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BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.
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INTRODUCTION: The multicenter CHAMPION study aimed to assess the impact of smoking cessation on post-operative complications (PCs) and smoking cessation patterns in Chinese patients undergoing lung surgery. METHODS: Patients undergoing elective lung surgery were prospectively enrolled from three major tertiary centers in China. Patients were categorized as smokers or quitters before surgery. Baseline characteristics and smoking status were analyzed. The incidence of PCs and pulmonary PCs (PPCs), smoking relapse rate, and causes within six months post-operatively were investigated. The questionnaire was conducted in all patients and 30 healthcare professionals (HCPs), regarding the awareness and effectiveness of smoking cessation methods. RESULTS: Of the 276 enrolled patients, 213 (77.2%) were smokers and 63 (22.8%) were quitters; 76.4% were diagnosed with primary lung cancer. PCs occurred in 13.8% of patients, with similar proportions in smokers (14.1%) and quitters (12.7%). PPCs occurred in 9.8% of patients with no significant differences between smokers and quitters (9.4% vs 11.1%, p=0.70). At six months, 9.2% of patients relapsed, with a lower rate in quitters compared to smokers (3.3% vs 11.0%, p=0.01). HCPs exhibited higher awareness of smoking cessation methods than patients. Perceived effectiveness of smoking cessation methods from the patients were low. CONCLUSIONS: In patients undergoing lung surgery with a low risk of PCs, active smoking does not significantly increase the risk of PCs or PPCs relative to quitters, suggesting that there is likely no need to postpone lung surgery for those who have not yet quit smoking. However, further large-scale studies are necessary to confirm these findings.
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BACKGROUND: With the extensive application of segmental lung resection in the treatment of early-stage lung cancer, how to complete segmentectomy more accurately and minimally invasively has become a research hotspot. The aim of this study is to explore the application of three-dimensional computed tomography bronchography and angiography (3D-CTBA) combined with perfusion area recognition technique in single-hole thoracoscopic complex segmentectomy. METHODS: From January 2021 to January 2022, the clinical data of 112 consecutive patients undergoing single-port thoracoscopic complex segmentectomy in the Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University were retrospectively analyzed. The three-dimensional reconstruction combined with perfusion area identification technique was used to perform the operation and the clinical data were analyzed. RESULTS: The average operation time was (141.1±35.4) min; the initial time of intersegmental plane display was (12.5±1.7) s; the maintenance time of intersegmental plane was (114.3±10.9) s; the intersegmental plane was clearly displayed (100%); the amount of bleeding was [10 (10, 20)] mL; the total postoperative drainage volume was (380.5±139.7) mL; the postoperative extubation time was (3.9±1.2) d; and the postoperative hospitalization time was (5.2±1.6) d. Postoperative complications occurred in 8 cases. CONCLUSIONS: The advantages of 3D-CTBA combined with perfusion area recognition technique are fast, accurate and safe in identifying intersegmental boundary in single-port thoracoscopic complex segmentectomy, which could provide guidances for accuratding resection of tumors, shortening operation time and reducing surgical complications.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Broncografía , Neumonectomía/métodos , Estudios Retrospectivos , Cirugía Torácica Asistida por Video/métodos , Tomografía Computarizada por Rayos X , Angiografía/métodos , PerfusiónRESUMEN
INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acrilamidas/uso terapéutico , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/inducido químicamente , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND AND OBJECTIVES: Lung cancer patients slated for surgery are at high risk of venous thromboembolism (VTE). Precise risk assessment is necessary for providing proper thromboprophylaxis and reducing morbidity and mortality of VTE. METHODS: A multicenter, observational, cross-sectional cohort study, involving patients with primary lung cancer undergoing surgery, was carried out from August 2016 to December 2019. All patients were assessed according to the Caprini risk assessment model (RAM) and a modified scoring system incorporating elevated D-dimer and new stratification of surgical time. The endpoint was confirmed VTE or patient discharge. RESULTS: Out of 1205 patients, 87 (7.2%) were diagnosed with VTE. The area under the curve of modified scores for VTE was 0.759, which was larger than that of the original one (0.589) (p < 0.05). By modified Caprini scoring system, a higher score was associated with increased VTE risk (odds ratio [OR], 1.345; 95% confidence interval [CI], 1.197-1.512; p < 0.001), and there was an increased OR of 4.090 (95% CI, 2.472-6.768, p < 0.001) for VTE in high-risk category patients. CONCLUSION: Modified Caprini RAM showed an improved prediction of high-risk patients with an elevated likelihood of postoperative VTE compared to the original one.
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Neoplasias Pulmonares , Tromboembolia Venosa , Anticoagulantes/uso terapéutico , Estudios Transversales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & controlRESUMEN
BACKGROUNDCurrent clinical management of patients with pulmonary nodules involves either repeated low-dose CT (LDCT)/CT scans or invasive procedures, yet causes significant patient misclassification. An accurate noninvasive test is needed to identify malignant nodules and reduce unnecessary invasive tests.METHODWe developed a diagnostic model based on targeted DNA methylation sequencing of 389 pulmonary nodule patients' plasma samples and then validation in 140 plasma samples independently. We tested the model in different stages and subtypes of pulmonary nodules.RESULTSA 100-feature model was developed and validated for pulmonary nodule diagnosis; the model achieved a receiver operating characteristic curve-AUC (ROC-AUC) of 0.843 on 140 independent validation samples, with an accuracy of 0.800. The performance was well maintained in (a) a 6 to 20 mm size subgroup (n = 100), with a sensitivity of 1.000 and adjusted negative predictive value (NPV) of 1.000 at 10% prevalence; (b) stage I malignancy (n = 90), with a sensitivity of 0.971; (c) different nodule types: solid nodules (n = 78) with a sensitivity of 1.000 and adjusted NPV of 1.000, part-solid nodules (n = 75) with a sensitivity of 0.947 and adjusted NPV of 0.983, and ground-glass nodules (n = 67) with a sensitivity of 0.964 and adjusted NPV of 0.989 at 10% prevalence. This methylation test, called PulmoSeek, outperformed PET-CT and 2 clinical prediction models (Mayo Clinic and Veterans Affairs) in discriminating malignant pulmonary nodules from benign ones.CONCLUSIONThis study suggests that the blood-based DNA methylation model may provide a better test for classifying pulmonary nodules, which could help facilitate the accurate diagnosis of early stage lung cancer from pulmonary nodule patients and guide clinical decisions.FUNDINGThe National Key Research and Development Program of China; Science and Technology Planning Project of Guangdong Province; The National Natural Science Foundation of China National.
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Metilación de ADN , ADN de Neoplasias/metabolismo , Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Nódulos Pulmonares Múltiples/diagnóstico , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND: Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE). METHODS: This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE. RESULTS: This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively. CONCLUSIONS: Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inmunoterapia/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , China , Ensayos Clínicos como Asunto , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/cirugía , Periodo Perioperatorio/estadística & datos numéricosRESUMEN
Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large-scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Inmunoterapia/efectos adversos , Neoplasias Pulmonares/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Periodo PerioperatorioRESUMEN
Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for cancer patients. With the widespread clinical application of ICIs, their adverse reactions have gradually been recognized. The side effects of ICIs are generally less severe than those of chemotherapy. However, some adverse events with ICIs can be life-threatening. Fatal adverse events require a deep understanding and vigilance. Here, we report the case of a 69-year-old patient with esophagogastric junction carcinoma who experienced multiple immune-related adverse events, including Stevens-Johnson syndrome/toxic epidermal necrolysis, myositis, myocarditis, and liver toxicity, after receiving pembrolizumab. The patient experienced skin rash, bilateral ptosis, limb weakness, and shortness of breath. The symptoms progressed rapidly. Following treatment with methylprednisolone, intravenous immunoglobulin, and plasmapheresis, the patient recovered well. No tracheal intubation or tracheotomy was required owing to the timely and effective treatment. From this case, it can be seen that severe skin rash is an important indication of abnormal immune status and an early warning sign of subsequent multiple-organ involvement. As the most dangerous adverse event, myocarditis is closely related to the patient's prognosis. Severe irAEs appear early, progress rapidly, and involve multiple systems and organs, resulting in a high fatality rate. Early recognition and high-dose corticosteroids are key to successful treatment of such patients.
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Objectives: This retrospective study aimed to evaluate the safety and efficacy of thulium laser pulmonary wedge resection under thoracoscopy. Methods: Sixty cases of thoracoscopic pulmonary wedge resection by thulium laser and sixty cases with mechanical stapler from February 2015 to September 2018 were selected. The operation time, intraoperative hemorrhage, postoperative hospital stay, severe air leaks, drainage time, and complications (including postoperative hemorrhage, hemoptysis, atelectasis, and pulmonary infection) were compared between groups. Results: The thulium laser group showed a lower incidence of intraoperative hemorrhage (10.0 [5.0-20.0] ml vs. 15.0 [10.0-50.0] ml, P = 0.010) and a shorter postoperative hospital stay (3.9 ± 2.5 days vs. 4.9 ± 2.0 days, P = 0.031).There was no significant difference between groups in the operation time, postoperative drainage time, the occurrence of severe air leaks, or complication rate (P > 0.05). No patients were lost during follow?up (median follow?up time: 28.4 months, range: 18.0-36.0 months). No statistically significant difference in overall survival was found (P = 0.547). Conclusion: pulmonary wedge resection with thulium laser under thoracoscopy had better safety, less damage, and higher accuracy compared with the control group.
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Toracoscopía , Tulio , Humanos , Rayos Láser , Neumonectomía/efectos adversos , Estudios Retrospectivos , Toracoscopía/efectos adversos , Resultado del TratamientoRESUMEN
This study aimed to investigate whether changes in progastrin-releasing peptide (ProGRP) levels correlate with treatment response and can be used to optimize clinical management of patients with small-cell lung cancer. Patients with small-cell lung cancer (any stage) receiving chemotherapy were eligible. ProGRP was measured in serum/plasma at baseline and after each chemotherapy cycle using the Elecsys® ProGRP assay (Roche Diagnostics). Treatment response was assessed by computed tomography scan. The primary objective was to examine whether changes in ProGRP levels correlated with computed tomography scan results after two cycles of chemotherapy. The prognostic value of ProGRP among patients receiving first-line chemotherapy was also assessed. Overall, 261 patients from six centers were eligible. Among patients with elevated baseline ProGRP (>100 pg/mL), a ProGRP decline after Cycle 2 was associated with nonprogression (area under the curve: 84%; 95% confidence interval: 72.8-95.1; n = 141). ProGRP changes from baseline to end of Cycle 1 were predictive of response, as determined by computed tomography scan 3 weeks later (area under the curve: 87%; 95% confidence interval: 74.1-99.2; n = 137). This was enhanced by repeat measurements, with a 92% area under the curve (95% confidence interval: 85.3-97.8) among patients with ProGRP data after both Cycles 1 and 2 (n = 123); if a patient experienced a ≥25% decline in ProGRP after Cycle 1, and ProGRP remained stable or decreased after Cycle 2, the probability of finding progression on the interim computed tomography scan at the end of Cycle 2 was almost zero (sensitivity: 100%, specificity: 71%). Both ProGRP levels at baseline and at the end of first-line chemotherapy were prognostic; the latter provided a moderately improved hazard ratio of 2.43 (95% confidence interval: 1.33-4.46; n = 110) versus 1.87 (95% confidence interval: 1.04-3.37; n = 216). In summary, for patients with small-cell lung cancer and elevated baseline ProGRP levels, ProGRP may be a simple, reliable, and repeatable tool for monitoring response to chemotherapy and provide valuable prognostic information.
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Neoplasias Pulmonares/sangre , Fragmentos de Péptidos/sangre , Carcinoma Pulmonar de Células Pequeñas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Biomarcadores de Tumor/sangre , China , Europa (Continente) , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Recombinantes/sangre , Sensibilidad y Especificidad , Carcinoma Pulmonar de Células Pequeñas/diagnóstico por imagen , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Tomografía Computarizada por Rayos XRESUMEN
The efficacy and possible role of epidermal growth factor receptor tyrosine kinase inhibitors in treating early-stage non-small-cell lung cancer have yet to be established. Therefore, we aimed to explore the efficacy and safety of icotinib in completely resected EGFR-mutant stage II-IIIA lung adenocarcinoma patients who underwent standard chemotherapy. This is a randomised, double-blinded, placebo-controlled, multicentre, Phase III trial. A total of 124 patients aged 18-75 years who qualified the inclusion criteria were recruited. These patients were randomised (1:1) to receive either icotinib (125 mg 3 times per day) or placebo (the same dosage and frequency) for 36 months, followed by a further 36 months of observational window. The primary endpoint is disease-free survival (DFS), while the secondary endpoints are overall survival, 3-year and 5-year DFS, safety and tolerability of the medication, and health-related quality-of-life. Analyses will be conducted in a full analysis set and a per-protocol set as well. To our knowledge, the present study is the first randomised, double-blinded, placebo-controlled, multicenter trial designed to explore efficacy and safety of icotonib in this population. The results obtained in the near future may provide potential guidance in clinical practice. Trial Registration: This trial was registered on www.ClinicalTrail.gov as NCT02125240.
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To compare the clinical efficacy and adverse reactions associated with nano-albumin paclitaxel combined with cisplatin and traditional paclitaxel combined with cisplatin for the treatment of non-small cell lung cancer. From December 2016 to August 2019, 78 patients with non-small cell lung cancer in our hospital were randomly allocated into either the observation group (n = 39) or the control group (n = 39). The observation group was treated with nano-albumin combined with cisplatin, and the control group was treated with traditional paclitaxel combined with platinum chemotherapy. After four cycles of treatment, the clinical efficacy and adverse reactions for the two groups were statistically analyzed. Before treatment, there was no statistically significant difference in age, sex, tumor type, and ECOG score between the two groups. After four cycles of treatment, the disease control rate in the observation group was 79.49%, which was significantly higher than that in the control group (38.46%, P <0.05), and the occurrence of myelosuppression, nausea, vomiting, and hyperglycemia in the observation group was significantly lower than that in the control group (P <0.05). Compared with the traditional paclitaxel combined with platinum chemotherapy regimen, the nanoalbumin combined with paclitaxel regimen had significant clinical effect and the adverse reactions were significantly reduced. Thus, it can be considered effective and safe and is suitable for clinical promotion.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Resultado del TratamientoRESUMEN
Osteopontin (OPN) is identified as a diagnostic and prognostic biomarker of tumor progression and metastasis. In non-small-cell lung cancer (NSCLC), the functions of OPN have not been well characterized. The current study sought to investigate the clinical implications of OPN expression in NSCLC and the role of OPN in the aggressiveness of the lung cancer cells. Using a proteomics approach, we identified that phospho-RON (p-RON) was one of the most remarkably up-regulated proteins in OPN-overexpressing cells. The levels of OPN and RON transcripts were unveiled as independent prognostic indicators of survival in NSCLC (p = 0.001). Higher levels of OPN, RON and p-RON proteins were observed in tumor tissues. Knock down of the OPN gene suppressed the migration and invasion abilities of the A549 lung cancer cells which endogenously expresses OPN. While ectopic expression of OPN in the SK-MES-1 lung cancer cells increased levels of cellular invasion and migration. In addition, these changes were accompanied by a phosphorylated activation of RON. Small-molecule inhibition of RON or siRNA silencing of RON significantly reduced OPN-induced migration and invasion of lung cancer cells and had an inhibitory effect on the OPN-mediated cell epithelial-mesenchymal transition. Our study suggests that in NSCLC, the aberrant expression of OPN can be considered as an independent survival indicator and is associated with disease progression. OPN plays a crucial role in promoting migration and invasion properties of lung cancer cells through its phosphorylation activation of the RON signaling pathway, implying its potential as a therapeutic target in the treatment of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Osteopontina/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Células A549 , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Línea Celular Tumoral , Activación Enzimática , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Osteopontina/genética , Fosforilación , Pronóstico , Análisis por Matrices de Proteínas , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
Ehm2 [also known as erythrocyte membrane protein band 4.1like protein 4B (EPB41L4B)] is a member of the NF2/ERM/4.1 superfamily. The overexpression of Ehm2 has been observed in metastatic cancer cells. Through alternative splicing, the Ehm2 gene produces two transcript variants that encode the two different isoforms, Ehm2/1 and Ehm2/2. The biological functions of these different Ehm2 transcript variants remain unclear. The present study aimed to determine the expression of the Ehm2 variants in lung adenocarcinoma and their involvement in the disease progression of the patients. The expression of Ehm2 transcript variants in human lung adenocarcinoma tissues was analyzed using immunohistochemistry and western blot analysis. Ehm2 variants were overexpressed or knocked down in A549 human lung adenocarcinoma cells. The consequent effects of the genetic modifications on the cellular functions of lung cancer cells were then examined using in vitro cell viability, invasion and migration assays. The expression of epithelialmesenchymal transition (EMT)related markers was evaluated by western blot analysis in the cell models. The association of Ehm2 variant expression with patient survival was analyzed using KaplanMeier survival analysis. The expression of Ehm2/1 was significantly decreased in lung cancers compared with the paired normal lung tissues (P<0.05), while the Ehm2/2 protein levels were higher in the tumors than in the paired normal lung tissues, although this was not statistically significant. The overexpression of Ehm2/1 exerted inhibitory effects, while the knockdown of Ehm2/1 promoted the growth, invasion and migration of A549 cells in vitro. Ehm2/2 was expressed at low levels in the A549 cells and the enforced expression of Ehm2/2 significantly increased the invasiveness and migration of the A549 cells. Immunofluorescence staining revealed that Ehm2/1 was confined to the plasma membrane, while Ehm2/2 was observed at both the plasma membrane and cytoplasm. The overexpression of Ehm2/1 resulted in the upregulation of the epithelial marker, Ecadherin, and in the decreased expression of the mesenchymal markers, Ncadherin and Snail1, while the knockdown of Ehm2/1 and the enforced expression of Ehm2/2 had the opposite effects on the protein levels of EMTrelated markers. KaplanMeier survival analysis revealed that higher Ehm2/1 transcript levels were associated with the longer survival of patients with lung adenocarcinoma, while the lower expression of Ehm2/2 exhibited a similar association with patient survival. Taken together, the two Ehm2 variants appear to be differentially expressed in lung adenocarcinoma. Ehm2/1 may function as a putative tumor suppressor in the disease progression of lung adenocarcinoma, while Ehm2/2 may have an opposite function.
Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Regulación hacia Abajo , Neoplasias Pulmonares/metabolismo , Células A549 , Adenocarcinoma del Pulmón/genética , Adulto , Empalme Alternativo , Movimiento Celular , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
Intraoperative bleeding is the most crucial safety concern of video-assisted thoracic surgery (VATS) for a major pulmonary resection. Despite the advances in surgical techniques and devices, intraoperative bleeding is still not rare and remains the most common and potentially fatal cause of conversion from VATS to open thoracotomy. Therefore, to guide the clinical practice of VATS lung surgery, we proposed the International Interest Group on Bleeding during VATS Lung Surgery with 65 experts from 10 countries in the field to develop this consensus document. The consensus was developed based on the literature reports and expert experience from different countries. The causes and incidence of intraoperative bleeding were summarised first. Seven situations of intraoperative bleeding were collected based on clinical practice, including the bleeding from massive vessel injuries, bronchial arteries, vessel stumps, and bronchial stumps, lung parenchyma, lymph nodes, incisions, and the chest wall. The technical consensus for the management of intraoperative bleeding was achieved on these seven surgical situations by six rounds of repeated revision. Following expert consensus statements were achieved: (I) Bleeding from major vascular injuries: direct compression with suction, retracted lung, or rolled gauze is useful for bleeding control. The size and location of the vascular laceration are evaluated to decide whether the bleeding can be stopped by direct compression or by ligation. If suturing is needed, the suction-compressing angiorrhaphy technique (SCAT) is recommended. Timely conversion to thoracotomy with direct compression is required if the operator lacks experience in thoracoscopic angiorrhaphy. (II) Bronchial artery bleeding: pre-emptive clipping of bronchial artery before bronchial dissection or lymph node dissection can reduce the incidence of bleeding. Bronchial artery bleeding can be stopped by compression with the suction tip, followed by the handling of the vascular stump with energy devices or clips. (III) Bleeding from large vessel stumps and bronchial stumps: bronchial stump bleeding mostly comes from accompanying bronchial artery, which can be clipped for hemostasis. Compression for hemostasis is usually effective for bleeding at the vascular stump. Otherwise, additional use of hemostatic materials, re-staple or a suture may be necessary. (IV) Bleeding from the lung parenchyma: coagulation hemostasis is the first choice. For wounds with visible air leakage or an insufficient hemostatic effect of coagulation, suturing may be necessary. (V) Bleeding during lymph node dissection: non-grasping en-bloc lymph node dissection is recommended for the nourishing vessels of the lymph node are addressed first with this technique. If bleeding occurs at the site of lymph node dissection, energy devices can be used for hemostasis, sometimes in combination with hemostatic materials. (VI) Bleeding from chest wall incisions: the chest wall incision(s) should always be made along the upper edge of the rib(s), with good hemostasis layer by layer. Recheck the incision for hemostasis before closing the chest is recommended. (VII) Internal chest wall bleeding: it can usually be managed with electrocoagulation. For diffuse capillary bleeding with the undefined bleeding site, compression of the wound with gauze may be helpful.