Search Results (4,190)

Introduction: Pneumonitis represents one of the clinically significant adverse events observed in patients with non-small-cell lung cancer (NSCLC) who receive durvalumab as consolidation therapy after chemoradiotherapy (CRT). Although clinical factors such as radiation dose (e.g., V20) and interstitial lung abnormalities (ILAs) have been reported as risk predictors, accurate and objective prognostication remains difficult. This study aimed to develop a radiomics-based machine learning model to predict grade ≥ 2 pneumonitis. Methods: This retrospective study included patients with unresectable NSCLC who received CRT followed by durvalumab. Radiomic features, including first-order and texture and shape-based features with wavelet transformation were extracted from whole-lung regions on pre-durvalumab computed tomography (CT) images. Machine learning models, support vector machines, k-nearest neighbor, neural networks, and naïve Bayes classifiers were developed and evaluated using a testing cohort. Model performance was assessed using five-fold cross-validation. Conventional predictors, including V20 and ILAs, were also assessed using logistic regression and receiver operating characteristic analysis. Results: Among 123 patients, 44 (35.8%) developed grade ≥ 2 pneumonitis. The best-performing model, a support vector machine, achieved an AUC of 0.88 and accuracy of 0.81, the conventional model showed lower performance with an AUC of 0.71 and accuracy of 0.64. Conclusions: Radiomics-based machine learning demonstrated superior performance over clinical parameters in predicting pneumonitis. This approach may enable individualized risk stratification and support early intervention in patients with NSCLC. Full article

Background: Cancer-associated fibroblasts (CAFs) are key mediators of metastatic progression in non-small cell lung cancer (NSCLC). Fibroblast activation protein (FAP) serves as the hallmark of CAF activation. However, the upstream regulation of FAP remains elusive, limiting stroma-targeted therapy development. Methods: ⁶⁸Ga-FAP inhibitor (FAPI)-04 PET/CT imaging was performed on 61 NSCLC patients to evaluate the clinical significance of FAP. CAFs and normal fibroblasts (NFs) were isolated from patient tissues. Bioinformatic analysis and qRT-PCR were employed to screen and validate miRNAs. Functional assays (CCK-8, collagen contraction, wound healing, transwell co-culture) were utilized to investigate the role of miR-624-5p in regulating fibroblast activation and the effects on the metastatic potential of NSCLC cells. The targeting relationship between miR-624-5p and FAP was validated using FISH, dual-luciferase assay, and Western blotting. Results: ⁶⁸Ga-FAPI-04 uptake was higher in advanced NSCLC (p < 0.001) and correlated with tumor size, lymph node metastases, and distant metastases (p < 0.05). Isolated primary CAFs significantly enhanced the migration and invasion of A549 and PC9 cells compared to NFs (p < 0.001). We identified miR-624-5p as a significantly downregulated miRNA in CAFs (p < 0.001). Functionally, miR-624-5p overexpression inhibited CAF proliferation and collagen contraction (p < 0.01) and reduced the proliferation, migration, and invasion capabilities of A549 and PC9 cells (p < 0.001). Mechanistically, miR-624-5p bound to FAP mRNA and negatively regulated FAP expression (p < 0.001), thus suppressing CAF activation and tumor metastasis. Conclusions: Our findings establish miR-624-5p as a novel upstream regulator that suppresses FAP expression, consequently inhibiting CAF activation and its pro-metastatic function. Targeting the miR-624-5p/FAP axis represents a promising therapeutic strategy for NSCLC metastasis. Full article

Background: Non-small cell lung cancer (NSCLC), particularly in advanced stages, has poor prognosis. The main objective of the study is to evaluate real-world treatment outcomes in advanced NSCLC patients harboring an EGFR mutation and being treated with TKIs. Methods: The EGFR mutation status was ascertained by next-generation sequencing. The observational cohort study used prospectively maintained registry data. Patient data were collected at two high-volume institutions in Austria between November 2020 and February 2025. The prevalence of EGFR mutations was 11% (145 out of 1267 patients). Results: Among 53 patients (stage IIIB or higher) with an EGFR mutation, median overall survival (OS) and median progression-free survival (PFS) were 17.7 months (95% CI: 10.4–24.9) and 14.2 months (95% CI: 7.4–20.9), respectively. A total of 36 patients harbored common EGFR mutations (exon 19 deletion or L858R point mutation) and exhibited a significantly better OS than those with an uncommon EGFR genotype (p < 0.005). Patients with exon 19 deletion (n = 25) showed the longest mOS, followed by those with L858R mutation (32.5 vs. 17 months). In multivariable analysis, the EGFR common mutation subtype (HR = 3.71 95%CI: 1.23–11.2) was associated with better OS. Patients with common EGFR genotypes, especially exon 19 deletion obtained longer OS and PFS compared with those with uncommon mutations in exon 18–21. Conclusions: The results underscore the prognostic role of distinct EGFR genotypes and the urgency of determining the mutation status in non-small cell lung cancer patients to ensure the best treatment decision. The study also highlights the challenges regarding to EGFR uncommon mutations and the resulting need for further research to investigate alternative treatment options. Full article

The landscape of first-line treatment for metastatic non-small cell lung cancer (NSCLC) without actionable driver mutations is rapidly evolving, currently dominated by pembrolizumab-based regimens. This review discusses the unique molecular characteristics of cemiplimab, a newer anti-PD-1 antibody, and defines its optimal positioning against established standards. Cemiplimab is a fully human IgG4 monoclonal antibody distinguished by two key features: an engineered hinge-region mutation that prevents Fab-arm exchange, ensuring exceptional molecular stability which minimizes anti-drug antibody (ADA) risks associated with unstable molecules; and a unique interaction with PD-1 glycosylation sites, potentially enhancing binding efficacy. These structural advantages may be particularly relevant in histologies like squamous NSCLC, where accumulating somatic mutations drive high neoantigen loads and heightened immune responses, creating an environment historically prone to ADA formation. Based on data from the pivotal EMPOWER-Lung program, we highlight cemiplimab’s exceptional promise in specific populations. Firstly, in the EMPOWER-Lung 1 trial, cemiplimab monotherapy demonstrated extraordinary survival benefits in a pre-specified analysis of the distinct “ultra-high” PD-L1 expression subgroup (TPS ≥90%), potentially surpassing historical benchmarks. Secondly, cemiplimab displays consistent, robust efficacy in challenging-to-treat squamous histology, both as monotherapy for patients with high PD-L1 expression and in combination with chemotherapy for patients with PD-L1 < 50%. In conclusion, cemiplimab establishes a unique therapeutic niche for patients with squamous histology and ultra-high PD-L1 expression, likely driven by its distinct structural stability and reduced immunogenicity. Full article

Over the last decades, a significant improvement in cancer patient outcomes has occurred due to advances in cancer cell biology, systemic immunity, tumor-immune microenvironment (TIME) and precision cancer therapy. Despite this explosion of knowledge, its usefulness in clinical practice has been limited by the ability to translate multidimensional data into clinical care. Progress in artificial intelligence (AI) opens up a new frontier, with the promise of achieving synergistic and comprehensive integration. The classification of cancer biology and immunobiology into hallmarks of cancer by Hanahan and Weinberg provides a framework for organizing this information. This systematic classification has enabled the understanding of the interplay and cross-talk between its parts. Targeted cancer therapies and immunotherapies have achieved considerable success, yet their combinatorial potential is still being uncovered. Molecular diagnostics has worked hand-in-hand with precision oncology in deploying new therapies in a cancer-informed and patient-specific way. Harnessing the full power of the advances in these three fields with the aid of AI promises a transformation of molecular diagnostics. This review conceptualizes molecular diagnostics in the context of cancer hallmarks using nonsmall cell lung cancer (NSCLC) as a template, highlighting the potential of a new diagnostic science through the integrative power of AI. Full article

The mammalian lung operates under a biological paradox, requiring architectural fragility for gas exchange while maintaining robust regenerative plasticity to withstand injury. The Hippo signaling pathway has emerged as a central “rheostat” in orchestrating these opposing needs, yet the distinct roles of its downstream effectors remain underappreciated. This review synthesizes recent genetic and mechanobiological advances to propose a “Tale of Two Effectors” model, arguing for the functional non-redundancy of YAP and TAZ. We posit that YAP functions to drive airway progenitor expansion, mechanical force generation, and maladaptive remodeling. Conversely, TAZ—regulated uniquely via transcriptional mechanisms and mechanotransduction—acts as an obligate driver of alveolar differentiation and adaptive repair through an NKX2-1 feed-forward loop. Furthermore, we introduce the “See-Saw” model of tissue fitness, where mesenchymal niche collapse releases the mechanical brake on the epithelium, triggering the bronchiolization characteristic of pulmonary fibrosis. Finally, we extend this framework to malignancy, illustrating how Small Cell Lung Cancer (SCLC) subtypes mirror these developmental and regenerative states. This integrated framework offers new therapeutic distinct targets for modulating tissue fitness and resolving fibrosis. Full article

Background/Objectives: Non-small-cell lung cancer (NSCLC) is a common disease with a high mortality rate and is often treated with immunotherapies; however, prognostic markers are required to identify patients who are most likely to benefit from these treatments. Therefore, we designed this study to assess the prognostic significance of the C-PLAN index, which includes performance status (PS) and C-reactive protein (CRP). Methods: A total of 560 patients were included in this multicenter study. Patients had been diagnosed with NSCLC and had received nivolumab therapy. The C-PLAN index, defined in 2022, is a score derived from the combination of PS, CRP, lactate dehydrogenase (LDH), albumin, and neutrophil–lymphocyte ratio (NLR). Patients were classified into good-, moderate-, and poor-prognosis groups according to the C-PLAN score. Results: The median metastatic overall survival was 25 months in the group with a C-PLAN score < 2 and 6 months in the group with a C-PLAN score ≥ 2 (p < 0.001). The median metastatic progression-free survival was 11 months in the group with a C-PLAN score < 2 and 3 months in the group with a C-PLAN score ≥ 2. Conclusion: This is the first comprehensive study demonstrating that the C-PLAN index can be used for prognostic purposes in immunotherapy. This score, which can be easily, economically, and practically calculated in outpatient clinics, can predict patient prognosis and determine who should receive longer durations of immunotherapy. Full article

Objective: The aim of this study was to assess the association between the Lung Immune Prognostic Index (LIPI) measured at diagnosis and both event-free survival (EFS) and overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC). Methods: This retrospective cohort included patients diagnosed with stage III NSCLC between September 2022 and July 2024, all of whom had a minimum follow-up duration of six months. LIPI was calculated using the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase levels at diagnosis. Clinical, demographic, and treatment-related data were systematically collected. Survival outcomes were estimated using the Kaplan–Meier approach, while factors associated with prognosis were examined through Cox proportional hazards models. Results: The study population consisted of 68 patients, predominantly male (86.8%), with a mean age of 63.4 ± 8.7 years. According to the Lung Immune Prognostic Index classification, 29 patients (42.6%) were categorized as having a good score, 27 (39.7%) as intermediate, and 12 (17.6%) as poor. During a median follow-up of 15.4 months, a total of 40 progressions and 22 deaths occurred. Median EFS was 17.7, 9.4, and 5.8 months for good, intermediate, and poor LIPI groups, respectively (p < 0.001). Median OS was 25.7 months in the good LIPI group, was not reached in the intermediate group due to insufficient events, and was 6.7 months in the poor group (p < 0.001). In multivariate Cox analysis, poor LIPI was independently associated with inferior survival (EFS: HR = 2.87, 95% CI: 1.85–4.46, p < 0.001; OS: HR = 2.59, 95% CI: 1.40–4.78, p = 0.002). Conclusions: LIPI calculated at diagnosis is an independent prognostic factor for both EFS and OS in stage III NSCLC. Validation in larger, prospective cohorts is warranted to further define its prognostic role in stage III NSCLC. Full article

Background/Objectives: Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer (NSCLC), is frequently diagnosed at advanced stages with distant metastasis, underscoring the need for effective prognostic biomarkers. Fibroblast growth factor 2 (FGF2), a multifunctional regulator, has shown to play contradictory roles in cancer progression. Methods: We analyzed three independent Gene Expression Omnibus (GEO) datasets (GSE19804, GSE18842, and GSE19188) to identify consistently dysregulated genes in LUAD. Functional enrichment (GO, KEGG, and cancer hallmark analysis), protein–protein interaction (PPI) network construction, and hub gene prioritization were performed using public bioinformatic tools. Survival analyses were conducted via the Kaplan–Meier Plotter. The expression of FGF2 was validated across multiple platforms, including TCGA, CPTAC, TNMplot, LCE, and the Human Protein Atlas. Functional assays (Transwell migration and wound healing) demonstrated that exogenous FGF2 significantly suppressed LUAD cell motility in vitro. Results: A total of 949 differentially expressed genes (DEGs) were commonly identified across datasets, with enrichment in cell adhesion and metastasis-related pathways. Among the 11 hub genes identified, FGF2 was consistently downregulated in LUAD tissues across all datasets and stages. Higher FGF2 expression was associated with longer overall and progression-free survival. In vitro, FGF2 treatment significantly suppressed the migration and wound healing abilities of LUAD cell lines. Conclusions: FGF2 is downregulated in LUAD and inversely associated with metastatic progression and poor prognosis. The observed reduction in cancer cell motility upon FGF2 treatment in vitro, together with its expression pattern, supports a potential tumor-suppressive role and suggests that FGF2 may serve as a candidate non-invasive biomarker for monitoring LUAD metastasis. Full article

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive tumor for which the most effective systemic therapy remains uncertain. In metastatic LCNEC, chemotherapy approaches typically alternate between small-cell lung cancer (SCLC)-like and non-small-cell lung cancer (NSCLC)-like regimens. Emerging data indicate that treatment selection may be optimized through molecular subtype classification. This study aimed to evaluate the outcomes of SCLC-like and NSCLC-like chemotherapy (CT) regimens in relation to LCNEC molecular subtypes. Methods: This retrospective analysis included all patients diagnosed with LCNEC at Gaziantep University between January 2010 and October 2024. Individuals with available tumor tissue and complete clinical data were enrolled. LCNEC cases were categorized as SCLC-subtype or NSCLC-subtype according to the presence of TP53 and RB1 alterations. Platinum combined with etoposide, irinotecan, or topotecan was defined as SCLC-like CT, whereas platinum with taxanes or gemcitabine was considered NSCLC-like CT. Survival outcomes of both treatment types were compared across molecular subgroups using the Kaplan–Meier method. Results: Sixty-one patients met the inclusion criteria. The median overall survival (mOS) was 11.0 months (95% CI: 6.3–15.7). No significant difference in mOS was observed between SCLC-like and NSCLC-like regimens in the total cohort. When stratified by molecular subtype, patients with the SCLC subtype who received SCLC-like CT showed a longer mOS compared to those treated with NSCLC-like CT (15 [9.9–20.1] vs. 6 [3.9–8.1] months, respectively; p = 0.47), although this difference did not reach statistical significance. Conclusions: These findings suggest that molecular subclassification may help inform the choice of optimal systemic therapy in patients with LCNEC. Full article

Background and Objectives: Lung cancer in never-smokers (LCINS) has become a major global health concern, ranking as the fifth leading cause of cancer-related mortality. Unlike smoking-related lung cancer, LCINS arises from complex interactions between environmental carcinogens and distinct genomic alterations. This review summarizes current evidence on environmental risks, molecular features, and therapeutic progress shaping lung cancer management. Methods: A narrative review was conducted to examine risk factors for lung cancer in non-smokers. Studies reporting driver mutations in never-smokers and smokers were identified across major lung cancer histological subtypes, including small-cell lung cancer (SCLC), lung adenocarcinoma (LUAD), squamous cell carcinoma (SCC), and large-cell carcinoma (LCC). In addition, PubMed was searched for phase III trials and studies on targeted therapies related to driver mutations published between 2016 and 2025. Results: Environmental factors such as cooking oil fumes, radon, asbestos, arsenic, and fine particulate matter (PM_2.5) are strongly associated with LCINS through oxidative stress, DNA damage, and chronic inflammation. EGFR, PIK3CA, OS9, MET, and STK11 mutations are characteristic of never-smokers, in contrast to TP53 mutations, which are more common in smokers. Recent advances in targeted therapy and immunotherapy have improved survival and quality of life, emphasizing the importance of molecular profiling for treatment selection. Conclusions: LCINS represents a distinct clinical and molecular entity shaped by complex interactions between environmental exposures and genetic susceptibility. Genetic alterations promote tumor immune evasion, facilitating cancer development and progression. Continued advances in air quality control, molecular diagnostics, and precision therapies are essential for prevention, early detection, and reduction of the global disease burden. Full article

Lung cancer remains a major clinical challenge, with therapy resistance in non-small-cell lung cancer (NSCLC) driving the search for novel selective agents. This study demonstrates that 2,3′-dihydroxy-5′-methoxystilbene exhibits significant anticancer activity in NSCLC cell lines (A549, H23, and H460) while displaying substantially lower toxicity toward normal NIH/3T3 fibroblasts. The compound reduced the viability of H23 and H460 cells after 48 h. (IC50: 23.39 ± 3.27 μM and 24.20 ± 2.61 μM, respectively), with NIH/3T3 cells remaining comparatively resistant (IC50 > 100 μM). At 25 μM, it suppressed proliferation by approximately 40% in H23, 30% in H460, and 20% in A549 cells, and dose-dependently impaired colony formation and migration, leading to near-complete migration arrest in H460 cells. Apoptosis induction peaked at 19% in H23, 17% in H460, and 8% in A549 cells at 25 μM. Mechanistic studies and molecular modeling revealed AKT-dependent activity, with decreased p-AKT and p-GSK3β levels (0.70 and 0.75 in H23; 0.65 and 0.70 in H460 at 25 μM), without changes in total protein expression. Combination treatment with cisplatin yielded synergistic effects in A549 (CI = 0.83) and H460 (CI = 0.94) cells, but antagonistic effects in H23 cells (CI = 1.32). These findings identify 2,3′-dihydroxy-5′-methoxystilbene as a selective AKT-targeting stilbene with promising anticancer potential and context-dependent chemosensitizing activity in NSCLC cells. Full article

In this study, three point mutations of EGFR relevant to lung cancer therapy are detected. Mutated EGFR is the target of a therapy for non-small cell lung cancer (NSCLC) using tyrosine kinase inhibitors (TKIs) as treatment drugs. Background/Objectives: Point mutations in exon 21 (L858R and L861Q) of the EGFR gene are TKI-sensitive; however, mutations in exon 20 (T790M) are TKI-resistant. Therefore, a fast detection method that classifies an NSCLC patient to be drug sensitive or drug resistant is highly clinically relevant. Methods: Probes were designed to detect three point mutations in genomic samples based on DNA hybridization on a solid surface. A method has been developed to detect single nucleotide polymorphism (SNP) for these mutation detections in the 16-channel nanobioarray chip. The wash by gold-nanoparticles (AuNP) was used to assist the differentiation detection. Results: The gold nanoparticle-assisted wash method has enhanced differentiation between WT and mutated sequences relevant to the EGFR sensitivity to tyrosine kinase inhibitors. Conclusions: The WT and mutated sequences (T790M, L858R and L861Q) in genomic samples were successfully differentiated from each other. Full article

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article