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The diagnosis of brain metastases (BMs) in patients with lung cancer (LC) predominantly relies on magnetic resonance imaging (MRI), a method that is constrained by high costs and limited accessibility. This study explores the potential of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) as screening biomarkers for BMs in LC patients. We conducted a retrospective analysis of 700 LC cases at the National Cancer Center, Korea, from July 2020 to June 2022, measuring sNfL and sGFAP levels at initial LC diagnosis. The likelihood of BM was evaluated using multivariate analysis and a predictive nomogram. Additionally, we prospectively monitored 177 samples from 46 LC patients initially without BM. Patients with BMs (n= 135) had significantly higher median sNfL (52.5 pg/mL) and sGFAP (239.2 pg/mL) levels compared to those without BMs (n = 565), with medians of 17.8 pg/mL and 141.1 pg/mL, respectively (p < 0.001 for both). The nomogram, incorporating age, sNfL, and sGFAP, predicted BM with an area under the curve (AUC) of 0.877 (95% CI 0.84-0.914), showing 74.8% sensitivity and 83.5% specificity. Over nine months, 93% of samples from patients without BM remained below the cutoff, while all patients developing BMs showed increased levels at detection. A nomogram incorporating age, sNfL, and sGFAP provides a valuable tool for identifying LC patients at high risk for BM, thereby enabling targeted MRI screenings and enhancing diagnostic efficiency.
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Biomarcadores de Tumor , Neoplasias Encefálicas , Proteína Ácida Fibrilar de la Glía , Neoplasias Pulmonares , Proteínas de Neurofilamentos , Humanos , Proteínas de Neurofilamentos/sangre , Femenino , Masculino , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Proteína Ácida Fibrilar de la Glía/sangre , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico , Estudios Retrospectivos , Nomogramas , Adulto , Imagen por Resonancia Magnética/métodos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy. METHODS: A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed. RESULTS: A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n = 173) had a significantly lower risk of progression or death from immunotherapy than the other group (n = 311) (PFS: hazard ratio [HR], 0.77 [95% confidence interval (CI), 0.62-0.96]; p = .018; OS: HR, 0.77 [95% CI, 0.1-0.98]; p = .032). In a propensity score-matched population, the winter group (n = 162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p = .009) than the other group (n = 162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p = .012). The trend toward longer survival in the winter group continued in subgroup analyses. CONCLUSIONS: Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons.
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PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.
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Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Humanos , Acrilamidas/uso terapéutico , Acrilamidas/farmacocinética , Acrilamidas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Compuestos de Anilina/farmacocinética , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Femenino , Persona de Mediana Edad , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Anciano , Adulto , Anciano de 80 o más Años , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Carcinomatosis Meníngea/secundario , Carcinomatosis Meníngea/tratamiento farmacológico , Carcinomatosis Meníngea/genética , Neoplasias Meníngeas/secundario , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/genética , Indoles , PirimidinasRESUMEN
Brain plasticity refers to the brain's ability to modify its structure, accompanied by its functional changes. It is influenced by learning, experiences, and dietary factors, even in later life. Accumulated researches have indicated that ginseng may protect the brain and enhance its function in pathological conditions. There is a compelling need for a more comprehensive understanding of ginseng's role in the physiological condition because many individuals without specific diseases seek to improve their health by incorporating ginseng into their routines. This review aims to deepen our understanding of how ginseng affects brain plasticity of people undergoing normal aging process. We provided a summary of studies that reported the impact of ginseng on brain plasticity and related factors in human clinical studies. Furthermore, we explored researches focused on the molecular mechanisms underpinning the influence of ginseng on brain plasticity and factors contributing to brain plasticity. Evidences indicate that ginseng has the potential to enhance brain plasticity in the context of normal aging by mediating both central and peripheral systems, thereby expecting to improve age-related declines in brain function. Moreover, given modern western diet can damage neuroplasticity in the long term, ginseng can be a beneficial supplement for better brain health.
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Self-assembly of designed molecules has enabled the construction of a variety of functional nanostructures. Specifically, adaptable self-assembly has demonstrated several advantageous features for smart materials. Here, we demonstrate that an α-helical coiled coil conjugated with a dendrimer can adapt to spatial restriction due to the strong steric repulsion between dendrimer chains. The adaptable transformation of a tetrameric coiled coil to a trimeric coiled coil can be confirmed using analytical ultracentrifugation upon conjugation of the dendrimer to the coiled coil-forming building block. Interestingly, circular dichroism spectroscopy analysis of the dendrimer conjugate revealed an unconventional trend: the multimerization of the coiled coil is inversely dependent on concentration. This result implies that the spatial crowding between the bulky dendritic chains is significantly stronger than that between linear chains, thereby affecting the overall assembly process. We further illustrated the application potential by decorating the surface of gold nanorods (AuNRs) with the adaptable coiled coil. The dendrimer-coiled coil peptide conjugate can be utilized to fabricate organic-inorganic nanohybrids with enhanced colloidal and thermal stabilities. This study demonstrates that the coiled coil can engage in the adaptable mode of self-assembly with the potential to form dynamic peptide-based materials.
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PURPOSE: STK3 has a central role in maintaining cell homeostasis, proliferation, growth, and apoptosis. Previously, we investigated the functional link between STK3/MST2, and estrogen receptor in MCF-7 breast cancer cells. To expand the investigation, this study evaluated STK3's higher expression and associated genes in breast cancer intrinsic subtypes using publicly available data. METHODS: The relationship between clinical pathologic features and STK3 high expression was analyzed using descriptive and multivariate analysis. RESULTS: Increased STK3 expression in breast cancer was significantly associated with higher pathological cancer stages, and a different expression level was observed in the intrinsic subtypes of breast cancer. Kaplan-Meier analysis showed that breast cancer with high STK3 had a lower survival rate in IDC patients than that with low STK3 expression (p < 0.05). The multivariate analysis unveiled a strong correlation between STK3 expression and the survival rate among IDC patients, demonstrating hazard ratios for lower expression. In the TCGA dataset, the hazard ratio was 0.56 (95% CI 0.34-0.94, p = 0.029) for patients deceased with tumor, and 0.62 (95% CI 0.42-0.92, p = 0.017) for all deceased patients. Additionally, in the METABRIC dataset, the hazard ratio was 0.76 (95% CI 0.64-0.91, p = 0.003) for those deceased with tumor. From GSEA outcomes 7 gene sets were selected based on statistical significance (FDR < 0.25 and p < 0.05). Weighted Sum model (WSM) derived top 5% genes also have higher expression in basal and lower in luminal A in association with STK3. CONCLUSION: By introducing a novel bioinformatics approach that combines GSEA and WSM, the study successfully identified the top 5% of genes associated with higher expression of STK3.
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Biomarcadores de Tumor , Neoplasias de la Mama , Carcinoma Ductal de Mama , Regulación Neoplásica de la Expresión Génica , Serina-Treonina Quinasa 3 , Anciano , Femenino , Humanos , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/metabolismo , Perfilación de la Expresión Génica , Estimación de Kaplan-Meier , Estadificación de Neoplasias , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Serina-Treonina Quinasa 3/análisis , Serina-Treonina Quinasa 3/genéticaRESUMEN
Interleukin-6 (IL-6) is a major pro-inflammatory cytokine for which the levels in plasma demonstrate a robust correlation with age and body mass index (BMI) as part of the senescence-associated secretory phenotype. IL-6 cytokines also play a crucial role in metabolic homeostasis and regenerative processes, primarily via the canonical STAT3 pathway. Thus, selective modulation of IL-6 signaling may offer a unique opportunity for therapeutic interventions. Recently, we discovered that a non-canonical signaling pathway downstream of tyrosine (Y) 814 within the intracellular domain of gp130, the IL-6 co-receptor, is responsible for the recruitment and activation of SRC family of kinases (SFK). Mice with constitutive genetic inactivation of gp130 Y814 (F814 mice) show accelerated resolution of inflammatory response and superior regenerative outcomes in skin wound healing and posttraumatic models of osteoarthritis. The current study was designed to explore if selective genetic or pharmacological inhibition of the non-canonical gp130-Y814/SFK signaling reduces systemic chronic inflammation and multimorbidity in a high-fat diet (HFD)-induced model of accelerated aging. F814 mice showed significantly reduced inflammatory response to HFD in adipose and liver tissue, with significantly reduced levels of systemic inflammation compared to wild type mice. F814 mice were also protected from HFD-induced bone loss and cartilage degeneration. Pharmacological inhibition of gp130-Y814/SFK in mice on HFD mirrored the effects observed in F814 mice on HFD; furthermore, this pharmacological treatment also demonstrated a marked increase in physical activity levels and protective effects against inflammation-associated suppression of neurogenesis in the brain tissue compared to the control group. These findings suggest that selective inhibition of SFK signaling downstream of gp130 receptor represents a promising strategy to alleviate systemic chronic inflammation. Increased degenerative changes and tissue senescence are inevitable in obese and aged organisms, but we demonstrated that the systemic response and inflammation-associated multi-morbidity can be therapeutically mitigated.
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In this study, we conduct simulation research on simultaneous desulfurization and denitrification in a multistaggered baffle spray scrubber. By employing two-phase flow simulations within the Euler-Lagrange framework and calculating the gas-liquid mass transfer rate with user-defined functions, we comprehensively analyzed the effects of various operational parameters. Initially, we validated our simulation model by comparing the simulation results with experimental data. Under conditions of a 0.2 mm droplet diameter, a liquid-to-gas ratio (L/G) of 12 L/m3, and a gas flow rate of 5 CMM using a full cone nozzle, the simulation indicated a desulfurization efficiency of 99.90 versus 99.84% obtained experimentally and a denitrification efficiency of 92.01 versus 90.67% obtained experimentally. This comparison confirmed the reliability of the simulation model. Our findings indicate that a droplet size of 2 mm is optimal, enhancing the desulfurization efficiency from 99.90 to 99.98% and the denitrification efficiency from 92.01 to 99.76%. However, when the droplet size exceeds 2 mm, efficiencies marginally decrease. Increasing the liquid-to-gas ratio to 16 L/m3 further improves desulfurization and denitrification efficiencies to 99.98 and 99.80%, respectively. In contrast, higher inlet flue gas flow rates reduce these efficiencies, with a decline observed from 100% to as low as 93.90% for denitrification with 2 mm droplets. Additionally, the use of a swirl cone nozzle, compared to full or hollow cone nozzles, better disperses droplets, enhancing the gas-liquid contact and achieving efficiencies of 99.99% for desulfurization and 99.81% for denitrification with 2 mm droplets. These insights are valuable for optimizing operational conditions in industrial-scale spray scrubbers, significantly contributing to mitigating the environmental impacts of industrial emissions.
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Immune checkpoint blockade (ICB) therapy targeting PD-L1 via monoclonal antibody (mAb) has shown extensive clinical benefits in the diverse types of advanced malignancies. However, most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism. Herein, we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes (immune checkpoint blockade liposomes; ICB-LPs) to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells. The ICB-LPs are prepared by formulation of DC8,9PC with photo-polymerized diacetylenic moiety, 1,2-dipalmitoylphosphatidylcholine (DPPC) and anti-PD-L1 peptide (D-form NYSKPTDRQYHF)-conjugated DSPE-PEG2k (anti-PD-L1-DSPE-PEG2k) in a molar ratio of 45:45:10, followed by cross-linking of liposomal bilayer upon UV irradiation. The 10 mol% anti-PD-L1-DSPE-PEG2k incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7 ± 1.04 nm, showing a high stability in serum condition. Importantly, the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane, which are endocytosed with aim to deliver PD-L1 to the lysosomes, wherein the durable PD-L1 degradation is observed for 72 h, in contrast to anti PD-L1 mAbs showing the rapid PD-L1 recycling within 9 h. The in vitro co-culture experiments with CD8+ T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis. When ICB-LPs are intravenously injected into colon tumor-bearing mice, they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting, inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation. Collectively, this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosomes.
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Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8-4.1] vs. 11.8 months [95% CI, 6.5-17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations.
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Immunosuppressants are increasingly being used in the clinic to manage immune-related adverse effects. Consequently, the incidence of secondary infections associated with immunosuppression is increasing. However, little is known about primary infections during immune checkpoint inhibitor (ICI) treatment without immunosuppressants. We aimed to evaluate primary infectious diseases during antiprogrammed death ligand-1 immunotherapy without immunosuppressants. We retrospectively screened medical records of 233 patients who underwent ICI treatment for advanced non-small cell lung cancer between January 2014 and May 2018 at National Cancer Center, Republic of Korea. Subsequently, we evaluated the clinical characteristics and treatment outcomes of selected patients hospitalized for potential infectious disease without immunosuppressive treatment (n=80). Eight cases (3.4%) were identified as bacterial pneumonia (n=5) and cellulitis, inflamed epidermoid cyst, and wound infection (n=1 each). The bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae were identified in 4 patients with pneumonia. The period between the start of ICI treatment and infection varied between 3 and 189 days (median, 24.5 days). Five (62.5%) patients were infected within a month after ICI treatment initiation. All patients were treated with empirical antibiotics and discharged without complications. The median progression-free and overall survival for ICI treatment was 11.5 and 25.5 months, respectively. Six patients experienced ICI-associated adverse effects postinfection: Herpes zoster infection (n=4) and pneumonitis (n=2). Infectious disease independent of immunosuppression is a rare, but possible event in patients with lung cancer receiving ICI treatment. Clinical awareness would enable prompt diagnosis of primary infection during immunotherapy.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Enfermedades Transmisibles , Neoplasias Pulmonares , Neumonía , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunosupresores/efectos adversos , Estudios Retrospectivos , Antineoplásicos Inmunológicos/uso terapéutico , Neumonía/epidemiología , Neumonía/etiología , Enfermedades Transmisibles/inducido químicamente , Enfermedades Transmisibles/tratamiento farmacológico , HospitalizaciónRESUMEN
PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC. MATERIALS AND METHODS: This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling. RESULTS: A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor ß, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS. CONCLUSION: NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Femenino , Persona de Mediana Edad , Masculino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Clorhidrato de Erlotinib/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Terapia Neoadyuvante , Microambiente Tumoral , Estadificación de Neoplasias , Proteínas Hedgehog/genética , Proteínas Hedgehog/uso terapéutico , Receptores ErbB/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
PURPOSE: This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment-related AEs occurred with lazertinib than gefitinib. CONCLUSION: Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Morfolinas , Pirazoles , Pirimidinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas , Receptores ErbB/genética , Receptores ErbB/metabolismo , República de Corea , Mutación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Understanding cancer treatment-related cardiovascular (CV) events is important for cancer care; however, comprehensive evaluation of CV events in patients with lung cancer is limited. This study aimed to assess the cumulative incidence and associated risks of various CV event types in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 7868 individuals aged 40 years and older, recently diagnosed with NSCLC (2007-2018), were assessed with data obtained from the National Cancer Center, Korea. This study included nine types of CV events. A 2-year cumulative incidence function (CIF) of CV events was estimated, with death as a competing event. The associated risks were assessed by subdistribution hazard ratio (sHR) in the Fine-Gray competing risks model. RESULTS: CV events were observed in 7.8% of patients with NSCLC, with the most frequently observed types being atrial fibrillation and flutter (AF) (2.7%), venous thromboembolic disease (2.0%), and cerebrovascular disease (CeVD) (1.5%). Overall, all CV events were highest in the group treated with systemic therapy (CIF, 10.6%; 95% confidence interval [CI], 9.5%-11.8%), followed by those treated with surgery (CIF, 10.0%; 95% CI, 8.6%-11.6%); the incidence of AF (CIF, 5.7%; 95% CI, 4.6%-7.0%) was highest in patients treated with surgery. Individuals treated with systemic therapy were found to exhibit a higher CeVD risk than those treated with surgery (sHR, 4.12; 95% CI, 1.66-10.23). Among the patients who underwent surgery, those with lobectomy and pneumonectomy had a higher AF risk (vs. wedge resection/segmentectomy; sHR, 7.79; 95% CI, 1.87-32.42; sHR, 8.10; 95% CI, 1.60-40.89). CONCLUSIONS: These findings revealed treatment-related CV event risks in patients with NSCLC, which suggests that the risk of AF in surgery and CeVD in systemic therapy should be paid more attention to achieve a better prognosis and improve cancer survivorship outcomes. PLAIN LANGUAGE SUMMARY: Atrial fibrillation and flutter (AF) is the most common cardiovascular event, particularly at a high risk in patients with non-small cell lung cancer (NSCLC) undergoing surgery. Patients receiving surgery with poor performance status, diagnosed with regional stage, and undergoing lobectomy or pneumonectomy are at a high risk of AF. Systemic/radiotherapy is associated with cerebrovascular and ischemic heart disease in patients with NSCLC.
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Fibrilación Atrial , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Adulto , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/radioterapia , Fibrilación Atrial/epidemiología , Fibrilación Atrial/cirugía , Pronóstico , Incidencia , NeumonectomíaRESUMEN
Recently, proton beam therapy (PBT) has gathered attention for improving outcomes and reducing toxicities in various cancers; however, the evidence for esophageal squamous cell carcinoma (ESCC) is lacking. Our study retrospectively evaluated the outcomes of PBT for ESCC patients at a single institute. The patients treated with PBT between November 2015 and February 2022 were included in the study, excluding those with distant metastases or those that had undertaken prior treatment for esophageal cancer (EC). The 3 year overall survival (OS) and progression-free survival (PFS) rates were calculated based on stage grouping. The patterns of failure, salvage treatment outcomes, and toxicity profiles were analyzed. The median follow-up was 35.1 months, and 132 patients were analyzed. The 3 year OS and PFS rates for the stages I, II, and III disease cases were 81.0%, 62.9%, and 51.3%; and 70.6%, 71.8%, and 39.8%, respectively. Nineteen patients presented isolated local progression, ten patients underwent appropriate salvage procedures, and nine were successfully salvaged. One patient with isolated regional progression was also salvaged. No cases of grade ≥ 4 lymphopenia were observed. One patient had grade 4 pericardial effusion and esophageal fistula. For the patients with ESCC, PBT is an effective treatment in terms of the survival outcomes and toxicities.
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Amivantamab is the first drug approved in EGFR exon 20 insertion-mutated NSCLC. Nevertheless, primary or secondary resistance to amivantamab is a frequent problem in clinical practice. We report a case of a patient with EGFR exon 20-mutated NSCLC who had primary resistance to amivantamab but was successfully treated by combining therapy of another EGFR exon 20 insertion-specific targeted drug mobocertinib and bevacizumab.
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OBJECTIVE: Based on the development of artificial intelligence (AI), an emerging number of methods have achieved outstanding performances in the diagnosis of acute myocardial infarction (AMI) using an electrocardiogram (ECG). However, AI-ECG analysis using a multicenter prospective design for detecting AMI has yet to be conducted. This prospective multicenter observational study aims to validate an AI-ECG model for detecting AMI in patients visiting the emergency department. METHODS: Approximately 9,000 adult patients with chest pain and/or equivalent symptoms of AMI will be enrolled in 18 emergency medical centers in Korea. The AI-ECG analysis algorithm we developed and validated will be used in this study. The primary endpoint is the diagnosis of AMI on the day of visiting the emergency center, and the secondary endpoint is a 30-day major adverse cardiac event. From March 2022, patient registration has begun at centers approved by the institutional review board. DISCUSSION: This is the first prospective study designed to identify the efficacy of an AI-based 12-lead ECG analysis algorithm for diagnosing AMI in emergency departments across multiple centers. This study may provide insights into the utility of deep learning in detecting AMI on electrocardiograms in emergency departments. Trial registration ClinicalTrials.gov identifier: NCT05435391. Registered on June 28, 2022.
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BACKGROUND: Understanding the mechanism behind immune cell plasticity in cancer metastasis is crucial for identifying key regulators. Previously we found that mitotic factors regulate epithelial-mesenchymal transition, but how these factors convert to metastatic players in the tumor microenvironment (TME) is not fully understood. METHODS: The clinical importance of mitotic factors was analyzed by heatmap analysis, a KM plot, and immunohistochemistry in lung adenocarcinoma (LUAD) patients. Immunoprecipitation, LC-MS/MS, kinase assay, and site-directed mutagenesis were performed for the interaction and phosphorylation. A tail-vein injection mouse model, Transwell-based 3D culture, microarray analysis, coculture with monocytes, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated FoxM1 in metastasis of TME. RESULTS: The phosphorylated FoxM1 at Ser25 by PLK1 acquires the reprogramming ability to stimulate the invasive traits in cancer and influence immune cell plasticity. This invasive form of p-FoxM1 upregulates the expression of IL1A/1B, VEGFA, and IL6 by direct activation, recruiting monocytes and promoting the polarization of M2d-like tumor-associated macrophages (TAMs). Upregulation of PD-L1 in LUAD having phosphomimetic FoxM1 facilitates immune evasion. In invasive LUAD with phosphomimetic FoxM1, IFITM1 is the most highly expressed through the activation of the STING-TBK1-IRF3 signaling, which enhances FoxM1-mediated signaling. Clinically, higher expression of FOXM1, PLK1, and IFITM1 is inversely correlated with the survival rate of advanced LUAD patients, providing a promising therapeutic strategy for the treatment of LUAD. CONCLUSION: FoxM1-based therapy would be a potential therapeutic strategy for LUAD to reduce TAM polarization, immune escape, and metastasis, since FoxM1 functions as a genetic reprogramming factor reinforcing LUAD malignancy in the TME.
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Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Animales , Ratones , Humanos , Factores de Transcripción Forkhead/metabolismo , Proteína Forkhead Box M1/genética , Macrófagos Asociados a Tumores/metabolismo , Cromatografía Liquida , Espectrometría de Masas en Tándem , Adenocarcinoma/patología , Neoplasias Pulmonares/genética , Microambiente TumoralRESUMEN
Organ cryopreservation would revolutionize transplantation by overcoming the shelf-life limitations of conventional organ storage. To prepare an organ for cryopreservation, it is first perfused with cryoprotectants (CPAs). These chemicals can enable vitrification during cooling, preventing ice damage. However, CPAs can also cause toxicity and osmotic damage. It is a major challenge to find the optimal balance between protecting the cells from ice and avoiding CPA-induced damage. In this study, we examined the organ perfusion process to shed light on phenomena relevant to cryopreservation protocol design, including changes in organ size and vascular resistance. In particular, we compared perfusion of kidneys (porcine and human) with CPA in either hypotonic or isotonic vehicle solution. Our results demonstrate that CPA perfusion causes kidney mass changes consistent with the shrink-swell response observed in cells. This response was observed when the kidneys were relatively fresh, but disappeared after prolonged warm and/or cold ischemia. Perfusion with CPA in a hypotonic vehicle solution led to a significant increase in vascular resistance, suggesting reduced capillary diameter due to cell swelling. This could be reversed by switching to perfusion with CPA in isotonic vehicle solution. Hypotonic vehicle solution did not cause notable osmotic damage, as evidenced by low levels of lactate dehydrogenase (LDH) in the effluent, and it did not have a statistically significant effect on the delivery of CPA into the kidney, as assessed by computed tomography (CT). Overall, our results show that CPA vehicle solution tonicity affects organ size and vascular resistance, which may have important implications for cryopreservation protocol design.
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Criopreservación , Hielo , Humanos , Animales , Porcinos , Criopreservación/métodos , Crioprotectores/farmacología , Riñón/diagnóstico por imagen , Soluciones Hipotónicas , PerfusiónRESUMEN
The adulteration of meat products using colourants and curing agents has heightened concerns over food safety, thereby necessitating the development of advanced detection methods. This study introduces a deep-learning-based spectroscopic method for swiftly identifying counterfeit beef altered to appear fresh. The experiment involved 60 beef samples, half of which were artificially adulterated using a colouring solution. Despite meticulous analysis of the beef's colour attributes, no significant differences were observed between the fresh and adulterated samples. However, our method, utilising a 344-1040 nm spectral range, achieved a classification accuracy of 98.84%. To enhance practicality, we employed gradient-weighted class activation mapping and identified the 580-600 nm range as particularly influential for classification. Remarkably, even when we narrowed the input to the model to this spectral range, a high level of classification accuracy was maintained. To further validate the model's robustness and generalisability, we allocated 70 beef samples to an external validation set. Comparative performance analysis revealed that our model outperformed traditional machine learning algorithms, such as SVM and logistic regression, by 9.3% and 28.4%, respectively. Overall, this study offers invaluable insights for detecting counterfeited beef, thereby contributing to the preservation of meat product quality and integrity within the food industry.