Search Results (3,558)

Background: Non-small cell lung cancer (NSCLC) constitutes about 80–85% of lung cancers, and ~60–70% of NSCLC patients are diagnosed at an advanced stage of the disease. Concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab has become the standard of care for unresectable stage III NSCLC, following the phase III PACIFIC trial, which demonstrated significantly improved progression-free survival (PFS) and overall survival (OS) with durvalumab. Methods: We conducted a single-center retrospective study with unresectable stage III NSCLC patients who received cCRT between January 2021 and December 2025 at the Białystok Oncology Center (Poland). Patients with an ECOG performance status of 0–1 and no disease progression (PD) after cCRT were treated with durvalumab consolidation up to 12 months or until PD or unacceptable toxicity. The clinical outcomes and treatment tolerance were analyzed. Results: Out of 94 cCRT-treated patients (pts), 78 received durvalumab consolidation therapy. The median age of the pts was 66.5 years; 64.1% pts were >65 years old. Squamous carcinoma was the predominant histology (56.4%). The median time from cCRT completion to durvalumab initiation was 45 days (range: 15–85). A majority (57.7%) of patients completed the full 12 months of durvalumab. With a median follow-up of 40 months, the median PFS was ~1224 days (40.2 months). At 3 years, PFS was 52.8%. There were no significant differences in PFS by age (<65 vs. ≥65 years), HR:0.65, clinical stage (IIIA vs. IIIB/IIIC) HR:1.01, histology (squamous vs. non-squamous carcinoma), HR:0.76; sex HR:0.6, ECOG 0 vs. 1 HR:0.82; or initiation of durvalumab ≤42 vs. >42 days after cCRT, HR:0.62 (p > 0.05 for all). The sole factor significantly affecting PFS was smoking status: ever-smokers had a longer PFS than never-smokers (median ~46 months vs. ~21 months, HR:2.11, p = 0.04). Durvalumab consolidation was generally well tolerated. Grade 3–4 adverse events (mainly pneumonitis and esophagitis) leading to permanent durvalumab discontinuation occurred in 7 patients (9%), almost all over 65 years old. Conclusions: Real-world data from our single-center study confirm that consolidation durvalumab therapy after cCRT provides substantial clinical benefit in unresectable stage III NSCLC, even in older patients. The PFS and safety outcomes in our cohort, which had a higher proportion of elderly and locally advanced cases, were comparable with those reported in clinical trials (PACIFIC) and observational studies (PACIFIC-R), underscoring the effectiveness and tolerability of this approach in routine practice. We acknowledge the limitations of the retrospective design and sample size, but our findings support the use of cCRT followed by durvalumab in eligible stage III NSCLC patients and highlight the need for further research on optimizing outcomes (e.g., the impact of smoking and other biomarkers). Full article

Background: Segmentectomy is increasingly used and is emerging as a key treatment option for early-stage non-small cell lung cancer (NSCLC). However, questions remain regarding the adequacy of lymph node evaluation, particularly differences in N1 versus N2 dissection, and the implications for staging accuracy and adjuvant therapy. Methods: This narrative review synthesizes evidence from studies published between 2019 and 2025 comparing nodal upstaging, survival outcomes, and the role of completion lobectomy following segmentectomy versus lobectomy. Results: Twelve studies, including more than 175,000 patients, were analyzed. Lobectomy was associated with a significantly higher overall nodal upstaging rate (14.5% vs. 6.6%, p < 0.001), driven primarily by increased detection of N1 disease (13.3% vs. 3.7%, p < 0.001), while N2 upstaging rates were similar between procedures (5.5% vs. 3.2%, p = 0.07). Despite lower N1 detection, adjusted analyses reported comparable survival outcomes among patients with occult pathologic N1 (pN1) or N2 (pN2) disease who received adjuvant therapy. Segmentectomy provided outcomes comparable to lobectomy, whereas wedge resection was associated with inferior survival (HR 1.23, p = 0.042). Completion lobectomy has not demonstrated a consistent survival benefit and was associated with substantial morbidity in limited retrospective series, including high rates of thoracotomy conversion and major complications. Conclusions: When performed with systematic nodal dissection, adequate surgical margins, and appropriate adjuvant therapy, segmentectomy appears to provide survival outcomes comparable to lobectomy in selected patients with early-stage NSCLC. Completion lobectomy may not be routinely required and should be considered on a case-by-case basis within a multidisciplinary context. These findings support the use of segmentectomy in carefully selected patients when high-quality surgical staging and integrated oncologic care are ensured, while highlighting the need for prospective studies addressing occult nodal disease in the modern treatment era. Full article

Historically, stage T4 non-small cell lung cancer (NSCLC) with direct spinal invasion was considered a definitive surgical contraindication due to the perceived inability to achieve negative margins without catastrophic morbidity. This paradigm has shifted through the advancement of specialized surgical techniques, which facilitate radical en-bloc resection in highly selected candidates by adhering to the en-bloc concept. This concept mandates the retrieval of the tumor and invaded vertebral segments as a single, contiguous unit to prevent intralesional transgression and local recurrence. Achieving microscopic negative margins (R0) stands as the most critical prognostic factor, as radical resection offers a significantly improved potential for long-term survival. Technical success requires a meticulously planned multidisciplinary approach encompassing varied surgical corridors—ranging from combined anterior–posterior windows to single-stage posterior-only approaches—tailored to the tumor’s anatomical level. Furthermore, preoperative hemostatic optimization using dual-energy computed tomography (DECT) for vascular assessment and transarterial embolization (TAE) has become indispensable for managing the hypervascularity of the invaded vertebral bone. This review synthesizes these evolving strategies, illustrated by a case of a 74-year-old male with stage T4 NSCLC where an R0 resection was achieved through a two-stage approach integrating uniportal video-assisted thoracoscopic surgery (VATS). Ultimately, en-bloc management provides a feasible and potential surgical strategy toward long-term survival for localized, spine-invasive lung cancer within a multidisciplinary treatment framework. Full article

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Although EGFR-TKIs can cause various adverse events (AEs), their profiles have not been fully elucidated in Thai patients. This study aimed to determine the incidence, characteristics, severity, and duration of the first AEs and to evaluate their association with tumor response in patients with NSCLC receiving EGFR-TKIs. Method: This retrospective cohort study was conducted at a super-tertiary care hospital in Thailand. Patients with NSCLC who received EGFR-TKIs between August 2021 and July 2024 were included. Descriptive statistics were used to summarize safety profiles and tumor response. The association between AEs and objective response was assessed using logistic regression. Results: A total of 187 patients were included in this study. Overall, 177 AEs were observed in patients receiving erlotinib, osimertinib, or gefitinib. The most common cutaneous AEs were rash (30.7%), xerosis (24.1%), and acneiform rash (19.3%), while diarrhea (20.3%) was the most frequent gastrointestinal toxicity. Most AEs were grade 1–2 and occurred within 1 month after treatment initiation. In multivariable logistic regression analysis, pruritus (OR 8.26, 95% CI: 1.00–67.75, p = 0.049) and treatment line (OR 0.27, 95% CI: 0.10–0.68, p = 0.006) were independently associated with objective response. Conclusion: Most of the AEs occurred early during EGFR-TKI therapy, with cutaneous reactions being the most common and generally mild to moderate. Pruritus and treatment line were independently associated with objective response, suggesting that pruritus may serve as a potential clinical indicator of treatment response and highlighting the importance of monitoring of the EGFR-TKI-related AEs during therapy. Full article

Background: Immune checkpoint inhibitors (ICIs) have become the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression. However, the optimal selection between immunotherapy monotherapy and chemo-immunotherapy in patients with a PD-L1 tumor proportion score (TPS) ≥ 50% remains uncertain in routine clinical practice. Methods: We retrospectively reviewed patients with metastatic NSCLC and a PD-L1 TPS ≥ 50% who initiated first-line treatment with pembrolizumab monotherapy or pembrolizumab combined with platinum-based chemotherapy at the Istanbul Medipol University Department of Medical Oncology between July 2017 and December 2024. Survival outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated and compared according to PD-L1 expression levels and treatment strategy. Prognostic factors associated with survival outcomes were also explored. Results: A total of 65 patients were included, of whom 36 received pembrolizumab plus chemotherapy and 29 received pembrolizumab monotherapy. The estimated median PFS and OS for the entire cohort were 24.2 months (95% CI, 6.5–33.0) and 34.6 months (95% CI, 6.5–62.7), respectively. Patients with very high PD-L1 expression (TPS ≥ 90%) experienced significantly longer survival outcomes compared with those with a TPS of 50–89%, and a PD-L1 TPS ≥ 90% remained an independent prognostic factor for OS. When treatment strategies were compared across the entire cohort, no statistically significant differences in PFS or OS were observed between immunotherapy monotherapy and chemo-immunotherapy. Hypertension was identified as an independent negative prognostic factor for PFS. In patients with a PD-L1 TPS ≥ 90%, survival outcomes numerically favored pembrolizumab monotherapy, although this difference did not reach statistical significance. Conclusions: In this real-world cohort of patients with PD-L1 high metastatic NSCLC, PD-L1 expression, particularly very high TPS levels, was strongly associated with survival outcomes. While no survival differences were observed between treatment strategies in the overall population, pembrolizumab monotherapy may represent an appropriate first-line option in selected patients with a PD-L1 TPS ≥ 90%. Larger prospective studies are warranted to refine treatment selection in this setting. Full article

Objectives: This study aimed to evaluate the setup accuracy and intrafractional geometric stability of surface-guided radiation therapy (SGRT) under frameless immobilization in lung cancer radiotherapy and to assess its clinical utility in a relatively large patient cohort. Materials and Methods: A total of 678 treatment fractions from 52 patients with primary non-small cell lung cancer (NSCLC), treated between October 2024 and November 2025, were retrospectively analyzed. Patient setup was performed using SGRT with the Identify system, and cone-beam computed tomography (CBCT) served as the reference for internal target localization Intrafractional setup displacements, center-of-mass (COM) shifts, residual setup errors, and intrafractional clinical target volume (CTV) variations were evaluated. Spatial agreement between planned and intrafractional tumor volumes was quantified using the Dice Similarity Coefficient (DSC). Results: The mean CBCT-based intrafractional shifts were −0.01 mm (vertical), 0.03 mm (longitudinal), and 0.01 mm (lateral), indicating negligible systematic errors. The greatest variability was observed in the longitudinal direction (standard deviation, 1.32 mm), with a maximum displacement of 4.58 mm. COM-based analysis demonstrated near-zero mean displacements in all directions, with standard deviations ranging from 0.01 to 0.02 mm. DSC values ranged from 0.91 to 0.98, with a mean of 0.96, indicating excellent spatial agreement between planned and intrafractional tumor volumes. Residual setup errors were predominantly within ±1 mm, and the mean intrafractional CTV volume change was minimal (0.27 cm³). Conclusions: SGRT-based frameless lung cancer radiotherapy demonstrated high setup accuracy and robust intrafractional geometric stability. Although slightly greater variability was observed in the longitudinal direction, overall positional deviations and volumetric changes remained within clinically acceptable limits. These findings support the feasibility of integrating SGRT with CBCT-guided radiotherapy and suggest potential benefits for workflow efficiency and planning target volume margin optimization. Full article

Background: The development of advanced genomic sequencing techniques now makes it possible to identify novel biomarkers and guide the design of targeted therapeutic strategies. For advanced squamous non-small cell lung cancer (NSCLC), V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) fusions have not been evaluated as a therapeutic target. However, agents that block the pathway activated by these fusions have shown efficacy in other solid tumors, such as melanoma, astrocytoma, acinar carcinoma of the pancreas, and papillary thyroid tumors. Case Report: Here, we present the case of a patient with locally advanced squamous NSCLC and minimal smoking history who was found to harbor a TMEM178B::BRAF fusion. Following curative-intent chemoradiotherapy (CRT) and subsequent maintenance immunotherapy, the patient achieved a complete radiological response at 12 months, accompanied by a marked improvement in both quality of life and overall clinical status. Conclusions: The findings in this patient underscore the importance of extending molecular genetic studies to patients with squamous histology who lack toxic habits or known risk factors. Gene alterations such as BRAF rearrangements may not only predict the response to immunotherapy-based treatments but also represent a promising avenue for the development of new therapeutic strategies. Full article

Background: First-line chemoimmunotherapy (I + C) is the standard of care for advanced non-squamous non-small cell lung cancer (NSCLC) without oncogenic mutation. Bevacizumab has been shown to enhance the efficacy of chemotherapy in non-squamous NSCLC, yet its added value when combined with I + C (I + C + B) remains unclear. To address this gap, we conducted a real-world comparative study and a network meta-analysis to evaluate I + C + B versus I + C in this setting. Methods: This retrospective study included patients with advanced EGFR/ALK-negative non-squamous NSCLC treated with first-line I + C + B or I + C. Propensity score matching (PSM) was employed to balance baseline characteristics between groups. Efficacy endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses examined outcomes by PD-L1 expression, age, metastases, and chemotherapy, among other factors. In parallel, a network meta-analysis of four randomized trials (n = 2026) indirectly compared I + C + B against I + C for PFS, OS, and safety outcomes. Results: A total of 277 patients were included, with 167 (60.3%) receiving I + C + B and 110 (39.7%) receiving I + C. Before PSM, the I + C + B regimen significantly prolonged PFS versus I + C (hazard ratio [HR] = 0.69, 95% CI 0.52–0.92, p = 0.010), with this benefit maintaining post-matching (HR = 0.70, 95% CI 0.49–0.99, p = 0.045). However, OS did not differ significantly between groups in either the pre-PSM (HR = 0.93, 95% CI: 0.67–1.30; p = 0.665) or matched analyses (HR = 0.84, 95% CI: 0.54–1.29; p = 0.421). Subgroup analyses suggested greater PFS benefit from I + C + B among PD-L1-negative, older patients, those with brain metastases or multiple metastatic sites, and in patients receiving specific chemotherapy doublets. The network meta-analysis confirmed a PFS advantage for I + C + B over I + C (HR = 0.84, 95% CI: 0.71–0.98) without an OS benefit (HR = 0.95, 95% CI: 0.79–1.14). Toxicity was higher with I + C + B; rates of grade 3–5 adverse events, serious adverse events, and treatment discontinuation were all significantly increased compared to I + C. Conclusions: In the first-line treatment of advanced EGFR/ALK-negative non-squamous NSCLC, adding bevacizumab to I + C improved PFS but did not translate into an OS gain. Although PFS benefits were observed in certain subgroups, these were accompanied by significantly increased treatment-related toxicities. Our findings suggest that no clear subgroup has been identified where the benefit outweighs the risks, necessitating extreme clinical caution. Full article

Background/Objectives: The management and prognosis of ALK-rearranged non-small-cell lung cancer have substantially improved over the past decade. However, challenges remain in timely molecular identification, prediction of treatment response, and understanding resistance mechanisms. This systematic review evaluates and synthesizes the evidence on artificial intelligence (AI) approaches leveraging imaging, pathology, molecular, and clinical data in this setting. Methods: A systematic search was conducted for peer-reviewed studies published between 2020 and 2025. Eligible studies involved human subjects and applied AI, machine learning, or deep learning methods to predict ALK status or treatment-related outcomes using imaging, pathology, molecular, or multimodal data. Study selection followed the PRISMA 2020 guidelines. Data were extracted on study design, data modality, AI methodology, clinical objectives, and performance metrics. Bibliometric co-occurrence analysis was performed to characterize thematic patterns and temporal trends. Results: Thirteen studies met the inclusion criteria, most of which were retrospective and single-center. AI approaches were applied to radiologic, pathologic, molecular, or multimodal data. Models predicting ALK status reported area under the curve values ranging from 0.73 to 0.99, while prognostic and treatment-response models reported moderate to high discriminative performance. Bibliometric analysis identified two dominant research themes focused on molecular characterization and computational methodology, with a recent shift toward treatment-specific and integrative analyses. External validation and clinical implementation remained limited across studies. Conclusions: AI shows promising potential to support diagnosis, prognostication, and treatment assessment in ALK-rearranged lung cancer. However, methodological heterogeneity, limited external validation, and a lack of prospective studies currently constrain clinical translation. Full article

Background/Objectives: Cancer cells are subjected to various stress conditions and have stress adaptability strategies to survive. Various types of stresses lead to the aggregation of cytoplasmic RNA granules known as stress granules (SGs), seen in normal and tumor cells, and aid in cell survival by avoiding cell apoptosis. G3BP stress granule assembly factor 2 (G3BP2) encodes a multifunctional protein with known roles as a critical component of SGs and is also associated with chemoresistance in cancer, but its known roles in non-small cell cancer (NSCLC) are limited. Methods: We evaluated the expression of G3BP2 via qPCR and immunohistochemistry on a retrospective cohort of NSCLC isolated at surgery in St James’s Hospital, Dublin, Ireland. Expression levels were correlated with clinicopathological parameters. Survival analyses, including Kaplan–Meier analyses, were used to determine the prognostic value. Additional correlations with other available NSCLC datasets were explored. Results: In contrast to other studies, we did not observe upregulated expression of G3BP2. Furthermore, Kaplan–Meier analyses did not identify any prognostic value associated with G3BP2 expression in patient tissues in contrast to other published data. Bioinformatic analyses on these other datasets found strong correlations between G3BP2 and core stress granule genes in NSCLC. Additional analyses also identified correlations between G3BP2 expression and immune cell infiltration, immune cell exhaustion, and DNA Damage Response pathways. An examination of the available datasets did not find any overall prognostic value for altered DNA methylation and survival. However, two individual CpG residues were identified for which higher methylation was associated with worse overall survival. Finally, the effects of a G3BP2 inhibitor on cellular proliferation were assessed. Conclusions: In our analysis, G3BP2 was not associated with survival benefit. However, clear associations were observed between altered expression of this gene and a number of important pathways linked to cancer pathogenesis, and further studies are warranted to assess this gene (and/or) stress granules in cancer. Full article

Background/Objectives: Lung cancer remains a major global health burden, largely driven by cigarette use. Although electronic cigarettes (e-cigarettes) are viewed as safer alternatives due to their reduced chemical load, growing evidence shows their vapor can disrupt cellular transcriptomes, including long noncoding RNAs (lncRNAs). In this study, we examined the regulation and function of vape-associated lncRNA transcript 1 (VALT1), a novel transcript upregulated in the oral transcriptomes of e-cigarette users and similarly elevated in non-small-cell lung cancer (NSCLC) tumors. Methods: Publicly available RNA-seq datasets were analyzed, and VALT1 was identified as an e-cigarette-responsive lncRNA. Its dose-dependent induction by e-cigarette smoke extract (eCSE) and cytoplasmic localization were confirmed via RT-qPCR. Its effects on cancer-associated phenotypes including proliferation, ROS detoxification, resistance to apoptosis, migration, cytoskeletal disorganization, and nuclear remodeling were assessed through overexpression and siRNA-mediated knockdown in A549 and BEAS-2B cells. Results: Acute eCSE exposure induced a biphasic, dose-dependent increase in VALT1 expression, accompanied by enhanced proliferation, ROS detoxification, apoptosis resistance, migration, cytoskeletal disorganization, and nuclear remodeling in A549 cells. VALT1 overexpression reproduced these phenotypes in both cell lines without eCSE treatment, whereas knockdown attenuated them. VALT1 promoted survival under cytotoxic stress in A549 but not BEAS-2B cells. Conclusions: These findings support an active role for VALT1 as an e-cigarette vapor-upregulated transcript that contributes to its phenotypic readout and enhances cellular survival under extracellular chemical stress—thereby aggravating tumorigenic phenotypes even in the absence of mutations that contribute to malignant transformation. Full article

Non-small cell lung cancer (NSCLC) is the leading cause of lung cancer deaths, with resistance to targeted therapies posing a major clinical challenge. Drug-tolerant persister (DTP) cells are key contributors to resistance, and targeting them offers new strategies to enhance existing treatments. MicroRNAs (miRNAs), particularly the tumour-suppressive miR-15/107 family, offer promise due to their ability to target multiple oncogenic pathways. This study evaluated a synthetic consensus miRNA mimic, conmiR-15/107, in NSCLC cell line models. Dose–response assays showed robust, dose-dependent growth inhibition in both EGFR-mutant (PC9) and KRAS-mutant (H358 and A549) lung adenocarcinoma cells, but not in the human bronchial epithelial cell line BEAS-2B. When combined with EGFR inhibitors (osimertinib and gefitinib) in PC9 cells, the mimics showed a higher rate of growth inhibition compared with the controls and reduced IC₅₀ values. Similarly, conmiR-15/107 enhanced growth inhibition by the KRAS inhibitors sotorasib and adagrasib in H358 cells. RT-qPCR confirmed downregulation of conmiR-15/107 targets, including MEK1, BCL2 and BRCA1, suggesting a multi-target mechanism of action. Long-term assays showed that the mimics reduced the survival and delayed the proliferation of DTPs in osimertinib-treated PC9 cells as well as sotorasib-treated H358 cells. These findings support conmiR-15/107 as a potential adjunct to targeted therapy, capable of enhancing treatment efficacy and delaying resistance in lung adenocarcinoma. Full article

Background/Objectives: Several studies have demonstrated feasible oncologic outcomes of segmentectomy for pure-solid or solid-dominant non-small cell lung cancer (NSCLC) measuring ≤2 cm in diameter and ground-glass opacity (GGO)-dominant NSCLC up to 3 cm in maximum tumor size. However, the applicability of segmentectomy for solid-dominant NSCLC with a tumor diameter of 2–3 cm remains controversial. This retrospective study aimed to investigate the outcomes of segmentectomy for solid-dominant NSCLC with a tumor diameter of 2–3 cm. Methods: We included patients who underwent lung cancer surgery at Tokyo Women’s Medical University Hospital, Tokyo, Japan, from January 2011 to December 2017. The number of patients included in this study was 743. Of the 96 eligible patients, 76 and 20 underwent lobectomy and segmentectomy, respectively. Results: The lobectomy and segmentectomy groups had similar 5-year overall survival rates (93.7% vs. 94.4%, respectively; HR 0.693, 95% CI 0.183–2.621, p = 0.586) and 5-year recurrence-free survival rates (75.8% vs. 83.6%, respectively; HR 0.639, 95% CI 0.188–2.171, p = 0.468). The recurrence pattern was not significantly different between the lobectomy and segmentectomy groups (locoregional 11.8% vs. 10.0%, and distant 10.5% vs. 5.0%, respectively; p = 0.679). Multivariable Cox regression analysis demonstrated that surgical procedure was not independently associated with OS or RFS after adjustment for confounders. Conclusions: Segmentectomy may be a feasible option for selected patients with solid-dominant NSCLC measuring 2–3 cm in diameter. Full article

Immunotherapy, particularly effective in tumors with a high mutational burden, is very often administered in combination with chemotherapy. Several tumor types with a high mutational rate include melanoma and non-small cell lung cancer (NSCLC), which are particularly sensitive to immunotherapy. For NSCLC, conventional platinum-based doublet chemotherapy has been extended with drugs targeting signaling pathways (such as the epidermal growth factor receptor) and immune checkpoint inhibitors (ICI) directed against PD-1 and PD-L1. This review highlights the potential role of the membrane antigens CD73 and CD39 in enhancing the efficacy of combined immuno-chemotherapy. These ecto-nucleotidases catalyze the degradation of extracellular ATP to AMP and subsequently to adenosine (Ado), a potent immunosuppressive metabolite that acts through adenosine receptors. Consequently, CD73 and CD39 function as key downregulators of immunogenic signaling. Both CD73 and CD39 are highly expressed not only on tumor cells but also on immune and endothelial cells within the tumor microenvironment. Conventional chemotherapy may further upregulate their expression, contributing to drug resistance and impaired immune responses. To counteract these effects, inhibitors of CD73 and CD39, both monoclonal antibodies and small molecules, are currently under clinical evaluation, with early results indicating potential therapeutic benefit. Although this evidence supports the involvement of CD73 and CD39 in modulating responses to immunotherapy, particularly in combination with chemotherapy, the precise mechanisms underlying these interactions remain unclear. Elucidating these pathways will be critical for optimizing treatment strategies and improving clinical outcomes in malignancies such as NSCLC. This review highlights the critical role of these pathways in optimizing treatment strategies and improving clinical outcomes in malignancies such as NSCLC. Full article

Background: Malignant pleural effusion (MPE) represents a frequent and clinically challenging manifestation of advanced malignancy, particularly in metastatic non-small cell lung cancer (NSCLC). Its management requires integration of diagnostic imaging, symptom-directed therapeutic strategies, and, increasingly, molecular profiling technologies. Recent advancements in this field based on liquid medium (so-called liquid biopsy) have achieved a significant increase in sensitivity, enhancing our ability to investigate biofluids and suggesting their potential integration into standard diagnostic practices, far beyond the canonical plasma biopsies. Fluid obtained from MPE after cytological sample centrifugation is rich in cell-free DNA and less susceptible to nucleic acid degradation during processing, improving overall diagnostic accuracy. Methods: This narrative review summarizes current evidence on the clinical management of malignant pleural effusions in patients with metastatic NSCLC, integrating imaging, procedural management, and molecular profiling from a multidisciplinary tumor board perspective. The primary objective was to synthesize contemporary knowledge with particular attention to the feasibility, reliability, and reproducibility of pleural fluid-based molecular testing. Results: MPE poses diagnostic and therapeutic challenges for all members of the multidisciplinary tumor board, traditionally associated with an adverse prognosis. However, recent advances in cytopathology, histopathology, and liquid-based techniques demonstrate that MPE could be an important source of prognostic or predictive information. At the same time, optimal patient management requires careful integration of imaging findings and procedural strategies (such as pleurodesis or indwelling pleural catheters) with individualized systemic therapy selection. Cell-free DNA in pleural effusions is a promising field of exploration and study, potentially suitable for future guideline implementation, after validation in adequately powered studies, contributing to improving patient management, particularly useful in fragile subsets. Conclusions: The management of MPE in advanced NSCLC is evolving toward a multidisciplinary, precision-oriented model that integrates clinical evaluation, imaging, procedural interventions, and molecular testing. Liquid biopsy technology has gained enough analytical robustness and clinical feasibility to be a useful tool in routine analysis. Biofluid-based molecular testing may have outstanding potential, contributing to improving patient management, avoiding repetitive procedures, and optimizing the overall efficiency and cost-effectiveness of diagnostic practices. Moreover, collaborative projects among different specialties help in consolidating trust in the tumor board decision-making process. Full article