Search Results (2,671)

Lung cancer (LC), with non-small-cell lung cancer (NSCLC) as its predominant subtype, remains the leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors (ICIs) have redefined the therapeutic paradigm in advanced NSCLC, durable responses are confined to a limited subset of patients. A major clinical challenge persists: the inability to accurately predict which patients will derive meaningful benefit, which will exhibit primary resistance, and which are at risk for severe immune-related toxicities. The imperative to individualize ICI therapy necessitates robust, dynamic, and accessible biomarkers. Liquid biopsy has emerged as a transformative, minimally invasive tool that enables real-time molecular and immunologic profiling. Through analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and peripheral blood immune components, liquid biopsy offers a window into both tumor intrinsic and host-related determinants of ICI response. These biomarkers not only hold promise for identifying predictive signatures—such as tumor mutational burden, neoantigen landscape, or immune activation states—but also for uncovering mechanisms of acquired resistance and guiding treatment adaptation. Beyond immunotherapy, liquid biopsy plays an increasingly central role in the landscape of targeted therapies, allowing early detection of actionable driver mutations and resistance mechanisms (e.g., EGFR T790M, MET amplification, and ALK fusion variants). Importantly, serial sampling via liquid biopsy facilitates longitudinal disease monitoring and timely therapeutic intervention without the need for repeated tissue biopsies. By guiding therapy selection, monitoring response, and detecting resistance early, liquid biopsy has the potential to significantly improve outcomes in NSCLC. Full article

Background: Combining pemetrexed (PEM) with Osimertinib (OSI) improves outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), but optimal scheduling remains undefined. Sequential PEM → OSI strategies may outperform concurrent administration; however, the critical dosing interval determining synergy has not been explored. Methods: PEM pharmacodynamics were divided into an OSI-antagonized early phase (S-phase arrest and DNA damage accumulation) and OSI-synergized late phase (DNA damage peak, apoptosis initiation, and feedback EGFR activation). Time-course profiling of cell cycle, DNA damage, apoptosis, and EGFR pathways was evaluated under monotherapy or sequential combination regimens to elucidate the mechanisms underlying synergistic/antagonistic effects. Results: OSI antagonizes PEM’s early phase via G1 arrest but potently enhances late-phase apoptosis through Rad51/thymidylate synthase suppression, Bim upregulation, and inhibition of EGFR signaling. The 48 h interval PEM → OSI uniquely enabled complete early-phase execution and aligned OSI exposure with late-phase initiation, yielding robust synergy across OSI-sensitive cell lines. In contrast, the 24 h interval PEM → OSI sequence demonstrated synergy only in PEM-sensitive PC9 cells. Both concurrent PEM + OSI and OSI → PEM sequence induced attenuated DNA damage and apoptotic signaling. Conclusions: The 48 h interval PEM → OSI sequence maximizes efficacy by temporally segregating antagonistic and synergistic interactions. This pharmacodynamically optimized regimen represents a promising strategy for clinical translation. Full article

The efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) varies widely across patients. Growing evidence indicates that the gut microbiome, through its interaction with the tumor microenvironment, may influence the response to immunotherapy. To investigate this, we analyzed fecal and tumor samples from 63 patients with inoperable NSCLC undergoing ICI therapy. Based on microbiome profiling using 16S rRNA sequencing, patients were grouped according to treatment benefit, defined as progression-free survival (PFS) of six months or longer. Associations between α-diversity indices, microbial composition at the genus and phylum levels, and a composite Sum Index of Binary Abundance (SIBA) were examined in relation to clinical outcomes. Higher microbial α-diversity was linked to improved response to ICIs (p-value = 0.0078 for the Chao1 index). Multiple specific taxa, such as Ruminococcus gauvreauii (p-value = 2 × 10⁻⁴), Ruminiclostridium 9 (p-value = 8 × 10⁻⁴), and [Eubacterium] ventriosum (p-value = 9 × 10⁻⁴), were enriched in patients with favorable outcomes, whereas Oscillibacter and the Eubacterium hallii group were associated with disease progression (p-value = 2 × 10⁻³ and 9 × 10⁻³, respectively). The SIBA index, which reflects the absence of multiple beneficial bacterial taxa, proved to be a stronger predictor of treatment response than individual taxa alone. Median SIBA values were 18 vs. 24 in patients benefiting from IO therapy compared to non-responders (p-value = 9 × 10⁻⁷). These findings suggest that gut microbiome diversity and composition are closely tied to immunotherapy outcomes in NSCLC. Composite microbial metrics like SIBA may enhance predictive accuracy and inform personalized treatment approaches. Full article

Targeted therapies against specific driver gene mutations have become the standard first-line treatment for most patients with advanced non-small cell lung cancer (NSCLC). While these therapies significantly prolong survival, the entire cancer treatment journey remains challenging and distressing. To better understand these experiences, this study employed a qualitative descriptive approach, conducting semi-structured interviews with 18 advanced NSCLC patients receiving targeted therapy, supplemented by patient journey logs. The resulting journey map delineated five stages: diagnosis, initial treatment, maintenance therapy, disease progression, and end-of-life. The analysis identified four key themes characterizing patient experiences at each stage. These findings enable healthcare professionals to identify risk situations and determine optimal timing for support interventions. Similarly, preparing patients for the processes they must undergo and the side effects of medical treatment helps reduce their uncertainty and anxiety, thereby improving their quality of life. Full article

Background: Pneumonectomy is a major surgical option for non-small cell lung cancer (NSCLC). This study evaluates the predictive value of three-dimensional computed tomography (3D-CT)-based lung volume analysis for postoperative function and explores its potential role in preoperative planning, risk assessment, and surgical decision-making. Methods: We evaluated 59 NSCLC patients who underwent pneumonectomy. Pre- and 12-month postoperative spirometry results were compared with anatomical and 3D-CT-based predictions. Residual lung expansion was calculated, and patients were grouped by a 3D-CT-derived volume ratio of ≥1.2 or <1.2. Results: There was a significant correlation between 3D-CT-based predicted FVC and FEV1 and postoperative spirometric values (p < 0.001). The mean residual lung volume expansion ratio was 1.23. Patients with a ratio ≥1.2 had significantly higher postoperative FVC (p = 0.028). Lung expansion was observed in 81.4% of cases. Predicted postoperative FVC (p = 0.023) and FEV1 (p = 0.013) were significantly higher in patients with left pneumonectomy compared to right. Conclusions: 3D-CT-based lung volume calculation reliably predicts postoperative function and matches conventional methods. Contralateral lung expansion positively affects respiratory outcomes. Additionally, 3D-CT analysis supports preoperative planning and risk assessment, contributing to more accurate diagnosis and surgical decisions in NSCLC management. Full article

The treatment landscape for EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) has evolved significantly with multiple combination regimens demonstrating superiority over single agent Osimertinib over the past two years. Recent trials such as FLAURA2 and MARIPOSA have explored intensified front-line regimens, with FLAURA2 demonstrating improvement in PFS with the addition of chemotherapy to Osimertinib and MARIPOSA, showing both a PFS and OS benefit with a novel combination regimen of Amivantamab and Lazertinib. However, these regimens are associated with significantly higher toxicity to patients and pose a huge financial and logistical burden to the health care system; therefore, treatment selection must therefore be individualized, considering disease biology, patient fitness, and toxicity burden. Post-progression strategies remain challenging due to resistance mechanisms like EGFR C797S mutations and MET amplification and the lack of data post-progression on novel first-line combinations. Ongoing trials are investigating fourth-generation EGFR TKIs, MET inhibitors, antibody–drug conjugates, and bispecific antibodies in subsequent lines. While regimens like Amivantamab-Lazertinib show promise even in second-line settings, toxicity, cost, and access remain barriers. As therapeutic options expand, biomarker-driven sequencing and personalized care will be critical to optimizing long-term outcomes in EGFR-mutated mNSCLC. Full article

Background: This study evaluated the prognostic significance of quantitatively assessed interstitial lung abnormalities (ILAs) after lung cancer surgery. Methods: We included patients with pathologic stage I non-small-cell lung cancer (NSCLC) who underwent segmentectomy or lobectomy. ILAs were quantified using deep learning texture analysis software. Five-year overall survival (OS) was compared before and after propensity score matching. Competing risks for lung cancer and non-cancer mortality were also analyzed. Results: Among the 1711 patients, 263 (15.4%) comprised the ILA group. The ILA group was older and had a higher proportion of smokers and pathologic stage IB cases (all p < 0.001). The median follow-up period was 48.0 months. Before matching, 5-year OS was significantly worse in the ILA group than in the non-ILA group (82.5% vs. 93.4%, p < 0.001). After 2:1 matching (N = 697), 5-year OS remained lower in the ILA group (85.8% vs. 91.1%, p = 0.025). Multivariable Cox regression analysis showed that the presence of ILAs was associated with increased risk of all-cause mortality (HR 1.52, 95% CI 1.05–2.18, p = 0.025). Restricted cubic spline analysis revealed a nonlinear increase in mortality risk with greater fibrotic ILA burden. In competing risk analysis, death from lung cancer was similar between groups (2.9% vs. 4.2%, p = 0.3), whereas death from other causes was significantly higher in the ILA group (13.0% vs. 3.7%, p < 0.001). Conclusions: Quantitative assessment of ILAs may provide prognostic value in resected stage I NSCLC, particularly in patients with fibrotic changes. Full article

Background: Mediastinal staging plays a critical role in guiding treatment decisions for non-small cell lung cancer (NSCLC). While mediastinoscopy has been the gold standard for assessing mediastinal lymph node involvement, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a minimally invasive alternative with comparable diagnostic accuracy. This systematic review evaluates the diagnostic performance, safety, cost-effectiveness, and feasibility of EBUS-TBNA versus mediastinoscopy for mediastinal staging. Methods: A systematic literature review was conducted in accordance with PRISMA guidelines, including searches in Medline, Scopus, EMBASE, and Cochrane databases for studies published from 2010 onwards. A total of 1542 studies were identified, and after removing duplicates and applying eligibility criteria, 100 studies were included for detailed analysis. The extracted data focused on sensitivity, specificity, complications, economic impact, and patient outcomes. Results: EBUS-TBNA demonstrated high sensitivity (85–94%) and specificity (~100%), making it an effective first-line modality for NSCLC staging. Mediastinoscopy remained highly specific (~100%) but exhibited slightly lower sensitivity (86–90%). EBUS-TBNA had a lower complication rate (~2%) and was more cost-effective, while mediastinoscopy provided larger biopsy samples, essential for molecular and histological analyses. The need for general anaesthesia, longer hospital stays, and increased procedural costs make mediastinoscopy less favourable as an initial approach. Combining both techniques in select cases enhanced overall staging accuracy, reducing false negatives and improving diagnostic confidence. Conclusions: EBUS-TBNA has become the preferred first-line mediastinal staging method due to its minimally invasive approach, high diagnostic accuracy, and lower cost. However, mediastinoscopy remains crucial in cases requiring posterior mediastinal node assessment or larger tissue samples. The integration of both techniques in a stepwise diagnostic strategy offers the highest accuracy while minimizing risks and costs. Given the lower hospitalization rates and economic benefits associated with EBUS-TBNA, its widespread adoption may contribute to more efficient resource utilization in healthcare systems. Full article

Systemic chemotherapy is a standard treatment for patients with stage IV cancer with distant metastases, and there is little evidence of the effectiveness of local treatments for distant metastatic lesions. However, in recent years, randomized phase II trials targeting oligometastases in lung cancer and solid tumors have reported that local therapy combined with systemic chemotherapy improves clinical outcomes. We reviewed previous clinical trials and demonstrated the efficacy of radiotherapy for oligometastatic disease. Stereotactic body radiotherapy (SBRT) is a promising treatment that achieves high local control rates for oligometastatic disease. Although SBRT generally does not cause severe adverse events, the safety of SBRT combined with systemic chemotherapy needs to be carefully considered. We discussed the efficacy and safety of SBRT and summarized the details of SBRT methods and techniques for each metastatic site. Further research and clinical trials are warranted to improve the efficacy of SBRT combined with systemic chemotherapy for oligometastatic non-small cell lung cancer (NSCLC). Full article

Background: Epidermal growth factor receptor (EGFR) mutations are presented in approximately 50% of East Asian populations with advanced non-small cell lung cancer (NSCLC). While EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment, patient outcomes are also influenced by host-related factors. This study aimed to investigate clinical and radiological factors associated with early mortality and develop a prognostic prediction model in advanced EGFR-mutated NSCLC. Methods: A retrospective cohort was conducted in patients with EGFR-mutated NSCLC treated with first line EGFR-TKIs from January 2012 to October 2022 at Chiang Mai University Hospital. Clinical data and radiologic findings at the initiation of treatment were analyzed. A multivariable flexible parametric survival model was used to determine the predictors of death at 18 months. The predicted survival probabilities at 6, 12, and 18 months were estimated, and the model performance was evaluated. Results: Among 189 patients, 84 (44.4%) died within 18 months. Significant predictors of mortality included body mass index <18.5 or ≥23, bone metastasis, neutrophil-to-lymphocyte ratio ≥ 5, albumin-to-globulin ratio < 1, and mean pulmonary artery diameter ≥ 29 mm. The model demonstrated good performance (Harrell’s C-statistic = 0.72; 95% CI: 0.66–0.78). Based on bootstrap internal validation, the optimism-corrected Harrell’s C-statistic was 0.71 (95% CI: 0.71–0.71), derived from an apparent C-statistic of 0.75 (95% CI: 0.74–0.75) and an estimated optimism of 0.04 (95% CI: 0.03–0.04). Estimated 18-month survival ranged from 87.1% in those without risk factors to 2.1% in those with all predictors. A web-based tool was developed for clinical use. Conclusions: The prognostic model developed from fundamental clinical and radiologic parameters demonstrated promising utility in predicting 18-month mortality in patients with advanced EGFR-mutated NSCLC receiving first-line EGFR-TKI therapy. Full article

Background and Objective: Insulinoma-associated protein 1 (INSM1) is a novel immunohistochemical marker with potential utility in identifying neuroendocrine differentiation in lung cancer. Unlike conventional neuroendocrine (NE) markers, INSM1 can potentially serve as a standalone diagnostic biomarker. This study presents the first meta-analysis assessing the diagnostic accuracy of using INSM1 to distinguish LCNEC and SCLC from other lung cancer subtypes, addressing the variability across individual studies. Methods: A systematic review and meta-analysis were conducted to comprehensively evaluate the diagnostic performance of INSM1 in the pathological classification of lung cancer. The online databases PubMed, Web of Science, and Embase were systematically searched for data collection. Studies reporting the sensitivity and specificity of INSM1 in diagnosing LCNEC and SCLC were included. Pooled estimates were calculated using two models: the NSCLC model, which distinguishes LCNEC from other non-small cell lung cancers (NSCLCs), and the lung cancer model, which differentiates both LCNEC and SCLC from non-neuroendocrine (non-NE) lung cancer. Results: Fourteen studies comprising 3,218 specimens were included in this systematic review and meta-analysis. In the NSCLC model, INSM1 demonstrated a pooled sensitivity of 0.67 (95% CI: 0.61–0.73) and specificity of 0.97 (95% CI: 0.96–0.98), with an area under the curve (AUC) of 0.943. In the lung cancer model, the pooled sensitivity and specificity were 0.86 (95% CI: 0.84–0.88) and 0.97 (95% CI: 0.96–0.98), respectively, with an AUC of 0.974. Conclusions: INSM1 demonstrated excellent diagnostic accuracy and consistently high specificity for pulmonary neuroendocrine carcinomas, supporting its utility as a reliable standalone immunohistochemical marker with the potential to replace conventional NE markers in the pathological diagnosis of LCNEC and SCLC. Full article

Background and Purpose: Stratification based on specific image biomarkers applicable in clinical settings could help optimize treatment outcomes for recurrent non-small cell lung cancer patients. For this purpose, we aimed to determine the clinical impact of positive delta changes (any difference above zero > 0) between baseline [¹⁸F]FDG PET/CT metrics before the first treatment course and reirradiation. Material/Methods: Forty-seven patients who underwent thoracic reirradiation with curative intent at our institute between 2013 and 2021 met the inclusion criteria. All patients had histologically verified NSCLC, ECOG (Eastern Cooperative Oncology Group) ≤ 2, and underwent [¹⁸F]FDG PET/CT for initial staging and re-staging before primary radiotherapy and reirradiation, respectively. The time interval between radiation treatments was at least nine months. Quantitative metabolic volume and intensity parameters were measured before first irradiation and before reirradiation, and the difference above zero (>0; delta change) between them was statistically correlated to locoregional control (LRC), progression-free survival (PFS), and overall survival (OS). Results: Patients were followed for a median time of 33 months after reirradiation. The median OS was 21.8 months (95%-CI: 16.3–27.3), the median PFS was 12 months (95%-CI: 6.7–17.3), and the median LRC was 13 months (95%-CI: 9.0–17.0). Multivariate analysis revealed that the delta changes in SULpeak, SUVmax, and SULmax of the lymph nodes significantly impacted OS (SULpeak p = 0.017; SUVmax p = 0.006; SULmax p = 0.006), PFS (SULpeak p = 0.010; SUVmax p = 0.009; SULmax p = 0.009), and LRC (SULpeak p < 0.001; SUVmax p = 0.003; SULmax p = 0.003). Conclusions: Delta changes in SULpeak, SUVmax, and SULmax of the metastatic lymph nodes significantly impacted all clinical endpoints (OS, PFS and LRC) in recurrent NSCLC patients treated with reirradiation. Hence, these imaging biomarkers could be helpful with regard to patient selection in this challenging clinical situation. Full article

Objectives: Circulating tumor DNA (ctDNA) has emerged as a reliable prognostic biomarker in both early- and late-stage non-small cell lung cancer (NSCLC) patients. However, its role in NSCLC with pleural dissemination (M1a), a subset of disease with indolent biology, remains to be elucidated. Methods: We collected 41 M1a patients with serial ctDNA and CEA monitoring. Progression-free survival (PFS) was assessed between patients with different levels of ctDNA and CEA. An independent cohort of 61 M1a patients was included for validation. Results: At the diagnostic landmark, the detection rates for ctDNA and CEA were 22% and 55%, respectively. Among patients who experienced disease progression with pleural metastases, only ten had detectable ctDNA in longitudinal timepoints, resulting in a sensitivity of 50%. Moreover, there was no significant difference in PFS between patients with longitudinally detectable and undetectable ctDNA (HR: 0.86, 95% CI 0.33–2.23, p = 0.76). In contrast, patients with a decreasing CEA trend within 3 months after diagnosis were associated with an improved PFS (HR: 0.22; 95% CI, 0.03–1.48, p = 0.004). This finding is confirmed in an independent M1a patient cohort. Conclusions: Together, our findings suggest that M1a NSCLC with isolated pleural dissemination may represent a “non-shedding” tumor type, where ctDNA shows limited diagnostic and prognostic value. Monitoring early changes in CEA could be a more cost-effective predictor of disease progression. Full article

Background/Objectives: Alterations in DNA damage repair mechanisms can impair the therapeutic effectiveness of cisplatin. MicroRNAs (miRNAs), key regulators of DNA damage repair processes, have been proposed as promising biomarkers for predicting the response to platinum-based chemotherapy (CT) in non-small cell lung cancer (NSCLC). In this study, by using a bioinformatics approach, we identified six miRNAs, which were differentially expressed (DE) between NSCLC patients characterized as responders and non-responders to platinum-based CT. We further validated the differential expression of the selected miRNAs on tumor and matched normal tissues from patients with resected NSCLC. Methods: Two miRNA microarray expression datasets were retrieved from the Gene Expression Omnibus (GEO) repository, comprising a total of 69 NSCLC patients (N = 69) treated with CT and annotated data from their response to treatment. Differential expression analysis was performed using the Linear Models for Microarray Analysis (Limma) package in R to identify DE miRNAs between responders (N = 33) and non-responders (N = 36). Quantitative real-time PCR (qRT-PCR) was used to assess miRNA expression levels in clinical tissue samples (N = 20). Results: Analysis with the Limma package revealed 112 DE miRNAs between responders and non-responders. A random-effects meta-analysis further identified 24 miRNAs that were consistently up- or downregulated in at least two studies. Survival analysis using the Kaplan–Meier plotter (KM plotter) indicated that 22 of these miRNAs showed significant associations with prognosis in NSCLC. Functional and pathway enrichment analysis revealed that several of the identified miRNAs were linked to key pathways implicated in DNA damage repair, including the p53, Hippo, PI3K and TGF-β signaling pathways. We finally distinguished a six-miRNA signature consisting of miR-26a, miR-29c, miR-34a, miR-30e-5p, miR-30e-3p and miR-497, which were downregulated in non-responders and are involved in at least three DNA damage repair pathways. Comparative expression analysis on tumor and matched normal tissues from surgically treated NSCLC patients confirmed their differential expression in clinical samples. Conclusions: In summary, we identified a signature of six miRNAs that are suppressed in NSCLC and may serve as a predictor of cisplatin response in NSCLC. Full article

Background: Consolidation therapy with durvalumab after definitive chemoradiotherapy (CRT) has become the standard care for patients with stage III non-small-cell lung cancer (NSCLC) following the PACIFIC trial. However, real-world data evaluating outcomes under routine clinical conditions remain limited, particularly in European cohorts. Methods: In this retrospective single-center study, we analyzed clinical data from 72 patients with stage III NSCLC treated with definitive CRT between 2017 and 2022. The patients were stratified by receipt of durvalumab consolidation. Univariable and multivariable Cox regression models were used to assess overall survival (OS) and progression-free survival (PFS). Stepwise variable selection based on the Akaike Information Criterion (AIC) was used to construct an optimized multivariable model. A sensitivity analysis with adjustment for treatment period (2017–2018 vs. 2019–2022) was conducted to account for the introduction of durvalumab into routine clinical practice. Results: Among 72 patients, 35 received durvalumab and 37 did not. The median OS was 2.08 years; the 3- and 5-year OS rates were 38.6% and 30.3%, respectively. Multivariable regression revealed significantly improved OS associated with Karnofsky performance status (KPS) > 80% (HR 0.29, p = 0.003), Charlson Comorbidity Index (CCI) ≤ 2 (HR 0.39, p = 0.009), and durvalumab treatment (HR 3.99, p = 0.008). PD-L1 expression ≥ 1% showed a trend toward improved OS (HR 3.72, p = 0.063). The median progression-free survival (PFS) for the total cohort was 1.17 years. The estimated 3- and 5-year PFS rates were 31.1% and 26.3%, respectively. Patients treated with durvalumab had a longer median PFS (20.5 months) compared to those without durvalumab (12.0 months). In the multivariable analysis, KPS > 80% (HR 0.29, p < 0.001), CCI ≤ 2 (HR 0.53, p = 0.048), and durvalumab treatment (HR 2.81, p = 0.023) were significantly associated with improved PFS. A sensitivity analysis adjusting for treatment period—reflecting the introduction of durvalumab into routine clinical practice from 2019—confirmed the robustness of these findings. Conclusions: Our findings support the clinical benefit of durvalumab consolidation following CRT in a real-world population, especially in patients with good performance status and low comorbidity burden. These results confirm and extend the PACIFIC trial findings into routine clinical practice, highlighting the prognostic value of functional status and comorbidity alongside PD-L1 expression. Full article