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Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificaciónAsunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: The efficacy and safety of video-assisted thoracoscopic surgery (VATS) versus open thoracotomy in the treatment of non-small cell lung cancer (NSCLC) were evaluated with a focus on mediastinal lymph node dissection, postoperative recovery, and longterm outcomes including survival rates and disease-free intervals. Materials and Methods: This retrospective study analyzed data from 228 NSCLC patients treated at the Institute of Oncology Bucharest from 2016 to 2022. Both VATS and open surgical approaches were compared, with variables including demographic data, comorbidities, surgical outcomes, and postoperative complications meticulously recorded. Statistical significance was assessed using chi-square and independent samples t-tests. Results: Among the findings, VATS demonstrated significantly better two-year progression-free survival rates for patients in early stages (Stages 1-3) of NSCLC compared to open surgery, with p-values 0.01 and 0.001, respectively. In contrast, no significant difference was observed in Stage 4. Furthermore, VATS resulted in shorter operative times (mean 299 vs. 347 minutes, p 0.001), less estimated blood loss (98.68 mL vs. 160.88 mL, p 0.001), reduced chest tube duration (5.78 days vs. 12.17 days, p 0.001), and decreased hospital stays (12.0 days vs. 27.7 days, p 0.001). Conclusions: VATS is associated with improved long-term disease-free survival for early-stage NSCLC and more favorable short-term surgical outcomes, highlighting its advantages over open thoracotomy. Despite its benefits, VATS did not significantly reduce postoperative complications compared to open surgery.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Escisión del Ganglio Linfático , Estadificación de Neoplasias , Tempo Operativo , Neumonectomía , Cirugía Torácica Asistida por Video , Toracotomía , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Cirugía Torácica Asistida por Video/métodos , Estudios Retrospectivos , Masculino , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Femenino , Persona de Mediana Edad , Toracotomía/métodos , Anciano , Resultado del Tratamiento , Neumonectomía/métodos , Neumonectomía/mortalidad , Escisión del Ganglio Linfático/métodos , Tasa de Supervivencia , Adulto , Rumanía/epidemiología , Supervivencia sin Enfermedad , Tiempo de Internación/estadística & datos numéricosRESUMEN
PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Clorhidrato de Erlotinib , Gefitinib , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Anciano , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Receptores ErbB/antagonistas & inhibidores , Gefitinib/administración & dosificación , Gefitinib/uso terapéutico , Gefitinib/farmacología , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Afatinib/administración & dosificación , Afatinib/uso terapéutico , Afatinib/farmacología , Estudios de Cohortes , Anciano de 80 o más Años , AdultoRESUMEN
OBJECTIVES: Although neoadjuvant immunochemotherapy has been widely applied in non-small cell lung cancer (NSCLC), predicting treatment response remains a challenge. We used pretreatment multimodal CT to explore deep learning-based immunochemotherapy response image biomarkers. METHODS: This study retrospectively obtained non-contrast enhanced and contrast enhancedbubu CT scans of patients with NSCLC who underwent surgery after receiving neoadjuvant immunochemotherapy at multiple centers between August 2019 and February 2023. Deep learning features were extracted from both non-contrast enhanced and contrast enhanced CT scans to construct the predictive models (LUNAI-uCT model and LUNAI-eCT model), respectively. After the feature fusion of these two types of features, a fused model (LUNAI-fCT model) was constructed. The performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. SHapley Additive exPlanations analysis was used to quantify the impact of CT imaging features on model prediction. To gain insights into how our model makes predictions, we employed Gradient-weighted Class Activation Mapping to generate saliency heatmaps. RESULTS: The training and validation datasets included 113 patients from Center A at the 8:2 ratio, and the test dataset included 112 patients (Center B n=73, Center C n=20, Center D n=19). In the test dataset, the LUNAI-uCT, LUNAI-eCT, and LUNAI-fCT models achieved AUCs of 0.762 (95% CI 0.654 to 0.791), 0.797 (95% CI 0.724 to 0.844), and 0.866 (95% CI 0.821 to 0.883), respectively. CONCLUSIONS: By extracting deep learning features from contrast enhanced and non-contrast enhanced CT, we constructed the LUNAI-fCT model as an imaging biomarker, which can non-invasively predict pathological complete response in neoadjuvant immunochemotherapy for NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Aprendizaje Profundo , Neoplasias Pulmonares , Terapia Neoadyuvante , Tomografía Computarizada por Rayos X , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Masculino , Femenino , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Tomografía Computarizada por Rayos X/métodos , Inmunoterapia/métodos , Imagen Multimodal/métodosRESUMEN
This study aimed to explore potential radiomics biomarkers in predicting the efficiency of chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients were prospectively assigned to receive chemo-immunotherapy, and were divided into a primary cohort (n = 138) and an internal validation cohort (n = 58). Additionally, a separative dataset was used as an external validation cohort (n = 60). Radiomics signatures were extracted and selected from the primary tumor sites from chest CT images. A multivariate logistic regression analysis was conducted to identify the independent clinical predictors. Subsequently, a radiomics nomogram model for predicting the efficiency of chemo-immunotherapy was conducted by integrating the selected radiomics signatures and the independent clinical predictors. The receiver operating characteristic (ROC) curves demonstrated that the radiomics model, the clinical model, and the radiomics nomogram model achieved areas under the curve (AUCs) of 0.85 (95% confidence interval [CI] 0.78-0.92), 0.76 (95% CI 0.68-0.84), and 0.89 (95% CI 0.84-0.94), respectively, in the primary cohort. In the internal validation cohort, the corresponding AUCs were 0.93 (95% CI 0.86-1.00), 0.79 (95% CI 0.68-0.91), and 0.96 (95% CI 0.90-1.00) respectively. Moreover, in the external validation cohort, the AUCs were 0.84 (95% CI 0.72-0.96), 0.75 (95% CI 0.62-0.87), and 0.86 (95% CI 0.75-0.96), respectively. In conclusion, the radiomics nomogram provides a convenient model for predicting the effect of chemo-immunotherapy in advanced NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Nomogramas , Tomografía Computarizada por Rayos X , Humanos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Anciano , Tomografía Computarizada por Rayos X/métodos , Inmunoterapia/métodos , Curva ROC , Resultado del Tratamiento , Estudios Prospectivos , RadiómicaRESUMEN
PURPOSE: Non-small cell lung cancer (NSCLC) is a highly fatal malignancy. The Kirsten rat sarcoma viral oncogene (KRAS) gene profoundly impacts patient prognosis. This study aims to explore the correlation between KRAS mutation subtypes, clinical data, and the impact of these subtypes on immunotherapy. MATERIALS AND METHODS: Tumor samples from 269 NSCLC patients at the Affiliated Cancer Hospital of Xinjiang Medical University were analyzed. Patients received first- or second-line therapy without targeted therapy. Molecular and clinical data were used to analysis KRAS mutation subtypes and treatment outcomes. RESULTS: KRAS mutations predominantly included G12C, G12D, and G12V subtypes. TP53 had the highest mutation frequency among KRAS mutations, followed by MST1, STK11, and KMT2C. Gender differences were noted among KRAS mutation subtypes, with G12C and G12V mutations prevalent in males, while G12D mutations were less common among males. Smokers exhibited varied KRAS mutation subtypes, with G12C and G12V prevalent in smokers and G12D in nonsmokers. KRAS mutations were mainly in lung adenocarcinoma. TTF-1 and PD-L1 expression differed significantly among KRAS mutations. Patients with G12C and G12V mutations showed higher TMB levels and better immunotherapy outcomes compared to those without KRAS mutations. Conversely, patients with G12D mutations had poorer immunotherapy responses. CONCLUSIONS: KRAS mutation subtypes exhibit distinct clinical and molecular characteristics and varying responses to immunotherapy. G12C and G12V mutations correlate with better immunotherapy outcomes, while G12D mutations are associated with poorer responses.
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Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Masculino , Proteínas Proto-Oncogénicas p21(ras)/genética , Femenino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/inmunología , Persona de Mediana Edad , Pronóstico , China/epidemiología , Anciano , Inmunoterapia/métodos , Adulto , Anciano de 80 o más Años , Biomarcadores de Tumor/genéticaRESUMEN
Patients with lung cancer have a high incidence of tumor recurrence even after curative surgical resection. Some reports indicated that immunosuppressive cells induced by surgical stress could contribute to tumor recurrence after surgery; however, the underlying mechanisms are not fully understood. In this study, we found that increased postoperative blood monocytes served as a risk factor for tumor recurrence in 192 patients with non-small cell lung cancer (NSCLC). We established the lung cancer recurrent mouse model after tumor resection and showed that the surgical stress immediately increased the level of serum monocyte chemoattractant protein-1 (MCP-1), which subsequently increased blood monocytes. These blood monocytes were rapidly recruited into distant micrometastases and became tumor growth-promoting tumor associated macrophages (TAMs). Furthermore, even after the blood MCP-1 and monocytes decreased enough 72 h after tumor resection, TAMs in micrometastases remained rich because the MCP-1 secreted by micrometastases themselves continued to recruit monocytes around the tumor. Consequently, tumor resection triggered the outgrowth of distant metastases via the MCP-1-Monocyte-TAM axis. When we administered the MCP-1 inhibitor to the lung cancer recurrent model mice, blood monocytes decreased after tumor resection, and TAMs in micrometastases also dramatically decreased. Finally, peri- and postoperative treatment with the MCP-1 inhibitor suppressed distant metastases after surgery. Targeting the MCP-1-Monocyte-TAM axis may inhibit surgical stress-induced NSCLC recurrence by attenuating postoperative immunosuppressive monocytes in micrometastases.
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Carcinoma de Pulmón de Células no Pequeñas , Quimiocina CCL2 , Neoplasias Pulmonares , Monocitos , Recurrencia Local de Neoplasia , Animales , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Monocitos/inmunología , Monocitos/metabolismo , Ratones , Humanos , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Masculino , Femenino , Quimiocina CCL2/metabolismo , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Persona de Mediana Edad , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , AncianoRESUMEN
Interstitial lung abnormalities (ILAs) are immune checkpoint inhibitor (ICI)-related pneumonitis (ICI-P) risk factors. However, the relationship between imaging patterns and immunotherapy outcomes, and treatment strategies remain unclear in patients with non-small cell lung cancer (NSCLC) and ILAs. We retrospectively evaluated patients with ILAs-complicated NSCLC who received ICI therapy. ILAs were subcategorized as non-subpleural, subpleural non-fibrotic, and subpleural fibrotic (SF) based on the 2020 position paper by the Fleischner Society. We investigated ICI-P incidence, ICI-P risk factors, lung cancer prognosis, and ILAs radiological progression. Of the 481 ICI-treated patients, 79 (16.4%) had ILAs (45 non-SF and 34 SF). The ICI-P cumulative incidence (hazard ratio, 4.57; 95% confidence interval [CI], 1.90-10.98; p = 0.001) and any grade and grade ≥ 3 ICI-P incidences were higher in patients with SF-ILAs than in those with non-SF-ILAs (all grades: 7/45 [15.6%)] vs. 18/34 [52.9%]; p < 0.001; grade ≥ 3: 1/45 [2.2%] vs. 10/34 [29.4%]; p = 0.001). According to multivariate analysis, SF-ILAs independently predicted ICI-P (odds ratio, 5.35; 95% CI 1.62-17.61; p = 0.006). Patients with SF-ILAs had shorter progression-free and overall survival and higher ICI-P-related respiratory failure death rates than those with non-SF-ILAs. Approximately 2.5 times more patients with SF-ILAs showed progression by the 2-year follow-up than those with non-SF-ILAs. SF-ILAs is an independent strong predictor of ICI-P development in patients with NSCLC, may increase ICI-P severity, worsen prognosis, and accelerate ILAs progression. ILAs subcategorization is an important treatment strategy for patients with lung cancer treated with ICIs.
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Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Enfermedades Pulmonares Intersticiales , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/complicaciones , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Pronóstico , Anciano de 80 o más Años , Resultado del Tratamiento , AdultoRESUMEN
BACKGROUND: Treatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood-brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival. METHODS: In this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher's exact test, and survival curves were estimated with the Kaplan-Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk. RESULTS: From an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43-0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18-0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683). CONCLUSION: Our study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.
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Inhibidores de la Angiogénesis , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios Retrospectivos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/tratamiento farmacológico , Masculino , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Inhibidores de la Angiogénesis/uso terapéutico , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , AdultoRESUMEN
Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens.
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Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Femenino , Masculino , Persona de Mediana Edad , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Terapia Molecular Dirigida/métodos , Adulto , MutaciónRESUMEN
BACKGROUND: Immunotherapy represents a groundbreaking and monumental achievement in the field of cancer therapy, marking a significant advancement in fighting against this devastating disease. Lung cancer has showed consistent clinical improvements in response to immunotherapy treatments, yet, it is undeniable that challenges such as limited response rates acquire resistance, and the unclear fundamental mechanisms were inevitable problems. METHODS: The cellular composition was defined and distinguished through single-cell RNA sequencing (scRNA-seq) analysis of MPR (major pathologic response) and NMPR (non-major pathologic response) samples in GSE207422, including four primary MPR samples and eight primary NMPR samples. RESULTS: We found obvious difference in CD8+ T cell population between MPR and NMPR samples, with high expression of TYMS, RRM2, and BIRC5 in NPMR samples. Meanwhile, the proportion of macrophages and tumor epithelial cells infiltration increased in the NMPR samples. We discovered biomarkers (ACTN4, ATF3, BRD2, CDKN1A, and CHMP4B) in epithelial cells which were potentially represented worse outcomes. CONCLUSIONS: By exploring the difference of tumor microenvironment (TME) in samples with different corresponding degrees of neoadjuvant immunotherapy, this research introduces a number of novel biomarkers for predicting the response of treatment and a theoretical basis for overcoming immunotherapy resistance.
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Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Inmunoterapia/métodos , Análisis de la Célula Individual/métodos , Biomarcadores de Tumor/genética , Análisis de Secuencia de ARN/métodos , Regulación Neoplásica de la Expresión Génica , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Perfilación de la Expresión GénicaRESUMEN
The main bottleneck in training a robust tumor segmentation algorithm for non-small cell lung cancer (NSCLC) on H&E is generating sufficient ground truth annotations. Various approaches for generating tumor labels to train a tumor segmentation model was explored. A large dataset of low-cost low-accuracy panCK-based annotations was used to pre-train the model and determine the minimum required size of the expensive but highly accurate pathologist annotations dataset. PanCK pre-training was compared to foundation models and various architectures were explored for model backbone. Proper study design and sample procurement for training a generalizable model that captured variations in NSCLC H&E was studied. H&E imaging was performed on 112 samples (three centers, two scanner types, different staining and imaging protocols). Attention U-Net architecture was trained using the large panCK-based annotations dataset (68 samples, total area 10,326 [mm2]) followed by fine-tuning using a small pathologist annotations dataset (80 samples, total area 246 [mm2]). This approach resulted in mean intersection over union (mIoU) of 82% [77 87]. Using panCK pretraining provided better performance compared to foundation models and allowed for 70% reduction in pathologist annotations with no drop in performance. Study design ensured model generalizability over variations on H&E where performance was consistent across centers, scanners, and subtypes.
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Carcinoma de Pulmón de Células no Pequeñas , Aprendizaje Profundo , Neoplasias Pulmonares , Patólogos , Humanos , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Procesamiento de Imagen Asistido por Computador/métodos , AlgoritmosRESUMEN
Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is widely used in the clinical treatment of tumors. This study aims to explore the active fractions and underlying mechanisms of Fuzi in the treatment of non-small cell lung cancer (NSCLC). Fuzi alkaloids (FZA) is prepared and found to inhibit the growth of NSCLC both in vitro and in vivo significantly. A total of 53 alkaloids are identified in FZA by UPLC-Q-TOF-MS. Proteomics experiment show that 238 differentially expressed proteins regulated by FZA are involved in amino acid anabolism, pyrimidine metabolism and PI3K/Akt-mTOR signaling pathway. Metabolomics analyses identify 32 significant differential metabolites which are mainly involved in amino acid metabolism, TCA cycle and other pathways. Multi-omics research combined with molecular biological assays suggest that FZA might regulate glycolysis through PI3K/Akt-mTOR pathway to treat NSCLC. The study lays a foundation for the anti-cancer investigation of Fuzi and provides a possible scientific basis for its clinical application.
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Aconitum , Alcaloides , Carcinoma de Pulmón de Células no Pequeñas , Glucólisis , Neoplasias Pulmonares , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Humanos , Alcaloides/farmacología , Glucólisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Aconitum/química , Ratones , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Línea Celular Tumoral , Ratones Desnudos , Antineoplásicos Fitogénicos/farmacología , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors. METHODS: ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT-qPCR) were conducted to verify the impact of ZMIZ2-SIRT1 combination on Hippo/Wnt pathways. RESULTS: ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells-establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2-SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear ß-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of ß-catenin-transcription factor 4 (TCF4) and YAP-TEA domain family transcription factors (TEADs) were amplified. CONCLUSIONS: ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.
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Carcinoma de Pulmón de Células no Pequeñas , Vía de Señalización Hippo , Neoplasias Pulmonares , Proteínas Inhibidoras de STAT Activados , Proteínas Serina-Treonina Quinasas , Sirtuina 1 , Vía de Señalización Wnt , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Sirtuina 1/metabolismo , Sirtuina 1/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Vía de Señalización Wnt/genética , Proteínas Inhibidoras de STAT Activados/genética , Proteínas Inhibidoras de STAT Activados/metabolismoRESUMEN
OBJECTIVE: To explore the survival effect of thoracic gross tumor volume (GTV) in three-dimensional (3D) radiotherapy for stage IV non-small cell lung cancer (NSCLC). METHODS: The data cases were obtained from a single-center retrospective analysis. From May. From 2008 to August 2018, 377 treatment criteria were enrolled. GTV was defined as the volume of the primary lesion and the hilus as well as the mediastinal metastatic lymph node. Chemotherapy was a platinum-based combined regimen of two drugs. The number of median chemotherapy cycles was 4 (2-6), and the cut-off value of the planning target volume (PTV) dose of the primary tumor was 63 Gy (30-76.5 Gy). The cut-off value of GTV volume was 150 cm3 (5.83-3535.20 cm3). RESULTS: The survival rate of patients with GTV <150 cm3 is better than patients with GTV ≥150 cm3. Multivariate Cox regression analyses suggested that peripheral lung cancer, radiation dose ≥63 Gy, GTV <150 cm3, 4-6 cycles of chemotherapy, and CR + PR are good prognostic factors for patients with stage IV non-small cell lung cancer. The survival rate of patients with GTV <150 cm3 was longer than patients with ≥150 cm3 when they underwent 2 to 3 cycles of chemotherapy concurrent 3D radiotherapy (p < 0.05). When performing 4 to 6 cycles of chemotherapy concurrent 3D radiotherapy, there was no significant difference between <150 cm3 and ≥150 cm3. CONCLUSIONS: The volume of stage IV NSCLC primary tumor can affect the survival of patients. Appropriate treatment methods can be opted by considering the volume of tumors to extend patients' lifetime to the utmost.
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Carcinoma de Pulmón de Células no Pequeñas , Quimioradioterapia , Neoplasias Pulmonares , Estadificación de Neoplasias , Carga Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Femenino , Quimioradioterapia/métodos , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Pronóstico , Tasa de SupervivenciaRESUMEN
OBJECTIVES: The associations between the neutrophil-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with the responses of non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICI) and the NLR/PLR predictive potential were evaluated via meta-analysis. METHODS: A systematic review was conducted using the PubMed, Embase, and The Cochrane Library databases until October 2021. The relationship between NLR/PLR and overall survival (OS) and progression-free survival (PFS) was evaluated using pooled hazard ratios (HR). The relationship between NLR/PLR and overall response rate (ORR) and disease control rate (DCR) was assessed via pooled odds ratios (OR). Heterogeneity between studies, publication bias, subgroup and sensitivity analyses, trim and fill meta-analysis, and the contour-enhanced funnel plot were performed using the R software. RESULTS: A total of 44 (out of 875) studies met the eligibility criteria, providing a sample size of 4597 patients. Patients with a high NLR were statistically significantly associated with worse outcomes, including OS (pooled HR = 2.44; P < 0.001), PFS (pooled HR = 2.06; P < 0.001), DCR (pooled OR = 0.71; P < 0.001), and ORR (pooled OR = 0.33; P < 0.001). Similarly, a high PLR was associated with poorer outcomes in response to ICI drugs, including OS (pooled HR = 2.13; P < 0.001) and PFS (pooled HR = 1.61; P < 0.001). CONCLUSION: High NLR and PLR were associated with a statistically significant reduction in the efficacy of ICI drugs in NSCLC patients. Thereby, it is possible to use NLR and PLR as potential and available biomarkers in the clinical practice to predict the outcome of ICI treatment in NSCLC patients.
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Plaquetas , Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Linfocitos , Neutrófilos , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Plaquetas/efectos de los fármacos , Recuento de Linfocitos , Recuento de Plaquetas , PronósticoRESUMEN
BACKGROUD: Supernatants from various cytological samples, including body cavity effusion, sputum, bronchoalveolar lavage fluid (BALF), and needle aspiration, have been validated for detecting genetic alterations using cell-free DNA (cfDNA) in patients with non-small cell lung cancer (NSCLC). However, the sensitivity of fusion variations detection remains challenging. The protection of cell-free RNA (cfRNA) is critical for resolving the issue. METHODS: A protective solution (PS) was applied for preserving cfRNA in cytological supernatant (CS), and the quality of protected cfRNA was assessed by cycle threshold (CT) values from reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, we collected an additional set of malignant cytological and matched tumor samples from 84 NSCLC patients, cfDNA & cfRNA extraction and double detection for driver gene mutations was validated using the multi-gene mutations detection by RT-qPCR. RESULTS: Under the optimal protection system, 91.0% (101/111) of cfRNA were protected effectively. Among the 84 NSCLC patient samples, seven cytological samples failed the tests. In comparison with tumor samples, the overall sensitivity and specificity of detecting driver genes of supernatant cfDNA and cfRNA were 93.8% (74/77) and 100% (77/77), respectively. Notably, when focusing exclusively on patients with fusion gene changes, both sensitivity and specificity reached 100% (11/11) for EML4-ALK, ROS1, RET fusions, and MET ex14 skipping. CONCLUSION: These findings suggest that cfDNA & cfRNA extraction and double detection strategy recommended in this study improve the accuracy of driver genes mutations test, especially for RNA-based assay.
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Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Ácidos Nucleicos Libres de Células/genética , Mutación , Masculino , Femenino , Biomarcadores de Tumor/genética , Sensibilidad y Especificidad , Persona de Mediana Edad , Anciano , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas , Proteínas Proto-OncogénicasRESUMEN
The combination of the standard platinum-based chemotherapy with EGFR-tyrosine kinase inhibitor Gefitinib (Gef) principally boosts the anticancer efficacy of advanced non-small cell lung cancer (NSCLC) through non-overlapping mechanisms of action, however the clinical trials of cisplatin (Cis) and Gef combination failed to show a therapeutic improvement likely due to compromised cellular influx of Cis with the Gef interference. To overcome the antagonism between Cis and Gef in anti-NSCLC therapy, here we demonstrated a self-targeted hyaluronan (HA) nanogel to facilitate the anticancer co-delivery by utilizing the HA's intrinsic targeting towards CD44, a receptor frequently overexpressed on lung cancer cells. The co-assembly between HA, Cis and Gef generated a HA/Cis/Gef nanogel of 177.8 nm, featuring a prolonged drug release. Unlike the Gef inhibited the Cis uptake, the HA/Cis/Gef nanogel efficiently facilitated the drug internalization through CD44-targeted delivery as verified by HA competition and CD44 knocking down in H1975 NSCLC model both in vitro and in vivo. Moreover, the HA/Cis/Gef nanogel significantly improved the anticancer efficacy and meanwhile diminished the side effects in reference to the combination of free Cis and Gef. This CD44-targeted HA/Cis/Gef nanogel provided a potent strategy to advance the platinum-based combination therapy towards optimized NSCLC therapy.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Cisplatino , Gefitinib , Receptores de Hialuranos , Ácido Hialurónico , Neoplasias Pulmonares , Nanogeles , Ácido Hialurónico/química , Receptores de Hialuranos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Cisplatino/farmacología , Cisplatino/administración & dosificación , Cisplatino/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Gefitinib/farmacología , Gefitinib/química , Gefitinib/administración & dosificación , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Ratones , Nanogeles/química , Línea Celular Tumoral , Ratones Desnudos , Liberación de Fármacos , Ratones Endogámicos BALB C , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/químicaRESUMEN
With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti-PD-1/PD-L1 axis therapy. Anti-PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-ß, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti-PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti-PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti-PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.