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1.
Medicine (Baltimore) ; 99(39): e22301, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991436

RESUMO

RATIONALE: Cardiotoxicity related to osimertinib, including cardiac failure, QT prolongation, and atrial fibrillation, has been reported as an extremely rare incidence in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the occurrence of osimertinib-induced cardiomyopathy. PATIENT CONCERNS: A 76-year old woman was treated with afatinib (40 mg/day) as the 1st line treatment due to recurrence after surgical resection for pulmonary adenocarcinoma. However, she experienced recurrence with positive T790 M, and osimertinib (80 mg/day) was administered as the 2nd line therapy. DIAGNOSIS: Four months after osimertinib initiation, she complained of fever and progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating osimertinib-induced cardiomyopathy. INTERVENTIONS AND OUTCOMES: She was treated with furosemide, carvedilol, and enalapril, and her cardiac function, her symptoms, and condition improved 3 weeks after the withdrawal of osimertinib. LESSONS: Physicians should be alert of the cardiomyopathy-causing potential of osimertinib in advanced NSCLC patients.


Assuntos
Acrilamidas/efeitos adversos , Compostos de Anilina/efeitos adversos , Cardiomiopatias/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Afatinib/uso terapêutico , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Anilina/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/fisiopatologia , Carvedilol/uso terapêutico , Diuréticos/uso terapêutico , Enalapril/uso terapêutico , Feminino , Furosemida/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Resultado do Tratamento , Suspensão de Tratamento
2.
Anticancer Res ; 40(10): 5361-5369, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988855

RESUMO

BACKGROUND/AIM: The aim of this study was to evaluate the role of toll-like receptor 2 (TLR2) in the proliferation of human lung cancer cells and identify the signaling pathway that mediates this effect. MATERIALS AND METHODS: Adenocarcinoma (A549 and H1650) and adenosquamous (H125) cells were treated with increasing doses of Pam3CSK4, a TLR2 agonist. Cell proliferation and NF-ĸB activation were evaluated. NF-ĸB was inhibited prior to treatment with Pam3CSK4 and proliferation was assessed. RESULTS: TLR2 expression was significantly higher in A549 and H1650 cells compared to H125 cells (p<0.001). TLR2 stimulation induced proliferation in adenocarcinoma cells only and led to a corresponding increase in NF-ĸB activity (p<0.05). Inhibition of NF-ĸB prior to treatment with Pam3CSK4 attenuated this proliferative response. CONCLUSION: TLR2 activation induced proliferation of lung adenocarcinoma cells through activation of NF-ĸB. Thus, the TLR2 signaling pathway may be a potential therapeutic target in lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Lipopeptídeos/farmacologia , Receptor 2 Toll-Like/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , NF-kappa B/genética , Receptor 2 Toll-Like/agonistas
3.
Medicine (Baltimore) ; 99(36): e22128, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899099

RESUMO

RATIONALE: Brain metastasis (BM) is a serious complication in non-small cell lung cancer (NSCLC) patients. Pemetrexed is one of the preferred agents in nonsquamous NSCLC with BM; however, the traditional chemotherapy demonstrated limited efficacy partly due to drug resistance and the blood-brain barrier. PATIENT CONCERNS: A 52-year-old male non-smoker was admitted for irritating cough, chest distress, and back pain. DIAGNOSES: Epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative primary lung adenocarcinoma with an asymptomatic solitary BM (cTxNxM1b, IVA). INTERVENTIONS: Pemetrexed (500 mg/m of body surface area) and carboplatin (area under the curve of 5) were firstly administered every 3 weeks for 3 cycles, followed by pemetrexed/carboplatin plus anlotinib (12 mg daily; 2 weeks on and 1 week off) for another 3 cycles. Then maintenance anlotinib monotherapy was continued for a year, without unacceptable adverse events. OUTCOMES: The BM was slightly enlarged after 3 cycles of pemetrexed/carboplatin; however, a complete remission was achieved after the combination therapy. His intracranial progression-free survival was more than 2 years. LESSONS: Pemetrexed/carboplatin plus anlotinib could be considered for the treatment of epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative lung adenocarcinoma with BM. Further well-designed trials are warranted to verify this occasional finding.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico/metabolismo , Carboplatina/uso terapêutico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Quinolinas/uso terapêutico
4.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
5.
Life Sci ; 259: 118157, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735888

RESUMO

AIMS: Previous studies have demonstrated that circular RNAs play significant roles in several tumors, including lung adenocarcinoma; however, specific biological functions and molecular mechanisms underlying this process remain unclear. MATERIALS AND METHODS: Here, we conducted real-time quantitative PCR (qRT-PCR) to measure hsa_circ_0001588 expression levels in 60 paired lung adenocarcinoma tissues and cell lines. Furthermore, the association between hsa_circ_0001588 and clinical features of lung adenocarcinoma was analyzed. Functional experiments were conducted to assess the influence of hsa_circ_0001588 on proliferation, migration, and invasion in lung adenocarcinoma cells. We detected possible downstream targets of hsa_circ_0001588 using bioinformatics analysis. Luciferase reporter assays, qRT-PCR, and western blotting assays were performed to verify the molecular mechanism underlying hsa_circ_0001588 functions. KEY FINDINGS: We found that hsa_circ_0001588 was prominently upregulated in lung adenocarcinoma tissues and cell lines; elevated expression of hsa_circ_0001588 was positively correlated with poor clinicopathological features of lung adenocarcinoma. Functional experiments revealed that hsa_circ_0001588 acts as an oncogene to promote the proliferation, migration, and invasion of lung adenocarcinoma in vitro. Mechanistically, hsa_circ_0001588 promoted the proliferation, migration, and metastasis of lung adenocarcinoma by binding to miR-524-3p to promote nucleus accumbens-associated protein 1(NACC1) expression. SIGNIFICANCE: Together, our results revealed that hsa_circ_0001588 upregulated the expression of NACC1 by combining with miR-524-3p to promote the proliferation, migration, and invasion of lung adenocarcinoma cells, suggesting that hsa_circ_0001588 may be an underlying therapeutic target for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Circular/genética , RNA Neoplásico/genética , Proteínas Repressoras/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Invasividade Neoplásica/genética , Reação em Cadeia da Polimerase , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Medicine (Baltimore) ; 99(29): e21275, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702917

RESUMO

This observational study evaluated the treatment outcomes of clinical factors on the patients with lung adenocarcinoma with epidermal growth factor receptor mutations who received tyrosine kinase inhibitors as first-line treatment.Patients with stage IIIb or IV lung adenocarcinoma with mutated epidermal growth factor receptor were enrolled retrospectively between March 2010 and December 2017. The hematologic markers on progression-free survival (PFS) and overall survival (OS) were analyzed.Totally 190 patients were enrolled. In univariate analysis by hematologic markers, lower lymphocyte percentage and higher platelet count were associated with significantly poor PFS and OS. Multivariate analysis showed lower lymphocyte percentage was independent poor prognostic factors for PFS and OS. Higher platelet count was an independent poor prognostic factor for OS only.Patients with lung adenocarcinoma receiving tyrosine kinase inhibitors with lower lymphocyte percentage and higher platelet count had poorer prognoses compared with other patients.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Contagem de Linfócitos , Contagem de Plaquetas , Proteínas Tirosina Quinases/antagonistas & inibidores , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
7.
J Nat Med ; 74(4): 777-787, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32666278

RESUMO

Lung adenocarcinoma (LUAD) is the top prevalent histological kind of lung cancer worldwide. Recent evidences have demonstrated that Sauchinone plays an anticancer role in tumor cell invasion and migration. Therefore, we performed this investigation to explain the potential role of Sauchinone in LUAD as well as the potential mechanism involved. Cell counting kit 8 (CCK-8) and transwell experiments were implemented to measure the proliferative, invasive and migratory abilities of LUAD cells. qRT-PCR and Western blot were performed to detect the transfection efficiency of si-EIF4EBP1s. Additionally, Western blot was also implemented to evaluate the effect of Sauchinone on EIF4EBP1 expression level as well as cell cycle-related proteins. Our findings showed that Sauchinone remarkably suppressed the proliferative ability of LUAD cells in a dose-dependent and time-dependent manner. EIF4EBP1 was a candidate target gene of Sauchinone. EIF4EBP1 expression was increased in LUAD tissues, and its high expression induced a poorer prognosis of LUAD patients. EIF4EBP1 expression was positively associated with cell cycle in LUAD. Sauchinone treatment attenuated EIF4EBP1 expression and cell cycle-related protein levels. Knockdown of EIF4EBP1 repressed the proliferation, invasion and migration of LUAD cells; furthermore, Sauchinone stimulation enforced its inhibitory effect. Meanwhile, the treatment of Sauchinone intensified the arrest of cell cycle induced by EIF4EBP1 knockdown. To sum up, our discovery indicated that Sauchinone exerts an anticancer role through down-regulating EIF4EBP1 and mediating cell cycle in LUAD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Benzopiranos/uso terapêutico , Proteínas de Ciclo Celular/uso terapêutico , Dioxóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Adenocarcinoma de Pulmão/patologia , Benzopiranos/farmacologia , Proteínas de Ciclo Celular/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Dioxóis/farmacologia , Regulação para Baixo , Humanos , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Estudos Prospectivos , Transfecção
8.
Anticancer Res ; 40(5): 2911-2916, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366442

RESUMO

BACKGROUND: Although oncogene-targeted therapy is a first-line treatment for advanced, unresectable lung adenocarcinoma harboring a target gene mutation, its effect on potentially resectable, locally advanced lung adenocarcinoma remains unclear. PATIENTS AND METHODS: Ten patients with clinically diagnosed stage III lung adenocarcinoma harboring a target gene mutation were enrolled in the current feasibility study of targeted therapy followed by cytotoxic chemotherapy (platinum and pemetrexed) before radical surgery. RESULTS: Complete resection was accomplished in all nine patients who went on to surgery (one patient refused surgery), and all of these patients recovered without major postoperative complications. Overall, almost all of the patients who underwent surgery remain disease-free after a median follow-up of 22 months since the initial treatment, with only one patient dying of recurrence. CONCLUSION: Radical surgery after the sequential use of cytostatic and cytotoxic drugs resulted in a favorable short-term outcome.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Cuidados Pré-Operatórios/métodos , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
J Cancer Res Clin Oncol ; 146(9): 2411-2417, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32356178

RESUMO

PURPOSE: We aimed to investigate the treatment effect of chemotherapy on ground-glass opacity (GGO)-featured lung adenocarcinoma radiologically and pathologically. METHODS: This retrospective study included patients who met the following criteria: (1) presence of lung GGO lesions before chemotherapy for other concurrent malignancies; (2) underwent surgical resection of GGO-featured primary lung adenocarcinoma. The last computed tomography images before chemotherapy (CT1) and the last images before GGO resection (CT2) were reviewed to assess radiologic response. Specimens of the resected tumors were reviewed to evaluate the histopathologic response. Immunohistochemical staining of ki-67, caspase-3 and ß-gal was performed and compared between these tumors and a propensity score-matched (1:1) cohort of GGO-featured lung adenocarcinoma without prior chemotherapy. RESULTS: Forty-four patients with 55 GGO lesions were included. There were 20 mixed GGOs and 22 invasive adenocarcinomas. These patients all received at least three cycles of chemotherapy for other concurrent malignancies in breast, lung, cervix, ovary or rectum. Thirty-four (77%) patients received chemotherapy regimens that contained platinum, pemetrexed, paclitaxel, docetaxel or gemcitabine. The median interval between CT1 and CT2 was 10 months. Radiologically, all the GGO lesions either remained unchanged or enlarged. There was no chemotherapy-induced histopathologic response (necrosis, fibrosis or inflammation) in any of these tumors. The protein expression of ki-67, caspase-3 and ß-gal was comparable between GGO-featured lung adenocarcinoma with or without prior chemotherapy. CONCLUSION: GGO-featured lung adenocarcinoma has no response to chemotherapy. For these patients, chemotherapy should not be a treatment option.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Adulto , Idoso , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pneumonectomia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
10.
Gan To Kagaku Ryoho ; 47(3): 445-447, 2020 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-32381912

RESUMO

Herein, we report a case of unresectable lung cancer in which S-1 monotherapy contributed to an improvement in the patient's quality of life and to prolonged survival. A 44-year-old man with primary pulmonary adenocarcinoma(negative driver mutation and a PD-L1 tumor proportion score of 1-24%)of clinical stage ⅢA(cT4N0M0)underwent multidisciplinary treatment as follows: 1 ) weekly carboplatin and paclitaxel plus radiotherapy as induction chemoradiotherapy, 2 ) surgery that revealed that the lesion was unresectable, 3 ) cisplatin plus pemetrexed as second-line treatment, and 4 ) pembrolizumab as third-line treatment. However, the disease progressed after 19 courses of pembrolizumab, and the patient developed cachexia due to esophageal stenosis caused by tumor enlargement. He underwent percutaneous gastrostomy and was fed via a gastrostomy tube. S-1 monotherapy(2-week administration every 3 weeks)was introduced as fourth-line treatment. After 3 courses of S-1 monotherapy, the patient complained of regurgitation of stomach fluid. Computed tomography( CT)revealed that the primary tumor had decreased in size, and he developed the ability to drink water. After 6 courses of S-1, CT revealed progressive disease, so atezolizumab was administered as fifth-line treatment. However, after 2 courses, mediastinitis due to esophageal penetration into the mediastinum occurred. The patient died 28 months after the initial treatment.


Assuntos
Adenocarcinoma de Pulmão , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Pulmonares , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adulto , Combinação de Medicamentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Qualidade de Vida
11.
Cancer Sci ; 111(5): 1652-1662, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32133706

RESUMO

Lung cancer is the most commonly diagnosed cancer worldwide, and metastasis in lung cancer is the leading cause of cancer-related deaths. Thus, understanding the mechanism of lung cancer metastasis will improve the diagnosis and treatment of lung cancer patients. Herein, we found that expression of cluster of differentiation 109 (CD109) was correlated with the invasive and metastatic capacities of lung adenocarcinoma cells. CD109 is upregulated in tumorous tissues, and CD109 overexpression was associated with tumor progression, distant metastasis, and a poor prognosis in patient with lung adenocarcinoma. Mechanistically, expression of CD109 regulates protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling via its association with the epidermal growth factor receptor (EGFR). Inhibition of CD109 decreases EGFR phosphorylation, diminishes EGF-elicited activation of AKT/mTOR, and sensitizes tumor cells to an EGFR inhibitor. Taken together, our results show that CD109 is a potential diagnostic and therapeutic target in lung cancer patients.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antígenos CD/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Antígenos CD/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias/genética , Fosforilação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais
12.
Oncol Rep ; 43(6): 1906-1914, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32186774

RESUMO

Circulating tumor cells (CTCs) that are shed from the primary tumor invade the blood stream or surrounding parenchyma to form new tumors. The present study aimed to explore the underlying mechanism of cisplatin resistance in lung adenocarcinoma CTCs and provide clinical treatment guidance for lung cancer treatment. CTCs from the blood samples of 6 lung adenocarcinoma patients were treated with different concentrations of cisplatin along with A549 and H1299 cells. The sensitivity of CTCs to cisplatin was explored by detecting the inhibitory rate via CCK­8 assay. The related molecular mechanism was investigated by western blot analysis. miR­10a expression was detected using quantitative real­time PCR (RT­qPCR). The relationship between miR­10a and phosphatidylinositol­4,5­bisphosphate 3­kinase catalytic subunit α (PIK3CA) was verified and further confirmed by luciferase reporter assay, western blotting and RT­qPCR assay. The results revealed that CTCs exhibited lower cisplatin sensitivity than A549 and H1299 cells. Moreover, CTCs treated with cisplatin demonstrated higher miR­10a expression and lower PIK3CA expression than that in A549 and H1299 cells (P<0.01). Expression of phosphoinositide 3­kinase (PI3K) and protein kinase B (Akt) phosphorylation were also decreased in A549 and H1299 cells compared with CTCs after cisplatin treatment. PIK3CA is a target of miR­10a, and both miR­10a overexpression and PIK3CA knockdown obviously decreased the sensitivity of A549 and H1299 cells to cisplatin as well as the expression of PI3K and phosphorylation of Akt. PIK3CA overexpression attenuated the cisplatin resistance of A549 and H1299 cells induced by miR­10a. In conclusion, miR­10a suppressed the PI3K/Akt pathway to strengthen the resistance of CTCs to cisplatin via targeting PIK3CA, providing a new therapeutic target for lung cancer treatment.


Assuntos
Adenocarcinoma de Pulmão/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/genética , MicroRNAs/genética , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Idoso , Linhagem Celular Tumoral , Cisplatino/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Am J Case Rep ; 21: e920809, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32018275

RESUMO

BACKGROUND Nivolumab is a human IgG4 monoclonal antibody against human programmed cell death 1 (PD-1). It has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). Treatment with nivolumab is sometimes associated with immune-related adverse events (ir AEs) in patients. These specific ir AEs include pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy. However, hematological toxicity is rare. CASE REPORT A 57-year-old man with lung adenocarcinoma, with brain and adrenal gland metastases, was therefore started on nivolumab therapy as third-line treatment. After administration of the second dose with nivolumab, grade 3 febrile neutropenia (FN) and grade 2 liver dysfunction developed in the patient. The patient was started to on intravenous antibiotics, granulocyte colony-stimulating factor (G-CSF), and corticosteroids. Neutrophil counts and liver function gradually improved, and corticosteroids were tapered over 6 weeks. However, the patient was re-treated with G-CSF because the neutrophil counts decreased again. CONCLUSIONS Care needs to be taken with such patients because neutropenia due to treatment with nivolumab can recur, as well as other ir AEs.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neutropenia Febril/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias Encefálicas/secundário , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Hepatopatias/terapia , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/administração & dosagem
14.
Anticancer Res ; 40(2): 1117-1121, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014962

RESUMO

BACKGROUND/AIM: The survival benefit of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy without pleurodesis in EGFR-mutant lung adenocarcinoma patients with malignant pleural effusions (MPE) remains unclear. PATIENTS AND METHODS: We retrospectively evaluated overall survival (OS) among EGFR wild-type lung adenocarcinoma patients with MPE who received chemotherapy with pleurodesis (CT+PLD) and without pleurodesis (CT-PLD), and EGFR-mutant lung adenocarcinoma patients with MPE who received EGFR-TKI therapy with pleurodesis (TKI+PLD) and without pleurodesis (TKI-PLD). RESULTS: There was no difference in OS between the CT+PLD and the CT-PLD groups (10.8 months vs. 7.4 months). As compared to the TKI+PLD group, OS tended to be longer in the TKI-PLD group (21.8 months vs. 31.1 months). Patients in the TKI-PLD group had no hypoalbuminemia or deterioration of performance status during management of MPE and could receive second- and further-line therapy. CONCLUSION: EGFR-mutant patients with MPE who received first-line EGFR-TKI therapy without pleurodesis may show a better prognosis than those with pleurodesis.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Mutação , Derrame Pleural Maligno/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural Maligno/tratamento farmacológico , Pleurodese , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
15.
Arch Med Res ; 51(1): 8-12, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32086110

RESUMO

BACKGROUND: Lung adenocarcinoma (LAC) is a major worldwide cause of death by cancer, it shows high aggressiveness, functional decline, systemic compromise and severe cachexia, which might be counteracted by dietary redox-active phytochemicals. Therefore, our aim was to establish the anticancer effects of the oral intake of quercetin and 5 caffeoylquinic acid. METHODS: LAC-1-bearing male Balb/c mice received quercetin (0-25 µg/kg/d) and 5 caffeoylquinic acid (0-120 µg/kg/d) for three weeks, with different organic and biochemical variables being then compared with ANOVA and the Fisher Test (p <0.05). RESULTS: Quercetin delayed 1.18 fold tumour appearance and increased 8.87 fold non-neoplastic body weight gain, whereas 5 caffeoylquinic acid did it in a lesser extent (1.17 and 2.48 fold, respectively), with tumour weight being consequent with the evolution time. Quercetin induced >1.15 fold tumour hydroperoxides and lipoperoxides, whereas 5 caffeoylquinic acid induced only lipoperoxides. Although both phytochemicals reduced <0.85 fold hydroperoxides and lipoperoxides in the kidney, only quercetin was also antioxidant in the liver. Additionally, 5 caffeoylquinic acid increased >1.15 fold hepatic and renal weights. Although these phytochemicals did not modify telencephalic interleukin 6 production, quercetin augmented 2.51 fold interleukin 6 in the diencephalon, whereas 5 caffeoylquinic acid decreased it 0.43 fold. CONCLUSIONS: Quercetin delayed lung adenocarcinoma appearance and increased the non-neoplastic body weight gain in mice with tumour oxidative stress, without brain interleukin 6 participation. 5 caffeoylquinic acid showed similar effects, although they were weaker. Additionally, quercetin acted as a hepatic and renal antioxidant, whereas 5 caffeoylquinic acid only exerted this effect in the kidney. Therefore, safe oral doses of this flavonoid are promissory to modulate lung cancer progression, with further studies being encouraged.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quercetina/administração & dosagem , Ácido Quínico/análogos & derivados , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Peso Corporal/efeitos dos fármacos , Caquexia/tratamento farmacológico , Caquexia/metabolismo , Caquexia/patologia , Progressão da Doença , Interleucina-6/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Ácido Quínico/administração & dosagem , Ácido Quínico/farmacologia
17.
BMC Cancer ; 20(1): 148, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093629

RESUMO

BACKGROUND: Lung adenocarcinoma (LAC) is composed of lepidic, papillary, mucinous, micropapillary and solid components in its parenchyma. Complex responses to therapeutics result from intratumoral heterogeneity. However, it remains confused that what components in a mixed LAC tumor are responsible to the heterogeneous EGFR mutation and PD-L1 expression. METHODS: We investigated EGFR status via laser microdissection to capture spatially separated cancer cell subpopulations and digital droplet PCR to determine the abundance of EGFR sensitizing mutation and naïve T790M. Whilst, PD-L1 expression level via tumor proportion score (TPS) was evaluated by Ventana immunohistochemistry using SP263 antibody. PD-L1 expression levels were tiered in < 1, 1-49% and > =50% groups. RESULTS: EGFR mutation harbored in 154 (59%) of 261 LAC patients and more frequently occurred in papillary, lepidic and micropapillary constituents. Higher levels of PD-L1 were found in LACs at stage III and IV (68.3%) versus those at stage I and II (31.7%) (P = 0.04). Solid predominant LACs (41.3%) expressed PD-L1 with TPS > =50%, versus mucinous and lepidic LACs (P < 0.01). LACs with solid constituents also had more positive proportion of PD-L1 protein. Cut-offs < 1, 1-49% or > =50% were associated with patients' progression-free survival and longer in the < 1% group (22.9 month, 95% CI 17.6-28.2) (P < 0.05). LACs consisting of two constituents with PD-L1 TPS < 1% had a better prognosis than the groups with single component and more than two components (P < 0.05). Eighteen LACs (6.9%) had concomitantly deletion in exon 19 or L858R and naïve T790M mutation. The abundance of T790M varied diversely with sensitizing mutation. PD-L1 expression was not concordant in same components and usually negative in the EGFR-mutated constituents. Heterogeneous PD-L1 expression occurred in the vicinity of stromal tissues. 58.8, 29.4 and 11.8% in ALK positive LACs (N = 17) were found PD-L1 expression via cutoffs of < 1, 1-49% and > =50%, respectively (P > 0.05). CONCLUSION: Intratumoral genetic heterogeneity of LACs was demonstrated associated with histological patterns. Heterogeneous PD-L1 expression in higher level usually occurred in solid component both in EGFR mutated and EGFR wild-typed LACs. EGFR mutated LACs heterogeneously had sensitizing and resistant mutation and was accompanied with PD-L1 expression, but discordant among histological constituents. Immune checkpoint inhibitor combined with third generation EGFR tyrosine kinase inhibitor should be more effective to these LACs.


Assuntos
Adenocarcinoma de Pulmão/genética , Antígeno B7-H1/biossíntese , Neoplasias Pulmonares/genética , Mutação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Heterogeneidade Genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Taxa de Sobrevida , Adulto Jovem
18.
Intern Med ; 59(8): 1075-1080, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32009093

RESUMO

Immune checkpoint inhibitors have changed the landscape of classic cancer treatment. However, their use is associated with the emergence of new adverse events. An elderly man with rheumatoid arthritis was started on pembrolizumab for newly diagnosed advanced lung cancer. He subsequently developed hemophagocytic lymphohistiocytosis (HLH), which is potentially fatal but has not been properly established as an immune checkpoint inhibition-induced event. We herein report the case of a patient with pembrolizumab-induced HLH.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Adenocarcinoma de Pulmão/complicações , Idoso , Artrite Reumatoide/complicações , Humanos , Neoplasias Pulmonares/complicações , Masculino
19.
Lancet Oncol ; 21(3): 387-397, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32035514

RESUMO

BACKGROUND: Pembrolizumab plus pemetrexed-platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexed-platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189. METHODS: In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1-5, every three cycles thereafter during year 1, and every four cycles during years 2-3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680. FINDINGS: Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10·5 months (range 0·2-20·4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed-platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed-platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed-platinum group and 180 (90%) of 200 in the placebo plus pemetrexed-platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed-platinum (least-squares mean change: 1·0 point [95% CI -1·3 to 3·2] increase) and placebo plus pemetrexed-platinum (-2·6 points [-5·8 to 0·5] decrease; between-group difference: 3·6 points [-0·1 to 7·2]; p=0·053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed-platinum (least-squares mean change: 1·3 points [95% CI -1·2 to 3·6] increase) than with placebo plus pemetrexed-platinum (-4·0 points [-7·7 to -0·3] decrease; between-group difference: 5·3 points [1·1 to 9·5]; p=0·014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10·2 months to not reached) with pembrolizumab plus pemetrexed-platinum, and was 7·0 months (4·8 months to not reached) with placebo plus pemetrexed-platinum (hazard ratio 0·81 [95% CI 0·60-1·09], p=0·16). INTERPRETATION: The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed-platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer. FUNDING: Merck Sharp & Dohme.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Adenocarcinoma de Pulmão/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Pemetrexede/administração & dosagem , Prognóstico , Taxa de Sobrevida , Adulto Jovem
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