PAFs also showed that in patients aged less than 45 years at NAFLD onset, 17.83% (95% CI, 4.92%-29.86%) of cancer risk was attributable to NAFLD.‬‬‬‬., Conclusions and Relevance: This study found that NAFLD was associated with increased cancer risk and there was an interaction with onset age, such that the younger the onset age of NAFLD, the greater the cancer risk.

Lung cancer is the leading cause of cancer death, and non-small cell lung cancer (NSCLC) accounts for 85%. Immunotherapy has significantly improved the clinical prognosis of patients with NSCLC. However, because of the complexity and heterogeneousness of the tumor microenvironment, only a subset of individuals can benefit from immunotherapy. Therefore, it is necessary to explore effective predictive biomarkers for immunotherapy of NSCLC. Tertiary lymphoid structure (TLS) is an ectopic lymphoid organ that is highly similar to secondary lymphoid organs (SLO), and the presence of TLS has been found to be closely associated with a good prognosis in immunotherapy for a variety of solid tumors, including NSCLC. This article provides a review of the prognostic role of tertiary lymphoid structures in immunotherapy of NSCLC, in order to offer references for screening suitable candidates for immunotherapy of NSCLC and develop personalized and precise treatment plans.
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Purpose: This retrospective study aimed to investigate 18 F-fluorodeoxyglucose ( 18 F-FDG)-positron emission tomography/computed tomography (PET/CT) as a predictor of response to hypofractionated radiotherapy (HFRT) combined with programmed cell death-1 (PD-1) blockade for lung cancer., Methods: We included 41 patients with advanced non-small cell lung cancer (NSCLC) in this study. PET/CT was performed before (SCAN-0) and one month (SCAN-1), three months (SCAN-2), and six months (SCAN-3) after treatment. Using the European Organization for Research and Treatment of Cancer 1999 criteria and PET response criteria in solid tumors, treatment responses were classified as complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), or progressive metabolic disease (PMD). Patients were further categorized as those with metabolic benefits (MB; SMD, PMR, and CMR) and those without MBs (NO-MB; PMD). We analyzed the prognosis and overall survival (OS) of patients with new visceral/bone lesions during treatment. Based on the findings, we generated a nomogram to predict survival. Receiver operating characteristics and calibration curves were used to evaluate the accuracy of the prediction model., Results: The mean OS based on SCANs 1, 2, and 3 was significantly higher in patients with MB and those without new visceral/bone lesions. The prediction nomogram for survival had a high area under the curve and a high predictive value based on the receiver operating characteristics and calibration curves., Conclusion: 18 FDG-PET/CT has the potential to predict the outcomes of HFRT combined with PD-1 blockade in NSCLC. Therefore, we recommend using a nomogram to predict patient survival., 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 © 2023 Tang, Zhang, Li, Zhang, Xu, Ding, Chen, Ren, Ye, Fu and Lin.)

Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/β-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/β-catenin signaling by LiCl (GSK3β agonist). IL-6-promoted LCSC properties and Wnt/β-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound., Competing Interests: Declaration of Competing Interests The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Abstract: A 50-year-old man presented with cough and hemoptysis for 1 month. Chest CT showed an irregular mass in the right lung, with enlarged lymph nodes in the mediastinum and right hilum. These findings were suggestive of lung cancer with lymph node metastases. The patient was subsequently enrolled in a 68Ga-DOTA-FAPI-04 PET/CT clinical trial. 68Ga-DOTA-FAPI-04 PET/CT revealed a mass in the upper lobe of right lung, with intense tracer uptake. Meanwhile, PET/CT showed enlarged lymph nodes in the mediastinum and right hilum, with mild FAPI uptake. However, pathological examination confirmed the mass was tuberculous granuloma., Competing Interests: Conflicts of interest and sources of funding: The authors have no conflicts of interest to declare. This work was supported by the school-level scientific research project of Southwest Medical University, China (grant no. 2021ZKQN066)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Combination of Breast Cancer 1 protein-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) in the peritoneal mesothelioma (PeM) has yet to be explored. We aim to assess the diagnostic value of combined BAP1 and MTAP to distinguish biphasic mesothelioma (BM) from epithelioid mesothelioma (EM) with reactive stroma in peritoneum, as well as its prognostic value in PeM., Methods: This is a retrospective study from June 2014 to December 2021. This study included 18 cases of BM and 27 cases of EM with reactive stroma, excluded sarcomatoid, and EM without reactive stroma cases, and clinicopathological information was collected. The associations between MTAP and BAP1 levels and clinicopathological features or prognosis were analyzed. Clinical follow-up data were reviewed to correlate with pathological prognostic factors using Kaplan-Meier estimator and univariate/multivariate Cox proportional hazards regression models., Results: Loss/decrease of BAP1/MTAP was observed in 6 (33.3%) BM cases and 12 (44.4%) EM cases. In 5 (27.8%) cases, loss of or decreased BAP1/MTAP expression was observed in both EC and SC of BM. BAP1/MTAP loss/decrease was observed in 12 (44.4%) cases of only EC of EM but not in reactive stroma. Compared with histology alone, a combination of BAP1 and MTAP immunohistochemistry (IHC) in spindled PeM provides a more objective mean to distinguish BM from EM with reactive stroma. Loss/decrease of BAP1/MTAP was associated with peritoneal cancer index (PCI) score ( P = 0.047) and completeness of cytoreduction (CC) score ( P = 0.038). BM patients have worse overall survival (OS) than EM with reactive stroma ( P = 0 .007)., Conclusions: Combination of BAP1/MTAP by IHC is helpful for differential diagnosis of peritoneal BM from EM with reactive stroma. Nevertheless, BAP1/MTAP may help to evaluate the biological behavior of PeM., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Traditional observational studies have shown an inverse association between body mass index (BMI) and lung cancer risk. Mendelian randomization (MR) analysis using genetic variants as instruments for BMI may clarify the nature of the association., Aims: We studied the causal association between BMI and lung cancer incidence using observational and MR approaches., Methods: We followed up 62,453 cancer-free Norwegian adults from 1995-97 (HUNT2) until 2017. BMI at baseline in HUNT2 was classified as < 25.0, 25.0-29.9 and ≥ 30.0 kg/m 2 . BMI change over ten years between HUNT1 (1984-86) and HUNT2 was calculated and classified into quartiles. Seventy-five genetic variants were included as instruments for BMI (among which 14 also associated with smoking behavior). Incident lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariable MR was used to examine the effect of BMI after genetically controlling for smoking., Results: During a median follow-up of 21.1 years, 1009 participants developed lung cancer including 327 with lung adenocarcinoma. The HRs and 95% CIs for incidence of adenocarcinoma were 0.73 (0.58-0.92) for BMI 25.0-29.9 kg/m 2 and 0.53 (0.37-0.76) for BMI ≥ 30 kg/m 2 compared with BMI < 25.0 kg/m 2 in HUNT2 (P for trend < 0.001). However, there was little evidence of a dose-response relationship between the BMI change from HUNT1 to HUNT2 in quartiles and the incidence of adenocarcinoma (P for trend = 0.08). Furthermore, multivariable MR approach suggested a positive association between genetically determined 1 kg/m 2 increase in BMI and the incidence of adenocarcinoma (HR 1.25, 95% CI 1.02-1.53). No associations were found with other lung cancer histologic types., Conclusions: Our study suggests that the inverse association between baseline BMI and lung adenocarcinoma in observational analysis may not be causal. More MR studies are needed to confirm our finding of a positive association between BMI and lung adenocarcinoma., (© 2022. The Author(s).)

Background: Only a minority of patients benefit from immune checkpoint inhibitors (ICIs) therapy, although they have become the standard of care for patients of non-small cell lung cancer (NSCLC) without driver mutations. Zoledronic acid (ZA) enhances the anti-tumor efficacy of endocrine therapy, chemotherapy and targeted therapy. However, little is known about the effect of ZA on the clinical outcomes of ICIs, or its possible mechanisms., Methods: Patients with advanced NSCLC treated with ICIs alone or in combination with ZA were recruited. The clinical efficacy was compared between the two cohorts. We used an LL2 mouse model to confirm the combined effects of ZA with ICIs. Immune cell populations and cytokines in the tumor microenvironment and circulation were assayed and analyzed., Results: The median PFS for the patients treated with and without ZA was 5.4 months and 2.8 months, respectively. The combination group showed a higher rate of disease control. In the mouse LL2 lung cancer model, tumor growth was significantly inhibited in mice treated with the combination treatment. More CD8 + IFN-γ + T cells and γδ T cells, and fewer CD11b cells were found in the circulation and TILs in the combination group. Anti-tumor cytokines INF-γ and IL-18 were elevated in the sera after combination therapy., Conclusion: Our study provides preclinical and clinical evidence to show that ZA could improve the therapeutic effects of ICIs. This effect was likely related to the activation of immune cells and elevated cytokines, which provided a new way to improve the effect of ICIs therapy, and is worth exploring further., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Protein-protein interaction networks (PPIs) govern the majority of biological processes, but how oncogenic mutations impact these interactions and their functions at a network scale is poorly understood. Mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) is a pre-requisition for EGFR tyrosine kinase inhibitor (TKI) treatment. Identification of interaction partners that bind to mutated EGFR can help understand the mechanism of action and pathways that mediate drug resistance. In this study, we characterized the dynamic interaction network of a pair of EGFR wildtype and mutant NSCLC cell lines. We performed immunoprecipitation of endogenous EGFR at various time points following EGF treatment and analyzed the associated proteins by quantitative mass spectrometry. Our results showed that the core signaling modules and key downstream pathways are maintained in the mutant cell line, but receptor internalization and intracellular trafficking in the mutant is delayed. Furthermore, we identified mutant EGFR-associated proteins that could affect EGFR functions in lung adenocarcinoma. SIGNIFICANCE: We analyzed the dynamic EGFR interaction network in NSCLC cell lines expressing wild-type and mutant EGFR. By comparing the similarities and differences in the EGFR proteome, we gained a better understanding of EGFR signal transduction network, and identified new factors for further functional characterizations and clinical significance assessment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: We aimed to explore the current status of medication adherence, safety awareness and practice among patients with lung cancer., Methods: We conducted a questionnaire-guided cross-sectional study in Xi'an, Yulin, Hanzhong and Weinan in Shaanxi Province, China, from April to June 2021 for a period of 3 months. The study questionnaire was developed according to previous related studies reported in the literature, and includes basic demographic information and patients' medication safety questions. The data were double-entered using EpiData 3.1 software; descriptive statistics, t-test, analysis of variance, the Kruskal-Wallis test and the Mann-Whitney U-test were performed to analyse the data., Results: A total of 567 participants were included, and 409 valid questionnaires were finally completed, with an effective response rate of 72.13%. More than 80% of patients showed good medication adherence; the average adherence score was 22 ± 2.68 of 25. The average score for medication safety awareness was 16.40 ± 4.41, which was significantly lower than that of medication adherence (p < .001). Only 22.74% of patients always checked their medicines before a nurse administered them; 17.60% of patients never checked their medicines. Few patients actively consulted an health care professional to understand safety information before taking a medication. A significant difference existed in safety awareness scores among age groups (p = .039) and geographic regions (p < .001). Patients with three or more comorbidities had the lowest awareness scores (p = .027)., Conclusion: We found that patients with lung cancer showed better medication adherence, but their awareness about medication safety was poor. Older patients, those with comorbidities and patients in regions with poor medical resources may have worse awareness about safety. Current medication education for patients should not only aim to improve adherence but should also encourage patients to take greater responsibility for their own safety and to actively participate in their medication safety. Greater systematic and individualized medication safety information is needed for older patients, those with more comorbidities and patients in areas with poor medical resources., Patient Contribution: We conducted a questionnaire-guided cross-sectional study on hospitalized lung cancer patients in Shaanxi Province to explore the patients' practices related to safety medication, including medication adherence and medication safety awareness., (© 2022 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H + tandem catalytic system. With thoroughly bioactivity exploration, we found benzo[d] [1,3]dioxol-5-yl(9-(pyrimidin-2-yl)-9H-carbazol-1-yl)methanone (compound 5n) showed notable activity in disrupting the mitochondrial homeostasis, induced cell cycle arrest and apoptosis in human adenocarcinoma cells, and finally showed anti-tumor activity in an NSCLC-xenograft mice model., 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 © 2022 Elsevier Masson SAS. All rights reserved.)

Abstract: We report a case of organizing pneumonia, which revealed intense uptake on both 18F-FDG and 68Ga-FAPI (fibroblast activation protein inhibitor) PET/CT. Our findings indicate that organizing pneumonia should be taken into consideration when diagnosing a cancer-like pulmonary mass with intense 68Ga-FAPI uptake., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Anti-angiogenesis therapy, a promising strategy against cancer progression, is limited by drug-resistance, which could be attributed to changes within the tumor microenvironment. Studies have increasingly shown that combining anti-angiogenesis drugs with immunotherapy synergistically inhibits tumor growth and progression. Combination of anti-angiogenesis therapy and immunotherapy are well-established therapeutic options among solid tumors, such as non-small cell lung cancer, hepatic cell carcinoma, and renal cell carcinoma. However, this combination has achieved an unsatisfactory effect among some tumors, such as breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma. Therefore, resistance to anti-angiogenesis agents, as well as a lack of biomarkers, remains a challenge. In this review, the current anti-angiogenesis therapies and corresponding drug-resistance, the relationship between tumor microenvironment and immunotherapy, and the latest progress on the combination of both therapeutic modalities are discussed. The aim of this review is to discuss whether the combination of anti-angiogenesis therapy and immunotherapy can exert synergistic antitumor effects, which can provide a basis to exploring new targets and developing more advanced strategies., 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 Hu, Chen, Tan, Wu, Huang, Fu, Luo and He.)

This study aimed to determine the spatial effects of traffic- and industrial-related pollution on the mortality for lung cancer (LC). We conducted a retrospective cohort study by using the data from LC registry in Jiading District for the period from 2002 to 2012. Standard parametric model with Weibull distribution was used for spatial survival analysis. Shorter distance to highway (adjusted odds ratio (aOR) = 1.15, 95% confidence interval (CI): 1.03-1.30) and higher factory density (aOR = 1.20, 95% CI: 1.05-1.37) were significantly associated with an increased risk of LC death, and there was a spatial difference in the associations between northern and southern areas of Jiading District. The risk was high in suburbs as compared with urban areas. Traffic- and industrial-related pollution were significantly associated with an increased risk of LC death, which showed a spatial variation. Further studies are needed to better understand the current LC status in the suburbs and to reduce health disparities., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Endostatin (ES) can effectively inhibit neovascularization in most solid tumors and has the potential to make oxygen delivery more efficient and increase the efficacy of radiotherapy (RT). With a short half-life, ES is mainly administered systemically, which leads to low intake in tumor tissue and often toxic systemic side effects. In this study, we used hyaluronic acid-tyramine as a carrier to synthesize an ES-loaded hydrogel drug (ES/HA-Tyr) that can be injected locally. ES/HA-Tyr has a longer half-life and fewer systemic toxic side effects, and it exerts a better anti-angiogenic effect and anti-tumor effect with RT. In vitro , ES/HA-Tyr showed sustained release in the release assay and a stronger ability to inhibit the proliferation of human umbilical vascular endothelial cells (HUVECs) in the MTT assay; it exhibited a more potent effect against HUVEC invasion and a stronger anti-angiogenic effect on HUVECs in tube formation. In vivo , ES/HA-Tyr increased local drug concentration, decreased blood drug concentration, and caused less systemic toxicity. Further, ES/HA-Tyr effectively reduced tumor microvessel density, increased tumor pericyte coverage, decreased tumor hypoxia, and increased RT response. ES/HA-Tyr + RT also had increased anti-tumor and anti-angiogenic effects in Lewis lung cancer (LLC) xenograft models. In conclusion, ES/HA-Tyr showed sustained release, lower systemic toxicity, and better anti-tumor effects than ES. In addition, ES/HA-Tyr + RT enhanced anti-angiogenic effects, reduced tumor hypoxia, and increased the efficacy of RT in LLC-bearing mice.

Background: It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development., Methods: We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer., Results: The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer., Conclusions: DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear., Methods: MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors., Results: We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo., Conclusion: Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling., (© 2021. The Author(s).)

Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs to regulate gene expression. However, little is known concerning circRNA, which is crucial in the pathogenesis of lung cancer. To date, limited studies have explored the role of circ&#95;0044516 in lung cancer progression. Recently, we observed that circ&#95;0044516 expression levels were obviously elevated in lung cancer tissues and cells. A549 and SPCA1 cells were transfected with circ&#95;0044516 siRNA. We observed that knockdown of circ&#95;0044516 dramatically repressed cell proliferation, increased cell apoptosis, and repressed the cell cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were greatly repressed by circ&#95;0044516 siRNA. Due to accumulating evidence demonstrating the vital role of cancer stem cells, their mechanism of involvement has drawn increasing attention in tumor progression and metastasis research. We also found that cancer stem cell properties were restrained by silencing circ&#95;0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft experiments showed that circ&#95;0044516 downregulation reduced tumor growth. Mechanistically, in lung cancer and using bioinformatics, we demonstrated that circ&#95;0044516 sponges miR-136 targeting MAT2A . Furthermore, rescue assays were carried out to identify that circ&#95;0044516 modulates cell proliferation, invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In summary, our study revealed that the circ&#95;0044516/miR-136/ MAT2A axis is involved in lung cancer progression. Our findings may provide novel targets for diagnosis and therapeutic intervention in lung cancer patients., Competing Interests: The authors declare no financial or commercial conflict of interest., (Copyright © 2021 Yue-Wei Chen et al.)

Hyaluronan (HA) is a negatively charged linear polysaccharide that can interact with cluster determinant 44 (CD44) overexpressed cancers. However, HA can also bind to excess substrates in the human body leading to the lower specificity of tumor targeting. Conjugation of other targeting group to HA could enhance the uptake by cancer cell comparing to that of native HA. In this study, we develop the multi-functionalized HA ( 177 Lu-DOTA/Alexa647-HA100-N) for malignant tumor targeting. An asparagine-glycine-arginine (NGR) based peptide was selected for HA functionalization. The peptide is known to target CD13 receptor that is overexpressed in malignant tumors with abundant blood vessels, such as lung cancer. Furthermore, the fluorescent probe Alexa Fluor 647 for ex vivo/in vivo tracking and the radionuclide 177 Lu for radioactive therapy were both labeled on the material. The functionalized HA could be bound by lung cancer cells and breast cancer cells. In vivo fluorescent imaging showed that the material could accumulate in the tumor site for more than 96 h. The 177 Lu labeling of functionalized HA was stable for more 48 h at physiological conditions. The accumulation of 177 Lu-DOTA/Alexa647-HA100-N in the tumor of lung cancer (NCI-H292) bearing mice was 1.91±0.97%ID/g, and it was about 17 times higher than the value in blood. Conclusion: The multimodality labeled functional HA was successfully prepared and could be fluorescent trackable ex vivo and in vivo. It showed high potential to be used for malignant cancer radiotherapy for its specific targeting property to tumors and radiotoxicity from the labeled 177 Lu radionuclide., (Copyright © 2021. Published by Elsevier B.V.)

Large prospective studies on asthma, especially asthma symptom control, as a potential risk factor for lung cancer are limited. We followed up 62,791 cancer-free Norwegian adults from 1995-1997 to 2017. Self-reported doctor-diagnosed asthma was categorized into active and non-active asthma. Levels of asthma symptom control were classified into controlled and partially controlled (including partly controlled and uncontrolled) according to the Global Initiative for Asthma guidelines. Incident lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for possible associations. Totally, 984 participants developed lung cancer during a median follow-up of 21.1 years. After adjustment for smoking and other potential confounders, an increased incidence of lung cancer was found for adults with partially controlled asthma (HR 1.39, 95% CI 1.00-1.92) compared with those without asthma at baseline. Adults with active asthma had a tendency of increased lung cancer incidence (HR 1.29, 95% CI 0.95-1.75). Sensitivity analyses indicated that the observed associations were less likely resulted from reverse causation or residual confounding by smoking. Our findings suggested that proper control of asthma symptoms might contribute to a reduced incidence of lung cancer.

A 51-year-old woman with newly diagnosed lung cancer experienced progressive left hip pain for 1 month. F-FDG PET/CT showed multiple hypermetabolic lesions throughout the body, including a suspicious lesion in the brain. Elevated FDG activity in select muscles was visualized, which was attributed to altered weight bearing. Unexpectedly, Ga-fibroblast activation protein inhibitor PET/CT showed the FDG-avid lesion in the brain with excellent imaging contrast. Brain metastasis was confirmed by a cerebral MRI.

Localized malignant mesothelioma is rare. The prognosis is generally more favorable for this condition than for diffuse malignant mesothelioma. An elderly woman recently complained of abdominal pain, fever, and weight loss. She had no history of asbestos exposure. Her serum CEA level was elevated. Plain CT revealed a mass under the left diaphragm, with liquefaction and necrosis. A contrast-enhanced scan showed circular enhancement of the mass. A subsequent biopsy of the mass revealed a poorly differentiated carcinoma. PET/CT showed a significant FDG-avid subphrenic mass without any indications of metastasis. Postoperative pathological and immunohistochemical examination confirmed a case of malignant mesothelioma.

Objectives: The efficacy of anti- programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) immune checkpoint inhibitors remains controversial in patients with KRAS mutation. In addition, whether and how KRAS gene and its mutant subtypes might influence immunity has not been clarified yet. Here we examine some important biomarkers for the efficacy of immunotherapy in specific KRAS subtypes., Materials and Methods: We conducted a bioinformatics analysis on somatic mutations data, transcriptome sequencing data and proteomic data from The Cancer Genome Atlas (TCGA) database. CIBERSORT was used to provide an estimation of the abundances of immune cells using gene expression data., Results: From a cohort of 567 patients with lung adenocarcinoma (LUAD) based on TCGA, the overall mutation rate of KRAS was 26.29 %, including KRAS/TP53 co-mutation rate of 9.7 %. We observed increased Tumor mutation burden (TMB) in KRAS mutant group compared with wild type, while no difference in PD-L1 expression and immune cell infiltration. More importantly, TP53 and KRAS/TP53 co-mutation group not only significantly increased tumor mutation burden, but also had higher PD-L1 protein level and immune cell infiltration. We further focused on influence of KRAS mutant subtype on immune biomarker. The most prevalent mutant subtype of KRAS in lung adenocarcinoma was G12C(9.88 %,56/567), followed by G12 V(5.82 %,33/567), G12D(3.00 %,17/567), G12A(3.00 %,17/567), respectively. Among them, G12D mutation appeared to be a special mutant subtype with an obviously lower TMB. This low mutation load was more significant when co-mutation with TP53. Besides, our results also revealed significantly decreased expressions of PD-L1 protein level and immune cell infiltration (activated CD4 memory T cell, helper T cell, M1 macrophage and NK cell) in KRAS G12D/TP53 mutant group., Conclusion: KRAS G12D/TP53 co-mutation drives immune suppression and might be a negative predictive biomarker for anti-PD-1/PD-L1 immune checkpoint inhibitors in patients with lung adenocarcinoma., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We have previously discovered that HDAC6 regulates the DNA damage response (DDR) via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6's ubiquitin E3 ligase activity. Here, we have reported HDAC6's second potential E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo and in vitro. Specifically, HDAC6 interacts with Chk1 via the DAC1 domain, which contains its ubiquitin E3 ligase activity. During the cell cycle, Chk1 protein levels fluctuate, peaking at the G2 phase, subsequently resolving via the ubiquitin-proteasome pathway, and thereby allowing cells to progress to the M phase. However, in HDAC6 knockdown non-small cell lung cancer (NSCLC) cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), and this enhanced Chk1 activity leads to preferential G2 arrest in HDAC6 knockdown cells accompanied by a reduction in colony formation capacity and viability. Depletion or pharmacological inhibition of Chk1 in HDAC6 knockdown cells reverses this radiosensitive phenotype, suggesting that the radiosensitivity of HDAC6 knockdown cells is dependent on increased Chk1 kinase activity. Overall, our results highlight a novel mechanism of Chk1 regulation at the post-translational level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting HDAC6's E3 ligase activity.

Smoking-related lung tumors are characterized by profound epigenetic changes including scrambled patterns of DNA methylation, deregulated histone acetylation, altered gene expression levels, distorted microRNA profiles, and a global loss of cytosine hydroxymethylation marks. Here, we employed an enhanced version of bisulfite sequencing (RRBS/oxRRBS) followed by next generation sequencing to separately map DNA epigenetic marks 5-methyl-dC and 5-hydroxymethyl-dC in genomic DNA isolated from lungs of A/J mice exposed whole-body to environmental cigarette smoke for 10 weeks. Exposure to cigarette smoke significantly affected the patterns of cytosine methylation and hydroxymethylation in the lungs. Differentially hydroxymethylated regions were associated with inflammatory response/disease, organismal injury, and respiratory diseases and were involved in regulation of cellular development, function, growth, and proliferation. To identify epigenetic changes in the lung associated with exposure to tobacco carcinogens and inflammation, A/J mice were intranasally treated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the inflammatory agent lipopolysaccharide (LPS), or both. NNK alone caused minimal epigenetic alterations, while exposure either to LPS or NNK/LPS in combination led to increased levels of global cytosine methylation and formylation, reduced cytosine hydroxymethylation, decreased histone acetylation, and altered expression levels of multiple genes. Our results suggest that inflammatory processes are responsible for epigenetic changes contributing to lung cancer development.

Background: Soft-tissue metastasis (STM) is a relatively rare, but not exceptional, manifestation of lung cancer. The purpose of this study was to evaluate the imaging features of STM from lung cancer using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT), and assess the impact of STM detected at baseline PET/CT on patient survival., Methods: Out of 4543 patients with lung cancer who underwent 18 F-FDG PET/CT in our hospital between January 2013 and September 2018, 85 were diagnosed with STM (78 at baseline PET/CT and 7 at restaging PET/CT) and included in the imaging study. We conducted a comparative survival analysis between patients with stage 4 lung cancer with and without STM at baseline PET/CT (n = 78 in each group) and performed univariate and multivariate analyses to investigate the factors affecting the prognosis of lung cancer., Results: A total of 219 lesions were identified by 18 F-FDG PET/CT: 215 were detected by PET and 139 by CT. Muscle STM were primarily found in the hip and upper limb muscle, whereas subcutaneous STM were mainly distributed in the chest, abdomen, and back. In 68 patients, STM were found incidentally during routine 18 F-FDG PET/CT staging. Isolated STM were detected in 6 patients, whose tumor staging and treatment were affected by PET/CT findings. There were no significant differences in the 1-, 3-, and 5-year survival rates between patients with and without STM at baseline PET/CT. Brain and adrenal metastases, but not STM, were associated with poor prognosis of stage 4 lung cancer., Conclusions: We described the PET/CT imaging characteristics of STM from lung cancer, and confirmed that PET/CT can detect unsuspected STM to change the staging and treatment of some patients. Our analysis indicates that STM is not a useful prognostic indicator for patients with advanced lung cancer, while brain and adrenal metastases portend a poor prognosis.

Jahanyne, a lipopeptide with a unique terminal alkynyl and OEP (2-(1-oxo-ethyl)-pyrrolidine) moiety, exhibits anticancer activity. We synthesized jahanyne and analogs modified at the OEP moiety, employing an α-fluoromethyl ketone (FMK) strategy. Preliminary bioassays indicated that compound 1b (FMK-jahanyne) exhibited decreased activities to varying degrees against most of the cancer cells tested, whereas the introduction of a fluorine atom to the α-position of a hydroxyl group ( 2b ) enhanced activities against all lung cancer cells. Moreover, jahanyne and 2b could induce G0/G1 cell cycle arrest in a concentration-dependent manner.

Background: Commonly used miRNA detection methods cannot be applied for high-throughput analyses. However, this study was aimed to performed a liquid bead array detection system (LBAS) to detect tissue 6 miRNAs in non-small cell lung cancer (NSCLC)., Methods: In this study, evaluation of LBAS was performed to observe the precision, specificity, limitation and stability. Then, a total of 52 primary NSCLC patients who received resection operation without preoperative radiotherapy and chemotherapy between June 2013 and March 2014 were selected, and then the total RNA of the tissues were extracted. We prepared six NSCLC-related miRNAs for LBAS. After optimization and evaluation, LBAS was verified by detecting the relative expression levels of 6 microRNAs in the pathological tissues and corresponding normal tissues of 52 NSCLC patients., Results: The results of evaluation of LBAS showed that the Mean Fluorescence Intensity (MFI) of the reaction only added with chimeric probes and beads showed no significant change after 180 days (P > 0.05). And the intra-assay Coefficient of Variation (CV) was between 1.57 and 3.5%, while the inter-assay CV was between 4.24 and 11.27%, indicating this system was ideal for diagnostic reagents. In addition, only the beads corresponding to the additional miRNAs showed high MFIs from 8426 to 18,769, whereas the fluorescence values of the other beads were under background levels (MFIs = 20 to 55) in each reaction, indicating no cross reactivity among the miRNAs. The limit of detection of miR-21, miR-210, miR-125b, miR-155, miR-375, and miR-31 were 5.27, 1.39, 1.85, 2.01, 1.34, and 2.73 amol/μL, respectively, showing that the lowest detection limit of miRNA by this system was under pM level. Then, the relative expression levels of miR-21, miR-210, miR-125b, miR-155, miR-375, and miR-31 by using this system were significantly correlated with NSCLC (P < 0.05). And the results of AUC method indicated that specific of the LBAS system was 94.2%., Conclusions: Our findings suggest that LBAS was simple, high-throughput, and freely combined with absolute quantification. Thus, this system could be applied for tumor miRNAs detection.

The aim of this study was to explore the synergistic anti-tumor effects of cytarabine hyaluronic acid-tyramine (Ara-HA-Tyr) hydrogel conjugates and radiotherapy (RT) in the Lewis lung cancer (LLC) xenograft model, and the mechanisms involved. The radiotherapy sensitization ratio (SER) of 0.5 μg cytarabine (Ara-C) was 1.619 in the LLC cells. Ara-HA-Tyr was prepared by encapsulating Ara-C into hyaluronic acid-tyramine (HA-Tyr) conjugates. The hydrogels were formed through the oxidative coupling of tyramines by hydrogen peroxide (H 2 O 2 ) and horseradish peroxidase (HRP). Mice engrafted with the LLC cells were given intra-tumoral injections of saline, Ara-C or Ara-HA-Tyr, with or without RT. The combination of Ara-HA-Tyr and RT increased survival compared to free Ara-C and RT (p < 0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Ara-HA-Tyr combination therapy significantly reduced 18 F-FDG uptake, induced cell cycle arrest at G2/M-phase, increased apoptosis and histone H2AX phosphorylation (γ-H2AX), and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. Taken together, Ara-C encapsulated with HA-Tyr effectively sensitized tumor xenografts to RT and showed significantly less systemic toxicity. Graphical abstract In this work, Ara-C encapsulated with hyaluronic acid-tyramine conjugates (HA-Tyr) was prepared and used to investigate its synergistic anti-tumor efficacy by combination with radiotherapy in the Lewis lung cancer xenograft model. The synergistic mechanism may be related to tumor cell cycle redistribution, apoptosis and expression of histone H2AX phosphorylation.

Epithelial-mesenchymal transition (EMT) contributes to the initiation, invasion, metastasis and drug resistance of cancer. The function of extracellular signal-regulated kinase 5 (ERK5) in lung cancer progression remains elusive. In this study, we investigated the effect of sulforaphane (SFN) on lung cancer EMT and the role of ERK5 in its effect. Wound healing and Transwell assays were applied to examine the migratory and invasive capacity in vitro. Quantitative real-time polymerase chain reaction and immunoblotting analysis were performed to investigate the expression of mRNA and protein levels. Small-interfering RNA was used to silence ERK5. Xenograft model was used to confirm the effect of SFN in vivo. Enhanced EMT and decreased ERK5 activation were observed in lung cancer cells in comparison with normal human bronchial epithelial cells. SFN diminished the migratory and invasive capacity of lung cancer cells. Additionally, significantly increased expression of epithelial markers (E-cadherin and ZO-1), decreased expression of mesenchymal markers (N-cadherin and Snail1) and activation of ERK5 were observed after SFN treatment. The inhibitory effect of SFN on lung cancer cell EMT was attenuated by ERK5 silencing. SFN-induced EMT suppression and ERK5 activation were further confirmed in lung cancer xenograft mouse model. The present study illustrated for the first time that ERK5 activation mediates SFN suppression of lung cancer cell EMT. These findings could provide new insights into the function of ERK5 in EMT regulation and the potential therapeutic application of SFN in cancer intervention., (Copyright © 2019 Elsevier Inc. All rights reserved.)

As a critical feature of the tumor microenvironment, hypoxia is known to be a potent inducer of tumor metastasis, and it has been proposed that the initial steps in metastasis involve epithelial-mesenchymal transition (EMT). The strong correlation among hypoxia, EMT, and metastasis suggests that integrative assessment of gene expression and the DNA modification program of hypoxia-induced EMT via high-throughput sequencing technologies may increase our understanding of the molecular basis of tumor invasion and metastasis. Here, we present the genomewide transcriptional and epigenetic profiles of non-small-cell lung cancer (NSCLC) cells under normoxic and hypoxic conditions. We demonstrate that hypoxia induces EMT along with dynamic alterations of transcriptional expression and epigenetic modifications in both A549 and HCC827 cells. After training using a dataset from patients with invasive and noninvasive lung adenocarcinomas with an artificial neural network algorithm, a characteristic 17-gene panel was identified, consisting of genes involved in EMT, hypoxia response, glycometabolism, and epigenetic modifications. This 17-gene signature clearly stratified NSCLC patients with significant differences in overall survival across three independent datasets. Our study may be suitable as a basis for further selection of gene signatures to potentially guide prognostic stratification in patients with NSCLC., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Few studies have investigated the spatial variation in road traffic indicators associated with lung cancer risk. The purpose of this study was to explore the relationship between road traffic-related indicators and lung cancer risk and to estimate its spatial variability. The population-based case control study was conducted, including all the newly diagnosed lung cancer patients (cases) and colorectal cancer patients (controls) in Jiading District, Shanghai from 2014 to 2016. Traffic intensity variable (traffic intensity in a 500 m buffer), residential distance to major road or highway, and greenness exposure at the residence were estimated for each individual. We conducted unconditional logistic regression with adjustment for age, sex, smoking status and NDVI values and geographically weighted logistic regression (GWLR). The clustering of lung cancer risk was analyzed by Bernoulli model of the SaTScan software. This study included 1461 lung cancer patients and 954 colorectal cancer patients. In multivariate logistic regression, smoking [OR 1.25 95% CI (1.15-1.35)], living <50 m from the major road [OR 1.43 95% CI (1.02-2.03)] were significantly associated with lung cancer risk. Residential Proximity to highway, residential greenness, and traffic intensity were not significantly associated with lung cancer risk. The GWLR model showed that the degree of correlation between residential proximity to major road and lung cancer risk varied geographically. The SaTScan results showed a lung cancer cluster in the southwest of Jiading District, Shanghai. Our study suggested that the distance from residence to the main road was significantly associated with lung cancer risk, which varied geographically. It is helpful to further study the traffic factors' spatial variation related to lung cancer risk and carry out reasonable regional planning., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Poly (ADP-ribose) polymerase (PARP) is a key enzyme in the repair process of DNA strand breaks (DSBs). Olaparib (Ola) is a PARP inhibitor that is involved in arresting PARP release from radiotherapy (RT)-induced damaged DNA to potentiate the effect of RT. Although the underlying mechanisms for the radiosensitization effects of Ola are well understood in vitro, the radiosensitization effects in vivo are still unclear. Moreover, poor water solubility and severe toxicity are two major impediments for the clinical success of Ola., Materials and Methods: Here, we developed olaparib nanoparticles (Ola-NPs) and investigated their radiosensitization mechanisms and toxicity using human non-small-cell lung cancer xenograft models in mice., Results: The prepared Ola-NPs showed a mean size of 31.96±1.54 nm and a lower polydispersity index of about 0.126±0.014. In addition, the sensitization enhancement ratio of Ola-NPs (3.81) was much higher than that of free Ola (1.66). The combination of Ola-NPs and RT (Ola-NPs + RT) significantly inhibited tumor growth and prolonged survival in mice. The mechanism of enhanced antitumor efficacy might be related to the inhibition of DSB repair and the promotion of cell apoptosis in vivo. No additional toxicity caused by Ola-NPs was observed., Conclusion: This study demonstrated the principle of using Ola-NPs as a potent radiosensitizer to improve the therapeutic effect of RT relative to free Ola ( P <0.05 in all cases)., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar)., Methods: Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments., Results: We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects., Conclusion: These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.

Background: Epithelial growth factor receptor tyrosine kinase inhibitor (EGFR TKI) revolutionize the standard of care for advanced non-small cell lung cancer (NSCLC) harboring sensitive EGFR mutation. Liver toxicity is the dose-limiting factor for TKI but its importance is largely overlooked. Here the relationship between the elevation of transaminase and progression-free survival (PFS) was explored. Methods: This was a retrospective study where patients with advanced NSCLC were screened. And those treatment-naïve and with sensitive EGFR mutation who were prescribed with EGFR TKI were enrolled. The highest level of transaminase (alanine aminotransferase, ALT, and aspartate transaminase, AST) during the treatment course was recorded. Results: Totally 208 patients were recruited, and most of them (48.6%) took gefitinib. The whole cohort achieved a median PFS of 11.2 months (95%CI: 10.0-12.3 m). 73 (35.1%) patients had elevated transaminase and most was attributed to gefitinib (n=43, 42.5%). Specifically, ALT was elevated in 65 patients (31.3%) while AST in 24 patients (11.5%). Again, gefitinib was associated with more cases of ALT (40.6%) and AST (17.8%) elevation. The elevation of AST was not related to PFS (P=0.259, HR=0.751, 95%CI: 0.464-1.214). Interestingly, those with normal ALT level had a longer PFS (12.6m, 95%CI: 10.6-14.5 m) than those with elevated ALT (9.5m 95%CI: 7.9-11.0 m, P=0.025, HR=0.682, 95%CI: 0.488-0.953). The inverse relationship was confirmed in the COX regression analysis (P=0.047). Conclusion: This study revealed the side effects of elevated ALT was inversely related to the PFS of EGFR TKI treatment. The liver impairment by TKI should not be overlooked., (Creative Commons Attribution License)

Lung cancer is the leading cause of cancer-related death worldwide; tobacco smoke (TS) constitutes the main causes of lung cancer. Acquisition of cancer stem cells (CSCs)-like properties is the essential progression for the initiation of lung cancer. However, the mechanisms for tobacco smoke-induced lung carcinogenesis remain elusive. In the present study, we demonstrated that long-term exposure of human bronchial epithelial (HBE) cells to TS resulted in malignant transformation and acquisition of CSC-like properties. Moreover, Wnt/β-catenin pathway was involved in acquisition of the CSC-like phenotype during neoplastic transformation of HBE cells induced by TS. Downregulation of β-catenin reduced the tumorsphere and decreased the protein expression of lung CSCs markers in TS-transformated HBE sphere-forming cells. Furthermore, Diallyl trisulfide (DATS) inhibited the CSCs activity of TS-transformed HBE cells, as well as Wnt/β-catenin suppression. Activation of Wnt/β-catenin diminished the inhibitory effects of DATS on TS-induced stemness of HBE cells. Together, the present investigation elucidates the modulation of Wnt/β-catenin in chronic TS exposure-triggered pulmonary acquisition of CSCs properties and DATS intervention, which may provide new insights into the interventional strategies against lung CSCs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93-1.06) per allele score. A 25 nmol·L -1 increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54-1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study., Competing Interests: Conflict of interest: Y-Q. Sun reports grants from the Norwegian Cancer Society (project ID 5769155-2015), during the conduct of the study. B.M. Brumpton reports grants from the Liaison Committee for education, research and innovation in Central Norway, during the conduct of the study., (Copyright ©ERS 2018.)