Search Results (3,194)

Background/Objectives: Clinical outcomes with immune checkpoint inhibitors (ICIs), such as nivolumab, vary among patients with metastatic non-small cell lung cancer (NSCLC). The Lung Immune Prognostic Index (LIPI) may help stratify prognosis. This study evaluated the prognostic significance of LIPI in patients receiving second- or third-line nivolumab and developed a nomogram for individualized survival estimation. Methods: This single-center retrospective study included 142 patients with metastatic NSCLC who received second- or third-line nivolumab between February 2022 and December 2024, after progression on platinum-based chemotherapy. LIPI was calculated from baseline values obtained within 14 days before nivolumab initiation, based on a derived neutrophil-to-lymphocyte ratio (dNLR) > 3 and lactate dehydrogenase (LDH) > 225 U/L (institutional upper limit of normal), classifying patients as good-, intermediate-, or poor-risk (0, 1, or 2 factors, respectively). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method; independent prognostic factors were assessed by multivariable Cox regression, and a prognostic nomogram combining ECOG performance status, serum albumin, and LIPI was developed and internally validated. Results: By LIPI, 34.5%, 45.1%, and 20.4% of patients were at good, intermediate, and poor risk, respectively. Objective response and disease control rates were 29.6% and 55.6%. Median OS and PFS were 19.3/8.0/3.1 and 8.6/3.1/2.5 months across good, intermediate, and poor LIPI groups (log-rank p < 0.001). In multivariable analysis, ECOG 2 (hazard ratio [HR], 4.94), albumin per 1 g/dL (HR 0.27), and poor versus good LIPI (HR 3.74) were independently associated with OS. A nomogram combining these three factors showed acceptable discrimination (optimism-corrected Harrell C-statistic 0.742). Conclusions: LIPI was independently associated with prognosis in this cohort. Combining LIPI with ECOG and albumin may aid individualized risk assessment, pending external validation. Full article

Background: Host-related factors such as skeletal muscle and adipose tissue characteristics are increasingly recognized as determinants of outcome in advanced non-small cell lung cancer (aNSCLC). However, the prognostic relevance of integrated body composition phenotypes in patients receiving first-line immunotherapy-based treatment remains unclear. Methods: We retrospectively analyzed patients with aNSCLC treated with first-line immune checkpoint inhibitors (ICI) alone or combined with chemotherapy (ICI–CT) between October 2018 and December 2023 at LMU University Hospital. AI-derived CT biomarkers included skeletal muscle volume index (SMVI), skeletal muscle density (SMD), visceral adipose volume index (VAVI), and subcutaneous adipose volume index (SAVI), normalized for height. Individual body composition parameters were analyzed as standardized continuous variables. For exploratory phenotype analyses, SMVI and VAVI were categorized using cohort-specific sex-stratified median values. An integrated body composition phenotype was defined as “high-muscle/low-visceral-adiposity” (high SMVI/low VAVI) or “low-muscle/high-visceral-adiposity” (low SMVI/high VAVI), with patients not meeting either definition classified as having an intermediate phenotype. Multivariable Cox regression adjusted for age, sex, treatment modality, and metastatic burden evaluated associations with progression-free survival (PFS) and overall survival (OS). Results: Of 116 screened patients, 103 with evaluable baseline CT imaging were included. The cohort predominantly comprised ever-smokers (81.6%) and patients with adenocarcinoma (62.1%). Higher SMD (per one standard deviation increase) was associated with improved overall survival (HR 0.72, 95% CI 0.52–1.00; p = 0.047), and higher VAVI was associated with a higher risk of death (HR 1.29, 95% CI 1.00–1.65; p = 0.048). Neither SMD nor VAVI was significantly associated with PFS, and SMVI and SAVI were not significantly associated with OS or PFS. In the exploratory integrated phenotype analysis, median OS was 29.5 months in the high-muscle/low-visceral-adiposity group, 16.2 months in the intermediate group, and 19.3 months in the low-muscle/high-visceral-adiposity group; however, the overall Kaplan–Meier comparison was not statistically significant (log-rank p = 0.385). Conclusions: AI-derived CT body composition assessment may provide complementary prognostic information in patients with aNSCLC receiving first-line immunotherapy-based treatment. Higher skeletal muscle density was associated with a lower risk of death, whereas higher visceral adiposity was associated with a higher risk of death. The exploratory integrated phenotype analysis did not demonstrate a consistent risk gradient across phenotype categories. These findings require validation in larger prospective cohorts before clinical implementation. Full article

Non-small-cell lung cancer (NSCLC) treatment is hampered by its complex pathogenesis and high heterogeneity. N6-methyladenosine (m⁶A) represents the most common post-transcriptional modification regulating RNA stability and function in eukaryotes. This methylation is catalyzed by methyltransferase complexes, with METTL14 being the core catalytic subunit. Abnormal expression of lncRNA MSTRG.292666.16 is related to poor prognosis of NSCLC. However, the mechanism by which it regulates NSCLC progression through m⁶A modification remains unclear. We employed cell function experiments, molecular mechanism analysis, RNA interaction experiments, and a nude mouse tumor model to explore the roles of METTL14-mediated MSTRG.292666.16 m⁶A modification in NSCLC and the potential MAPK signaling pathway involved. METTL14 was significantly upregulated in NSCLC cell lines and promoted m⁶A modification of MSTRG.292666.16 by forming a stable association with it. METTL14 knockdown significantly inhibited the viability, migration and invasion of A549 cells and promoted apoptosis, whereas MSTRG.292666.16 overexpression reversed these effects. Mechanistically, METTL14 upregulated the expression of MSTRG.292666.16 through m⁶A modification, thereby activating the MAPK pathway (manifested as elevated levels of MAPK8IP3 and p-ERK1/2). The use of a selective p38 MAPK inhibitor SB203580 stimulated the tumor-suppressive effect of METTL14 knockdown, whereas the activator U-46619 reversed it. In vivo experiments confirmed that METTL14 knockdown significantly inhibited tumor growth, whereas MSTRG.292666.16 overexpression partially restored the malignant phenotype of the tumor, which was associated with MAPK pathway activation. This study revealed that METTL14-dependent m⁶A modification of MSTRG.292666.16 may act as an upstream driver to activate the MAPK cascade and facilitate NSCLC progression. These findings clarify a key epitranscriptomic regulatory mechanism driving NSCLC development and offer preliminary molecular clues for exploring potential therapeutic targets in subsequent clinical NSCLC research. Full article

Actionable ALK, ROS1, RET, NTRK, and NRG1 fusions define biologically distinct subsets of advanced non-small cell lung cancer (NSCLC), yet real-world data across these rare populations remain limited. We retrospectively evaluated patients with advanced NSCLC treated at Memorial Healthcare System who received genotype-matched fusion-directed therapy; the first fusion-directed agent defined the index treatment, and survival was measured from its initiation. Progression was determined from radiographic reports and treating-oncologist documentation. After patient-level reconciliation, 59 unique patients were included: 29 ALK, 14 ROS1, 11 RET, 3 NTRK, and 2 NRG1. Median follow-up was 47.7 months (95% CI, 28.6–58.7), median progression-free survival was 44.8 months (95% CI, 17.1–not estimable), and median overall survival was not reached. No statistically significant survival differences were detected among ALK, ROS1, and RET subgroups, although limited sample sizes preclude exclusion of clinically meaningful differences. Later-line index therapy was not significantly associated with progression-free survival in exploratory unadjusted analysis. These findings provide descriptive real-world evidence of precision-oncology implementation across actionable fusion-defined NSCLC while underscoring that pooled outcomes should not be interpreted as evidence of equivalent efficacy across molecular subtypes or therapies. Full article

Circulating tumor cell (CTC) clustering is a key driver of metastatic progression in non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms remain largely unknown. Here, we performed single-cell proteomic sequencing on CTC clusters and individual CTCs isolated from lung cancer patients, identifying 912 proteins in total, of which 246 were significantly upregulated in clusters versus single CTCs. Enrichment analyses revealed a prominent involvement of lipid and cholesterol metabolism pathways. Apolipoprotein E (APOE) emerged as a central hub, exhibiting marked upregulation in CTC clusters. Functional experiments showed that cholesterol supplementation promoted cluster formation in NSCLC cell lines and accelerated metastatic dissemination in vivo, whereas APOE depletion impaired clustering capacity. Mechanistically, we identified USF2 as a potential transcriptional regulator of APOE through direct binding to the promoter, as supported by Chromatin Immunoprecipitation (ChIP) and reporter assays. Clinical validation in a cohort of 75 lung cancer patients demonstrated that elevated APOE expression was strongly associated with advanced pathological grade, distant metastasis, and poor survival. Taken together, these findings establish a novel USF2–APOE–cholesterol axis that governs CTC clustering and metastatic progression, positioning APOE as both a prognostic biomarker and a potential therapeutic target for NSCLC metastasis. Full article

Background: The optimal first-line treatment for advanced BRAF V600-mutant non-small cell lung cancer (NSCLC) remains uncertain. We compared the real-world effectiveness of first-line Dabrafenib plus trametinib (Dab+Tram) with immunochemotherapy (ICT) and other systemic regimens. Methods: This single-centre retrospective cohort study included 142 patients with unresectable stage III/IV BRAF-mutant NSCLC treated between April 2017 and May 2024. Patients were grouped by first-line regimen Dab+Tram, ICT, chemotherapy alone, or others. Primary endpoint was real-world progression-free survival (rwPFS). Propensity score matching (PSM) and multivariable Cox regression were applied to reduce measured confounding. Results: Forty-seven patients received Dab+Tram and 30 received ICT. In unadjusted analysis, Dab+Tram yielded significantly longer median rwPFS than ICT (32.5 vs. 13.3 months; p = 0.004). After PSM (25 pairs), median rwPFS was 19.6 months for Dab+Tram versus 12.6 months for ICT (HR = 1.74, 95%CI 0.85–3.66, p = 0.12). Multivariable Cox regression showed ICT, chemotherapy alone, and other regimens were independently associated with worse rwPFS versus Dab+Tram (all p < 0.05). Overall survival showed no significant difference. Dab+Tram showed some antitumor activity in later-line settings. Findings regarding pyrexia and PD-L1 subgroups were exploratory. Conclusions: In this real-world cohort, first-line Dab+Tram suggested a potential rwPFS benefit over ICT and chemotherapy. The matched comparison did not reach statistical significance, but multivariable analysis consistently supported an association between Dab+Tram and improved rwPFS. These findings provide complementary real-world evidence and require prospective validation. Full article

Molecular residual disease (MRD) testing approaches with plasma next-generation sequencing (NGS) testing to identify circulating tumor DNA (ctDNA) in resectable-stage non-small cell lung cancer (NSCLC) are evolving. The MRD concept is to better guide perioperative systemic treatment and identify recurrent NSCLC before symptomatic radiographic recurrences. Multiple tumor-informed assays are available with technology driving lower levels of ctDNA detection. However, it remains unclear that individual patients derive survival outcome benefit from MRD testing. NSCLC tumor biology of spatial heterogeneity, early parallel metastases, and recurrence clonal evolution can impact tumor-informed approaches irrespective of specific assay level of ctDNA detection. Clinical decision making guided by tumor-informed MRD testing to date have been limited by recurrence risks of up to 20% when landmark MRD-negative, improved outcomes benefit of adjuvant treatment even when landmark MRD-negative, and lead times with longitudinal MRD-positive conversion of several months or longer before overt radiographic recurrences with no proven strategy of survival benefit with intervening treatment. Cautionary tumor biology and clinical issues remain in the clinical utility of tumor-informed MRD testing in resected NSCLC. These need to be clarified with certainty before MRD testing should step beyond a technology-driven prognostic recurrence risk indicator before becoming an absolute clinical guide to meaningfully impact individual patient management and outcomes. Full article

Acquired resistance to targeted therapies is inevitable in EGFR-mutant non-small cell lung cancer (NSCLC), yet the principles governing its emergence in vivo remain incompletely understood. In particular, how lesion-level response patterns vary across distinct EGFR allele contexts during therapy has not been systematically examined at single-lesion resolution. Here, we establish a longitudinal in vivo imaging platform enabling single-lesion resolution tracking of tumor behavior during therapy in genetically engineered mouse models representing clinically relevant EGFR alleles. Using high-resolution micro-computed tomography (micro-CT) and three-dimensional reconstruction, we monitor tumor growth, therapeutic response, and resistance during osimertinib treatment. EGFR genotype is associated with distinct patterns of tumor growth, response kinetics, and resistance timing. Therapeutic response is spatially heterogeneous, with coexisting lesions undergoing complete regression, persistence, or progression within the same lung. During treatment, spatially distinct lesion-level behaviors included persistent growth during therapy and initial regression followed by regrowth. These findings demonstrate the utility of longitudinal micro-CT imaging to investigate allele-associated differences in treatment response and resistance timing at single-lesion resolution in vivo. Full article

KRAS G12C mutation is a clinically relevant driver in non-small cell lung cancer (NSCLC), yet the signaling networks that modulate malignant behavior in this context remain incompletely defined. In this study, we examined the functional role of FOXD3 and its relationship with NF-κB signaling in KRAS G12C-mutant NSCLC models. Stable FOXD3 overexpression was established in SW1573 and LU65 cells. FOXD3 reduced cell viability, migration, and invasion while increasing caspase 3/7 activity in both cell lines. Transcriptomic profiling in LU65 cells followed by Hallmark enrichment analysis identified TNFα signaling via NF-κB as a prominently altered pathway associated with FOXD3 overexpression. Consistently, NF-κB dual-luciferase assays showed reduced basal NF-κB transcriptional activity in FOXD3-overexpressing cells. TNFα stimulation partially reversed the inhibitory effects of FOXD3 on proliferation, migration, and invasion and attenuated FOXD3-induced apoptosis. In addition, stable FOXD3 overexpression suppressed xenograft growth in vivo. Collectively, these findings support a functional association between FOXD3 overexpression and reduced NF-κB-related transcriptional activity in KRAS G12C-mutant NSCLC models, although the present data do not establish direct causal mediation by NF-κB. Full article

Non-small cell lung cancer (NSCLC) represents most lung cancer diagnoses worldwide and remains a leading cause of cancer-related mortality. The advent of precision oncology has transformed the therapeutic landscape of NSCLC through the identification of druggable genetic alterations, enabling the use of targeted therapies with significant clinical benefit. However, the reported prevalence of these alterations varies widely across studies and populations, raising important questions about the underlying determinants of such discrepancies. In this context, molecular epidemiology provides a framework to understand the distribution of genomic alterations and their interplay with demographic, clinical, and methodological factors. This narrative review examines the spectrum of druggable genetic alterations in NSCLC and critically analyzes the sources of variability in their reported frequencies. We discuss geographic and ethnic differences, particularly between East Asian, European, and North American populations, as well as the influence of smoking status, environmental exposures, histologic subtypes, and sex-related factors. Furthermore, we explore how disease stage and sample source may contribute to heterogeneity in molecular profiles. A substantial focus is placed on methodological sources of discrepancy, including differences in molecular testing platforms, analytical sensitivity and limits of detection, tissue versus liquid biopsy approaches, tumor heterogeneity, and gene panel design. Finally, emerging trends in the field, such as the use of ultra-large genomic datasets, real-world evidence, multi-omics integration, and artificial intelligence, alongside ongoing efforts toward standardization of molecular testing, are discussed. Full article

Adjuvant and perioperative immune checkpoint inhibitors (ICIs) have created a growing population of patients who relapse after prior programmed death-1 or programmed death-ligand 1 blockade, yet these patients were underrepresented in many trials that established metastatic standards. We performed a structured narrative review of PubMed/MEDLINE, ClinicalTrials.gov, reference lists, and international oncology guideline repositories through 15 August 2026. Eligible reports addressed recurrence patterns or treatment after curative-intent ICI in melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple-negative breast cancer (TNBC); landmark metastatic studies were included only when direct evidence was unavailable and are labeled as extrapolation. Timing was standardized as on-treatment recurrence, early off-treatment recurrence (after the last ICI dose through 12 months), and late recurrence (>12 months). Shorter disease-free interval is consistently prognostic, but treatment-by-timing interactions are rarely available; timing should not be described as a validated pan-tumor predictive biomarker. Direct post-adjuvant evidence supports switching away from anti-PD-1 monotherapy for melanoma recurring on treatment, while selected late relapses may retain sensitivity. In RCC, retrospective post-adjuvant data support VEGF-targeted options, whereas CONTACT-03 and TiNivo-2 discourage routine ICI-TKI rechallenge specifically after prior ICI-treated metastatic RCC. Evidence in NSCLC, urothelial carcinoma, and TNBC is largely indirect. IMpassion132 was not an ICI-rechallenge trial, and only a small minority of ASCENT-04 participants had prior perioperative ICI. Treatment should integrate tumor-specific biology, actionable alterations, recurrence distribution, prior toxicity, comorbidity, access, and patient preference. Prospective trials dedicated to post-adjuvant ICI recurrence are needed. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Over the past decade, immune checkpoint inhibitors have become a core component of first-line treatment for advanced-stage NSCLC lacking driver mutations. Programmed death-ligand 1 (PD-L1) expression is currently used as the standard biomarker, yet its predictive value remains limited, and in most immunotherapy trials, treatment efficacy has been observed independently of PD-L1 expression status. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator, promotes immune escape by suppressing antigen presentation and impairing CD8+ T-cell function, thereby generating an immune-cold tumor microenvironment, positioning it as a promising candidate biomarker. Methods: We retrospectively analyzed 102 NSCLC patients treated with immunotherapy at a single center between 2018 and 2024. EZH2 expression was assessed by immunohistochemistry. A cohort-derived 25% threshold was used for the primary exploratory analysis, and the analyses were repeated using a 50% threshold as a sensitivity analysis. Patients were classified as EZH2-high (45.1%) and EZH2-low (54.9%) at the 25% threshold. Results: At the 25% threshold, objective response rate (ORR) was 53.6% in the EZH2-low group and 45.7% in the EZH2-high group (Fisher’s exact p = 0.551), while disease control rate (DCR) was 64.3% and 60.9%, respectively (p = 0.837). Median overall survival (OS) was 37 versus 27 months (log-rank p = 0.323), and median progression-free survival (PFS) was 15 versus 12 months (p = 0.387). No significant correlation was found between EZH2 and PD-L1 expression (r = 0.167, p = 0.138). In treatment-line-adjusted Cox models, EZH2 expression was not associated with OS (hazard ratio (HR) 0.953, 95% confidence interval (CI) 0.533–1.704; p = 0.870) or PFS (HR 0.996, 95% CI 0.573–1.733; p = 0.989), whereas squamous histology was an independent predictor of survival. Results remained non-significant at the 50% threshold. Early progression was uncommon and did not differ significantly by EZH2 status overall or within PD-L1 strata. Conclusions: In this real-world cohort, EZH2 expression was not independently associated with response, early progression, OS, or PFS, and showed no correlation with PD-L1. These exploratory findings do not support the clinical use of EZH2 as a biomarker at this stage; prospective, multicenter studies using predefined thresholds and standardized immunohistochemical methods are needed to clarify its potential role as a marker complementary to PD-L1. Full article

Background: The sequential use of anti-programmed cell death (ligand)-1 [PD-(L)1] immune-checkpoint inhibitors (ICIs) followed by targeted tyrosine-kinase inhibitors (TKIs) for advanced non-small cell lung cancer (NSCLC) with oncogenic alterations raises questions about tolerance and efficacy. Recent study results suggested an increased risk of adverse events (AEs) with this sequence. Methods: Multicenter retrospective study on advanced NSCLC patients treated with ICIs followed by targeted therapies between 2015 and 2021. The primary endpoint was the rate of grade 3–5 adverse events (AEs). Main secondary endpoints were progression-free survival (PFS), time-to-treatment failure and overall survival (OS). Results: The analysis included 109 patients (most with EGFR, 30.3%; BRAF, 17.4%; MET exon-14, 17.4%; ALK, 10.1%; and RET, 6.4% gene alterations); 28/109, which is 25.7% of the patients, experienced grade 3/4 AEs and 4/109 (3.7%) experienced grade 5 AEs, leading to the definitive cessation of targeted therapy treatment in 14/32 (44%) of cases; higher grade 3–5 rates were observed with the dabrafenib–trametinib combination (12/16, 75%), capmatinib (4/8, 50%) and crizotinib (8/16, 50%). A last ICI-administration-to-targeted therapy-start interval of <90 days appeared to be associated with grade ≥ 3 AEs (32/82, 39% vs. 0/27 p = 0.001). In these sequential strategies, effectiveness of targeted therapies, in this second-line or later setting, appears to be lower than that in the published historical data. Conclusion: According to this analysis, sequential ICI–targeted therapy use for advanced NSCLC appeared to be associated with more grade 3–5 AEs. Full article

Background and Objectives: Non-small cell lung cancer (NSCLC) comprises biologically distinct histologic subtypes, including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We evaluated whether the prognostic association of cyclin-dependent kinase-like 2 (CDKL2) differs by histology. Materials and Methods: TCGA CDKL2 expression was linked to harmonized clinical data. The primary analysis used a pooled multivariable Cox model with continuous standardized CDKL2 expression, histology, and a CDKL2 × histology interaction, adjusted for age, sex, pathologic stage, and smoking. Additional analyses assessed model assumptions, tumor purity, tumor-versus-normal expression, KEGG pathways, the tumor microenvironment, and single-cell RNA sequencing. External evaluation used GSE30219. Results: The primary TCGA cohort included 943 patients (471 LUAD, 472 LUSC; 375 deaths). Higher CDKL2 expression was associated with lower mortality in LUAD (HR per 1 pooled SD = 0.721, 95% CI 0.603–0.862, p < 0.001) but higher mortality in LUSC (HR = 1.237, 95% CI 1.011–1.515, p = 0.039), with a significant interaction (HR = 1.717, p < 0.001) persisting after tumor-purity adjustment. CDKL2-low tumors were enriched for cell-cycle, DNA-replication, proteasome, and DNA-repair programs. Single-cell analyses showed predominant epithelial detection and greater malignant-cell CDKL2 detection in LUAD. In GSE30219, the favorable LUAD association was supported in a median-split-adjusted analysis of 207073_at (HR = 0.473, 95% CI 0.250–0.897, p = 0.022), whereas the corresponding continuous estimate was directionally favorable but nonsignificant; 236331_at was nonsignificant in both models; neither probe supported the adverse LUSC association or histology interaction. Conclusions: Higher CDKL2 expression showed a favorable prognostic association in LUAD, with consistent TCGA sensitivity analyses and limited but suggestive independent-cohort support. The adverse LUSC association remains preliminary, and CDKL2 should be regarded as a candidate prognostically associated marker rather than an established clinical biomarker. Full article

Background/Objectives: ALK tyrosine kinase inhibitors (TKIs) have improved outcomes in patients with metastatic ALK-rearranged non-small cell lung cancer (NSCLC). However, real-world data on long-term outcomes, prognostic factors, and treatment sequencing remain limited. This study aimed to evaluate treatment outcomes, prognostic factors, and lorlatinib efficacy in different treatment settings. Methods: We retrospectively analyzed 83 patients with metastatic ALK-rearranged NSCLC treated with ALK TKIs at a tertiary oncology center. Survival outcomes, prognostic factors, treatment sequences, and adverse events were analyzed using Kaplan–Meier and Cox regression methods. Results: The median follow-up duration was 69.4 months, and the median overall survival (OS) was 73.9 months (95% CI, 58.51–89.32). Median OS was 84.8 months with first-line alectinib and 63.6 months with crizotinib. Median progression-free survival (PFS) durations were 47.5, 23.0, and 14.9 months for alectinib, brigatinib, and crizotinib, respectively. ECOG performance status, histological subtype (adenocarcinoma vs. non-adenocarcinoma), and PD-L1 expression were significant prognostic factors. First-line lorlatinib demonstrated durable disease control, with median PFS not reached and a 24-month PFS rate of 80%. Later-line lorlatinib showed continued activity, with median PFS-2 and PFS-3 of 12.2 and 6.1 months, respectively. Treatment-related adverse events were generally manageable. Conclusions: This real-world study provides long-term outcomes and prognostic insights in metastatic ALK-rearranged NSCLC. ECOG performance status, histological subtype, and PD-L1 expression were independent prognostic factors for OS. First-line lorlatinib findings suggest durable disease control but remain preliminary and require confirmation with longer follow-up. Full article