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PURPOSE: Few studies have so far focused on the preoperative presence of venous thromboembolism (VTE) in lung cancer patients undergoing surgery. In this study, we investigated the prevalence and risk factors for preoperative deep venous thrombosis (DVT) in patients scheduled to undergo lung cancer surgery. METHODS: Between June 2013 and December 2018, 948 consecutive patients underwent lung cancer surgery in Kindai University Hospital. Four patients did not undergo screening for DVT; thus, 944 patients were enrolled in this study. Preoperatively, venous ultrasonography of the lower extremities was performed in patients deemed at risk for DVT, and the prevalence and risk factors for preoperative DVT were examined. RESULTS: Ninety-one patients (9.6%) were diagnosed with preoperative DVT, and postoperative symptomatic pulmonary thromboembolism occurred in one patient (0.11%). A multivariable logistic regression analysis demonstrated that female sex, age ≥ 72 years, history of VTE, a Wells score ≥ 2 points, chronic obstructive pulmonary disease (COPD), and lower hemoglobin levels were significantly associated with preoperative DVT. CONCLUSION: Female sex, age ≥ 72 years, history of VTE, Wells score ≥ 2 points, COPD, and lower hemoglobin levels were identified to be independent risk factors for preoperative DVT. Monitoring for these risk factors and management considering them should help improve the outcomes after lung cancer surgery.
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Neoplasias Pulmonares/cirurgia , Trombose Venosa/epidemiologia , Trombose Venosa/etiologia , Fatores Etários , Idoso , Feminino , Hemoglobinas/deficiência , Humanos , Neoplasias Pulmonares/complicações , Masculino , Complicações Pós-Operatórias , Período Pré-Operatório , Prevalência , Doença Pulmonar Obstrutiva Crônica , Embolia Pulmonar , Fatores de Risco , Fatores Sexuais , Resultado do Tratamento , Ultrassonografia , Trombose Venosa/diagnóstico por imagemRESUMO
PURPOSE: A high plasma level of either fibrinogen or D-dimer has been shown to correlate with a poor prognosis in patients with surgically resected non-small-cell lung cancer (NSCLC). The present study aimed to identify whether or not both markers combined had a superior prognostic value to either alone. METHODS: Of the 1344 patients who underwent surgical resection for NSCLC at our institution between January 2007 and December 2016, 1065 had preoperative plasma fibrinogen and D-dimer data available and were included in the analysis. RESULTS: The recurrence-free survival (RFS) and overall survival (OS) rates were similar for patients with high plasma levels of either or both fibrinogen (> 4.0 g/L) or D-dimer (> 1.0 µg/mL); therefore, these three groups were combined for a further analysis into a single group with high plasma levels of either or both proteins. The high-level group had significantly lower 5-year RFS (53% vs. 68%, p < 0.001) and 5-year OS (65% vs. 80%, p < 0.001) rates than patients with normal plasma levels of fibrinogen and D-dimer (control group). CONCLUSIONS: Our results suggest that preoperative tests for both plasma fibrinogen and D-dimer are necessary to identify patients with surgically resected NSCLC likely to have a poor RFS and OS.
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Biomarcadores Tumorais/sangue , Transtornos da Coagulação Sanguínea/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Trombofilia/diagnóstico , Tromboembolia Venosa/diagnóstico , Idoso , Transtornos da Coagulação Sanguínea/etiologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Fibrinólise , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/mortalidade , Masculino , Período Pré-Operatório , Prognóstico , Taxa de Sobrevida , Trombofilia/etiologia , Tromboembolia Venosa/etiologiaRESUMO
PURPOSE: The morbidity and mortality associated with lung cancer surgery in patients on chronic hemodialysis (CHD) is high; however, the relationship between the severity of postoperative complications and clinicopathological features is unclear. METHODS: Among 1214 consecutive patients who underwent pulmonary resection for primary lung cancer in our institute between 2004 and 2015, we identified 21 patients on CHD, who were the subjects of this study. Life-threatening postoperative complications were defined as grade 4 and 5 per the Clavien-Dindo classification. RESULTS: Fourteen (67%) of these 21 patients suffered postoperative complications, which were life threatening in 5. There was a higher frequency of interstitial pneumonia (IP) in the patients with life-threatening postoperative complications than in those with complications that were not life threatening (p = 0.032). The rates of acute exacerbation and 90-day mortality in the patients with IP were 50% and 75%, respectively. The overall survival (OS) rate of the patients with life-threatening postoperative complications was significantly lower than that of those with complications that were not life threatening (1- and 3-year OS rates: 40% and 0% vs. 80% and 57%, respectively, p = 0.001). CONCLUSIONS: Postoperative mortality and morbidity were high in patients on CHD who underwent pulmonary resection, especially if they had coexisting IP. Although IP is not a contraindication to pulmonary resection, the surgical strategy for CHD patients with IP should be considered carefully.
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Doenças Pulmonares Intersticiais/mortalidade , Neoplasias Pulmonares/cirurgia , Pneumonectomia/efeitos adversos , Pneumonectomia/mortalidade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/epidemiologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Fatores de TempoRESUMO
The current case was 73-year-oldwoman. She was referredto our hospital for an abnormal shadow of chest X-ray in the upper right lung field. Chest CT showed 3.5 cm of tumor located at the apex of right lobe with invasion of the chest wall. The tumor was diagnosed as squamous cell carcinoma using CT guided needle biopsy(superior sulcus tumor, clinical T3N0M0, Stage II B). The neoadjuvant therapy, 4 courses of chemotherapy(CBDCA plus PTX)andconcurrent radiotherapy(45 Gy/25 Fr)was performed. Chest CT revealed that tumor size was decreased to 2.3 cm in a diameter, and therapeutic effect was decided as partial response(34%). Upper right lobectomy combinedwith the chest wall(1th to 3th ribs)andmed iastinal lymph node dissection were performed. The pathological specimens showed no residual cancer cells(Ef3, pathological complete response[pCR]). She discharged without complications at 10 days after surgery. It is important to collect cases which obtainedpCR for development of more effective preoperative therapy.
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Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Idoso , Carcinoma de Células Escamosas/diagnóstico por imagem , Feminino , Humanos , Neoplasias Pulmonares/patologia , Pneumonectomia , Resultado do TratamentoRESUMO
Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKI. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose describing this phenomenon as an "oncogene swap." Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of an oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, an "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKI. This novel mechanism should be considered in order to avoid futile inhibition of the original oncogene.
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Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/genética , Acrilamidas/administração & dosagem , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Gefitinibe , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Oncogenes , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinas/administração & dosagemRESUMO
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR-TKI, erlotinib, has been shown in lung cancer patients with the wild-type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR-TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild-type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib-resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP-AEW541, an IGF1R-TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR.
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Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Quinazolinas/farmacologia , Receptor IGF Tipo 1/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Relação Dose-Resposta a Droga , Cloridrato de Erlotinib , Humanos , Mutação , Fosforilação , RNA Interferente Pequeno/metabolismoRESUMO
BACKGROUND: The use of soft coagulation is becoming common in thoracic surgery. Soft coagulation provides rapid hemostasis from small vessels during surgery by dehydrating tissue and denaturing proteins, without burning the tissue. CASE PRESENTATION: A 68-year-old man, with a history of right lower lobectomy 3 years prior, underwent a partial resection of the right upper lobe for a pulmonary nodule suspicious for secondary lung cancer. During the surgery, dissection of the adhesion caused a bleeding from the 6th intercostal artery, and hemostasis was achieved using soft coagulation (some degree of tissue carbonization was noticed at later mortality and morbidity conference). He experienced hemoptysis at postoperative day 18 and was transferred to our hospital. Contrast-enhanced CT scan revealed bleeding from the pseudoaneurysm of the 6th intercostal artery. Embolization was performed by angiography to stop the bleeding. CONCLUSIONS: We experienced a case of late-onset bleeding from a pseudoaneurysm related to soft coagulation hemostasis. Lessons learned from this patient are that additional hemostasis, such as ligation, would be considered for small arteries after hemostasis has been achieved by soft coagulation, especially when some degree of tissue carbonization is suspected.
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INTRODUCTION: Approximately 10% of mutations in the EGFR gene in NSCLC are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR tyrosine kinase inhibitors (TKIs). Several novel EGFR TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the U.S. Food and Drug Administration. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR TKIs of earlier generations. METHODS: We chronically exposed murine pro-B-cell line cells transduced with the five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations. RESULTS: All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH, and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib exhibited good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR TKIs, except for erlotinib, which was active for insFQEA with C797S. CONCLUSIONS: T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.
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Genes erbB-1 , Neoplasias Pulmonares , Animais , Camundongos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB , Éxons , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
This report presents the case of a late relapse of an ovarian granulosa cell tumor (GCT) that metastasized to the lung 36 years after the initial diagnosis. A 72-year-old female demonstrated multiple nodules with extrapleural signs on chest computed tomography. Positron emission tomography with (18)F-fluorodeoxyglucose ([(18)F]FDG-PET) showed that the nodules had no FDG avidity. The nodules, which appeared as polypoid lesions of the visceral pleura on thoracoscopy, were resected and diagnosed as pulmonary metastases from the GCT. This case report indicates that thorough thoracoscopic exploration of the pleural cavity is essential when intrathoracic nodules are seen on postoperative imaging examinations in GCT patients, even when the [(18)F]FDG-PET results are negative.
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Tumor de Células da Granulosa/diagnóstico , Tumor de Células da Granulosa/secundário , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundário , Neoplasias Ovarianas/patologia , Idoso , Feminino , HumanosRESUMO
Introduction: Lung tumor organoids (LTOs) have attracted attention as in vitro preclinical models; however, their clinical and experimental applications have not been fully established. Methods: We attempted to establish LTOs from resected specimens of patients with lung cancer who underwent lung resection. Clinicopathologic characteristics related to the establishment of LTOs were evaluated. Histologic assessment and genetic analysis were conducted for both LTOs and their parental tumors. Organoid-derived xenografts were generated in immunocompetent mice. Drug sensitivity was assessed using cell proliferation assays. Results: We established 53 LTOs from 79 lung cancer samples, including 10 long-term culture models. The establishment rate was significantly lower in squamous cell carcinomas than in other histologic types (48% versus 75%, p = 0.034). Histologic similarities were confirmed among LTOs, the parental tumors, and organoid-derived xenografts. Seven mutations, including two EGFR L858R and one EGFR exon 20 H773delinsYNPY mutations, were detected in both LTO and parental tumors; the other four mutations were detected in either LTO or parental tumors. The extensive culture ability of LTO (passaged >10 times) correlated with poor patient prognosis. LTO9 cells harboring EGFR H773delinsYNPY were sensitive to osimertinib. The parental patient, who had new metastatic lesions, was treated with osimertinib and exhibited a remarkable response. Conclusions: The establishment and growth rates of LTOs were associated with the histologic subtype and tumor size. LTOs derived from resected specimens have become preclinical models that can be used to predict drug responses and accelerate the development of treatment strategies for patients with rare mutations.
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BACKGROUND: The differential diagnosis of a solitary solid-type lung nodule is diverse. 18F-fluorodeoxyglucose positron emission tomography (PET) has a high sensitivity in the diagnosis of solid-type lung cancers; however, PET-negative, solid-type lung cancers are rarely observed. In this study, we analyzed the clinical/genetic features and prognosis of PET-negative, solid-type lung cancers. PATIENTS AND METHODS: Between January 2007 and February 2020, 709 patients with solid-type lung cancers (tumor size ≥2.0 cm) underwent pulmonary resection. Clinical, genetic, and prognostic features were evaluated in 27 patients (3.8%) with tumors showing negative PET results defined as SUVmax <2.0. RESULTS: All 27 patients had lung adenocarcinoma; 23 had invasive adenocarcinomas and 4 had invasive mucinous adenocarcinomas. The PET-negative group showed high frequencies of females and never-smokers. Recurrence-free survival was significantly better in the PET-negative group compared with PET-positive counterparts extracted using propensity score matching from patients who underwent pulmonary resection during the same period (P = .0052). Furthermore, 83% of PET-negative, solid-type invasive lung adenocarcinoma patients harbored EGFR mutation, which was significantly higher than that of PET-positive, solid-type invasive lung adenocarcinoma patients (38%, n = 225) who received EGFR mutation testing in our cohort (P < .0001). PET-negative, solid-type lung adenocarcinoma patients with EGFR mutations had significantly better recurrence-free survival compared with PET-positive, solid-type lung adenocarcinoma patients with EGFR mutations extracted using propensity score matching (P = .0030). CONCLUSION: PET-negative, solid-type lung cancers are characterized with a high incidence of EGFR mutation and a better prognosis compared with PET-positive, solid-type lung cancer.
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Adenocarcinoma de Pulmão/diagnóstico , Receptores ErbB , Neoplasias Pulmonares , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , PrognósticoRESUMO
BACKGROUND: Capmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14. METHODS: The inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs. RESULTS: All 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models. CONCLUSIONS: The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anilidas , Benzamidas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Éxons , Humanos , Imidazóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Piridazinas , Pirimidinas , Quinolinas , TriazinasRESUMO
Introduction: Recent studies have suggested that including presence or absence of ground-glass opacity (GGO) may improve the tumor descriptor (T descriptor) classification in clinical stage I NSCLC. In this study, we analyzed prognostic implications of presence or absence of GGO, size of the solid component, and predominant histology to identify the true prognostic determinant for early-stage NSCLC. Methods: We retrospectively examined 384 patients with clinical stage I NSCLC (solid: 242, part solid: 142) who underwent complete resection between 2009 and 2013. Results: Survival curves of the whole cohort revealed good separation using the current TNM classification. Nevertheless, the part-solid group had a favorable prognosis irrespective of solid component size. Conversely, patients in the solid tumor group with tumors between 3 and 4 cm had a worse prognosis than patients whose tumors were less than or equal to 3 cm. Thus, we propose the following novel T descriptor classification: IA, part-solid tumors; IB, solid tumors less than or equal to 3 cm; and IC, solid tumors between 3 and 4 cm. This novel classification system stratified patient prognosis better than the current classification. On pathologic evaluation, the part-solid group always had better prognoses than the solid group in each subgroup divided by pathologic grade. Conclusions: These results suggest that presence of GGO is the true prognostic determinant of stage I NSCLC, irrespective of the size of the solid component. Our novel T descriptor classification system could more accurately predict prognoses of clinical stage I NSCLC cases.
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OBJECTIVE: Emergence of acquired resistance is almost inevitable during EGFR-tyrosine kinase inhibitor therapy for non-small-cell lung cancer (NSCLC) harboring EGFR mutations. Drug tolerance, a reversible state of drug insensitivity in the early phases of tyrosine kinase inhibitor therapy, is considered to serve as the basis of recurrent disease. Therefore, it is important to elucidate the molecular mechanisms of drug tolerance. MATERIALS AND METHODS: Five EGFR-mutated NSCLC cell lines were used in this study. We established drug-tolerant cells (DTCs) via 72â¯h treatment with osimertinib (600â¯nM) or afatinib (60â¯nM). Acquisition of drug tolerance was evaluated by growth inhibitory assay, and the molecular mechanisms of drug tolerance were analyzed by phospho-RTK array. RESULTS: DTCs were successfully induced in PC9, HCC4006, and H1975 cells against osimertinib and in PC9 cells against afatinib. We observed that a high drug concentration was required to induce DTCs, and HCC4006 cells become tolerant when a higher dose of afatinib (>180â¯nM) was used. In the analysis of HCC4006 DTCs against osimertinib, we observed increased receptor-like tyrosine kinase (RYK) expression, and siRNA-mediated RYK knockdown inhibited the proliferation of DTCs. CONCLUSIONS: These results suggest that induction of DTCs is dose-dependent, and increased RYK expression was the mechanism of drug tolerance in HCC4006 cells against osimertinib.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Preparações Farmacêuticas , Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Tolerância a Medicamentos/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina QuinasesRESUMO
INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance. METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated. RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib. CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Piperazinas , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas , PirimidinasRESUMO
OBJECTIVES: The LUX-Lung 8 randomized trial (LL8) demonstrated a prolonged progression-free survival (PFS) in patients with metastatic squamous cell carcinoma (SCC) of the lung after treatment with afatinib compared with erlotinib. A secondary analysis of the LL8 reported that the presence of rare HER2/HER4 mutations may be partly responsible for this result. Patients with HER2 (hazard ratio [HR] 0.06/p-value 0.02) or HER4 (HR 0.21/p-value unreported) mutations had longer PFS after treatment with afatinib. However, the biological function of these mutations is unclear. MATERIALS AND METHODS: Ten HER2 and 13 HER4 point mutations that were detected in the secondary analysis were transduced into the mouse pro-B cell line (Ba/F3) to determine changes in interleukin-3 (IL-3) dependence and sensitivity to six EGFR or pan-HER tyrosine kinase inhibitors (TKIs), including afatinib and erlotinib. The efficacy of the six TKIs was compared using a sensitivity index, defined as the 50% inhibitory concentration divided by trough concentration of each drug at clinically recommended doses. RESULTS: Seven out of 10 Ba/F3 clones expressing HER2 mutations and all 13 Ba/F3 clones expressing HER4 mutations did not grow in the absence of IL-3, indicating these mutations were non-oncogenic. Three Ba/F3 clones expressing the HER2 mutations E395K, G815R, or R929W acquired IL-3-independent growth. The sensitivity indices for afatinib were ≤ one-fifth of those for erlotinib in all three lines. Other second/third-generation (2G/3G) TKIs showed high efficacy against clones expressing these HER2 mutations. CONCLUSIONS: The majority of HER2/4 mutations detected in lung SCC from LL8 were not oncogenic in the Ba/F3 models, suggesting that the presence of HER2/4 mutations were not responsible for the superior outcomes of afatinib in the LL8 study. However, SCC of the lung in some patients may be driven by rare HER2 mutations, and these patients may benefit from 2G/3G pan-HER-TKI treatment.
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Neoplasias Pulmonares , Quinazolinas , Animais , Humanos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Recent studies of advanced lung cancer patients have shown that circulating tumor DNA (ctDNA) analysis is useful for molecular profiling, monitoring tumor burden, and predicting therapeutic efficacies and disease progression. However, the usefulness of ctDNA analysis in surgically resected lung cancers is unclear. METHODS: This study included 20 lung cancer patients with clinical stage IIA-IIIA disease. Preoperative and postoperative (3-12 days) plasma samples were collected for ctDNA analysis. Cancer personalized profiling by deep sequencing, which can detect mutations in 197 cancer-related genes, was used for ctDNA detection. The cohort consisted of 18 men and 2 women with a median age of 69 (range, 37-88) years. Sixteen patients (80%) had a history of smoking. Histologically, there were four squamous cell carcinomas, 13 adenocarcinomas, two adenosquamous cell carcinomas, and one small cell carcinoma. RESULTS: At the time of data analysis, the 20 patients had been monitored for a median follow-up of 12 months. Eight patients (40%) were positive for preoperative ctDNA, and this was significantly correlated with tumor size (≥5 vs. <5 cm, P=0.018). Four patients (20%) were positive for postoperative ctDNA, and this was significantly correlated with histological grade (3 vs. 1 or 2, P=0.032). Postoperative positivity for ctDNA also predicted shorter recurrence-free survival (RFS) (P=0.015), while pre- and post-operative carcinoembryonic antigen levels (P=0.150 and P=0.533, respectively) and preoperative positivity for ctDNA (P=0.132) were not correlated with RFS. CONCLUSIONS: Detecting ctDNA postoperatively was a poor prognostic factor in surgically resected lung cancer patients that may suggest there is minimal residual disease (MRD).
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Although lung adenocarcinomas (LADs) with ground-glass opacity (GGO; part-solid tumors) have been shown to differ from those without GGO (pure-solid tumors) in clinicopathological features and prognoses, whether programmed death ligand-1 (PD-L1) protein expression differs between these two tumor types is unclear. This study included 124 patients with clinical T1a-c LAD who received pulmonary resections during 2007-2009. The E1L3N antibody was used to stain for PD-L1 in primary LAD specimens. The specimens were considered PD-L1+ if ≥1% of tumor cells showed membrane staining, and were classified as having a high PD-L1+ tumor proportion score (TPS) if ≥50% of the tumor cells did so. Among the 124 patients, 45 had part-solid tumors and 79 had pure-solid tumors. These two groups did not significantly differ in terms of clinical factors. However, the rates for PD-L1 positivity (4% vs. 25%, p < 0.01) and high PD-L1+ TPS (2% vs. 16%, p = 0.02) were significantly higher in the pure-solid tumors. The multivariate analyses (logistic regression model) showed that the odds ratios for PD-L1 positivity and high PD-L1+ TPS in pure-solid LADs were 5.9 (95% CI; 1.2-29.7) and 8.0 (95% CI; 1.0-63.8), respectively. In conclusion, LADs with GGO were correlated with a lower incidence of PD-L1 expression than pure-solid tumors.
Assuntos
Adenocarcinoma de Pulmão/metabolismo , Antígeno B7-H1/biossíntese , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Análise Multivariada , Estudos RetrospectivosRESUMO
BACKGROUND: MNNG HOS transforming gene (MET) exon 14 mutations in lung cancer, including exon 14 skipping and point mutations, have been attracting the attention of thoracic oncologists as new therapeutic targets. Tumors with these mutations almost always acquire resistance, which also occurs in other oncogene-addicted lung cancers. However, the resistance mechanisms and treatment strategies are not fully understood. METHODS: We generated Ba/F3 cells expressing MET exon 14 mutations by retroviral gene transfer. The sensitivities of these cells to eight MET-tyrosine kinase inhibitors (TKIs) were determined using a colorimetric assay. In addition, using N-ethyl-N-nitrosourea mutagenesis, we generated resistant clones, searched for secondary MET mutations, and then examined the sensitivities of these resistant cells to different TKIs. RESULTS: Ba/F3 cells transfected with MET mutations grew in the absence of interleukin-3, indicating their oncogenic activity. These cells were sensitive to all MET-TKIs except tivantinib. We identified a variety of secondary mutations. D1228 and Y1230 were common sites for resistance mutations for type I TKIs, which bind the active form of MET, whereas L1195 and F1200 were common sites for type II TKIs, which bind the inactive form. In general, resistance mutations against type I were sensitive to type II, and vice versa. CONCLUSIONS: MET-TKIs inhibited the growth of cells with MET exon 14 mutations. We also identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 mutations.
Assuntos
Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia/patologia , Neoplasias Pulmonares/patologia , Mutação , Células Precursoras de Linfócitos B/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Alquilantes/efeitos adversos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Células Cultivadas , Etilnitrosoureia/efeitos adversos , Éxons , Humanos , Técnicas In Vitro , Interleucina-3/genética , Interleucina-3/metabolismo , Leucemia/tratamento farmacológico , Leucemia/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos B/metabolismo , Proto-Oncogene MasRESUMO
BACKGROUND: A total of 75% of patients with Sjögren's syndrome are complicated with pulmonary lesions, of which 12% are lymphoma and 6% are amyloid nodules; the coexistence of both is considered to be rare. CASE PRESENTATION: A 67-year-old female with Sjögren's syndrome presented with multiple pulmonary nodules on chest computed tomography. Since a definitive diagnosis by transbronchial biopsy was not obtained, wedge resection of the nodules was performed. Pathologic diagnosis revealed eosinophilic deposition that stained positive with Congo red. In addition, lymphoepithelial lesions and lymphocytic infiltration were observed. Lymphocytes with monoclonal proliferation predominantly had κ chain. Based on these findings, the nodules were diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma with amyloid deposition. CONCLUSIONS: The combination of these diseases is very rare, and this is the sixth resected case to the best of our knowledge.