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Introduction: Baicalein, a bioactive component of Scutellaria baicalensis Georgi, has been shown to promote apoptosis in non-small cell lung cancer cells. However, previous studies have not determined if baicalein exerts proapoptotic effects by modulating the metabolic pathways. Objective: To investigate if baicalein induces apoptosis in lung cancer cells by modulating the glutamine-mTOR metabolic pathway. Methods: The in vivo anti-lung cancer activity of baicalein (50, 100, and 200 mg/kg) was evaluated using a xenograft model. In vitro experiments were used to assess the efficacy of baicalein (for H1299: 12.5, 25, and 50 μM; for A549: 10, 20, and 40 μM) on lung cancer cell proliferation, colony formation, and apoptosis. Metabolomics analysis was performed using liquid chromatography-mass spectrometry. The binding of baicalein to glutamine transporters and glutaminase was examined using molecular docking. The overexpression of glutamine transporters was validated using qRT–PCR and western blot analyses. The levels of ASCT2, LAT1, GLS1, p-mTOR, mTOR, and apoptosis-related proteins were evaluated using western blot analysis. Results: Baicalein inhibited lung cancer xenograft tumor growth in vivo and suppressed proliferation and promoted apoptosis in lung cancer cells in vitro. Additionally, baicalein altered amino acid metabolites, especially glutamine metabolites, in H1299 and A549 cells. Mechanistically, baicalein interacted with glutamine transporters as well as glutaminase and inhibited their activation. The expression of mTOR, an apoptosis-related protein and downstream target of glutamine metabolism, was also inhibited by baicalein treatment. Importantly, we next demonstrated the suppression of mTOR signaling and the induction of apoptosis by baicalein were achieved by regulating glutamine metabolism. Conclusion: Baicalein inhibited the mTOR signaling pathway and induced apoptosis by downregulating glutamine metabolism. The potential of baicalein to induce apoptosis in lung cancer cells by selectively targeting the glutamine-mTOR pathway suggests an encouraging approach for treating lung cancer.

Cytokine release syndrome (CRS) is a well-described immune-related adverse event following chimeric antigen receptor T-cell therapy (CAR-T) but has rarely been reported following therapy with immune checkpoint inhibitors (ICI).We present a clinical case of severe CRS after ICI therapy for advanced non-small-cell lung cancer (NSCLC). After the third cycle of ipilimumab and nivolumab the patient presented with fever, hypotension and somnolence, leading to acute respiratory failure, acute kidney and hepatic failure, capillary leak syndrome, requiring ICU (intensive care unit) care. She recovered after receiving tocilizumab and steroid therapy.Subsequently, we found 17 clinical cases of advanced NSCLC patients in peer review, experiencing CRS as an adverse event of treatment with ICI. We review those cases in detail and compare the similarities and outcomes.Conclusion: CRS is a serious, life-threatening complication that is rare after ICI therapy for solid cancers but becoming increasingly frequent since ICI therapies are broadening indications. When presented with clinical symptoms, considering CRS is crucial, as early recognition is key to timely intervention and favorable outcome for the patient.

Non-small-cell lung cancer (NSCLC) represents a predominant histological subtype of lung cancer, characterized by high incidence and mortality rates. Despite significant advancements in therapeutic strategies and a deeper understanding of targeted therapies in recent years, tumor resistance remains an inevitable challenge, leading to poor prognostic outcomes. Several studies have indicated that sphingosine kinase 1 (SPHK1) plays a regulatory role in epidermal growth factor receptor (EGFR) signaling, and its elevated expression may be associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Furthermore, the catalytic product of SPHK1, sphingosine 1-phosphate (S1P), along with its receptor, sphingosine 1-phosphate receptor 3 (S1PR3), plays a regulatory role in the function of the EGFR. However, the specific effects of the SPHK1/S1P/S1PR3 axis on EGFR in NSCLC, as well as the combined effects of SPHK1/S1P/S1PR3 inhibitors with the EGFR-TKI gefitinib, remain to be elucidated. In the present study, we investigated the correlation between SPHK1 expression levels and the survival rates of NSCLC patients, the relationship between SPHK1 or S1PR3 and EGFR, and the impact of SPHK1 expression on the half-maximal inhibitory concentration (IC50) of gefitinib in NSCLC. In A549 cells, the phosphorylation of EGFR was significantly reduced following SPHK1 knockdown. Utilizing SPHK1/S1P/S1PR3 inhibitors, namely PF543, TY52156, and FTY720, we established that the SPHK1/S1P/S1PR3 axis modulates EGFR activation in NSCLC. Furthermore, these signaling inhibitors enhanced the anti-proliferative efficacy of the EGFR-TKI gefitinib. RNA sequencing analysis revealed substantial alterations in 85 differentially expressed genes in NSCLC cells treated with the combination of FTY720 and gefitinib. These genes were predominantly associated with pathways such as axon guidance, microRNAs in cancer, and the JAK-STAT signaling pathway, among others. Overall, targeting the SPHK1/S1P/S1PR3 signaling pathway represents a promising therapeutic strategy to enhance gefitinib sensitivity in NSCLC.

Background: Liquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB), are recognized as promising predictors of prognoses and responses to immune checkpoint inhibitors (ICIs), despite insufficient sensitivity of single biomarker detection. This research aims to determine whether the combinatorial utility of longitudinal ctDNA with bTMB analysis could improve the prognostic and predictive effects. Methods: This prospective two-center cohort trial, consisting of discovery and validation datasets, enrolled unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) patients and assigned them to chemoradiotherapy (CRT) or CRT + consolidation ICI cohorts from 2018 to 2022. Blood specimens were collected pretreatment, 4 weeks post-CRT, and at progression to assess bTMB and ctDNA using 486-gene next-generation sequencing. Dynamic ∆bTMB was calculated as post-CRT bTMB minus baseline bTMB levels. Decision curve analyses were performed to calculate Concordance index (C-index). Results: One hundred twenty-eight patients were enrolled. In the discovery dataset (n = 73), patients treated with CRT and consolidation ICI had significantly longer overall survival (OS; median not reached [NR] vs 20.2 months; P < 0.001) and progression-free survival (PFS; median 25.2 vs 11.4 months; P = 0.011) than those without ICI. Longitudinal analysis demonstrated a significant decrease in ctDNA abundance post-CRT (P < 0.001) but a relative increase with disease progression. Post-CRT detectable residual ctDNA correlated with significantly shorter OS (median 18.3 months vs NR; P = 0.001) and PFS (median 7.3 vs 25.2 months; P < 0.001). For patients with residual ctDNA, consolidation ICI brought significantly greater OS (median NR vs 14.8 months; P = 0.005) and PFS (median 13.8 vs 6.2 months; P = 0.028) benefit, but no significant difference for patients with ctDNA clearance. Dynamic ∆bTMB was predictive of prognosis. Patients with residual ctDNA and increased ∆bTMB (∆bTMB > 0) had significantly worse OS (median 9.0 vs 23.0 months vs NR; P < 0.001) and PFS (median 3.4 vs 7.3 vs 25.2 months; P < 0.001). The combinatorial model integrating post-CRT ctDNA with ∆bTMB had optimal predictive effects on OS (C-index = 0.723) and PFS (C-index = 0.693), outperforming individual features. In the independent validation set, we confirmed residual ctDNA predicted poorer PFS (median 50.8 vs 14.3 months; P = 0.026) but identified more consolidation ICI benefit (median NR vs 8.3 months; P = 0.039). The combined model exhibited a stable predictive advantage (C-index = 0.742 for PFS). Conclusions: The multiparameter assay integrating qualitative residual ctDNA testing with quantitative ∆bTMB dynamics improves patient prognostic risk stratification and efficacy predictions, allowing for personalized consolidation therapy for LA-NSCLC.

Lung cancer has one of the highest mortality rates worldwide, with non-small-cell lung cancer (NSCLC) constituting approximately 85% of all cases. Demethylzeylasteral (DEM), extracted from Tripterygium wilfordii Hook F, exhibits notable anti-tumor properties. In this study, we revealed that DEM could effectively induce NSCLC cell apoptosis. Specifically, DEM can dose-dependently suppress the viability and migration of human NSCLC cells. RNA-seq analysis revealed that DEM regulates the P53-signaling pathway, which was further validated by assessing crucial proteins involved in this pathway. Biacore analysis indicated that DEM has high affinity with the P53 protein. The CDX model demonstrated DEM's anti-tumor actions. This work provided evidence that DEM-P53 interaction stabilizes P53 protein and triggers downstream anti-tumor activities. These findings indicate that DEM treatment holds promise as a potential therapeutic approach for NSCLC, which warrants further clinical assessment in patients with NSCLC.

Summary: Background: The long-term survival and perioperative outcomes of robotic-assisted lobectomy (RAL) and video-assisted lobectomy (VAL) in resectable non-small-cell lung cancer (NSCLC) were found to be comparable in retrospective studies, but they have not been investigated in a randomized trial setting. We conducted the RVlob trial to investigate if RAL was non-inferior to VAL in patients with resectable NSCLC. Methods: In this single-center, open-label, and parallel-arm randomized controlled trial conducted in Ruijin Hospital (Shanghai, China) between May 2017 and May 2020, we randomly assigned patients with resectable NSCLC in a 1:1 ratio to receive either RAL or VAL. One of the primary endpoints was 3-year overall survival. Secondary endpoints included 3-year disease-free survival. The Kaplan–Meier approach was used to calculate overall survival and disease-free survival at 3 years. This study was registered with ClinicalTrials.gov, NCT03134534. Findings: A total of 320 patients were randomized to receive RAL (n = 157) or VAL (n = 163). The baseline characteristics of patients were well balanced between the two groups. After a median follow-up of 58.0 months, the 3-year overall survival was 94.6% (95% confidence interval [CI], 91.0–98.3) in the RAL group and 91.5% (95% CI, 87.2–96.0) in the VAL group (hazard ratio [HR] for death, 0.65; 95% CI, 0.33–1.28; P = 0.21); noninferiority of RAL was confirmed according to the predefined margin of −5% (absolute difference, 2.96%; a one-sided 90% CI, −1.39% to ∞; P = 0.0029 for noninferiority). The 3-year disease-free survival was 88.7% (95% CI, 83.6–94.1) in the RAL group and 85.4% (95% CI, 80.0–91.2) in the VAL group (HR for disease recurrence or death, 0.87; 95% CI, 0.50–1.52; P = 0.62). Interpretation: This study is the first randomized trial to show that RAL resulted in non-inferior overall survival compared with VAL in patients with resectable NSCLC. Based on our results, RAL is an equally oncologically effective treatment and can be considered as an alternative to VAL for resectable NSCLC. Funding: National Natural Science Foundation of China (82072557), National Key Research and Development Program of China (2021YFC2500900), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20172005, the 2nd round of disbursement), program of Shanghai Academic Research Leader from Science and Technology Commission of Shanghai Municipality (20XD1402300), Novel Interdisciplinary Research Project from Shanghai Municipal Health Commission (2022JC023), and Interdisciplinary Program of Shanghai Jiao Tong University (YG2023ZD04).

Background: Tyrosine kinase inhibitors (TKIs) are standard first-line treatments for advanced non-small-cell lung cancer (NSCLC) with driver gene mutations. The Response Evaluation Criteria in Solid Tumors (RECIST) are limited in predicting long-term patient benefits. A tumour marker-based evaluation criteria, RecistTM, was used to investigate the potential for assessing targeted-therapy efficacy in lung cancer treatment. Methods: We retrospectively analysed patients with stage IIIA–IV NSCLC and driver gene mutations, whose baseline tumour marker levels exceeded the pre-treatment cut-off value three-fold and who received TKI-targeted therapy as a first-line treatment. We compared efficacy, progression-free survival (PFS), and overall survival (OS) between RecistTM and RECIST. Findings: The median PFS and OS differed significantly among treatment-response subgroups based on RecistTM but not RECIST. The predicted 1-, 2-, and 3-year disease-progression risk, according to area under the receiver operating characteristic curve, as well as the 1-, 3-, and 5-year mortality risk, differed significantly between RecistTM and RECIST. The median PFS and OS of tmCR according to RecistTM, was significantly longer than (CR+PR) according to RECIST. Imaging analysis revealed that the ΔPFS was 11.27 and 6.17 months in the intervention and non-intervention groups, respectively, suggesting that earlier intervention could extend patients' PFS. Interpretation: RecistTM can assess targeted-therapy efficacy in patients with advanced NSCLC and driver gene mutations, along with tumour marker abnormalities. RecistTM surpasses RECIST in predicting short- and long-term patient benefits, and allows the early identification of patients resistant to targeted drugs, enabling prompt intervention and extending the imaging-demonstrated time to progression.

Among cancer-related disorders, lung carcinoma is one of the leading causes of mortality. Anaplastic lymphoma kinase (ALK) belongs to tyrosine kinase receptor family and exhibits similar characteristics to insulin type receptors. The treatment of advanced non-small cell lung cancer (NSCLC) associates with ALK gene rearrangement has significantly improved since the approval of Crizotinib in 2011 as the first generation ALK inhibitor. In continuation, the second-generation drugs like ceritinib, alectinib, and brigatinib were developed to address and counteract resistance that was associated with the first-generation agents. However, resistance can develop over time, necessitating ongoing research to enhance their effectiveness. Therefore, the third-generation drug lorlatinib, which has demonstrated broad-spectrum potency against the majority of known resistance mutations and better lipophilicity, has been developed. According to current reports, the USFDA has approved five ALK-TKIs crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib for ALK-associated lung cancer. Currently, several clinical trials are underway in search of better ALK inhibitors. Trials such as TPX-0131 and NVL-655 are considered fourth-generation ALK inhibitors for the treatment of patients with advanced ALK-positive or metastatic NSCLC. This review aims to provide specifics information on research works involving various ALK tyrosine kinase inhibitors, clinical studies, and the development of ALK TKIs. Additionally, we suggest potential future strategies involving sequential therapy and combination techniques for managing non-small cell carcinoma.

The alcohol extraction of P. sibiricum has exhibited significant inhibitory effects on the production of free radicals and the proliferation of non-small-cell lung carcinoma (NSCLC) A549 cells. Despite the diverse components found in alcohol extraction of P. sibiricum and its multiple targets, the active components and associated targets remain largely unidentified. Hence, there is a need for additional investigation into the pharmacodynamic elements and mechanisms of action. This study aimed to analyze and identify the components responsible for the anti-tumor activity of alcohol extraction from P. sibiricum using UPLC-Q-TOF-MS/MS for the first time. Subsequently, the targets of the active components were predicted using the SwissTargetPrediction database, whereas the targets for NSCLC were sourced from the Online Mendelian Inheritance in Man database (OMIM) and the GeneCards database. Next, the targets of chemical composition were integrated with disease targets via Venny online. GO and KEGG pathway enrichment analyses were performed utilizing DAVID. Subsequently, a network analysis of “components-targets-pathways” was established using Cytoscape 3.8.2 and assessed with the “network analyzer” plug-in. Molecular docking was conducted utilizing Autodock 1.5.6. The study aimed to examine the anti-proliferative impacts and underlying mechanisms of alcohol extraction from P. sibiricum on NSCLC through in vivo and in vitro investigations utilizing an animal model of transplanted tumor, CCK8 assay, cell scratch test, RT-qPCR, and western blotting. The study unveiled that 17 active components extracted from P. sibiricum alcohol demonstrated anti-non-small cell lung cancer (NSCLC) effects through the modulation of 191 targets and various significant signaling pathways. These pathways include Endocrine resistance, PI3K/AKT, Chemical carcinogenesis-receptor activation, Proteoglycans in cancer, EGFR tyrosine kinase inhibitor resistance, AMPK signaling pathway, and other related signaling pathways. Network analysis and molecular docking results indicated that specific compounds such as (25S)-26-O-(β-d-glucopyranosyl)-furost-5-en3β,22α,26-triol3-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranosyl-(1→4)-β-d-glucopyranoside, Timosaponin H1, Deapi-platycodin D3, (3R)-5,7-dihydroxy-6,8-dimethyl-3-(4′-hydroxybenzyl)-chroman-4-one, Disporopsin, Funkioside F, Kingianoside E, Parisyunnanoside H, and Sibiricoside B primarily targeted 17 key proteins (BCL2, EGFR, ESR1, ESR2, GRB2, IGF1R, JUN, MAP2K1, MAPK14, MAPK8, MDM2, MMP9, mTOR, PIK3CA, RAF1, RPS6KB1, and SRC) collectively. In conclusion, the alcohol extraction of P. sibiricum demonstrated inhibitory effects on cell proliferation, induction of apoptosis, and inhibition of metastasis through various pathways.

Summary: Background: Lung cancer diagnostic guidelines advocate for invasive mediastinal nodal staging (IMNS), but the survival benefits of this approach in patients with non-small cell lung cancer (NSCLC) without radiologic evidence of lymph node metastasis (rN0) remain uncertain. We aimed to investigate the impact of IMNS in patients with rN0 NSCLC by comparing the long-term survival between patients who underwent IMNS and those who did not (non-IMNS). Methods: In this retrospective cohort study, we included patients with NSCLC but without radiologic evidence of lymph node metastasis from the Registry for Thoracic Cancer Surgery and the clinical data warehouse at the Samsung Medical Centre, Republic of Korea between January 2, 2008 and December 31, 2016. We compared the 5-year overall survival (OS) rate as the primary outcome after propensity score matching between the IMNS and non-IMNS groups. The age, sex, performance statue, tumor size, centrality, solidity, lung function, FDG uptake in PET-CT, and histological examination of the tumor before surgery were matched. Findings: A total of 4545 patients (887 in the IMNS group and 3658 in the non-IMNS group) who received curative treatment for NSCLC were included in this study. By the mediastinal node dissection, the overall incidence of unforeseen mediastinal node metastasis (N2) was 7.2% (317/4378 patients). Despite the IMNS, 67% of pathological N2 was missed (61/91 patients with unforeseen N2). Based on propensity score matching, 866 patients each for the IMNS and non-IMNS groups were assigned. There was no significant difference in 5-year OS and recurrence-free survival (RFS) between two groups: 5-year OS was 73.9% (95% confidence interval, CI: 71%–77%) for IMNS and 71.7% (95% CI: 68.6%–74.9%; p = 0.23), for non-IMNS (hazard ratio, HR 0.90, 95% CI: 0.77–1.07), while 5-year RFS was 64.7% (95% CI: 61.5%–68.2%) and 67.5% (95% CI: 64.3%–70.9%; p = 0.35 (HR 1.08, 95% CI: 0.92–1.27), respectively. Moreover, the timing and locations of recurrence were similar in both groups. Interpretation: IMNS might not be required before surgery for patients with NSCLC without LN suspicious of metastasis. Further randomised trials are required to validate the findings of the present study. Funding: None.

Background: Somatic mutations in epidermal growth factor receptor (EGFR) genes, such as G719X and S768I, and tyrosine kinase inhibitors (TKIs) have been confirmed to be promising for developing new targeted therapies against advanced non-small-cell lung cancer (NSCLC). The G719X and S768I mutations are uncommon and often occur in the form of compound mutations. However, the efficacy of furmonertinib in patients with these uncommon compound mutations has not yet been elucidated. Case presentation: In this study, the G719X/S768I compound mutations were detected in a critically ill NSCLC patient. This patient received furmonertinib for 14 months and successfully responded to the treatment. The present case report highlights the ideal clinical response, with ongoing follow-up. Conclusion: We report the successful treatment of a critically ill NSCLC patient carrying rare compound EGFR G719X and S768I mutations using furmonertinib. To the best of our knowledge, this is the first reported case of a successful furmonertinib treatment of compound EGFR G719X and S768I mutations. Furmonertinib, a third-generation EGFR-TKI, may be effective in controlling the EGFR G719X and S768I compound mutations in NSCLC.

Histological transformation to small-cell lung cancer (SCLC) is a well-known mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and almost all patients receive EGFR-TKIs at the time of transformation. We herein report three cases of EGFR-mutated lung adenocarcinoma that transformed into SCLC long after the cessation of EGFR-TKIs. Rapid tumor progression and elevated SCLC marker levels were observed at the time of transformation. Our case highlights the importance of considering SCLC transformation throughout the clinical course. Careful observation of the tumor behavior and SCLC markers should be performed to avoid diagnostic delays.

Background: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been suggested to play roles in various diseases, yet there is little data on their changes in patients with non-small-cell lung cancer (NSCLC). A simple LC-MS/MS method for EPA and DHA determination is critical to exploring EPA and DHA level changes in NSCLC patients. Methods: 25 µL of serum was mixed with 25 µL of internal standard working solution, and then 450 µL of acetonitrile for protein precipitation. After vortex and centrifugation, the supernatant was directly used for LC-MS/MS analysis. The method was well validated with linearity, precision, recovery, and matrix effect. The concentrations of EPA and DHA in serum samples from 211 NSCLC patients and 227 healthy controls were determined by this LC-MS/MS method. Results: Good separation and reliable quantification of EPA and DHA in serum samples were achieved by our method. Compared with healthy controls, serum EPA and DHA were significantly reduced in both adenocarcinoma and squamous cell carcinoma patients. The concentrations of EPA and DHA showed a progressive decrease in healthy controls, early- and advanced-stage NSCLC patients. Conclusions: This study identified significant reductions in serum EPA and DHA in NSCLC patients through the development of an LC-MS/MS method.

Summary: Background: Currently, the role of EGFR-TKIs as adjuvant therapy for stage I, especially IA NSCLC, after surgical resection remains unclear. We aimed to compare the effect of adjuvant EGFR-TKIs with observation in such patients by incorporating an established 14-gene molecular assay for risk stratification. Methods: This retrospective cohort study was conducted at the First Affiliated Hospital of Guangzhou Medical University (Study ID: ChNCRCRD-2022-GZ01). From March 2013 to February 2019, completely resected stage I NSCLC (8th TNM staging) patients with sensitive EGFR mutation were included. Patients with eligible samples for molecular risk stratification were subjected to the 14-gene prognostic assay. Inverse probability of treatment weighting (IPTW) was employed to minimize imbalances in baseline characteristics. Findings: A total of 227 stage I NSCLC patients were enrolled, with 55 in EGFR-TKI group and 172 in the observation group. The median duration of follow-up was 78.4 months. After IPTW, the 5-year DFS (HR = 0.30, 95% CI, 0.14–0.67; P = 0.003) and OS (HR = 0.26, 95% CI, 0.07–0.96; P = 0.044) of the EGFR-TKI group were significantly better than the observation group. For subgroup analyses, adjuvant EGFR-TKIs were associated with favorable 5-year DFS rates in both IA (100.0% vs. 84.5%; P = 0.007), and IB group (98.8% vs. 75.3%; P = 0.008). The 14-gene assay was performed in 180 patients. Among intermediate-high-risk patients, EGFR-TKIs were associated with a significant improvement in 5-year DFS rates compared to observation (96.0% vs. 70.5%; P = 0.012), while no difference was found in low-risk patients (100.0% vs. 94.9%; P = 0.360). Interpretation: Our study suggested that adjuvant EGFR-TKI might improve DFS and OS of stage IA and IB EGFR-mutated NSCLC, and the 14-gene molecular assay could help patients that would benefit the most from treatment. Funding: This work was supported by China National Science Foundation (82022048, 82373121).

Background: Our study aimed to build a risk stratification system predicting the progression-free survival (PFS) to classify patients into diverse prognostic subgroups for advanced non-small-cell lung cancer patients treated with PD-(L)1 inhibitor. Methods: 404 patients from our center were enrolled in this study and 70% patients (n = 282) were randomly assigned into the training cohort and other 30% patients (n = 122) into the validation cohort. A testing cohort contained 81 patients from other centers were used to assess the generalizability of model. Cox regression analyses were used to identify the most significant clinical parameters. The model's performance was assessed by using concordance index (C-index), calibration curves, Decision Curve Analyses (DCAs), net reclassification improvement (NRI), integrated discrimination improvement (IDI) analyses, and survival curve. Results: Five clinical parameters were identified as the most significant predictors by using cox regression. We then integrated them into a Nomogram to Evaluate the relative PFS of ICIs Treatment (NEPIT). The C-index of NEPIT in the training cohort, the validation cohort and testing cohort was 0.789 (95%CI: 0.750–0.828), 0.745 (95%CI: 0.706–0.784), and 0.766 (95%CI: 0.744–0.788), respectively. The calibration curves presented a good congruence between the predictions and actual observations. The Decision Curve Analyses (DCAs) reflected positive net benefits can be obtained for NEPIT. The results from NRI and IDI analyses showed that the NEPIT could improve predictive power of TPS. In addition, the further constructed risk stratification system could effectively categorize patients into different risk subgroups. Conclusion: The tools developed in this study would have value in guiding the optimal patient selection for precision care.

This work describes an eco-friendly approach for the green formulation of Ag nanoparticles by Allium ampeloprasum extract, without using any toxic reducing and capping agents. The morphology, structure, and physicochemical properties were characterized by several analytical techniques such as fourier transformed infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), and Ultraviolet–visible spectroscopy (UV–Vis). The nanoparticles were explored biologically in the anticancer assays. Exposure of the nanoparticles samples to non-small-cell lung cancer cells resulted in cell death, which was mostly due to necrosis but slightly due to late apoptosis. The viability of malignant cell lines reduced dose-dependently in the presence of nanoparticles. The IC50 of nanoparticles were 301, 266, 255, and 250 µg/mL against EKVX, HOP-62, A549 and NCI-H460 cancer cell lines, respectively. The green-synthesized nanoparticles induced cell death, suggesting anticancer prospects that may offer new insight into the development of an anticancer nanomedicine.

Background: The objective of our study was to report predictive factors of local control (LC) and radionecrosis (RN) of brain metastases (BM) of non-small cell lung carcinoma (NSCLC) treated by multifractionated stereotactic radiotherapy (MF-SRT) according to French recommendations. Method: From 2012 to 2020, 87 patients with 101 BM were retrospectively included. The median age was 63 years (37–85). GTV was defined using contrast-enhanced T1w MRI and was isotropically extended by 2 mm to form PTV. Mean maximum BM diameter was 24.5 mm (10–46). Patients were treated with dynamic arctherapy from May 2012 to February 2016 and then with VMAT. The total prescribed dose was 23.1 Gy prescribed to the encompassing 70% isodose, in 3 fractions. Results: LC rates at 6 months, 1 year and 2 years was 95.7%, 90.7% and 87.9% respectively. In multivariate analysis, high GTV Dmin (HR = 0.822, p = 0.012) was in favor of better LC whereas a large maximum diameter was predictive of poor LC (HR = 1.124, p = 0.02). GTV Dmin of 27.4 Gy was identified as a discriminant threshold of LC. In case of GTV Dmin ≥ 27.4 Gy, LC at 1 year was 95.3% versus 75.1% with GTV Dmin

Purpose: Non-small-cell lung cancer (NSCLC) is a major public health concern with a high incidence worldwide. Coal-derived fulvic acids (FAs) contain functional groups in their chemical structures. Overexpression of cyclooxygenases-2 (COX-2), prostaglandin E2 (PGE2), and the PGE2 receptor EP4 subtype (EP4) can have a potential link with the increased tumor incidence and promoted tumor growth and metastasis in NSCLC. This study aimed to assess the biological roles of coal-derived FAs in the growth and development of NSCLC and to elucidate the underlying molecular mechanisms. Methods: A web-based tool for predicting small-molecule pharmacokinetics (pkCSM) was used to analyze the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of FAs. Molecular docking and dynamic simulations were performed to analyze the binding affinities of COX-2 and EP4 to FA. An acute toxicity test and an antitumor study were used to analyze the toxicity and anti-NSCLC effects of FAs. Thirty NSCLC-bearing nude mice were randomly divided into five groups (six mice per group): vehicle control, positive control with 20 mg/kg body weight (BW) 5-fluorouracil, and three treatments with 25, 50, and 100 mg/kg BW FAs. The BW and tumor volume were recorded, and the COX-2, PGE2, and EP4 protein expression were measured and analyzed. Results: Using the predictive pkCSM algorithm, we found that FA did not cause developmental toxicity. Molecular simulations revealed that COX-2 and EP4 expression was inhibited by FA. An acute toxicity test conformed that the maximum tolerated FAs dose was >3.0 g/kg BW. The animal study demonstrated that FA treatment significantly downregulated the expression of COX-2, PGE2, and EP4 in NSCLC-bearing mice compared to that in vehicle control mice (p

Objective: We aimed to utilize a nationally representative database to study the effect of Medicaid expansion on the receipt of adjuvant chemotherapy in eligible patients., Materials and Methods: Retrospective review of the National Cancer Database (NCDB) was performed between 2006 and 2019. Patients with clinical T1-T3, N1, and M0 were included. Patients with nodal disease or tumors > 4 cm were eligible for adjuvant therapy. Demographic and clinical information were collected. A difference-in-difference analysis was performed to compare changes in the rate of adjuvant chemotherapy., Results: Total 9954 eligible patients were treated in states that expanded Medicaid coverage in January 2014 or later, with 4809 patients treated in the pre-expansion years (2012-2013) and 5145 patients treated in the postexpansion years (2017-2018). Following Medicaid expansion, eligible patients were more likely to receive adjuvant therapy (70.2% vs. 62.3%; P < .001). Compared with the pre-expansion period, patients who received adjuvant therapy were more likely to use Medicaid insurance postexpansion (7.8% vs. 5%, P < .001). Among patients using Medicaid coverage only, a greater percentage started adjuvant therapy within 8 weeks of resection following Medicaid expansion (46.6% vs. 38.3%, P = .048). The observed difference-in-difference in the change in adjuvant therapy rate from the pre-expansion period to the postexpansion period between expansion and nonexpansion states was 1.25% (95% Bootstrap CI -0.36% to -3.18%). There was a modest survival benefit in expansion states postexpansion., Conclusion: Medicaid expansion appears to be associated with increased access to care, as shown by the increased receipt of adjuvant systemic therapy in eligible patients., Competing Interests: Disclosure OTO received research funding from the Bristol Myers Squibb Foundation, and was paid to his institution. Additionally, OTO has received speaker honoraria from Intuitive Surgical and Johnson & Johnson. The remaining authors have no conflicts of interests., (Published by Elsevier Inc.)

Non-small-cell lung cancer (NSCLC) is one of the most malignant tumors and the leading cause of death from cancer worldwide and is increasing at a massive rate every year. Most NSCLC patients are diagnosed at advanced stages, which is associated with a poor prognosis and a very low 5-year survival rate. Therefore, the purpose of this study is to investigate molecular markers for early diagnosis, prognosis and therapy of NSCLC through the integration of bioinformatics and statistical methods. A total of 93 overlapping differentially expressed genes (oDEGs) were identified between NSCLC and normal samples through Linear Models for Microarray (LIMMA) and Significance Analysis of Microarrays (SAM) methods. Six top-degree oDEGs (CCNA2, CDC6, AURKA, CCNB1, MKI67, and PRC1) were identified as key genes (KGs) through the protein-protein interaction (PPI) network. The predictive accuracy analysis of the identified KGs revealed an accuracy of 96.92 %, with a sensitivity of 91.73 % and a specificity of 98.15 %. KGs associated with 3 molecular functions (MFs), 5 cellular components (CCs), 3 biological processes (BPs), and 4 pathways were identified through FunRich software. Analysis of expression levels using the UALCAN database revealed that KGs are significantly associated with potential early diagnostic biomarkers. Survival analysis using the GEPIA database demonstrated that the KGs possessed strong prognostic power for NSCLC. Finally, seven repurposed candidate drugs ENTRECTINIB, SORAFENIB, CHEMBL1765740, TOZASERTIB, NERVIANO, AZD-1152-HQPA, and SELICICLIB were proposed through molecular docking analysis. In conclusion, the findings of this study have the potential to significantly impact the early diagnosis, prognosis, and treatment of NSCLC., Competing Interests: Declaration of competing interest We can confirm that the work entitled “Unraveling the molecular landscape of non-small cell lung cancer: Integrating bioinformatics and statistical approaches to identify biomarkers and drug repurposing” is an original work and neither this nor any similar manuscript, in whole or in part, is under consideration, in a press, published, or reported elsewhere., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Approximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUAD Muc ), which is associated with a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUAD Muc by comparing it with LUAD without mucinous histology (LUAD non-muc ) and determine the relative benefit of current treatments., Patients and Methods: Patients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUAD Muc or LUAD non-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUAD Muc and LUAD non-muc ., Results: Of 4082 patients with LUAD, 9.9% had LUAD Muc . Compared with LUAD non-muc , patients with LUAD Muc had a lighter smoking history (median 15 versus 20 pack-years; P = 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, P < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, P < 0.0001). Mutations in KRAS, NKX2-1 [thyroid transcription factor 1 (TTF-1)], STK11, SMARCA4, GNAS, and ALK rearrangements were enriched in LUAD Muc , while TP53, EGFR, BRAF, and MET mutations were enriched in LUAD non-muc . At stage IV diagnosis, LUAD Muc was more likely to have contralateral lung metastasis (55.2% versus 36.9%, P < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, P < 0.0001). Compared with LUAD non-muc , LUAD Muc cases showed lower intratumor CD8 + , PD-1 + , CD8 + PD-1 + , and FOXP3 + cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUAD non-muc (n = 1511), LUAD Muc (n = 112) had a lower objective response rate (ORR 8.4% versus 25.9%, P < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, P < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, P < 0.0001). Similarly, patients with LUAD Muc had worse outcomes to chemoimmunotherapy. LUAD Muc (n = 18) and LUAD non-muc (n = 150) had similar ORR (16.7% versus 34.9%, P = 0.12) and mPFS (4.6 versus 5.6 months, P = 0.17) to treatment with KRAS G12C inhibitors, but LUAD Muc had shorter mOS (6.8 versus 10.8 months, P = 0.018)., Conclusions: LUAD Muc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Here ginsenoside Rg1 was used to synthesise Rg1 carbon nanodots via a one-step hydrothermal method. The surface of the Rg1 carbon nanodots is rich in hydrophilic functional groups with good water solubility and biocompatibility. The Rg1 carbon nanodots exhibited a high inhibitory effect on the proliferation, migration, and proapoptotic ability of non-small cell lung cancer A549 cells. The changes in the levels of ROS, Ca 2+ , and MMP in A549 cells after the administration of Rg1 carbon nanodots were evaluated and further correlated with relevant proteins in the caspase apoptotic pathway. Proteomic screening revealed that the Rg1 carbon nanodots could regulate A549 cell apoptosis by activating the expression of MAPK pathway-related proteins. In the in vivo experiment, the therapeutic efficacy of the Rg1 carbon nanodots in inhibiting tumour growth was much higher than that of commonly used chemotherapy drugs, with negligible toxicity and side effects. Immunohistochemical staining showed that the expression of caspase- and MAPK pathway-related proteins in mouse tumour tissues was consistent with that at the cellular level. The results suggest that Rg1 carbon nanodots can promote tumour apoptosis and represent a potential therapeutic agent for human non-small-cell lung cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: To compare the long-term survival between robotic and video-assisted thoracic surgery (VATS) lobectomy for stage Ⅰ non-small-cell lung cancer (NSCLC) with radiologic solid tumors., Methods: Clinical stage Ⅰ NSCLC patients with radiologic solid tumors who underwent robotic-assisted thoracic surgery (RATS) or VATS lobectomy between 2015 and 2017 were retrospectively reviewed. A propensity score matching analysis was performed to balance the baseline characteristics. The primary end points were overall survival (OS) and recurrence-free survival (RFS)., Results: A total of 518 patients (225 RATS and 293 VATS) were included. After propensity score matching, there were 170 cases in each group. Patients undergoing RATS had shorter operative time than VATS (98.12 min vs. 112.26 min; P < 0.001). The RATS approach resulted in a higher number of resected lymph nodes (LNs) (11.75 vs. 9.77; P < 0.001). The postoperative complication rates were comparable (7.6% vs. 10.0%, P = .566). The rates of 5-year OS and RFS for the RATS and VATS were 92% versus 89% (P = .62) and 82% vs. 86% (P = .70), respectively. Multivariate analysis revealed that the number of resected LNs was significantly associated with overall survival (OR = 1.94 [95% confidence interval [CI]: 1.07-3.51], P = .029)., Conclusion: The long-term survival outcomes of RATS and VATS are similar for c-stage Ⅰ NSCLC with radiologic solid tumors. The use of robotics is associated with more lymph node dissection and shorter operative time. We suggested that the number of examined lymph nodes rather than surgical approaches was associated with overall survival., Competing Interests: Disclosure The authors have no conflicts of interest to declar., (Copyright © 2024. Published by Elsevier Inc.)

Objective: We aimed to discuss the underlying oncological issues in staging of mediastinal lymph node metastasis in patients with left lung cancer who underwent extended radical lymphadenectomy (ERL). Methods: This multi-institutional retrospective study analyzed 116 patients with left non-small-cell lung cancer who underwent bilateral paratracheal lymph node dissection (ERL) via median sternotomy. The clinicopathological records of patients with mediastinal lymph node metastasis were examined for prognostic factors, including age, sex, histology, tumor size, cN number, preoperative data, metastatic stations (number and distribution), pT, and adjuvant chemotherapy. Results: Mediastinal lymph node metastases were found in 43 patients, and right paratracheal lymph node metastases (pN3) were found in 13 patients. The 5-year overall survival rate was 25.2% in patients with pN3 tumors (n = 13) and 23.1% in patients with pN2 tumors (n = 30). The prognosis did not differ between patients with pN3 and pN2. Univariate analyses showed that histology, cN, and adjuvant chemotherapy were significant prognostic factors in patients with mediastinal lymph node metastasis. In these 43 patients, cN and adjuvant chemotherapy were significant independent prognostic factors in multivariate analysis. Conclusions: The prognostic factors for left lung cancer with mediastinal lymph node metastasis were cN status and adjuvant chemotherapy, and not pN status (pN2 or pN3). We hope that the study results, which suggest that there may be no difference in prognosis between pN2 and pN3, would broaden the discussion of oncological issues in the staging of mediastinal lymph node metastasis of left lung cancer.

A man with non-small-cell lung cancer who was negative for anti-nuclear antibodies was admitted for dyspnea after immune checkpoint inhibitor (ICI) administration. Computed tomography (CT) showed complexed radiologic features, including subpleural and basal predominant reticular shadow with cystic structures and peribronchovascular consolidation. Although we treated him with high-dose steroid under a diagnosis of ICI-related pneumonitis, he developed acute exacerbation of pneumonitis with progressive fibrosis and volume loss. A re-evaluation identified anti-aminoacyl-tRNA synthetase antibody in the serum collected before ICI administration. This case highlights the importance of re-evaluating pre-existing autoimmune disorders in patients who develop ICI-related pneumonitis with atypical radiologic features.

Introduction: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. Methods: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Results: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7–87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%–95%) and mean tumor mutational burden was 7.06 (range: 0–18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767–771, 83.1%) and the far loop (codons 771–775, 13%) and only in 3.9% within the C helix (codons 761–766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03). Conclusions: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.

Immune checkpoint inhibitors became the treatment of choice, in monotherapy or in association with platinum-based doublet chemotherapy, in first-line therapy for advanced-stage non-small-cell lung cancer without oncogenic driver. Nevertheless, it can be associated with diverse immune-related adverse events; several immune-related adverse events can also follow each other involving multiple organ systems, leading to immune checkpoint inhibitors discontinuation and immunosuppressive therapy that could compromise the prognosis of patients, with the exception of rare situations such as this clinical case.This case report illustrates a succession of immune-related adverse events including a rare and severe pembrolizumab-induced immune-related encephalitis in a patient with metastatic lung adeno-squamous carcinoma in whom we could observe a long-term and complete remission despite discontinuation of treatment and high-dose corticosteroids.In metastatic non-small-cell lung cancer, a disease with a poor initial prognosis, some patients can benefit from immune checkpoint inhibitors and can even now present a long-term and complete remission and this despite severe and rare immune-related adverse events, high-dose corticosteroids and an early discontinuation of treatment.

Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide. In recent years, the discovery of actionable molecular alterations has changed the treatment paradigm of the disease. Tissue biopsies have been the gold standard for the identification of targetable alterations but present several limitations, calling for alternatives to detect driver and acquired resistance alterations. Liquid biopsies reveal great potential in this setting and also in the evaluation and monitoring of treatment response. However, several challenges currently hamper its widespread adoption in clinical practice. This perspective article evaluates the potential and challenges associated with liquid biopsy testing, considering a Portuguese expert panel dedicated to thoracic oncology point of view, and providing practical insights for its implementation based on the experience and applicability in the Portuguese context.

Summary: Background: Long-term changes in lung cancer (LC) patients are difficult to evaluate. We report results from the French KBP-2020 real-life cohort. Methods: KBP-2020 was a prospective cohort that included all patients diagnosed with LC in 2020, in nonacademic public hospital in France. Patient and tumour characteristics were described and compared with similarly designed cohorts in 2000 and 2010. Findings: In 2020, 82 centers included 8,999 patients diagnosed with LC. The proportion of women increased: 34·6% (3114/8999) compared to, 24·3% (1711/7051) and 16·0% (904/5667) in 2010 and 2000 (p

Introduction: We report brigatinib long-term efficacy and safety from phase 1/2 and phase 2 (ALTA) trials in ALK–rearrangement positive (ALK+) NSCLC. Methods: The phase 1/2 study evaluated brigatinib 30 to 300 mg/d in patients with advanced malignancies. ALTA randomized patients with crizotinib-refractory ALK+ NSCLC to brigatinib 90 mg once daily (arm A) or 180 mg once daily (7-d lead-in at 90 mg; arm B). Results: In the phase 1/2 study, 79 of 137 brigatinib-treated patients had ALK+ NSCLC; 71 were crizotinib pretreated. ALTA randomized 222 patients (n = 112 in arm A; n = 110 in arm B). Median follow-up at phase 1/2 study end (≈5.6 y after last patient enrolled) was 27.7 months; at ALTA study end (≈4.4 y after last patient enrolled), 19.6 months (A) and 28.3 months (B). Among patients with ALK+ NSCLC in the phase 1/2 study, median investigator-assessed progression-free survival (PFS) was 14.5 months (95% confidence interval [CI]: 10.8–21.2); median overall survival was 47.6 months (28.6–not reached). In ALTA, median investigator-assessed PFS was 9.2 months (7.4–11.1) in arm A and 15.6 months (11.1–18.5) in arm B; median independent review committee (IRC)-assessed PFS was 9.9 (7.4–12.8) and 16.7 (11.6–21.4) months, respectively; median overall survival was 25.9 (18.2–45.8) and 40.6 (32.5–not reached) months, respectively. Median intracranial PFS for patients with any brain metastases was 12.8 (9.2–18.4) months in arm A and 18.4 (12.6–23.9) months in arm B. No new safety signals were identified versus previous analyses. Conclusions: Brigatinib exhibited sustained long-term activity and PFS with manageable safety in patients with crizotinib-refractory ALK+ NSCLC.

Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Because current treatment regimens show limited success rates, alternative therapeutic approaches are needed. We recently showed that treatment-naïve, stage I/II primary NSCLC tumors contain a high percentage of tumor-reactive T cells, and that these tumor-reactive T cells can be effectively expanded and used for the generation of autologous tumor-infiltrating T cell (TIL) therapy. Whether these promising findings also hold true for metastatic lesions is unknown yet critical for translation into the clinic. Materials and methods: We studied the lymphocyte composition using flow cytometry from 27 metastatic NSCLC lesions obtained from different locations and from patients with different histories of treatment regimens. We determined the expansion capacity of TILs with the clinically approved protocol, and measured their capacity to produce the key pro-inflammatory cytokines interferon-γ, tumor necrosis factor and interleukin 2 and to express CD137 upon co-culture of expanded TILs with the autologous tumor digest. Results: The overall number and composition of lymphocyte infiltrates from the various metastatic lesions was by and large comparable to that of early-stage primary NSCLC tumors. We effectively expanded TILs from all metastatic NSCLC lesions to numbers that were compatible with TIL transfusion, irrespective of the location of the metastasis and of the previous treatment. Importantly, 16 of 21 (76%) tested TIL products displayed antitumoral activity, and several contained polyfunctional T cells. Conclusions: Metastatic NSCLC lesions constitute a viable source for the generation of tumor-reactive TIL products for therapeutic purposes irrespective of their location and the pre-treatment regimens.

Objective: Days spent at home (DASH) near the end of life is considered an important patient-centered goal and outcome because many patients want to stay at home toward the end of life. This study aimed to estimate the individual DASH near the end of life and identify its early predictors, including muscle mass and physical function, among elderly patients with advanced non-small-cell lung cancer (NSCLC). Methods: We conducted a post hoc analysis of the prospective observational study (UMIN000009768) that recruited patients aged ≥ 70 years who were scheduled to undergo first-line chemotherapy because of advanced NSCLC. We measured the muscle mass by bioelectrical impedance analysis at baseline. DASH was calculated as 30 days minus the number of days spent in hospitals, palliative care facilities, or nursing homes during the last 30 days of life. We performed linear regression analyses to evaluate the predictors of DASH. Results: Altogether, 16 women and 28 men with a median overall survival of 15.5 months (range: 2.9–58.9) were included. The median DASH in the last 30 days of life was 8 days (range: 0–30, interquartile range: 0–23). Men had longer DASH than women by 7.3 days. Patients who had good trunk muscle mass index and hand-grip strength had significantly longer DASH than those who did not (4.7 days per kg/m2 increase [P = 0.017] and 0.4 days per kg increase [P = 0.032], respectively). Conclusions: Most elderly patients with advanced NSCLC had a limited DASH near the end of life. The risk factors for reduced DASH were women, reduced muscle mass, and poor physical function at the time of diagnosis of advanced NSCLC. Our findings would encourage early discussions about end-of-life care for patients with advanced cancers with risk factors for short DASH at the time of diagnosis, and thus, improve the quality of end-of-life care.

More efficient drug delivery system and formulation with less adverse effects are needed for the clinical application of broad-spectrum antineoplastic agent doxorubicin (DOX). Here we obtained outer-membrane vesicles (OMVs), a nano-sized proteoliposomes naturally released by Gram-negative bacteria, from attenuated Klebsiella pneumonia and prepared doxorubicin-loaded O0MVs (DOX-OMV). Confocal microscopy and in vivo distribution study observed that DOX encapsulated in OMVs was efficiently transported into NSCLC A549 cells. DOX-OMV resulted in intensive cytotoxic effects and cell apoptosis in vitro as evident from MTT assay, Western blotting and flow cytometry due to the rapid cellular uptake of DOX. In A549 tumor-bearing BALB/c nude mice, DOX-OMV presented a substantial tumor growth inhibition with favorable tolerability and pharmacokinetic profile, and TUNEL assay and H&E staining displayed extensive apoptotic cells and necrosis in tumor tissues. More importantly, OMVs’ appropriate immunogenicity enabled the recruitment of macrophages in tumor microenvironment which might synergize with their cargo DOX in vivo. Our results suggest that OMVs can not only function as biological nanocarriers for chemotherapeutic agents but also elicit suitable immune responses, thus having a great potential for the tumor chemoimmunotherapy.

Our previous study indicated that intravenous vitamin C (IVC) treatment concurrent with modulated electrohyperthermia (mEHT) was safe and improved the quality of life (QoL) of non-small-cell lung cancer (NSCLC) patients. The aim of this trial was to further verify the efficacy of the above combination therapy in previously treated patients with refractory advanced (stage IIIb or IV) NSCLC. A total of 97 patients were randomized to receive IVC and mEHT plus best supportive care (BSC) (n = 49 in the active arm, receiving 1 g/kg * d IVC concurrently with mEHT, three times a week for 25 treatments in total) or BSC alone (n = 48 in the control arm). After a median follow-up of 24 months, progression-free survival (PFS) and overall survival (OS) were significantly prolonged by combination therapy compared to BSC alone (PFS: 3 months vs 1.85 months, P

Reliable neurotrophin kinase (NTRK) fusion assessment is of special relevance since durable responses to targeted therapies have been observed regardless tumor type, NTRK gene or fusion partner. The most prevalent NTRK fusion in solid tumors is the ETV6-NTRK3, although alternative NTRK3 translocations with new partners are increasingly described across a wide variety of tumor types.NTRK fusions occur at low frequencies in non-small-cell lung cancer and are less common than other gene rearrangements. Here we describe a novel TRIM24-NTRK3 fusion in a lung adenocarcinoma patient that was missed by immunohistochemistry and DNA-based NGS but detected using a commercial targeted RNA-based NGS panel. To the best of our knowledge, this fusion has never been previously reported in any cancer type and allowed eligibility of patient for treatment with a small molecule inhibitor. This case also remarks the role of NGS in reliable detection of challenging novel NTRK fusions.

Introduction: Randomized controlled trials have investigated different first-line treatments for patients with advanced EGFR-mutated NSCLC. Nevertheless, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with L858R mutation, remains unclear. Methods: We performed a systematic review and frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE, Ovid, EMBASE, Cochrane Library, trial registries, and other sources. We included randomized controlled trials comparing two or more treatments in the first-line setting for Asian patients with L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD 42022295897). Results: There were a total of 18 trials that involved 1852 Asian patients and 12 treatments, including the following: EGFR tyrosine kinase inhibitors (TKIs) (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucirumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with L858R mutation had no significant OS benefits from all these treatments. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib, and erlotinib plus bevacizumab were found to be consistent in yielding the best progression-free survival benefit (p scores = 93%, 79%, 77%, and 70%). Combination treatments caused more toxicity, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, resulting in the greatest incidence of grade greater than or equal to 3 adverse events. Conclusions: In Asian patients harboring L858R mutation, EGFR TKIs and combination treatments had no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with this common but less favorable mutation.

Introduction: EGFR mutations are key oncogenic drivers in lung adenocarcinoma (LUAD), predominantly affecting Asian, nonsmoking, and female populations. Although common mutations, such as exon 19 deletions and L858R, respond well to tyrosine kinase inhibitors (TKIs), uncommon EGFR mutations and compound variants exhibit variable treatment responses. This study aims to compare clinical characteristics and molecular profiles of patients with common, uncommon, and compound EGFR mutations, assessing their implications for therapy outcomes., Methods: We analyzed a multi-cohort genomic dataset of 19,163 patients with LUAD (5,212 with EGFR mutations), categorizing mutations into common, uncommon, and compound classes. Patient demographics, mutational signatures, and tumor microenvironment factors were assessed, with particular attention to smoking status and concomitant alterations in KRAS and TP53. Treatment outcomes were analyzed by time under treatment as a surrogate measure of TKI efficacy., Results: Uncommon EGFR mutations, comprising 8.9% of EGFR-altered cases, were significantly more frequent among smokers and associated with tobacco-related mutational signatures. Compared with common EGFR-mutant cases, tumors harboring uncommon EGFR mutations reported higher rates of EGFR amplifications, KRAS, and TP53 mutations. Uncommon mutations also exhibited higher tumor mutational burden and distinct transcriptional profiles linked to cell cycle activity. Median time on treatment with TKIs was notably shorter in patients with uncommon mutations (4.1 mo) than those with common and compound mutations (10.9 mo and 12.4 mo, respectively)., Conclusions: This study underscores the clinical and molecular heterogeneity of EGFR mutation classes in LUAD, highlighting the unique profile of uncommon mutations, particularly their association with smoking and co-mutations in KRAS and TP53. Comprehensive molecular testing, including next-generation sequencing, is crucial to identify these uncommon mutations and inform therapeutic decisions. Further investigation into the role of immunotherapy in patients with uncommon EGFR mutations is warranted given the tobacco-related molecular signatures and high tumor mutational burden associated with this subgroup., Competing Interests: Disclosure Dr. Parikh reports advisory board fees from Guardant Health and Jazz Pharmaceuticals. Dr. Le declares Stock and Other Ownership Interests: BlossomHill Therapeutics; Consulting or Advisory Role: AstraZeneca, Lilly, EMD Serono, Spectrum Pharmaceuticals, Daiichi Sankyo/Lilly, Novartis, Hengrui Therapeutics, Janssen Oncology, Blueprint Medicines, Sensei Biotherapeutics, AbbVie, ArriVent Biopharma, Regeneron, ABION, Boehringer Ingelheim, Bayer, Taiho Pharmaceutical, Systimmune; Research Funding: Lilly (Inst), Boehringer Ingelheim (Inst), ArriVent Biopharma (Inst), Teligene (Inst), Regeneron (Inst), Janssen (Inst), EMD Serono (Inst); Travel, Accommodations, Expenses: Spectrum Pharmaceuticals, EMD Serono. Dr. Addeo reports having consulting or advisory role for Bristol-Myers Squibb, AstraZeneca, Roche, Merck Sharp & Dohme, Pfizer, Eli Lilly, Astellas, Amgen, Novartis, and Merck; serving on the speaker bureau of Eli Lilly, AstraZeneca, and Amgen; and receiving grant from AstraZeneca. The other authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here., Patients and Methods: Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints., Results: Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo., Conclusions: Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions., Materials and Methods: Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action., Results: Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority., Conclusions: Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: The discovery of oncogenic mutations that drive the growth and progression of Non-small-cell lung cancer (NSCLC) led to the development of a range of molecular targeted therapies. Tyrosine kinase inhibitors (TKIs) improve the overall outcome of patients with oncogene addicted NSCLC, ensure a better compliance to treatment and few side effects compared to traditional chemotherapy. However, the treatment is still completely "drug-centric", in a population of patients who usually survive for a long time and desire to regain their quality of life. Despite an extensive literature on the importance of complementary treatments and lifestyle promotion, the guidelines on physical exercise are general and usually refer to the entire lung cancer pathology., Methods and Objectives: EXcellenT is an Italian monocentric randomized prospective study enrolling 40 patients diagnosed with oncogene-addicted advanced NSCLC in active treatment with TKIs. Patients will be randomized (1:1 ratio) to an 'interventional' or a 'control' group. In the interventional arm (arm A), participants will receive a 3-month multicomponent personalized physical activity prescription combining a supervised coaching program at the training center and an app-based physical activity schedule at patients home. In the control group (arm B) patients will receive a fitness professional-guided montly session that will result in an unsupervised home-based physical activity counselling. Prospective collection of blood metabolome and immune phenotypes will be performed to investigate the integration with genetic alterations that drive the patient's disease. The overall aim of the project is to evaluate if a tailored physical program may have a significant impact on quality of life and performances of this specific homogeneous subgroup of patients. The exploratory goal is to elucidate a potential link between metabolites, immune parameters and genetic deregulations and how this interplay may be influenced by physical exercise., Conclusion: EXcellent trial aims to propose a new approach to personalized medicine in the specific subgroup of oncogene-addicted NSCLC patients, where targeted therapy is integrated with an equally tailored physical activity program. The homogeneity of this cancer population will provide insights on the influence of exercise on metabolism and immunity during treatment with TKIs., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors., Patients and Methods: In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1., Results: As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n = 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed., Conclusions: AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

The TP53 mutation is one of the most common gene mutations in non-small cell lung cancer (NSCLC) and plays a significant role in the occurrence, development, and prognosis of both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Recent studies have also suggested the predictive value of TP53 mutations in the response to immunotherapy for NSCLC. It is known that intratumoral microbiota, tumor immune microenvironment (TIME) and histology are associated with the roles of TP53 mutation in NSCLC. However, the intrinsic associations among these three factors and their underlying interaction with TP53 mutation are not well understood. Additionally, the potential of predicting TP53 mutations using deep learning methods has not yet been fully evaluated. In this paper, we comprehensively evaluated the tissue microbiome, host gene expression characteristics, and histopathological slides of 992 NSCLC patients obtained from the cancer genome atlas (TCGA) and validated the findings using multi-omics data of 332 NSCLC patients from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Compared to LUSC, LUAD exhibited more substantial differences between patients with and without TP53 mutation in all three aspects. In LUAD, our results imply underlying links between the tissue microbiome and immune cell components in the TIME, and show that the abundance of immune cells is reflected in histology slides. Furthermore, we propose a novel multimodal deep learning model that focuses on histopathology images, which achieves an area under the curve (AUC) of 0.84 in LUAD. In summary, TP53 mutation of LUAD resulted more significant changes in intratumoral microbiota, TIME and histology than that of LUSC. And histopathology images can be used to predict TP53 mutation in LUAD with reasonable accuracy., Competing Interests: Declaration of Competing Interest LJ and JY are currently employed in Geneis Beijing Co. Ltd. KH was employed in Shanghai Changzheng Hospital.The other authors have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) NSCLC. Factors such as variant allele frequencies (VAFs), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting., Methods: Adults with advanced or metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated., Results: A total of 307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n = 280), brigatinib (n = 15), lorlatinib (n = 9), or ceritinib (n = 3); 150 patients (49%) had ALK-fusion VAF greater than or equal to 1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF less than 1% versus greater than or equal to 1% had a median TTD of 32.2 (95% confidence interval [CI]: 20.7-not estimable [NE]) versus 14.7 months (10.4-19.9; hazard ratio [HR] = 1.57 [95% CI: 1.09-2.26]; p = 0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-NE) in patients with versus without TP53mt detected (HR = 1.53 [1.07-2.19]; p = 0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR = 1.29 [0.83-2.01]; p = 0.2641). Patients with TP53mt and v3 had a median TTD of 7.4 months (95% CI: 4.2-31.1)., Conclusion: High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs., Competing Interests: Disclosure Dr. Parikh holds consulting/advisory roles with AstraZeneca, Guardant Health (to institution) and receives honoraria from OncLive, MJH Life Sciences, and DAVA Oncology (to institution) and research funding from Verastem Oncology (to institution). Dr. Dimou holds consulting/advisory roles with TP Therapeutics, Guardant Health, Anheart Therapeutics, and ChromaCode and received travel, accommodations, and expenses from Guardant Health, honoraria from Roche/Genentech, Intellisphere, and (rest to institution) Intellisphere, research funding from Merck, Guardant Health, and (rest to institution) Syntrix Biosystems, Novartis, Sorrento Therapeutics, and AnHeart Therapeutics, and has other relationship (to institution) with Rising Tide Foundation. Dr. Leventakos holds consulting/advisory roles with (all to institution) AstraZeneca, Boehringer Ingelheim, Targeted Oncology, OncLive, Takeda, Jazz Pharmaceuticals, Mirati Therapeutics, Janssen Oncology, Regeneron, MJH Life Sciences, and Amgen and received research funding from (all to institution) AstraZeneca and Mirati Therapeutics. Dr. Mansfield was supported by a Mark Foundation ASPIRE award, NCI grant R21 CA251923, R33 CA272271, Department of Defense W81XWH-22-1-0021 Concept Award, received honoraria from advisory boards for (all to institution) AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech, Janssen, and Sanofi), travel and honoraria from Shanghai Roche Pharmaceuticals, was a non-renumerated member of the Mesothelioma Applied Research Foundation and is member of the Friends of Patan Hospital Board of Directors. Dr. Wan holds employment with Takeda. Dr. Lin holds employment with Takeda. Dr. Vincent holds employment with Takeda. Dr. Elliott holds employment with Takeda. Dr. Bonta holds consulting roles with Roche and advisory board for Roche and Bayer. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to assess the results of primary stereotactic body radiotherapy (SBRT) for spinal bone metastases (SBM) originating from lung adenocarcinoma (ADC). We considered the revised Tokuhashi score (rTS), Spinal Instability Neoplastic Score (SINS), and genetic characteristics., Methods: We examined adult patients with lung ADC who underwent primary SBRT (using the CyberKnife System) for SBM between March 2012 and January 2023., Results: We analyzed data from 99 patients, covering 152 SBM across 194 vertebrae. The overall local control (LC) rate was 77.6% for SBM from lung ADC, with a LC rate of 90.7% at 1 year. The median period for local progression (LP) occurrence was recorded at 10.0 (3-52) months. Additionally, Asian patients demonstrated higher LC rates than White patients. Utilizing the rTS and SINS as predictive tools, we revealed that a poor survival prognosis and an unstable spinal structure were associated with increased rates of LP. Furthermore, the presence of osteolytic bone destructions and pain complaints were significantly correlated with the occurrence of LP. In the cohort of this study, 108 SBM underwent analysis to determine the expression levels of programmed cell death ligand 1 (PD-L1). Additionally, within this group, 60 showed mutations in the epidermal growth factor receptor (EGFR) alongside PD-L1 expression. Nevertheless, these genetic differences did not result in statistically significant differences in the LC rate., Conclusion: The one-year LC rate for primary SBRT targeting SBM from lung ADC stood at 90.7%, particularly with the use of the CyberKnife System. Patients achieving LC exhibited significantly longer survival times compared to those with LP., Competing Interests: Disclosure The authors affirm that the content of this article was developed without any commercial or financial relationships that could be considered as potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There is a dearth of studies on the efficacy and safety of the tyrosine kinase inhibitors osimertinib (OSI) and gefitinib (GEF) in treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), even in patients with poor performance status (PS)., Methods: We retrospectively reviewed and compared data of 113 patients with EGFR mutation-positive NSCLC with Eastern Cooperative Oncology Group PS 2-4 who were administered OSI 80 mg/day or GEF 250 mg/day from May 2016 to March 2022., Results: The GEF group (39 patients; median age: 74 years) included 20 patients with a PS of 2, 17 with a PS of 3, and 2 with a PS of 4. The OSI group (74 patients; median age: 76 years) included 48 patients with a PS of 2, 24 with a PS of 3, and 2 with a PS of 4. The overall response rates were 69% and 66% in the GEF and OSI groups, respectively. The disease control and PS improvement rates were 89% and 51% in both groups, respectively. The median progression-free survival in the GEF and OSI groups was 6.9 and 9.2 months, respectively (p = 0.15). The OSI group experienced better overall survival than the GEF group (median: 20.9 vs. 13.0 months, p = 0.0031). The incidence of pneumonitis was 10% and 11% in the GEF and OSI groups, respectively. One treatment-related death owing to pneumonitis occurred in the GEF group., Conclusions: OSI may be a useful treatment for untreated EGFR mutation-positive NSCLC with poor PS., Competing Interests: Declaration of competing interest Kazuhisa Nakashima has received personal fees from Taiho Pharmaceutical, Chugai Pharma, AstraZeneca, Eli Lilly Japan, Nippon Kayaku, and Bristol-Myers Squibb. Hiroaki Kodama has received personal fees from Chugai Pharma and Novartis Pharma. Haruyasu Murakami has received personal fees from Chugai Pharma, Daiichi Sankyo, AstraZeneca, Takeda, Amgen, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Pfizer, Novartis, Eli Lilly Japan, Taiho Pharmaceutical, Eisai, and Nippon Kayaku, grants from Chugai Pharma, AstraZeneca, Abbvie, Daiichi Sankyo, IQvia, Taiho Pharmaceutical and Bayer. Toshiaki Takahashi has received personal fees from AstraZeneca and MSD, and grants from Chugai Pharma, MSD, Eli Lilly Japan, Merck Biopharma Japan, AnHeart Therapeutics Inc., and Amgen. Kosuke Hamai has received personal fees from Boehringer Ingelheim, Eli Lilly Japan, AstraZeneca, Ono Pharmaceutical, Chugai Pharma, Merck & Co., and Taiho Pharmaceutical. Nobuhisa Ishikawa has received personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Eli Lilly Japan, Chugai Pharma, Taiho Pharmaceutical, MSD, Takeda, and Pfizer. Shoichi Kuyama has received personal fees from Chugai Pharma, Boehringer Ingelheim, Pfizer, MSD, Kyowa Kirin, Daiichi Sankyo, Novartis, Bristol-Myers Squibb, Eli Lilly Japan, AstraZeneca, Taiho Pharmaceutical, Hisamitsu Pharmaceutical, and Nippon Kayaku. Takeshi Isobe has received personal fees from MSD, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, Amgen, Taiho Pharmaceutical, Takeda. Chugai Pharma, Nippon Kayaku, Eli Lilly Japan, Boehringer Ingelheim, Pfizer, and Bristol-Myers Squibb Japan, and grants from Daiichi Sankyo, Novartis, Chugai Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, and Boehringer Ingelheim. Yukari Tsubata has received personal fees from MSD, AstraZeneca, Amgen, Daiichi Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharma, Eli Lilly Japan, Nippon Kayaku, Novartis, Pfizer, and Bristol-Myers Squibb, and grants from Pfizer and Ono Pharmaceutical. The other authors declare that they have no conflict of interest., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Lung carcinoma, particularly non-small-cell lung cancer (NSCLC), accounts for a significant portion of cancer-related deaths, with a fatality rate of approximately 19 %. Niclosamide (NIC), originally an anthelmintic drug, has attracted attention for its potential in disrupting cancer cells through various intracellular signaling pathways. However, its effectiveness is hampered by limited solubility, reducing its bioavailability. This study investigates the efficacy of NIC against lung cancer using inhalable hybrid nano-assemblies with chitosan-functionalized Poly (ε-caprolactone) (PCL) as a carrier for pulmonary delivery. The evaluation encompasses various aspects such as aerodynamic and physicochemical properties, drug release kinetics, cellular uptake, biocompatibility, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Increasing NIC dosage correlates with enhanced inhibition of cell proliferation, showing a dose-dependent profile (approximately 75 % inhibition efficiency at 20 μg/mL of NIC). Optimization of inhaled dosage and efficacy is conducted in a murine model of NNK-induced tumor-bearing lung cancer. Following inhalation, NIC-CS-PCL-NA demonstrates significant lung deposition, retention, and metabolic stability. Inhalable nano-assemblies promote autophagy flux and induce apoptotic cell death. Preclinical trials reveal substantial tumor regression with minimal adverse effects, underscoring the potential of inhalable NIC-based nano-formulation as a potent therapeutic approach for NSCLC, offering effective tumor targeting and killing capabilities., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Rahul Kumar Verma reports financial support was provided by Institute of Nano Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: First-line tislelizumab plus chemotherapy significantly improved progression-free survival (PFS) versus chemotherapy alone in advanced squamous non-small-cell lung cancer (sq-NSCLC) at the interim analysis of the phase III RATIONALE-307 trial. We present the final analysis of this trial., Patients and Methods: Patients with treatment-naive, stage IIIB/IV, sq-NSCLC were randomized (1 : 1: 1) to 21-day cycles of i.v.: tislelizumab plus paclitaxel and carboplatin (arm A); tislelizumab plus nab-paclitaxel and carboplatin (arm B); or paclitaxel and carboplatin (arm C). The primary endpoint was independent review committee-assessed PFS; overall survival was a secondary endpoint., Results: In total, 360 patients were randomized; 355 received treatment. At the final analysis (median study follow-up: 16.7 months), tislelizumab plus chemotherapy had a manageable safety profile, consistent with that at the interim analysis. Improvement in PFS was maintained for arms A and B versus C {hazard ratio (HR) 0.45 [95% confidence interval (CI) 0.33-0.62] and 0.43 (95% CI 0.31-0.60), respectively}. Overall survival HRs for arms A and B versus C were 0.68 (95% CI 0.46-1.01) and 0.75 (95% CI 0.50-1.12), respectively., Conclusions: The RATIONALE-307 final analysis demonstrated superior clinical benefit with addition of tislelizumab to chemotherapy, and a manageable safety profile, as first-line treatment of advanced sq-NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The purpose of this study was to report an updated, final analysis with longer follow-up for the open-label phase III RATIONALE-304 study of first-line tislelizumab plus chemotherapy versus chemotherapy alone for advanced nonsquamous non-small-cell lung cancer (nsq-NSCLC)., Materials and Methods: Patients with histologically confirmed stage IIIB/IV nsq-NSCLC were randomized (2 : 1) to 4-6 cycles of tislelizumab plus platinum-based chemotherapy and pemetrexed every 3 weeks, followed by maintenance tislelizumab and pemetrexed, or platinum-based chemotherapy and pemetrexed alone every 3 weeks followed by maintenance pemetrexed. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS IRC ). Overall survival (OS), safety, and tolerability were secondary endpoints., Results: Overall, 334 patients were randomized (tislelizumab plus chemotherapy: n = 223; chemotherapy: n = 111). At final analysis (median follow-up 16.1 months), safety/tolerability profiles in both arms were consistent with the interim analysis. Tislelizumab plus chemotherapy continued to demonstrate prolongation of PFS IRC versus chemotherapy alone {stratified hazard ratio (HR) 0.63 [95% confidence interval (CI) 0.47-0.86]; median PFS IRC 9.8 months (95% CI 8.9-11.7 months) versus 7.6 months (95% CI 5.6-8.0 months), respectively}. OS stratified HR for tislelizumab plus chemotherapy versus chemotherapy was 0.90 (95% CI 0.63-1.28), with median OS of 21.4 months (95% CI 17.7 months-not estimable) versus 21.3 months (95% CI 15.6 months-not estimable), respectively. At a subsequent ad hoc analysis (median follow-up 19.3 months), OS HR between arms was 0.85 (95% CI 0.63-1.14); when adjusted for crossover using the two-stage method, the OS HR was 0.68 (95% CI 0.48-0.96)., Conclusions: After longer follow-up, first-line tislelizumab plus chemotherapy continued to demonstrate a manageable safety profile and a favorable PFS benefit over chemotherapy alone in patients with advanced/metastatic nsq-NSCLC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)