INTRODUCTION:Frozen section (FS) is the most widely used method to assess resected pulmonary lesions intraoperatively, although it also prolongs the operation time. We aimed to evaluate the accuracy of intraoperative rapid on-site evaluation (ROSE) and evaluate whether it can serve as a faster auxiliary judgment alongside FS. METHODS:A prospective study was conducted on patients undergoing complete resection. Rapid Romanowsky (DiffQuik) staining was used for ROSE. The results of intraoperative ROSE were compared with those of frozen section and final pathological diagnosis. RESULTS:A total of 75 patients were enrolled in the study, and 81 samples were taken for ROSE, which could assess biopsied samples within a few minutes. The time required for ROSE is significantly shorter than that for intraoperative frozen section analysis, and the mean time to diagnosis was significantly shorter for ROSE (by surgeon) than for FS (9.75 min vs. 29.70 min, p < 0.001). The diagnostic accuracy of ROSE was 90.1% for surgeons, 95.6% for experienced pathologists, and 81.5% for junior pathologists, respectively. CONCLUSION:ROSE can serve as an auxiliary judgment tool, enabling frozen sections to make intraoperative decisions more rapidly. It is a valuable technique for diagnosing lung tumor intraoperatively.
INTRODUCTION:Leptomeningeal metastasis (LM) is a devastating complication of lung cancer. We investigated the clinical and molecular evolution of LM in the modern targeted-therapy era and factors associated with post-LM survival. METHODS:We retrospectively analyzed 201 patients with cytologically confirmed lung cancer LM diagnosed between November 2012 and May 2026. Patients were classified by LM diagnosis date (2012-2016 vs. 2017-2026). Intervals from lung cancer and Stage IV diagnosis to LM were compared using the Mann-Whitney U test. Paired primary tumor and cerebrospinal fluid (CSF) molecular profiles were assessed in 80 patients. Overall survival (OS) was evaluated using Kaplan-Meier and prespecified multivariable cox analyses. RESULTS:Adenocarcinoma accounted for 93.0% of cases. The intervals from lung cancer and Stage IV diagnosis to LM were longer in the later cohort (23.7 vs. 13.8 months, p < 0.001; 17.4 vs. 10.4 months, p = 0.002). Unadjusted OS from LM diagnosis did not differ significantly between eras (9.8 vs. 11.3 months, p = 0.864). Tissue-CSF driver discordance occurred in 7/80 patients (8.75%). In multivariable analysis, later diagnostic era, smoking, and ECOG PS ≥ 2 were associated with higher mortality (adjusted HR, 1.826, p = 0.014; 1.847, p = 0.014; and 1.674, p = 0.007, respectively), whereas post-LM third-generation EGFR-TKI exposure was associated with lower mortality (adjusted HR, 0.385; p < 0.001). CONCLUSION:The later era was associated with a longer interval to LM diagnosis but no statistically significant improvement in unadjusted post-LM OS. Adjusted associations require cautious interpretation because of residual confounding and post-baseline treatment bias. CSF profiling may provide clinically relevant information beyond primary tumor genotyping.
BACKGROUND:Central nervous system (CNS) involvement remains a major cause of mortality in patients with epidermal growth factor receptor (EGFR)-mutated nonsmall cell lung cancer (NSCLC), particularly, after progression on EGFR tyrosine kinase inhibitors (TKIs). This pooled analysis evaluated the efficacy of lazertinib in patients with EGFR-mutated NSCLC and CNS involvement, using data from two Phase II trials. PATIENTS AND METHODS:Patients with EGFR-mutated NSCLC and CNS involvement following prior EGFR TKI therapy enrolled in the KCSG-LU20-15 and KCSG-LU21-01 were included. Overall and intracranial objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were assessed. RESULTS:Seventy-two patients were included. The median age was 63 years and 45 patients (62.5%) had leptomeningeal metastases (LM). T790M status was positive in 7 patients, negative in 44, and unknown in 21. Intracranial tumor responses were evaluable in 46 patients; the intracranial ORR was 50.0%, and the intracranial DCR was 97.8%. The median intracranial PFS was 15.2 months. Among 66 patients evaluable for systemic response, the overall ORR and DCR were 22.7% and 97.0%, respectively. The median PFS and overall survival were 10.6 and 17.8 months, respectively. Patients with LM experienced inferior OS and intracranial PFS compared with those without LM. No significant differences in clinical outcomes were observed according to T790M status. CONCLUSION:Lazertinib demonstrated meaningful CNS activity in patients with EGFR-mutated NSCLC and CNS involvement after prior EGFR TKI exposure, including those with LM. Notably, this activity was observed in a cohort with a low prevalence of confirmed T790M positivity.
ABSTRACT Background This study examined whether lobar‐specific dose‐volume histogram (DVH) parameters add predictive information for radiation pneumonitis (RP) beyond conventional whole‐lung parameters in patients with non‐small cell lung cancer (NSCLC) undergoing definitive radiotherapy. Methods We retrospectively analyzed 145 NSCLC patients treated between 2018 and 2023. Conventional whole‐lung parameters, including V5%, V20%, and mean lung dose (MLD), lobar‐specific parameters, including Low V20% (percentage of the bilateral lower lobes receiving ≥ 20 Gy), and clinical parameters were analyzed. The predictive performance of each parameter for Grade ≥ 2 RP was evaluated using receiver operating characteristic curve analysis. Associations with Grade ≥ 2 RP were assessed by Gray test and Fine‐Gray competing risks regression. Results Grade ≥ 2 RP had an incidence of 41% (60/145) and showed significant associations with V20% (p = 0.005), MLD (p = 0.025), Low V5% (p = 0.006), and Low V20% (p = 0.003). In multivariate analysis, a high Brinkman Index (BI) (HR = 2.10, 95% CI: 1.27–3.48, p = 0.004) and high Low V20% (HR = 2.31, 95% CI: 1.12–4.74, p = 0.023) were independent predictors for Grade ≥ 2 RP. The correlation between V20% and Low V20% was moderate (r = 0.505), with minimal multicollinearity (variance inflation factor 1.34). Conclusion Low V20% was independently associated with Grade ≥ 2 RP and may provide complementary information to conventional whole‐lung DVH parameters and BI. This simple lobar‐specific parameter may help refine pretreatment RP risk stratification, although external validation is required before its incorporation into individualized planning constraints.
ABSTRACT Osimertinib is standard therapy for EGFR‐mutant lung cancer, and HER2 amplification is a known resistance mechanism. We report HER2‐positive breast cancer showing durable regression during osimertinib monotherapy for synchronous EGFR‐mutated lung adenocarcinoma. Post‐treatment analysis showed marked regression, HER2 amplification, no detectable EGFR, HER2, or PIK3CA mutations, ER/PgR negativity, preserved PTEN, and reduced proliferative activity. These findings suggest ERBB pathway inhibition may have contributed, although the mechanism remains speculative without functional validation. This hypothesis‐generating observation describes unexpected breast cancer regression during osimertinib treatment.
ABSTRACT Tertiary lymphoid structures (TLS) have emerged as critical modulators of antitumor immunity in non‐small cell lung cancer (NSCLC), with growing evidence supporting their role as both prognostic biomarkers and functional targets in neoadjuvant chemoimmunotherapy. TLS are organized ectopic lymphoid aggregates that facilitate local antigen presentation, T and B cell activation, and memory immune responses within the tumor microenvironment. Their presence and maturation status correlate with favorable clinical outcomes and enhanced responsiveness to immune checkpoint inhibitors. Despite these insights, several obstacles hinder clinical translation. Current approaches remain limited in dynamically monitoring TLS evolution during treatment, and the underlying immunoregulatory mechanisms—particularly interactions among immune subsets, stromal components, and tumor cells—are not fully elucidated. Additionally, translation faces challenges including inter‐institutional variability, lack of standardized assessment criteria, and the need for multi‐center prospective validation. Integrating multimodal technologies—high‐plex imaging, spatial transcriptomics, and digital pathology—with AI‐based platforms holds promise for refined TLS characterization and real‐time monitoring. Near‐term priorities include optimizing dynamic monitoring techniques and establishing standardized scoring systems. Medium‐to‐long‐term priorities encompass multi‐center trials to validate TLS utility across diverse populations, identify novel drivers of TLS formation, and develop optimized combinatorial immunotherapy regimens that leverage TLS as both predictive biomarkers and therapeutic targets. By bridging basic immunology and clinical oncology, TLS are poised to emerge as key regulatory nodes in precision cancer immunotherapy, which may catalyze a paradigm shift in the neoadjuvant NSCLC landscape, enabling a closed‐loop management framework encompassing prediction, intervention, and dynamic efficacy optimization across the entire continuum of patient care.
ABSTRACT Background and Objective Non‐small cell lung cancer (NSCLC) is a leading cause of cancer‐related mortality worldwide. Cigarette smoke extract (CSE) is a major environmental factor driving NSCLC progression, yet the underlying molecular mechanisms remain incompletely understood. Protein arginine methyltransferase 6 (PRMT6) is implicated in various malignancies, including NSCLC, and epithelial–mesenchymal transition (EMT) contributes to metastasis and poor prognosis in this disease. However, the role of PRMT6 in CSE‐induced NSCLC progression has not been elucidated. Methods NSCLC progression under CSE exposure was assessed using a subcutaneous xenograft model in nude mice and in vitro assays in H1299 cells. Tumor growth and molecular alterations were evaluated by immunohistochemistry, CCK‐8, wound healing, Transwell, immunofluorescence, qRT‐PCR, and western blotting. Results CSE exposure enhanced H1299 cell proliferation, migration, and invasion in vitro and promoted xenograft tumor growth in vivo. This was accompanied by upregulated expression of PRMT6 and its effector H3R2me2a, elevated mesenchymal markers (N‐cadherin, MMP2, MMP9, vimentin), and transcription factors (Snail, TWIST1), and increased phosphorylation of PI3K p85, Akt, and mTOR. Notably, all CSE‐induced effects were abrogated by the PRMT6 inhibitor EPZ020411. Conclusion CSE promotes NSCLC progression by upregulating PRMT6, leading to PI3K/Akt/mTOR activation and EMT induction. These findings highlight PRMT6 as a potential therapeutic target in NSCLC.
ABSTRACT Background Type 2 diabetes mellitus (DM) is implicated in cancer development and associated with poor survival in patients with cancer. However, the impact of DM on the outcome of small cell lung cancer (SCLC) remains unknown. This study investigated the correlation between DM and clinical outcomes and long‐term prognosis of patients with extensive‐stage small cell lung cancer (ES‐SCLC). Methods This retrospective cohort study was conducted using the medical records of patients with ES‐SCLC treated with immune checkpoint inhibitors (ICIs) and chemotherapy. The demographic and clinical characteristics were retrospectively analyzed. Univariate and multivariate analyses were performed using Cox proportional hazards regression to evaluate the impact of the clinical characteristics on survival. Progression‐free survival (PFS) and overall survival (OS) were compared between patients with or without DM. Results Of the 91 patients with ES‐SCLC, 32 were diagnosed with DM before ES‐SCLC (35.2%). Patients with DM had significantly shorter median PFS (6 vs. 15 months, p = 0.026) and median OS (12 vs. 22 months, p = 0.013) than those without diabetes, despite receiving comparable chemoimmunotherapy. Multivariate cox regression analysis showed that DM was an independent risk factor for shorter mOS (HR 2.05, 95% CI 1.02–4.13, p = 0.044). Conclusions Patients with ES‐SCLC and comorbid diabetes exhibited significantly shorter OS and PFS compared with those without diabetes. DM serves as an independent adverse prognostic risk factor for ES‐SCLC.
ABSTRACT The clinicopathological and therapeutic landscape of lung neuroendocrine tumors (NETs) is continuously evolving. Although systemic chemotherapy has historically represented a management cornerstone, the available data are predominantly retrospective and outdated. A critical review of the current literature and public clinical trial registries was performed to evaluate the role of chemotherapy and targeted cytotoxic delivery systems in lung NETs. Given the nature of the review, the evidence was synthesized descriptively. In early‐stage disease, the clinical utility of perioperative (neoadjuvant and adjuvant) chemotherapy remains uncertain and lacks universal standardization. In the advanced or metastatic setting, traditional platinum/etoposide regimens demonstrate suboptimal efficacy in controlling well‐differentiated carcinoids. Conversely, oral alkylating agents (temozolomide) and combination schedules such as CAPTEM (capecitabine/temozolomide) or temozolomide paired with cabozantinib offer promising response and disease control rates. Future strategies are moving away from unselected systemic cytotoxicity toward targeted delivery and chemo‐immunotherapy platforms, leveraging peptide‐drug conjugates (PDCs like PEN‐221), antibody‐drug conjugates (ADCs), and bispecific T‐cell engagers (BiTEs) directed against emerging surface targets such as DLL3 (e.g., tarlatamab) and TROP2. There is an urgent, unmet clinical need for prospective, multicenter clinical trials and international registries. Dissecting the complex molecular landscape of lung NETs will be essential to identify predictive biomarkers and actionable therapeutic targets, ultimately transitioning clinical management from empirical, extrapolated choices to robust, evidence‐based, stage‐specific standards of care.
ABSTRACT MET exon 14 skipping is an actionable oncogenic driver in non–small cell lung carcinoma (NSCLC); however, noncanonical splice‐region variants are frequently classified as variants of unknown significance (VUS), which may result in missed therapeutic opportunities and highlight limitations in current DNA next‐generation sequencing (NGS) reporting criteria. We report a patient with pulmonary sarcomatoid carcinoma harboring a noncanonical MET splice donor–proximal indel (c.3022_3028 + 13delinsA), initially interpreted as a VUS, who achieved a rapid and durable response to capmatinib. Subsequent RNA sequencing and droplet digital PCR (ddPCR) confirmed MET exon 14 skipping, supporting the value of orthogonal transcript‐level validation for exon‐adjacent variants.
BACKGROUND:Phase II and III trials have demonstrated progression-free survival (PFS) benefits of pyrotinib plus capecitabine over lapatinib plus capecitabine in HER2-positive metastatic breast cancer (MBC). However, long-term overall survival (OS) data from a single-center cohort remain limited. This pooled analysis compared OS between the two regimens and explored outcomes across prespecified subgroups. METHODS:We included patients with HER2-positive MBC from our center enrolled in a Phase Ic study, a Phase II study, or the Phase III PHOEBE trial. The primary endpoint was OS. OS was analyzed using Kaplan-Meier estimates, log-rank tests, and a multivariable Cox model adjusted for ECOG performance status, pathological grade, prior anti-HER2 therapy, trastuzumab exposure duration, trastuzumab resistance, and prior chemotherapy lines. The proportional hazards assumption was assessed using Schoenfeld residuals. Exploratory subgroup analyses used prespecified categories. RESULTS:At data cutoff, 82 patients were included; 53 received pyrotinib plus capecitabine and 29 received lapatinib plus capecitabine. Baseline characteristics were comparable between groups. Median OS was 74.61 months (95% CI 41.10-not reached) with pyrotinib plus capecitabine and 30.98 months (26.12-50.76) with lapatinib plus capecitabine (log-rank p = 0.0053). Cox models suggested a reduced risk of death with pyrotinib plus capecitabine. Subgroup analyses were exploratory and should be interpreted cautiously because several subgroup estimates were imprecise. CONCLUSION:In this single-center pooled analysis, pyrotinib plus capecitabine was associated with significantly longer OS than lapatinib plus capecitabine in patients with HER2-positive MBC. These exploratory results are consistent with prior Phase II/III trials and provide evidence supporting the OS benefit of pyrotinib.
ABSTRACT Background Pleural mesothelioma (PM) is an aggressive cancer with limited therapeutic options and poor prognosis, necessitating comprehensive model systems for mechanistic studies and drug discovery. Methods Tumor cells were isolated from malignant pleural effusion of PM patients and subjected to primary culture and continuous passaging. Cell lines were successfully established after more than 40 continuous passages in vitro. Cell identification included morphological analysis, species identification, short tandem repeat (STR) profiling, mycoplasma detection, in vitro proliferation assays, in vivo tumorigenicity testing in NOD/SCID mice, and immunohistochemical characterization. Genomic landscapes and transcriptomic profiling were defined by whole‐exome, whole‐genome sequencing, and RNA‐sequencing. Results Three Chinese‐derived pleural mesothelioma cell lines (PUMC‐MESO1, PUMC‐MESO3, and PUMC‐MESO4) were successfully established. All three cell lines exhibited epithelioid morphology with adherent growth patterns. Upon subcutaneous transplantation into NOD/SCID mice, PUMC‐MESO1 and PUMC‐MESO4 demonstrated tumorigenicity, while PUMC‐MESO3 remained non‐tumorigenic after 3 months of observation. Histopathological examination confirmed their mesothelioma origin through positive staining for mesothelial markers including calretinin, WT‐1, and D2‐40. Genomic analysis revealed characteristic PM genomic alterations including mutations in BAP1 , NF2, and TP53 , along with CDKN2A deletions. Transcriptomic analyses revealed heterogeneous molecular features among the three cell lines. Although the PUMC‐MESO cell lines displayed distinct clustering patterns relative to the CCLE mesothelioma cohort, each retained transcriptomic similarities to specific established mesothelioma models. Drug sensitivity assays further demonstrated heterogeneous responses to standard therapeutic agents. Conclusion This study reports the establishment and characterization of three novel PM cell lines. These models recapitulate key aspects of PM biology, exhibit diverse therapeutic responses, and provide a valuable new resource for investigating disease mechanisms and advancing precision oncology research.
ABSTRACT Background Managing perioperative aspirin for secondary prevention during lung resection balances major bleeding against catastrophic thromboembolism. Evidence guiding this scenario, especially for real‐world strategies involving switches from other antiplatelets, remains limited for anatomical resections. Methods This retrospective study (2018–2025) included 625 patients undergoing anatomical lung resection. We compared aspirin continuation (Group 1, n = 94; chronic users or clopidogrel switchers) with no‐therapy controls (Group 3, n = 468). Inverse probability of treatment weighting (IPW) was used to balance 16 predefined covariates. The discontinuation group (Group 2, n = 63) served as a descriptive clinical reference. Primary endpoints were major bleeding (reoperation, ≥ 4 units RBC transfusion, or death) and major adverse cardiac and cerebrovascular events (MACCEs) within 30 days. Results After IPW adjustment, all covariates achieved satisfactory balance (SMD < 0.1). Group 1 showed a potential trend toward increased major bleeding (odds ratio [OR], 5.87; 95% confidence interval [CI], 0.80–42.91; p = 0.08), but no significant difference in MACCE (OR, 1.51; 95% CI, 0.35–6.45; p = 0.58) compared to Group 3. In adjusted linear regression, aspirin was not an independent predictor of intraoperative blood loss ( p = 0.25). Notably, Group 2 (discontinuation) exhibited alarmingly high rates of MACCE (7.9%) and 90‐day mortality (4.8%). Analyses for rare events were statistically underpowered. Conclusion Continuing aspirin showed a nonsignificant trend toward increased major bleeding, so its overall safety remains uncertain. However, the high event rates after stopping therapy highlight the significant risk of thromboembolism. Clinical judgment must carefully balance individual thrombotic benefits with potential bleeding risks.
ABSTRACT Background The prognostic value of CT‐detected tumor necrosis in advanced non‐small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) monotherapy remains unclear. This two‐center retrospective study investigated whether tumor necrosis on pretreatment CT independently predicts overall survival (OS). Methods A total of 151 advanced NSCLC patients who received ICI monotherapy between March 2016 and August 2021 at two Japanese institutions were retrospectively analyzed. Tumor necrosis was visually assessed and operationally defined as an intratumoral area of low attenuation or cavitary lesion ≥ 5 mm on pretreatment chest CT (contrast‐enhanced in 113 patients [75%] and non‐contrast in 38 [25%]). Cox regression analyses identified independent prognostic factors for OS, with internal validation using 1000 bootstrap resamples. Results Among 151 patients (mean age 69 years; 90% with ECOG PS 0–1), 121 (80%) had CT‐detected necrosis. Median OS was significantly shorter in necrosis‐positive patients than in necrosis‐negative patients (374 vs. 1035 days; log‐rank p = 0.02). A multivariate Cox regression analysis identified tumor necrosis as an independent adverse prognostic factor (HR = 1.84, 95% CI = 1.03–3.30; p = 0.04), along with blood‐based biomarkers, tumor size, and PD‐L1 expression. The detection rate of necrosis differed between CT modalities (contrast‐enhanced 84% vs. non‐contrast 68%, p = 0.04). Conclusion This exploratory two‐center retrospective study indicates the potential of CT‐detected tumor necrosis as a readily accessible prognostic marker in ICI‐treated NSCLC. However, the results obtained require validation in larger, prospective, multicenter studies with standardized CT imaging protocols before clinical implementation.
ABSTRACT Background In pathology‐enriched referred hospital cohorts, stable radiologic‐pathologic linkage is often unavailable, so patient‐level malignant pathology may be a more reliable endpoint than lesion‐specific malignancy. We aimed to develop and internally validate a blood‐based model for patient‐level malignant‐versus‐benign pathology discrimination. Methods We retrospectively reviewed 283 consecutive eligible source records from 22 February 2023 to 12 May 2025. After excluding unclassifiable pathology, lesions > 30 mm when verifiable, and obvious extrapulmonary primary tumors, we defined a strict primary cohort. A prespecified complete‐case logistic regression model including FR + CTC, peripheral CD8 count, age, and sex was developed and internally validated with bootstrap resampling. Results The strict primary cohort included 234 patients (166 malignant, 68 benign). In the main model ( n = 232), FR + CTC was associated with higher odds of malignant pathology (OR 1.31 per 1 FU/3 mL, 95% CI: 1.14–1.50; p < 0.001), whereas peripheral CD8 count was inversely associated (OR 0.50 per 100 cells/μL, 95% CI: 0.41–0.61; p < 0.001). Apparent and optimism‐corrected AUCs were 0.877 and 0.867, respectively. Adding an adjudicated patient‐level CT vascular sign yielded limited incremental value. Conclusion In this retrospective single‐center, pathology‐enriched cohort, FR + CTC and peripheral CD8 provided useful internally validated discrimination for patient‐level malignant pathology. The model requires external validation and setting‐appropriate recalibration before broader clinical use.
ABSTRACT Typical carcinoid tumors (TC) are a low‐grade neuroendocrine tumor characterized by low proliferation activity and an overall favorable prognosis. Lympho‐vascular invasion is uncommon in TC and is more frequently associated with atypical carcinoid. We reported a 46‐year‐old non‐smoking woman who underwent right lower lobectomy for a right pulmonary hilar mass after multidisciplinary team (MDT) evaluation (cT1cN0M0, AJCC 9th edition, IA3). Postoperative histopathological examination confirmed typical carcinoid tumor with a low Ki‐67 proliferation index (< 2%), and no tumor necrosis was identified, fulfilling the diagnostic criteria for typical carcinoid according to the current WHO classification of thoracic tumors. Unexpectedly, focal lympho‐vascular invasion in the form of tumor emboli was identified. Additionally, the resected lung showed caseating granulomatous inflammation with acid‐fast bacilli, suggestive of a non‐tuberculous mycobacteria (NTM) infection; however, species‐level identification was not performed. No lymph node metastasis was detected (pT1cN0M0, AJCC 9th edition, IA3). The patient had minimal pleural effusion on the surgical side postoperatively, and no signs of recurrence or metastasis have been detected during 20 months of follow‐up to date. This report highlights a pathological discordance between the low proliferation index and the presence of lympho‐vascular invasion in TC. The concomitant granulomatous inflammation may have contributed to diagnostic complexity, although a causal relationship cannot be established. This case underscores the importance of careful histopathological evaluation for invasive features in typical carcinoid tumors, even in the context of low proliferative activity. Surgical treatment alone might be safe in this specific scenario.
ABSTRACT Anaplastic lymphoma kinase (ALK) rearrangements are rare in lung squamous cell carcinoma (LSCC), with the clinical efficacy of ALK tyrosine kinase inhibitors (TKIs) in patients harboring uncommon ALK fusions remaining poorly characterized. We report here the first identification of a novel MTHFD1L‐ALK fusion in a 63‐year‐old male with a heavy smoking history diagnosed with stage IIIC LSCC. The patient initially received induction therapy with the ALK TKI iruplinalkib, achieving a best response of stable disease (SD). Although subsequent chemoradiotherapy yielded a partial response (PR), disease progression occurred after four cycles of maintenance iruplinalkib, with a progression‐free survival (PFS) of 8.28 months. Subsequent lorlatinib provided limited benefit, with disease progression at 5.3 months following treatment self‐discontinuation. Retrospective immunohistochemical staining of ALK (D5F3) was negative despite the positive genomic finding. This case demonstrates limited clinical benefit from ALK inhibitors in LSCC with this novel fusion, expands the known mutational spectrum in non‐small cell lung cancer (NSCLC), and underscores the critical importance of confirming novel fusions at the protein expression level through multimodal testing.
ABSTRACT Background The optimal sequencing of brain‐directed radiation and systemic therapy in stage IV non–small cell lung cancer (NSCLC) with brain metastases remains uncertain in the era of CNS‐active systemic agents. We evaluated survival outcomes using national real‐world data. Methods We conducted a retrospective cohort study of adults diagnosed between 2010 and 2022 with stage IV NSCLC and brain metastases in the National Cancer Database who received both brain‐directed radiation and systemic therapy. Treatment sequence was classified as radiation‐first or systemic‐first based on initiation dates. Multivariable Cox proportional hazards models, stratified by treatment era (pre‐2015 vs. 2015+), assessed associations with overall survival (OS), adjusting for demographic, clinical, tumor, and treatment factors. Propensity score matching and delayed‐entry sensitivity analyses were performed to address confounding and immortal time bias. Results Among 45 577 patients, 78.3% received radiation‐first and 21.7% received systemic therapy first. Unadjusted Kaplan–Meier analysis showed no significant difference in OS (log‐rank p = 0.624). In multivariable analysis, systemic‐first sequencing was associated with a modest increase in mortality (adjusted hazard ratio [aHR] 1.06; 95% CI: 1.04–1.09), which was consistent in propensity‐matched (HR 1.07; 95% CI: 1.04–1.11) and delayed‐entry analyses (aHR 1.09; 95% CI: 1.07–1.12). The use of systemic‐first therapy increased over time. Established prognostic factors demonstrated larger effect sizes. Conclusion Systemic‐first sequencing was associated with a modest increase in adjusted mortality; however, the effect size was small relative to established prognostic factors and likely influenced by residual confounding and selection bias. These findings support individualized, multidisciplinary treatment decisions rather than a uniform sequencing strategy.
ABSTRACT Background Lung cancer is the leading cause of cancer‐related deaths worldwide. Although osimertinib is more effective than previous‐generation drugs, its efficacy is often limited by both primary and acquired resistance. Cycling cancer persister cells (CPCs) have recently emerged as a transient, drug‐tolerant subpopulation that may contribute to early resistance to targeted therapies. However, their biological characteristics and role in osimertinib resistance remain poorly understood. Methods We established osimertinib‐resistant CPCs derived from epidermal growth factor receptor ( EGFR) ‐mutant non‐small‐cell lung cancer (NSCLC) cell lines PC9 and HCC827. RNA sequencing (RNA‐seq) was performed to identify CPC‐specific transcriptional programs. Results RNA‐seq analyses demonstrated that the tumor necrosis factor alpha (TNF‐α)/nuclear factor‐κB (NF‐κB) signaling pathway was upregulated in osimertinib‐resistant PC9 cells (PC9‐CPCs), with interleukin‐1 alpha (IL‐1α) being the most significantly overexpressed gene. Treatment with IL‐1α increased TNF‐α and NF‐κB p65 expression in PC9 parental cells, whereas IL‐1α inhibition decreased TNF‐α expression in PC9‐CPCs. Consequently, the inhibition of either IL‐1α or TNF‐α restored the sensitivity of EGFR ‐mutant NSCLC cells to osimertinib. Immunohistochemical analysis confirmed that NF‐κB expression was higher in tumor specimens from patients who had developed osimertinib resistance than in specimens collected before treatment. Conclusion CPCs exhibit a distinct inflammatory phenotype driven by IL‐1α–driven activation of the TNF‐α/NF‐κB axis, representing an alternative mechanism underlying osimertinib resistance. Targeting IL‐1α or TNF‐α may provide a promising strategy to overcome resistance in patients with EGFR ‐mutant NSCLC.
ABSTRACT Background Malignant pleural effusion (MPE) is a common manifestation in advanced malignancies. However, its differentiation from benign pleural effusions, such as parapneumonic effusion (PPE) and tuberculous pleural effusion (TPE), remains challenging. This study aimed to profile differentially expressed proteins and metabolites between MPE, PPE, and TPE. Methods Pleural effusion samples from patients with MPE, PPE, and TPE were collected and subjected to proteomic and metabolomic profiling. Differentially expressed proteins (DEPs) and differentially abundant metabolites (DAMs) were identified, followed by functional enrichment analyzes. Integrated proteome–metabolome analysis was performed to construct protein–metabolite interaction networks and reveal key pathways associated with malignant and benign pleural effusions. Results Proteomic and metabolomic profiles differed significantly between MPE and non‐MPE. Arginine‐proline and glutamate metabolism were commonly enriched at both protein and metabolite levels in MPE versus PPE and TPE. At the protein level, Isocitrate Dehydrogenase 1 (IDH1) was significantly upregulated in MPE compared with both PPE and TPE. At the metabolite level, sarcosine and l ‐glutamine were markedly elevated, while creatine was significantly decreased in MPE. Integrated analysis further indicated that these four molecules play important roles in distinguishing MPE from PPE and TPE. Conclusion Combined proteomic and metabolomic analyzes revealed the critical involvement of IDH1 in glutamate metabolism and arginine and proline metabolic pathways during MPE metabolic reprogramming. Identified molecules, including IDH1, l ‐glutamine, creatine, and sarcosine, may serve as potential diagnostic biomarkers for differentiating malignant from benign pleural effusions.
