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Introduction: Luteolin, a naturally occurring flavonoid compound, demonstrates promising anti-cancer properties. However, its mechanism against non-small-cell lung cancer (NSCLC) remains unknown. This study employed network pharmacology, molecular docking, molecular dynamics simulation (MDS), and in vitro experiments to investigate the potential mechanisms by which luteolin against NSCLC. Methods: Initially, the potential targets of luteolin and NSCLC-related targets were identified from public databases such as TCMSP, GeneCards, OMIM, DrugBank, and TTD. Subsequently, the protein-protein interaction (PPI) network screening and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. The binding affinity and stability of luteolin with the core targets were assessed using molecular docking and MDS. Finally, the results were validated by in vitro experiments. Results: A total of 56 luteolin targets and 2145 NSCLC-related targets were identified. Six core targets, TP53, EGFR, AKT1, TNF, JUN, and CASP3, were screened via the PPI network. The GO and KEGG analyses indicated that luteolin's activity against NSCLC potentially involves PI3K-Akt, NF-kappa B, and other signaling pathways. Molecular docking revealed that luteolin had high binding affinity with the core targets. MDS confirmed the stable interaction between luteolin and key proteins TP53 and AKT1. in vitro , luteolin significantly inhibited the proliferation and migration of A549 cells, while also inducing apoptosis. In addition, luteolin downregulated the expression of p-Akt (Ser473), MDM2, and Bcl-2 but upregulated the expression of p53 and Bax, which was consistent with the effect of LY294002. Conclusion: Luteolin had a good anti-NSCLC effect, and the apoptosis-inducing effect might be related to the Akt/MDM2/p53 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease (COVID)-19 can lead to chronic lung damage and respiratory issues, potentially increasing surgical difficulty and risk for patients with non-small-cell lung cancer (NSCLC). However, the impacts of a COVID-19 history on early outcomes in NSCLC patients remain controversial. Objectives: To evaluate the effect of COVID-19 history on early outcomes in NSCLC patients and identify high-risk groups undergoing radical resection based on the largest Chinese multi-center real-world data to date. Design: Multi-center retrospective cohort study. Methods: NSCLC patients with (POCVD group) or without (NCVD group) a history of COVID-19 who underwent radical surgery at six institutions from January 2022 to January 2024 were retrospectively reviewed from a prospectively maintained database. Propensity-score matching (PSM) was utilized to minimize patient selection bias. Results: Out of 7932 cases included, PSM resulted in 3021 cases per group. The two groups were comparable regarding the proportion of male patients (52.0% vs 51.6%) and those aged ⩾70 years (13.3% vs 13.8%). Although the two groups had comparable incidences of complications with Clavien-Dindo grades ⩾II (13.0% vs 14.4%, p = 0.117), the POCVD group had longer surgical durations (120.87 ± 40.23 min vs 110.74 ± 38.76 min, mean difference (95% confidence interval (CI) = 10.13 (8.138–12.122)) and higher rates of respiratory complications than the NCVD group. Subgroup logistic regression analysis indicated that patients aged ⩾70 years (odds ratio (OR) (95% CI) = 1.322 (1.022–1.876)) and those with a smoking history (OR (95% CI) = 1.235 (1.008–1.543)) had an increased risk of developing complications with Clavien-Dindo grades ⩾II. Further analysis confirmed that these high-risk patients experienced extended surgical durations, longer chest tube drainage, and prolonged postoperative hospital stay, along with increased postoperative respiratory complications following COVID-19. Conclusion: Generally, radical resection is safe for NSCLC patients with a COVID-19 history. However, these patients experienced prolonged surgical durations and a higher incidence of postoperative respiratory complications compared to those without a COVID-19 history. In addition, individuals aged ⩾70 years or with a smoking history faced elevated surgical risks following COVID-19. Plain language summary: Analyzing the impact of COVID-19 history on early outcomes and identifying high-risk groups among non-small cell lung cancer patients undergoing radical resection Aim and Purpose Research Question: Does a COVID-19 history affect the early outcomes of radical surgery (lobectomy/bi-lobectomy/pneumectomy) in patients with non-small cell lung cancer (NSCLC)? Hypothesis: Patients with a COVID-19 history face elevated surgical risks compared to those without. Objective: To understand how past COVID-19 infection impacts early outcomes in NSCLC patients undergoing surgery and to identify high-risk groups. Background Why This Study: COVID-19 can cause long-term lung damage, making surgery riskier for NSCLC. However, it's unclear how past COVID-19 infection affects NSCLC patients receiving surgery. Importance: The research helps to understand the additional risks for NSCLC patients with a COVID-19 history based on the largest cohort to date, aiming to improve their surgical outcomes. Method and Design Research Design: Multi-center retrospective cohort study. Methods and Participants: 7932 NSCLC patients undergoing radical surgery between January 2022 and January 2024 were included and divided into two groups: those with a COVID-19 history (POCVD group) and those without (NCVD group). Result and Importance Findings: 1. The POCVD group had longer surgical durations and higher rates of respiratory complications compared to the NCVD group. 2. The POCVD and NCVD groups were associated with a comparable incidence of postoperative complications with Clavien-Dindo grades ⩾II. 3. The elderly (aged ⩾70 years) and smokers were at higher risk for complications post-COVID-19. Implications: While surgery is generally safe for NSCLC patients with a COVID-19 history, they do face increased risks and complications. This highlights the need for special care and monitoring for older patients and those with smoking histories. Key Message: NSCLC patients with a COVID-19 history can safely undergo radical surgery, but they may experience longer surgical durations and more postoperative respiratory complications, especially the elderly and smokers. [ABSTRACT FROM AUTHOR]

Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) continues to pose challenges. Traditional treatment methods for LSCC encompass surgical resection, chemotherapy, and radiotherapy. The introduction of targeted therapy and immunotherapy has greatly benefited LSCC patients, but issues such as limited immune response rates and adverse reactions persist. Therefore, gaining a deeper comprehension of the underlying mechanisms holds immense importance. This review provides an in-depth overview of classical signaling pathways and therapeutic targets, including the PI3K signaling pathway, CDK4/6 pathway, FGFR1 pathway and EGFR pathway. Additionally, we delve into alternative signaling pathways and potential targets that could offer new therapeutic avenues for LSCC. Lastly, we summarize the latest advancements in targeted therapy combined with immune checkpoint blockade (ICB) therapy for LSCC and discuss the prospects and challenges in this field. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI) on the abscopal effect of radiotherapy in mice with lung cancer via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and the underlying mechanism. Methods Lung cancer LLC1 cells in the logarithmic growth phase were randomly divided into the control group and irradiation group. Cells in the control group were cultured normally without intervention, while cells in the irradiation group were irradiated with 4 Gy (2 Gy/min for 2 min). Twenty-four hours later, the mRNA levels of MB21D1, TMEM173, TBK1, IRF3, IRF5, IRF7, IFNAR1, IFNAR2, MX1, MX2, IFIT1, and IFIT related genes in the cells were determined by real-time PCR (rtPCR). In addition, 100 µL of LLC1 cell suspension in the logarithmic growth phase was injected subcutaneously into the groin of mice to prepare bilateral subcutaneous tumor-bearing models. The tumor-bearing mice were randomly divided into the control group, 8 Gy group, EGFRTKI group, and 8 Gy + EGFR-TKI group, with 3 mice in each group. The tumor-bearing mice in the control group were not intervened. The tumor-bearing mice in the 8 Gy group were radiated at 8 Gy for 3 times, the tumor-bearing mice in the EGFR-TKI group were intragastrically administered 1 mg/g EGFR-TKI for 3 times, and the tumor-bearing mice in the 8 Gy + EGFR-TKI group received both radiation and EGFR-TKI as above. The tumor on the right side of the mice was taken out after 17 days of intervention. The levels of cGAS, STING, p-STING, and type I interferon (IFN-1) proteins in the tumor tissues were determined by Western blotting. Tumor cell proliferation antigen (ki67) and tumor microenvironment-related proteins CD4, CD8, epidermal growth factor receptor (EGFR), forkhead transcription factor p3 (Foxp3), calreticulin (CRT), and major histocompatibility complex (MHC) were detected by immunohistochemistry. Results Compared with the control group, LLC1 cells in the radiation group showed significantly higher mRNA expression levels of MB21D1, TMEM173, TBK1, IRF3, IRF5, IFNAR1, IFNAR2, MX1, MX2, IFIT1, and IFIT (all P<0. 05), and lower IRF7 mRNA expression (P<0. 05). After 17 days of intervention, compared with the control group, tumor volume, tumor weight and relative expression of ki67 protein decreased in all three intervention groups (all P<0. 05), with the largest decrease in the 8 Gy + EGFR-TKI group. Compared with the control group, the EGFR-TKI group showed no significant difference in expression levels of cGAS, STING, p-STING or IFN-1 (all P>0. 05); the 8 Gy group showed no significant difference in expression levels of STING or IFN-1 proteins (both P>0. 05), but significantly elevated cGAS and p-STING protein expression (both P<0. 05); the 8 Gy + EGFR-TKI group showed significantly elevated expression of all cGAS, STING, p-STING and IFN-1 proteins (all P<0. 05). Compared with the 8 Gy + EGFR-TKI group, the expression levels of cGAS, IFN-1, and STING proteins were significantly lower in both the 8 Gy group and EGRF-TKI group (all P<0. 05). The expression levels of CD4, CD8, and MHC proteins in all three intervention groups significantly increased (all P<0. 05), and the expression levels of EGFR, Foxp3, and CRT proteins significantly decreased in comparison with those of the control group (all P< 0. 05). Compared with the radiation group, the 8 Gy+EGFR-TKI group had higher CD4, CD8, and MHC proteins, and lower EGFR and CRT protein levels (all P<0. 05). Similarly, CD4, CD8, and MHC were significantly higher, and EGFR, Foxp3, and CRT were significantly lower in the 8 Gy+ EGFR-TKI group than in the EGFR-TKI group (all P<0. 05). Conclusion EGFR-TKI improves the immune function of the tumor microenvironment by activating the cGAS-STING pathway, thereby enhancing the abscopal effect of radiotherapy in mice with lung cancer. [ABSTRACT FROM AUTHOR]

Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases. [ABSTRACT FROM AUTHOR]

Background: The value of pretreatment baseline 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/computed tomography (CT) as a prognostic factor for survival of patients with non-small-cell lung cancer (NSCLC) receiving immunotherapy remained uncertain. Objectives: To investigate the prognostic ability of baseline 18F-FDG PET/CT in patients with NSCLC receiving immunotherapy. Design: A systematic review and meta-analysis. Data sources and methods: We searched the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases until May 7, 2024, and extracted data related to patient characteristics, semiquantitative parameters of 18F-FDG PET/CT, and survival. We pooled hazard ratios (HRs) to evaluate the prognostic value of the maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for overall survival (OS) and progression-free survival (PFS). Results: A total of 22 studies (1363 patients, average age range 30–88 years) were included. Baseline 18F-FDG PET/CT-derived MTV was significantly associated with both OS (HR: 1.124, 95% confidence interval (CI) 1.058–1.195, I 2 = 81.70%) and PFS (HR: 1.069, 95% CI: 1.016–1.124, I 2 = 71.80%). Other baseline 18F-FDG PET/CT-derived parameters, including SUVmax (OS: HR: 0.930, 95% CI: 0.718–1.230; PFS: HR: 0.979, 95% CI: 0.759–1.262), SUVmean (OS: HR: 0.801, 95% CI: 0.549–1.170; PFS: HR: 0.688, 95% CI: 0.464–1.020), and TLG (OS: HR: 0.999, 95% CI: 0.980–1.018; PFS: HR: 0.995, 95% CI: 0.980–1.010), were not associated with survival. Sensitivity analyses by removing one study at a time did not significantly alter the association between MTV and PFS or between MTV and OS. There was no evidence of publication bias. Conclusion: Pretreatment baseline 18F-FDG PET/CT-derived MTV might be a prognostic biomarker in NSCLC patients receiving immunotherapy. Further studies are needed to support routine use. Plain language summary: Using PET/CT scans to predict survival in lung cancer patients receiving immunotherapy: a study review Aims and Purpose of the Research We wanted to know if a type of scan called 18F-FDG PET/CT can help predict how long people with a type of lung cancer (NSCLC) will live after treatment with immunotherapy. Background of the Research This research matters because NSCLC is a common and serious type of lung cancer. Knowing how long patients might live after treatment can help doctors plan better care. Many people are affected by this disease, so finding good ways to predict survival can help a lot of patients. Methods and Research Design They reviewed and analyzed data from 22 different studies involving 1363 patients, with ages ranging from 30 to 88 years.We focused on certain measurements from the scans, like SUVmax, SUVmean, MTV, and TLG. We checked if these measurements were linked to how long patients lived and how long they lived without their cancer getting worse. Results and Importance We found that one of these measurements, the Metabolic Tumor Volume (MTV), was linked to how long the patients lived and how long they stayed free of disease after treatment. Specifically, higher MTV was associated with poorer overall survival and progression-free survival. The other measurements (SUVmax, SUVmean, and TLG) did not show a significant connection to patient survival. In conclusion, the MTV from PET/CT scans might help doctors predict the outcomes for lung cancer patients undergoing immunotherapy. However, more studies are needed to confirm these findings and to consider using this measurement regularly in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Stereotactic body radiation therapy (SBRT) in treating non-small-cell lung cancer (NSCLC) exhibits a remarkable therapeutic efficacy. However, its effectiveness in overcoming resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced EGFR mutations (EGFRm) NSCLC remains uncertain. Objective: We aimed to analyze the effect of SBRT on patients with first-line EGFR-TKIs. Design and methods: Eligible patients with advanced NSCLC initially diagnosed with EGFRm were enrolled. Patients in the EGFR-TKIs group received only the first-generation EGFR-TKIs until disease progression or death, while the others in the EGFR-TKIs + SBRT group received EGFR-TKIs and early SBRT (dose of 40–60 Gy/5–8 F) targeting the primary lung tumor at 1 month after EGFR-TKIs. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were treatment-related adverse effects, overall survival (OS), and sites of initial failure. Results: A total of 184 advanced NSCLC patients with EGFRm were enrolled, including 39 patients in the EGFR-TKIs + SBRT group and 145 patients in the EGFR-TKIs group. The median PFS was 15.50 months in the EGFR-TKIs + SBRT group compared to 9.33 months in the EGFR-TKIs group (p = 0.0020). However, the median OS was 29.10 months in the EGFR-TKIs + SBRT group and 26.33 months in the EGFR-TKIs group, with no significant difference observed (p = 0.22). SBRT is an independent positive prognostic factor for PFS in advanced EGFRm NSCLC. EGFR exon 19 deletion mutation (16.33 vs 11.55 months, p = 0.0087) and fewer metastases (0–5) (31.94 vs 9.59 months, p = 0.0059) were associated with improved PFS in EGFR-TKIs + SBRT versus EGFR-TKIs. Combination therapy increased radiation pneumonitis mainly in Grades 1–2 (89.74% vs 0.0%). The EGFR-TKIs + SBRT group mainly had new site failure (57.10% vs 32.10%) rather than the original site failure. Conclusion: Early SBRT for primary lung tumors may overcome targeted resistance in advanced EGFRm NSCLC patients combined with EGFR-TKIs without serious toxicities, especially for EGFR exon 19-del. Trial registration: ChiCTR-OIN-17013920. [ABSTRACT FROM AUTHOR]

Simple Summary: A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. In this study, a high serum cytokeratin fraction 21–1 (CYFRA 21-1) level was found to be a poor prognostic marker in patients with NSCLC receiving anti-PD-1/L1 antibodies even stratifying by histology or treatment regimen. Thus, serum CYFRA 21-1 may be useful for precision medicine with anti-PD-1/PD-L1 antibody treatment. Background: A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. This study explored serum cytokeratin fraction 21–1 (CYFRA 21-1), which represents a squamous cell histology, as a prognostic factor in anti-PD-1/PD-L1 antibody treatment, stratifying by histology and treatment regimen. Methods: This study retrospectively evaluated patients with advanced NSCLC without driver mutations receiving anti-PD-1/PD-L1 antibodies between November 2015 and March 2023. Cutoff values for CYFRA 21-1 and carcinoembryonic antigen (CEA) were 3.5 and 5.0 ng/mL, respectively. The Kaplan–Meier method and a log-rank test were conducted. The Cox proportional hazards model was utilized for univariate and multivariate analyses. Results: This study included 258 patients. The squamous NSCLC group demonstrated a shorter overall survival (OS) than the non-squamous NSCLC group (median, 17.8 vs. 23.7 months, p = 0.141). Patients with high serum CYFRA 21-1 and CEA levels exhibited a significantly shorter OS than those with normal levels (median, 11.7 vs. 32.7 months, p < 0.005; 15.8 vs. 29.7 months, p < 0.005). The multivariate analysis identified a performance status (PS) of ≥2, a PD-L1 expression of ≥50%, and a serum CYFRA 21-1 of >3.5 ng/mL as independent prognostic factors. Patients with high serum CYFRA 21-1 levels exhibited a significantly shorter OS even focusing on non-squamous NSCLC, anti-PD-1/PD-L1 antibody and chemotherapy combination therapy, or anti-CTLA-4 antibody combination therapy. Conclusion: Serum CYFRA 21-1 is a poor prognostic marker for patients with NSCLC receiving anti-PD-1/PD-L1 antibody treatment even when stratifying by histology or treatment regimen. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examined the real-world effectiveness of osimertinib, a third-generation tyrosine kinase inhibitor, on EGFR-mutated non-small-cell lung cancer. Osimertinib has shown promising results in clinical trials, but this research study looked at how it performs in real-world settings, where patients may have different characteristics than those typically included in trials. This study reviewed data from over 600 patients treated with osimertinib, either as their first (L1) or second metastatic line (L2) of treatment. The results showed that patients who took osimertinib as L1 experienced a median progression-free survival of 12.4 months, compared to 7.4 months for those treated in L2. The presence of brain metastases was associated with a poorer prognosis. Overall survival rates were lower than those reported in clinical trials, likely due to differences in patient conditions, such as older age and worse overall health. This study highlights the challenges of applying trial results to everyday medical practice and emphasizes the need for tailored treatment approaches for patients with advanced lung cancer. Background: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), demonstrated superior efficacy over first-generation TKIs in the FLAURA trial, resulting in its approval as first-line therapy for metastatic non-small-cell lung cancer (NSCLC). However, the real-world application of these trial results requires an evaluation of sequential therapeutic strategies. Methods: This retrospective, non-interventional study utilized data from the Epidemiological Strategy and Medical Economics (ESME) platform, which includes information on patients treated for lung cancer since 2015. Out of 39,974 patients in the database, 624 patients with EGFR-mutant advanced NSCLC treated with osimertinib as first-line (L1, n = 198) or second-line (L2, n = 426) treatment after first- or second-generation TKIs (n = 1262) were identified. Patient demographics, disease characteristics, treatment strategies, and disease progression were examined. Survival analyses were performed using Kaplan–Meier estimates and Cox proportional-hazards models. Results: In the study population (n = 624), 73.4% were female, with a median age of 70 years (range 28–93). Brain metastases at the start of osimertinib treatment were observed in 282 patients. ECOG PS-2 was reported in 29.4% of patients. The T790M mutation in exon 20 was identified in 257/426 patients (60.3%) receiving osimertinib in L2. Median progression-free survival (PFS) was 12.4 months (95% CI [10.7–14.7]) for L1 and 7.4 months (95% CI [6.2–8.7]) for L2. Median overall survival (OS) from advanced diagnosis was 28.5 months (95% CI [26.3–38.7]) for osimertinib L1 and 29.9 months (95% CI [28.6–31.8]) for osimertinib L2 (HR = 0.93; 95% CI [0.75–1.16]; p = 0.50). For L1, median OS was 27.1 months (95% CI [22.0–30.2]) for patients with cerebral metastases and 38.7 months (95% CI [26.3–52.8]) for those without (HR = 0.73; 95% CI [0.48–1.11]; p = 0.15). Discussion: Patients in the real-world ESME database exhibited a poorer prognosis compared to those in the FLAURA trial. The presence of cerebral metastases at diagnosis worsens the prognosis. [ABSTRACT FROM AUTHOR]

Background/Aim: Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. Materials and Methods: A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. Results: The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). Conclusion: The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the combination of chemotherapy with staged Chinese herbal medicine (CHM) therapy could enhance health-related quality of life (QoL) in non-small-cell lung cancer (NSCLC) patients and prolong the time before deterioration of lung cancer symptoms, in comparison to chemotherapy alone. Methods: A prospective, double-blind, randomized, controlled trial was conducted from December 14, 2017 to August 28, 2020. A total of 180 patients with stage I B–IIIA NSCLC from 5 hospitals in Shanghai were randomly divided into chemotherapy combined with CHM (chemo+CHM) group (120 cases) or chemotherapy combined with placebo (chemo+placebo) group (60 cases) using stratified blocking randomization. The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life-Core 30 Scale (QLQ-C30) was used to evaluate the patient-reported outcomes (PROs) during postoperative adjuvant chemotherapy in patients with early-stage NSCLC. Adverse events (AEs) were assessed in the safety analysis. Results: Out of the total 180 patients, 173 patients (116 in the chemo+CHM group and 57 in the chemo+placebo group) were included in the PRO analyses. The initial mean QLQ-C30 Global Health Status (GHS)/QoL scores at baseline were 57.16 ± 1.64 and 57.67 ± 2.25 for the two respective groups (P>0.05). Compared with baseline, the chemo+CHM group had an improvement in EORTC QLQ-C30 GHS/QoL score at week 18 [least squares mean (LSM) change 17.83, 95% confidence interval (CI) 14.29 to 21.38]. Conversely, the chemo+placebo group had a decrease in the score (LSM change −13.67, 95% CI −22.70 to −4.63). A significant between-group difference in the LSM GHS/QoL score was observed, amounting to 31.63 points (95% CI 25.61 to 37.64, P<0.001). The similar trends were observed in physical functioning, fatigue and appetite loss. At week 18, patients in the chemo+CHM group had a higher proportion of improvement or stabilization in GHS/QoL functional and symptom scores compared to chemo+placebo group (P<0.001). The median time to deterioration was longer in the chemo+CHM group for GHS/QoL score [hazard ratio (HR)=0.33, 95% CI 0.23 to 0.48, P<0.0010], physical functioning (HR=0.43, 95% CI 0.25 to 0.75, P=0.0005), fatigue (HR=0.47, 95% CI 0.30 to 0.72, P<0.0001) and appetite loss (HR=0.65, 95% CI 0.42 to 1.00, P=0.0215). The incidence of AEs was lower in the chemo+CHM group than in the chemo+placebo group (9.83% vs. 15.79%, P=0.52). Conclusion: The staged CHM therapy could help improve the PROs of postoperative patients with early-stage NSCLC during adjuvant chemotherapy, which is worthy of further clinical research. (Registry No. NCT03372694) [ABSTRACT FROM AUTHOR]

Locoregional recurrence of non–small‐cell lung cancer (NSCLC) after complete resection lacks standard treatment. Durvalumab after chemoradiotherapy (CRT) or CRT alone is often selected in daily clinical practice for patients with locoregional recurrence; however, the therapeutic efficacy of these treatments remains unclear, and we aimed to assess this. This retrospective observational study used data from patients with NSCLC diagnosed with locoregional recurrence after complete resection who subsequently underwent concurrent CRT followed by durvalumab (CRT‐D group) or CRT alone (CRT group). We employed propensity score analysis with inverse probability treatment weighting (IPTW) to adjust for various confounders and evaluate efficacy in the CRT‐D group. After IPTW adjustment, the CRT‐D group contained 119 patients (64.7% male; 69.7% adenocarcinoma), and the CRT group contained 111 patients (60.5% male; 73.4% adenocarcinoma). Their mean ages were 66 and 65 years, respectively. The IPTW‐adjusted median progression‐free survival was 25.4 and 11.5 months for the CRT‐D and CRT groups, respectively (hazard ratio, 0.44; 95% confidence interval, 0.30–0.64); the median overall survival was not reached in either group favoring CRT‐D (hazard ratio, 0.49; 95% confidence interval, 0.24–0.99). Grade 3 or 4 adverse events were observed in 48.8% of patients during CRT, 10.7% after initiating durvalumab maintenance therapy in the CRT‐D group, and 57.3% in the CRT group. Overall, the sequential approach of CRT followed by durvalumab is a promising treatment strategy for locoregional recurrence of NSCLC after complete resection. [ABSTRACT FROM AUTHOR]

This study investigated the effectiveness of acoustic separation for platelet analysis in patients with non–small‐cell lung cancer (NSCLC), comparing it with traditional centrifugation methods. In total, 10 patients with NSCLC and 10 healthy volunteers provided peripheral blood samples, which were processed using either acoustic separation or centrifugation to isolate platelets. The study included whole transcriptome analysis of platelets, peripheral blood mononuclear cells, and tumor tissue samples, employing hierarchical clustering and Gene Ontology analysis to explore gene expression differences. Acoustic separation proved more efficient than centrifugation in terms of platelet yield, recovery rate, and RNA yield. Gene expression profiles of platelets from patients with NSCLC showed distinct patterns compared with healthy volunteers, indicating tumor‐influenced alterations. Gene Ontology analysis revealed enrichment in pathways associated with platelet activation and the tumor microenvironment. This finding indicates the potential of acoustic isolation in platelet separation and its relevance in understanding the unique gene expression profile of platelets in patients with NSCLC. The findings of this study suggested that platelets from cancer patients separated by acoustic techniques exhibited tumor‐specific alterations and provided new insights into the diagnosis of cancer in platelet analysis systems in clinical practice. [ABSTRACT FROM AUTHOR]

Echinoderm microtubule-associated protein 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene detection is of great significance in personalized tumor treatment. With the development of EML4-ALK fusion variants detection, it is necessary to establish traceability to ensure the consistency and comparability of its detection results in clinical practice. The establishment of traceability relies on SI traceable reference materials (RMs) and potential reference measurement procedures (RMPs). In this study, a potential RMP for the quantitative detection of V1 and V3 fusion mutations and the reference type (ALK-ref, including wild type, V1 and V3 mutant type) based on reverse transcription dPCR (RT-dPCR) and EML4-ALK fusion gene RMs were established. The proposed potential RMP has high specificity, good inter-laboratory reproducibility (CV < 7.3%) and good linear relationship (0.92 < slope < 1.06, R2 ≧ 0.99). The limit of detection (LoD) of V1, V3, and ALK-ref are 2 copies/reaction, 2 copies/reaction, and 1 copy/reaction, respectively. Interlaboratory studies using the EML4-ALK RMs and potential RMP showed that participating laboratories can produce consistent copy concentrations of fusion variant and ALK-ref as well as the ratio of EML4-ALK/ALK-ref. The established potential RMP with high specificity and accuracy can be used to characterize the EML4-ALK RMs, and the potential RMP and RM are useful to establish the traceability of EML4-ALK fusion measurement to improve the comparability and consistency in clinical tests. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectiveMethodsResultsConclusionsThe significance of local radiotherapy (RT) in advanced non-small-cell lung cancer (NSCLC) is well documented. However, the advent of immunotherapy has raised questions regarding the synergistic survival benefits or potential adverse effects.This study aimed to explore whether a combination of RT and systematic immune checkpoint inhibitors (ICIs) can improve the survival outcomes for NSCLC patients.Based on collected data patients who received RT were defined as the RT group, and those who had not for any site were defined as the non-RT group. Propensity score matching (PSM) was employed to mitigate bias. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and treatment-related adverse events (AEs).Out of 709 patients (235 in RT group and 474 in non-RT group) were included, with 213 patients per group. The median PFS of the RT group was better than that of the non-RT group (13.8 months versus 9.5 months; p < 0.0001), although no superiority in median overall survival (OS) of the RT group was observed (p = 0.715). However, among the cohort of patients with ≤3 metastases, the median OS of the RT group improved significantly (HR = 0.60, [95% CI 0.44–0.83]; p = 0.004). Treatment-related AEs occurred in 94.5% of RT group patients and in 94.9% of non-RT group patients (p = 0.792), which indicated no observable increase in AEs from RT.These results demonstrate the tolerability of RT when administered along with immunotherapy, suggesting its potential to positively impact the survival outcomes of NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: There has been significant improvement in treating metastatic non–small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC. Methods: This is a descriptive retrospective cohort study. All non–small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Results: A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%). Conclusions: The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications. [ABSTRACT FROM AUTHOR]

Aim: To describe patient and treatment characteristics associated with bevacizumab BS-Pfizer, rituximab BS-Pfizer and trastuzumab BS-Pfizer and their reference products in Japan. Methods: This retrospective observational study used an administrative claims database to identify patients with ≥1 biosimilar or reference product prescription from 2019 to 2022 for approved indications. Descriptive statistics were calculated. Results: Overall, 14–39% of biosimilar-prescribed patients initiated therapy with reference products. Biosimilar utilization significantly increased from 2019 to 2022. The most-commonly prescribed concomitant class of therapy with biosimilars was antineoplastic therapy. Conclusion: Reference products were most frequently prescribed among the Japanese cohorts, but substantial and increasing proportions received biosimilars over time. Future studies should extend our initial insights to assess biosimilar clinical outcomes in Japanese settings. Plain Language Summary This study examines the adoption of cancer biosimilar therapies in Japan from 2019 to 2022. Cancer biosimilars are complex treatments that closely resemble established cancer therapies already available in Japan. We looked into the characteristics of patients receiving three specific biosimilars – bevacizumab BS-Pfizer, rituximab BS-Pfizer and trastuzumab BS-Pfizer. We also investigated where patients received biosimilar treatment, other therapies they received alongside biosimilars and the proportion of patients using these therapies each year during the study. Our analysis utilized data from the 'Medical Data Vision' database, which records care provided in hospitals across Japan. We analyzed patient demographics and treatment patterns, and compared different groups using statistics to identify significant differences. Notably, we observed that between 14 and 39% of patients initially started treatment with the original version of the drug on the market, known as the 'reference product,' before switching to the biosimilar. Furthermore, our findings revealed a significant increase in the use of biosimilars each year during the study period. Biosimilars were most-commonly used alongside chemotherapy drugs. These initial findings shed light on the patient population using cancer biosimilars in Japan and the treatment contexts in which they are utilized. Future research should delve deeper into aspects such as cost of care, patient survival, side effects and other pertinent factors related to the use of biosimilars in cancer care in Japan. Article highlights The use of oncology biosimilars in clinical practice in Japan is limited, at least partly, by the lack of evidence demonstrating real-world outcomes in Japanese patients. This retrospective observational study provides descriptive insights into the real-world use of bevacizumab, rituximab and trastuzumab biosimilars in Japan for colorectal cancer and non-small-cell lung cancer, B-cell non-Hodgkin's lymphoma and HER2-positive breast and gastric cancers, respectively. We observed significant increases in biosimilar utilization over time from 2019 to 2022. Across indications, from 14 to 39% of biosimilar-prescribed patients switched to the biosimilar after initiating therapy with the corresponding refence product. The most commonly prescribed concomitant class of therapy with biosimilars was antineoplastic therapy across each setting. This study has several limitations that should be noted, including that the Medical Data Vision hospital-based claims database has missing data for some variables, lacks detailed diagnosis and prognosis data (histology, Eastern Cooperative Oncology Group performance status, disease severity, etc.) and does not record deaths that occur outside the hospital. Initial real-world insights in Japan demonstrate comparable patient characteristics, treatment patterns and treatment duration between bevacizumab, rituximab and trastuzumab biosimilar and originator-treated patients. [ABSTRACT FROM AUTHOR]

Objective To study the effect of integrin subunit α3 (ITGA3) on paclitaxel resistance in non-small-cell lung cancer (NSCLC) and its mechanism. Methods Tumor tissues from 50 NSCLC patients treated with paclitaxel combined with cisplatin chemotherapy, A549/Tax (paclitaxel-resistant human lung adenocarcinoma) cells, human A549 cell line and human embryonic lung fibroblasts (MRC-5) were selected. RT-qPCR was used to detect the expression levels of ITGA3 mRNA in tissues and cells. A549/Tax cells were used as the research objects and were transfected with pcDNA3. 1- ITGA3 plasmid (oe-ITGA3) and pcDNA3. 1 empty vector (oe-NC), silencing ITGA3 small RNA (sh-ITGA3) and negative control (sh-NC), respectively, which were recorded as the oe-ITGA3 group, oe-NC group, sh-ITGA3 group and shNC group, respectively. Untreated A549/Tax cells were used as the control group. CCK-8 was used to detect the OD450 values at 24 and 48 h. Western blotting was used to detect the expression of EMT-related proteins [vimentin, E-cadherin, snail] and TGF-β, and immune escape protein [programmed death ligand-1 (PD-L1)]; RT-qPCR was used to detect the expression of ITGA3 mRNA in A549/Tax cells; Transwell assay was used to detect the migration and invasion abilities of A549/Tax cells. Results After treatment, the expression of ITGA3 mRNA in the tumor tissues was higher than that before treatment (P<0. 05). The expression levels of ITGA3 mRNA in the A549 cells and A549/Tax cells were higher than that in the MRC-5 cells (all P<0. 05). After treatment, Vimentin, snail, TGF-β and PD-L1 in the tumor tissues of NSCLC patients increased in comparison with those before treatment, while E-cadherin decreased (all P<0. 05) . Compared with the control group and the oe-NC group, the OD450 values at 24 and 48 h, the number of cell migration and invasion, the ITGA3 mRNA expression, the expression levels of Vimentin, snail, TGF-β and PD-L1 increased, and the expression of Ecadherin decreased in the oe-ITGA3 group (all P<0. 05). Compared with the control group and the sh-NC group, the OD450 values at 24 and 48 h, the number of cell migration and invasion, the ITGA3 mRNA expression, and the expression levels of Vimentin, snail, TGF-β and PD-L1 decreased, and the expression of E-cadherin increased in the sh-ITGA3 group (all P<0. 05). Conclusion Down-regulating ITGA3 expression can inhibit the drug resistance of NSCLC cells to paclitaxel, and its mechanism may be related to the inhibition of TGF-β expression. [ABSTRACT FROM AUTHOR]

AIM: This study aimed to explore the induction of ferroptosis in non-small-cell lung cancer （NSCLC） cells by tubeimoside II （TBMS II） and to elucidate the underlying molecular mechanisms. METHODS: H460 NSCLC cells were cultured in vitro. Cell survival rates were assessed by using MTT assays, and doses of TBMS II resulting in below 50% survival were selected for further experimentation. Cell migration was evaluated using Transwell assays and the effects of TBMS II on H460 cell proliferation were assessed by colony formation assays. Flow cytometry and fluorescence microscopy were used to assess changes in lipid peroxidation （lipid ROS）, and the levels of GSH, T-AOC, MDA, and Fe2+ were measured using commercial kits. Protein levels of GPX4, SLC7A11, FTH1, NCOA4, P62, and LC3 were examined using Western blot. Changes in mitochondrial structure were detected by transmission electron microscopy, and immunofluorescence was used to assess LC3 co-localization of FTH1 and NCOA4, as well as co-localization of LC3 and NCOA4 with lysosomes. RESULTS: Compared with the control group, TBMS II dose-dependently reduced H460 cell viability, migration, and clone formation, accompanied by the appearance of vacuoles within the cells. TBMS II treatment also led to decreased GSH and T-AOC levels, while increasing the cellular contents of MDA, indicating oxidative stress. Additionally, there was a decrease in the expression of the antioxidant proteins SLC7A11 and GPX4 in the cells, while lipid ROS and Fe2+ levels were increased in proportion to the TBMS II concentration. The ferroptosis inhibitor ferrostatin-1 reversed cell death caused by TBMS II, suggesting ferroptosis induction. Furthermore, increasing the TBMS II concentration resulted in an upregulation of the autophagy marker proteins LC3 II/LC3 I and P62, indicative of increased autophagy. TBMS II also affected mitochondrial morphology in the cells, as seen in reduced mitochondrial fluorescence intensity. Protein expression of NCOA4 increased with higher TBMS II concentrations, while that of FTH1 decreased. Co-localization of LC3 II with FTH1 and NCOA4, as well as the lysosomal association of LC3 II and FTH1, also increased in a dosedependent manner. CONCLUSION: TBMS II induces ferritinophagy in H460 cells, leading to decreased cell viability and increased ferroptosis. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) represent an emerging class of targeted anticancer agents that have demonstrated impressive efficacy in numerous cancer types. In non-small cell lung cancer (NSCLC), ADCs have become a component of the treatment armamentarium for a subset of patients with metastatic disease. Emerging data suggest that some ADCs exhibit impressive activity even in central nervous system (CNS) metastases, a disease site that is difficult to treat and associated with poor prognosis. Herein, we describe and summarize the existing evidence surrounding ADCs in NSCLC with a focus on CNS activity. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the impact of radiation doses to the heart and lungs on overall survival (OS) in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) treated with radiotherapy. An analysis of 120 patients, each with exactly three years of follow-up, revealed that higher radiation doses to the heart and lungs were significantly associated with worse OS. Importantly, the combination of heart and lung radiation doses provided enhanced and more detailed risk stratification, making it a more powerful predictor of poor survival than individual doses alone. These findings suggest that minimizing combined radiation exposure to both organs may improve survival outcomes in LA-NSCLC patients. Background/Objectives: Despite advancements in treatment for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC), overall survival (OS) remains poor. The specific effects of varying heart and lung doses on OS in LA-NSCLC patients have not been thoroughly investigated, especially their combined impact on survival. This study aimed to examine the impact on OS of both individual and combined heart and lung doses in patients with LA-NSCLC treated with radiotherapy over a three-year follow-up period. Methods: A total of 120 patients who received definitive radiotherapy for LA-NSCLC (stage III, 92.5%) from January 2015 to January 2020 were retrospectively reviewed. The endpoint in this study was OS. Each patient was followed for a fixed period of three years. Results: Univariate Cox regression analysis showed that OS was significantly related to mean heart dose (MHD, hazard ratio [HR], 3.4 [1.8–6.3]; p < 0.001), pericardium V40 (HR, 3.2 [1.7–6.0]; p < 0.001), and total lung V20 (HR, 2.6 [1.4–5.0]; p = 0.003), and these were independent predictors for worse OS in multivariate analysis. Kaplan–Meier curve analysis with log-rank tests revealed that survival was significantly worse in patients with higher MHD (p < 0.001), pericardium V40 (p < 0.001), and total lung V20 (p = 0.002). Combining MHD and total lung V20, and pericardium V40 and total lung V20 provided enhanced risk stratification for OS (p < 0.001 for both combinations). Conclusions: The combination of heart and lung doses provided enhanced and more detailed risk stratification in prediction of OS for a fixed period of three years in LA-NSCLC patients treated with radiotherapy. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) stands as a prevalent subtype of lung cancer, with circular RNAs emerging as key players in cancer development. This study elucidates the role of circRNA-CPA4 in NSCLC. Elevated circRNA-CPA4 expression in NSCLC lines was confirmed through qRT-PCR. Silencing circRNA-CPA4 with shRNA revealed, through CCK-8, colony formation, and flow cytometry assays, a notable constraint on proliferation and promotion of apoptosis in NSCLC cells. Subcellular localization analysis, RNA immunoprecipitation, and expression level assessments were employed to decipher the intricate interplay among miR-1183, circRNA-CPA4, and PDPK1. Results demonstrated heightened circRNA-CPA4 levels in NSCLC, and its knockdown curtailed NSCLC growth in vivo. Acting as a molecular sponge for miR-1183, circRNA-CPA4 regulated PDPK1 expression. Conversely, inhibiting miR-1183 counteracted the impact of circRNA-CPA4 silencing, reinstating NSCLC cell proliferation, and impeding apoptosis. Overall, this study unveils a novel mechanism: circRNA-CPA4 promotes PDPK1 expression by sequestering miR-1183, fostering NSCLC cell proliferation, and hindering apoptosis. [ABSTRACT FROM AUTHOR]

Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ −50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274 , PDCD1LG2 , and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible. • Intrapatient paired PD-L1 TPS and TMB assessments have good concordance. • Variations in PD-L1 TPS and TMB with clinical implications may occur. • Intervening ICI therapy is associated with decrease in PD-L1 TPS. • Copy number loss in CD274 , PDCD1LG2 , and JAK2 genes are strongly associated with major decrease in PD-L1 TPS (−50% to −100%). • Variations in PD-L1 TPS and TMB have significant impact on outcomes to a subsequent ICI-based therapy. [ABSTRACT FROM AUTHOR]

Purpose: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe. Methods: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis. Results: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38). Conclusion: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe. [ABSTRACT FROM AUTHOR]

Objective Non-small-cell lung cancer (NSCLC) is a leading attributor to cancer deaths. High HDAC10 and low microRNA (miR)-223-5p levels have been observed in NSCLC. But their roles remain elusive. This study illustrated their roles in NSCLC cell ferroptosis and the mechanism. Methods HDAC10, miR-223-5p, and solute carrier family 7 member 11 (SLC7A11) levels in cells were determined by RT-qPCR. Iron ion content, reactive oxygen species (ROS), and glutathione (GSH) levels were tested using reagent kits, and levels of SLC7A11 and Acyl-CoA synthesis long chain family (ACSL4) were examined using Western blot. Chromatin immunoprecision was performed to analyze the enrichment of HDAC10 and acetylated lysine 9 of histone H3 (H3K9ac) on the miR-223-5p promoter. The targeted binding of miR-223-5p and SLC7A11 was analyzed by dual-luciferase assay. Joint experiments were designed to identify the role of miR-223-5p/SLC7A11 axis in HDAC10-regulated ferroptosis in NSCLC cells. Results HDAC10 was highly expressed in NSCLC cells. Silencing HDAC10 significantly reduced GSH and SLC7A11 levels, upregulated iron ion content, ROS levels, and ACSL4 expression, promoting cell ferroptosis. Mechanically, HDAC10 inhibited miR-223-5p expression through H3K9ac deacetylation of the miR-223-5p promoter, thereby targeting SLC7A11. The joint experimental results showed that overexpression of SLC7A11 or downregulation of miR-223-5p alleviated the promoting effect of silencing HDAC10 on ferroptosis in NSCLC cells. Conclusion HDAC10 inhibits miR-223-5p expression through H3K9ac deacetylation of the miR-223-5p promoter, thereby promoting SLC7A11 expression and inhibiting ferroptosis in NSCLC cells. [ABSTRACT FROM AUTHOR]

Rationale: Immune checkpoint inhibitor (ICI)–related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non–small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Measurements and Main Results: Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ IFN-γ–positive SP-B–specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Conclusions: Our data suggest that the cooccurrence of SP-B–specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is among the deadliest cancers worldwide. Despite the recent introduction of several new therapeutic approaches for the disease, improvements in overall survival and progression-free survival have been minimal. Conventional treatments for NSCLC include surgery, chemotherapy and radiotherapy. Except for surgery, these treatments can impair a patient's immune system, leaving them susceptible to bacterial infections. As such, Staphylococcus aureus infections are commonly seen in NSCLC patients receiving chemotherapy, and a major constituent of the S. aureus cell surface, lipoteichoic acid (LTA), is thought to stimulate NSCLC cancer cell proliferation. Thus, inhibition of LTA-mediated cell proliferation might be a useful strategy for treating NSCLC. Epinecidin-1 (EPI), a marine antimicrobial peptide, exhibits broad-spectrum antibacterial activity, and it also displays anti-cancer activity in glioblastoma and synovial sarcoma cells. Furthermore, EPI has been shown to inhibit LTA-induced inflammatory responses in murine macrophages. Nevertheless, the anti-cancer and anti-LTA activities of EPI and the underlying mechanisms of these effects have not been fully tested in the context of NSCLC. In the present study, we demonstrate that EPI suppresses LTA-enhanced proliferation of NSCLC cells by neutralizing LTA and blocking its effects on toll-like receptor 2 and interleukin-8. Moreover, we show that EPI induces necrotic cell death via mitochondrial damage, elevated reactive oxygen species levels, and disrupted redox balance. Collectively, our results reveal dual anti-cancer activities of EPI in NSCLC, as the peptide not only directly kills cancer cells but it also blocks LTA-mediated enhancement of cell proliferation. [ABSTRACT FROM AUTHOR]

Lung cancer is a type of cancer that can metastasize to the lungs, brain, bones, liver, adrenal glands, and other organs; however, the occurrence of brain metastases is the most common event. Symptoms of brain metastasis include motor dysfunction, mental dysfunction, seizures, headaches, nausea, and vomiting, and significantly reduce the quality of life of cancer patients. Brain metastases are a poor prognostic factor, and controlling them is extremely important for prolonging prognosis and improving the quality of life. Currently, local surgery and radiotherapy are recommended for their treatment. However, recently, cancer treatments using molecular-targeted drugs and immune checkpoint inhibitors have been introduced, which may also be effective against brain metastases. Therefore, it is necessary to determine whether local or systemic therapy is optimal for each case. In this review, we focus on recent findings regarding drug therapy in treating brain metastases from advanced non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the value of computed tomography (CT)‐based radiomics combined with clinical‐genetic features in predicting brain metastasis in patients with stage III/IV epidermal growth factor receptor (EGFR)‐mutant non‐small‐cell lung cancer (NSCLC). Methods: The study included 147 eligible patients treated at our institution between January 2018 and May 2021. Patients were randomly divided into two cohorts for model training (n = 102) and validation (n = 45). Radiomics features were extracted from the chest CT images before treatment, and a radiomics signature was constructed using the Least Absolute Shrinkage and Selection Operator regression. Kaplan–Meier survival analysis was used to describe the differences in brain metastasis‐free survival (BM‐FS) risk. A clinical‐genetic model was developed using Cox regression analysis. Radiomics, genetic, and combined prediction models were constructed, and their predictive performances were evaluated by the concordance index (C‐index). Results: Patients with a low radiomics score had significantly longer BM‐FS than those with a high radiomics score in both the training (p < 0.0001) and the validation (p = 0.0016) cohorts. The C‐indices of the nomogram, which combined the radiomics signature and N stage, overall stage, third‐generation tyrosine kinase inhibitor treatment, and EGFR mutation status, were 0.886 (95% confidence interval [CI] 0.823–0.949) and 0.811 (95% CI 0.719–0.903) in the training and validation cohorts, respectively. The combined model achieved a higher discrimination and clinical utility than the single prediction models. Conclusions: The combined radiomics‐genetic model could be used to predict BM‐FS in stage III/IV NSCLC patients with EGFR mutations. [ABSTRACT FROM AUTHOR]

Background: CD155 is a transmembrane protein that inhibits antitumor immune response and represents a predictor of worse prognosis in non-small-cell lung cancer (NSCLC). However, it remains unexplored its association with clinical characteristics and genomic status of Latin American patients. This study characterizes the CD155 expression and its clinical implications in this population. Methods: Tissue biopsies from 86 patients with locally-advanced or metastatic NSCLC were assessed for CD155 protein expression, ALK rearrangements and EGFR mutations. Cutoff values for high CD155 expression (CD155high) were determined from receiver operating characteristic (ROC) curves according to 2-year survival. It was evaluated its association with clinicopathological features, median progression-free survival (mPFS) and overall survival (mOS). Results: the cutoff score for CD155high was 155 in the entire cohort and in patients without oncogenic alterations, and it was 110 in patients with oncogenic alterations. Eighty-four patients (97.7%) were CD155 positive, of which fifty-six (65.0%) had CD155high. EGFR L858R mutation related to lower CD155 IHC score than exon 19 deletion. Individuals with CD155high showed a shorter mOS (13.0 vs. 30.8 months; HR: 1.96 [95% CI, 1.15–3.35]; p = 0.014). Patients without oncogenic alterations having a CD155high displayed shorter mPFS (1.6 vs. 6.4 months, HR: 2.09 [95% CI, 1.06–4.20]; p = 0.034) and mOS (2.9 vs. 23.1 months; HR: 1.27 [95% CI, 1.07– 4.42]; p = 0.032). Patients with oncogenic alterations having CD155high only showed a trend to shorter mOS (26.3 vs. 52.0 months; HR: 2.39 [95% CI, 0.98–5.83]; p = 0.058). Conclusion: CD155high is a predictor of worse outcomes in patients with advanced NSCLC, predominantly among those without oncogenic alterations. CD155 could be a potential biomarker and a molecular target in patients with poor responses to current therapies. [ABSTRACT FROM AUTHOR]

Background: Sasanlimab (PF-06801591), a humanized immunoglobulin G4 monoclonal antibody, binds to programmed cell death protein-1 (PD-1), preventing ligand (PD-L1) interaction. Objectives: To evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of two subcutaneous sasanlimab dosing regimens. Design: An open-label study consisting of phases Ib and II. Phase Ib: non-randomized, dose escalation, and expansion study in Asian participants with advanced malignancies. Phase II: conducted globally in participants with non-small-cell lung cancer with PD-L1 positive or PD-L1 status unknown tumors; participants were randomized 1:2 to receive subcutaneous sasanlimab 300 mg once every 4 weeks (300 mg-Q4W) or 600 mg once every 6 weeks (600 mg-Q6W). Methods: Primary endpoint in phase Ib: dose-limiting toxicity (DLT) occurring in first treatment cycle; in phase II: C trough and AUC. Results: A total of 155 participants (phase Ib, n = 34; phase II, n = 121) received sasanlimab. Phase Ib: no DLT reported. Phase II: ratio of adjusted geometric mean for AUCtau was 231.2 (90% CI, 190.1–281.2) and C trough was 111.5 (90% CI, 86.3–144.0) following 600 mg-Q6W (test) versus 300 mg-Q4W (reference). Phase Ib: grade 3 treatment-related adverse events (TRAEs) occurred in 1/4 (25%) and 3/12 (25%) participants treated in 300 mg-Q4W dose escalation and expansion cohorts, respectively. Phase II: grade 3 TRAEs occurred in 3/41 (7.3%) and 3/80 (3.8%) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively; no grade 4/5 TRAEs. Phase II: confirmed objective response was observed in 11/41 (26.8% (95% CI, 14.2–42.9)) and 12/80 (15.0% (95% CI, 8.0–24.7)) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively. Conclusions: Phase Ib regimens were considered safe with no DLTs reported. In phase II, 600 mg-Q6W regimen criteria were met for AUCtau and C trough metrics to support PK-based extrapolation of efficacy of alternative regimen. Regimens were well tolerated, showing anti-tumor activity in participants with advanced solid tumors. Administration of sasanlimab at a dose of 600 mg-Q6W subcutaneously may serve as a convenient alternative to 300 mg-Q4W administration. Trial registration: NCT04181788 (ClinicalTrials.gov); 2019-003818-14 (EudraCT). [ABSTRACT FROM AUTHOR]

Background: Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors. Methods: ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT–qPCR) were conducted to verify the impact of ZMIZ2–SIRT1 combination on Hippo/Wnt pathways. Results: ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells—establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2–SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear β-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of β-catenin-transcription factor 4 (TCF4) and YAP–TEA domain family transcription factors (TEADs) were amplified. Conclusions: ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effects of sodium selenite (SS) on viability, migration and angiogenesis of human non-small-cell lung cancer (NSCLC) H520 and A549 cells. METHODS: The H520 cells, A549 cells, and human umbilical vein endothelial cells (HUVEC) were divided into control group (0 μmol/L SS), low dose group (5 μmol/L SS), middle dose group (10 μmol/L SS), and high dose group (20 μmol/L SS). Cell viability was assessed using the CCK-8 assay, and the half-maximal inhibitory concentration (IC50) was calculated. Cell migration and invasion abilities were determined through wound healing and Transwell assays. The regulatory effects of SS on angiogenesis, vasculogenic mimicry and "mosaic" vascular formation between HUVEC and NSCLC cells were detected using vessel forming assays. The expression of vascular endothelial growth factor (VEGF) in the supernatant of lung cancer cells in each group was detected using chemiluminescence. RT-qPCR was used to assess the mRNA expression of VEGF, vascular endothelial growth factor receptor 2 (VEGFR2) and angiotensin II (Ang II). Western blot was used to examine the protein levels of VEGF, p-PI3K, and p-Akt in H520 and A549 cells. RESULTS : The IC50 values of SS to HUVEC, A549 cells and H520 cells for 48 h were 6. 762, 9. 003 and 7. 356 μmol/L, respectively. Compared with control group, the wound healing rate was significantly decreased in each group treated with SS for 48 h (p<0. 01). In HUVEC, the number of migrating cells in middle dose and high dose groups decreased (p<0. 01), whereas in lung cancer cells, the number of migrating cells in each group decreased after SS treatment (p<0. 01). The mRNA expression levels of VEGF, VEGFR2 and Ang II were lower in high-dose SS group than those in control group (p<0. 05 or p<0. 01). In H520 cells, compared with control group, the protein levels of VEGF, p-PI3K and p-Akt in SS treatment groups were significantly decreased (p<0. 05 or p< 0. 01). CONCLUSION: Sodium selenite inhibits the viability and migration of HUVEC, H520 cells and A549 cells, and inhibits the formation of vasculogenic mimicry and mosaic vessels in NSCLC cells. This mechanism may be related to the inhibition of PI3K-Akt signaling pathway activation and regulation of VEGF. [ABSTRACT FROM AUTHOR]

OBJECTIVES Invasive mucinous adenocarcinoma exhibits distinct prognostic outcomes compared to non-mucinous adenocarcinoma (ADC). This study investigated and compared the clinical outcomes and prognostic factors of invasive mucinous and non-mucinous ADC patients. METHODS This retrospective study included patients who underwent curative surgery for ADC between 2011 and 2021. Patient characteristics were balanced using propensity score matching. Cumulative incidence was analysed to evaluate cancer recurrence incidence, and the Kaplan–Meier method was used to calculate overall survival (OS) for each group. RESULTS A total of 6101 patients were included. After matching, the non-mucinous group and mucinous groups comprised 798 and 408 patients, respectively. The patients in the mucinous group had a lower recurrence incidence than those in the non-mucinous group (P  = 0.014). The recurrence incidence in the mucinous group was between those of grades 1 (P  = 0.011) and 2 (P  = 0.012) and the OS rates were comparable to those of grades 2 (P  = 0.6) and 3 (P  = 0.2). Multivariable analysis revealed that the maximal standardized uptake value [hazard ratio (HR): 1.13, P  = 0.11] and progressed pathological stages (pStage II, HR: 3.9, P  = 0.028; pStage III, HR: 8.33, P  = 0.038) served as adverse prognostic factors for the mucinous group. CONCLUSIONS Patients with mucinous ADC demonstrated lower recurrence incidence and similar OS rates compared to those with non-mucinous ADC. The recurrence incidence of mucinous ADC was between those of International Association for the Study of Lung Cancer grades 1 and 2, with the OS rates comparable to those of grades 2 and 3. CLINICAL REGISTRATION NUMBER None. [ABSTRACT FROM AUTHOR]

Since the initial US FDA approval of an immune checkpoint inhibitor (ICI) for the treatment of non-oncogene-driven non-small-cell lung cancer (NSCLC) nine years ago, this therapeutic strategy has been cemented as a crucial component of treatment for most of these patients. However, there is a clear efficacy–effectiveness gap whereby patients in the 'real world' seem to have more modest clinical outcomes compared to those enrolled in landmark clinical trials. This gap may be driven by the under-representation of important patient populations, including populations defined by clinical or molecular characteristics. In this review, we summarize the data outlining the evidence of ICIs in patients with poor Eastern Cooperative Oncology Group performance status (ECOG PS), underlying autoimmune disease (AID), older age, active brain metastases (BMs), and molecular aberrations such as EGFR mutations, ALK fusions, BRAF mutations and ROS1 fusions. [ABSTRACT FROM AUTHOR]

Non‐small‐cell lung cancer (NSCLC) accounts for the majority of lung cancer cases worldwide, with a significant proportion of patients harbouring actionable oncogenic alterations. Among these alterations, the ROS1 rearrangement represents a distinct subset with therapeutic implications. Here, we present the case of a 52‐year‐old man diagnosed with advanced NSCLC harbouring the ROS1 fusion gene. Despite the initial poor response to conventional chemotherapy, the patient exhibited an exceptional and sustained response to crizotinib, with a progression‐free survival of 94 months and complete metabolic response on PET scan. This case underscores the importance of molecular profiling in guiding treatment decisions and highlights the efficacy of targeted therapies for ROS1‐positive NSCLC. [ABSTRACT FROM AUTHOR]

Objective: The primary treatment for stage I non-small cell lung cancer (NSCLC) in medically inoperable patients is stereotactic body radiation therapy (SBRT). The current study aimed to retrospectively analyze patients who underwent SBRT. Methods: A total of 188 patients with stage I NSCLC treated with SBRT between 2014 and 2020 were enrolled. Local control (LC), progressionfree survival (PFS), overall survival (OS), and treatment-related toxicities were analyzed. Results: Patients were mostly male (65.7%, n=71), with a median age of 68 (56-88). Based on tumor size and location, 69 patients (63.9%) received between 50 and 60 Gy in 5 fractions, 26 patients (24.1%) received 54 Gy in 3 fractions, 11 patients (10.2%) received 60 Gy in 8 fractions, and 2 patients (1.8%) received 60 Gy in 3 fractions. The median follow-up time was 32 months (12-47 months). Locoregional relapse occurred in 11 patients, among whom 4 (3.7%) developed distant metastasis. The 3-year LC, OS, and PFS rates were 89.5%, 83%, and 72%, respectively. Advanced age and presence of chronic obstructive pulmonary disease were associated with a decreased 3-year OS. In smokers and those with large tumor volumes, PFS decreased to 3 years. No grade 3 or 4 treatment-related toxicities were observed. Conclusion: SBRT is a fast, safe, and valuable therapeutic approach for patients with early-stage medically inoperable NSCLC, providing significant tumor control rates with low toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Few studies have investigated the prognostic factors for non-adenocarcinoma of the lung. We retrospectively evaluated the prognostic factors on the basis of histological type of non-adenocarcinoma of the lung treated by pulmonary resection. Methods: We enrolled 266 patients with non-adenocarcinoma of the lung in this retrospective study: 196 with squamous cell carcinoma (SCC) and 70 with non-SCC. Results: Relapse-free survival (RFS) did not differ significantly between SCC and non-SCC patients (p = 0.33). For SCC patients, RFS differed significantly between patients who underwent wedge resection and non-wedge resection (p < 0.01) and between patients with Clavien-Dindo grade ≥3a and 0–2 postoperative complications (p < 0.01). For non-SCC patients, RFS rates were significantly different in the groups divided at neutrophil-to-lymphocyte ratio = 2.40 (p = 0.02), maximum standardized uptake value (SUVmax) = 8.39 (p < 0.01), between patients with pathological stage (pStage) 0–I and with pStage more than II (p < 0.01). For SCC patients, male sex (p = 0.04), wedge resection (p = 0.01), and Clavien-Dindo grade ≥3a (p = 0.02) were significant factors for RFS in multivariate analysis. For non-SCC patients, neutrophil-to-lymphocyte ratio >2.40 (p < 0.01), SUVmax >8.39 (p = 0.01), and pStage ≥II (p = 0.03) were significant factors for RFS in multivariate analysis. Conclusion: RFS did not differ significantly differently between SCC and non-SCC patients. It is necessary to perform more than segmentectomy and to avoid severe postoperative complications for SCC patients. SUVmax might be an adaptation criterion of adjuvant chemotherapy for patients with non-adenocarcinoma and non-SCC of the lung. [ABSTRACT FROM AUTHOR]

Background: Recent advancements in advanced non‐small‐cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first‐line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first‐line treatment for KRAS‐mutant NSCLC. Methods: We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression‐free survival (PFS) and overall survival (OS). A random‐effects network meta‐analysis was conducted to perform direct and indirect comparisons among treatment groups. Results: Six RCTs were eligible for inclusion. In the network meta‐analysis for KRAS‐mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22–0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47–0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49–0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34–0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48–0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56–0.92). Regarding OS in wild‐type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50–1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63–0.99). Conclusion: The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS‐mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first‐line treatment. [ABSTRACT FROM AUTHOR]

MitoAMPK was proved to inhibit the Warburg effect, but the specific mechanisms on non‐small‐cell lung cancer remain unclear. Here, we selected SIRT6 and MZF1 to clarify the mechanism. By western blotting, quantitative polymerase chain reaction, the CCK‐8 assay, and immunohistochemistry assays, we found SIRT6 expression was lower in NSCLC tissues and cell lines than normal tissues and cells. Moreover, SIRT6 could inhibit the Warburg effect by regulating glycolysis‐related genes of SLC2A2, SLC2A4 and PKM2. Finally, we demonstrated the interaction between SIRT6 and MZF1 using ChIP‐qPCR. In conclusion, mitoAMPK inhibits the Warburg effect by regulating the expression of the MZF1–SIRT6 complex. [ABSTRACT FROM AUTHOR]

Multiple epigenetic regulatory mechanisms exert critical roles in tumor development, and understanding the interactions and impact of diverse epigenetic modifications on gene expression in cancer is crucial for the development of precision medicine. We found that methyltransferase‐like 14 (METTL14) was significantly downregulated in non‐small‐cell lung cancer (NSCLC) tissues. Functional experiments demonstrated that overexpression of METTL14 inhibited the proliferation and migration of NSCLC cells both in vivo and in vitro, and the colorimetric m6A quantification assay also showed that knockdown of METTL14 notably reduced global m6A modification levels in NSCLC cells. By using the methylated‐RNA immunoprecipitation‐qPCR and dual‐luciferase reporter assays, we verified that long noncoding RNA LINC02747 was a target of METTL14 and was regulated by METTL14‐mediated m6A modification, and silencing LINC02747 inhibited the malignant progression of NSCLC by modulating the PI3K/Akt and CDK4/Cyclin D1 signaling pathway. Further studies revealed that overexpression of METTL14 promoted m6A methylation and accelerated the decay of LINC02747 mRNA via increased recognition of the "GAACU" binding site by YTHDC2. Additionally, histone demethylase lysine‐specific histone demethylase 5B (KDM5B) mediated the demethylation of histone H3 lysine 4 tri‐methylation (H3K4me3) in the METTL14 promoter region and repressed its transcription. In summary, KDM5B downregulated METTL14 expression at the transcriptional level in a H3K4me3‐dependent manner, while METTL14 modulated LINC02747 expression via m6A modification. Our results demonstrate a synergy of multiple mechanisms in regulating the malignant phenotype of NSCLC, revealing the complex regulation involved in the occurrence and development of cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens. Methods Histopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB. Results We successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure.

Abstract Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

Abstract Background No standard has been established for the clinical target volume (CTV) margins of lymph nodes (LNs) in patients with non-small-cell lung cancer (NSCLC) receiving chemotherapy or chemotherapy combined with immunotherapy followed by radiotherapy. This study aimed to discuss the CTV range of NSCLC after chemotherapy or chemotherapy combined with immunotherapy by observing the microscopic extent of tumor spread beyond the LN capsule. Methods We retrospectively analyzed the data of 240 patients with stage II and III NSCLC who underwent surgery without neoadjuvant therapy, with neoadjuvant chemotherapy (NAC), or with NAC combined with immunotherapy (NACI). We measured the maximal distance of extracapsular extension (ECE) using a digital microscope, analyzed the correlation between clinicopathological features and ECE distance, and determined the CTV margins of metastatic LN under different treatment methods. Results The ECE distance differed significantly among the three groups (p

Faustine X Luo,1,2 Zhaohui Liao Arter1,2 1University of California Irvine School of Medicine, Orange, CA, 92868, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, 92868, USACorrespondence: Zhaohui Liao Arter, Department of Medicine, Division of Hematology/Oncology, UC Irvine, Orange, CA, 92602, USA, Email zarter@hs.uci.eduAbstract: Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10– 13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRASG12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45– 0.76; P< 0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRASG12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRASG12C enigma code in NSCLC.Keywords: non-small-cell lung cancer, KRASG12C mutations, adagrasib, sotorasib, KRYSTAL, targeted therapy, intracranial efficacy

Antibody–drug conjugates (ADCs) represent an emerging class of targeted anticancer agents that have demonstrated impressive efficacy in numerous cancer types. In non-small cell lung cancer (NSCLC), ADCs have become a component of the treatment armamentarium for a subset of patients with metastatic disease. Emerging data suggest that some ADCs exhibit impressive activity even in central nervous system (CNS) metastases, a disease site that is difficult to treat and associated with poor prognosis. Herein, we describe and summarize the existing evidence surrounding ADCs in NSCLC with a focus on CNS activity.

Abstract Echinoderm microtubule-associated protein 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene detection is of great significance in personalized tumor treatment. With the development of EML4-ALK fusion variants detection, it is necessary to establish traceability to ensure the consistency and comparability of its detection results in clinical practice. The establishment of traceability relies on SI traceable reference materials (RMs) and potential reference measurement procedures (RMPs). In this study, a potential RMP for the quantitative detection of V1 and V3 fusion mutations and the reference type (ALK-ref, including wild type, V1 and V3 mutant type) based on reverse transcription dPCR (RT-dPCR) and EML4-ALK fusion gene RMs were established. The proposed potential RMP has high specificity, good inter-laboratory reproducibility (CV

Kang Wang,1 Fengchang Yang,1 Changxing Feng,1 Fuhao Xu,1 Li Li,1 Jinghao Duan,1 Shuanghu Yuan1,2 1Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 2Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Shuanghu Yuan, Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, No. 440 Jiyan Road, Jinan, Shandong, 250117, People’s Republic of China, Tel +86-531-67626931, Fax +86-531-87984079, Email yuanshuanghu@sina.comPurpose: This study aims to identify risk factors associated with symptomatic radiation pneumonitis (RP, Grade ≥ 2) following immunotherapy preceding thoracic radiotherapy (ICI-TRT) and establish safe dose constraints.Patients and Methods: This retrospective study enrolled patients diagnosed with non-small-cell lung cancer (NSCLC) who underwent thoracic radiotherapy (TRT) following immune checkpoint inhibitors (ICIs) treatment. The primary endpoint was the occurrence of symptomatic RP (Grade ≥ 2), as defined by the Common Terminology Criteria for Adverse Events version 5.0. Clinical and lung dosimetric parameters were analyzed to determine their associations with symptomatic RP. Dosimetric parameters included mean lung dose (MLD) and the percentage of lung volume receiving ≥ 10 Gy (V10), ≥ 20 Gy (V20), ≥ 30 Gy (V30), and ≥ 40 Gy (V40). Receiver operating characteristic curves were used to predict the risk of developing symptomatic RP to establish optimal threshold values for each dosimetric predictor.Results: Among the 118 patients included, the incidence of symptomatic RP was 25.4%. Tumor locations, intervals between immunotherapy and radiotherapy, and MLD, V10, V20, V30, and V40 were identified as independent risk factors for symptomatic RP. The area under the curve (AUC) values for MLD, V10, V20, V30, and V40 were 0.788 (95% confidence interval [CI] 0.704– 0.873), 0.789 (95% CI 0.705– 0.874), 0.791 (95% CI 0.706– 0.876), 0.784 (95% CI 0.697– 0.871), and 0.749 (95% CI 0.656– 0.842), respectively. The optimal threshold values for MLD, V10, V20, V30, and V40 were 9.7 Gy, 26.3%, 15.9%, 13.3%, and 8.6%, respectively. These thresholds are lower than current guideline recommendations, and maintaining dosimetric parameters below these values resulted in a cumulative symptomatic RP incidence of < 12%.Conclusion: The recommended dose thresholds for MLD, V10, V20, V30, and V40 are lower than the current guidelines, underscoring the importance of radiotherapy planning to minimize symptomatic RP occurrence in patients receiving ICI-TRT.Keywords: radiation therapy, immunotherapy, non-small-cell lung cancer, radiation pneumonitis, risk factors

Abstract Purpose To evaluate the value of computed tomography (CT)‐based radiomics combined with clinical‐genetic features in predicting brain metastasis in patients with stage III/IV epidermal growth factor receptor (EGFR)‐mutant non‐small‐cell lung cancer (NSCLC). Methods The study included 147 eligible patients treated at our institution between January 2018 and May 2021. Patients were randomly divided into two cohorts for model training (n = 102) and validation (n = 45). Radiomics features were extracted from the chest CT images before treatment, and a radiomics signature was constructed using the Least Absolute Shrinkage and Selection Operator regression. Kaplan–Meier survival analysis was used to describe the differences in brain metastasis‐free survival (BM‐FS) risk. A clinical‐genetic model was developed using Cox regression analysis. Radiomics, genetic, and combined prediction models were constructed, and their predictive performances were evaluated by the concordance index (C‐index). Results Patients with a low radiomics score had significantly longer BM‐FS than those with a high radiomics score in both the training (p

Since the initial US FDA approval of an immune checkpoint inhibitor (ICI) for the treatment of non-oncogene-driven non-small-cell lung cancer (NSCLC) nine years ago, this therapeutic strategy has been cemented as a crucial component of treatment for most of these patients. However, there is a clear efficacy–effectiveness gap whereby patients in the ‘real world’ seem to have more modest clinical outcomes compared to those enrolled in landmark clinical trials. This gap may be driven by the under-representation of important patient populations, including populations defined by clinical or molecular characteristics. In this review, we summarize the data outlining the evidence of ICIs in patients with poor Eastern Cooperative Oncology Group performance status (ECOG PS), underlying autoimmune disease (AID), older age, active brain metastases (BMs), and molecular aberrations such as EGFR mutations, ALK fusions, BRAF mutations and ROS1 fusions.