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1.
Anticancer Res ; 41(9): 4609-4617, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475089

RESUMO

BACKGROUND/AIM: This study aimed to assess the yield of an Oncomine comprehensive assay v3 (OCAv3)-based next-generation sequencing (NGS) analysis for detecting anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusions in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: NGS data from 85 NSCLC cases were reviewed. ALK and ROS1 fusion status was compared to conventional tests. RESULTS: ALK or ROS1 fusion reads were detected in 17 NSCLC cases. Results in 10 NSCLC cases showed concordance with conventional tests, high-count fusion reads, a lack of mutually exclusive mutations of ALK or ROS1, and frequent signet-ring cell component. Seven NSCLC cases showing discordant results exhibited low to intermediate fusion read counts and mutations mutually exclusive from ALK or ROS1. CONCLUSION: Cases showing high-count fusion reads in OCAv3-based NGS have a strong possibility of carrying ALK or ROS1 fusion. Cases with low- to intermediate-count fusion reads should be interpreted with caution and may require additional confirmative tests.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Análise de Sequência de RNA/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Citogenética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
Anal Chim Acta ; 1178: 338800, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34482860

RESUMO

Accurate quantification of multiple miRNAs biomarkers in body fluid is still a challenge for early screening of cancer. Herein, by catalytic hairpin assembly as a signal amplification strategy, we designed a novel surface-enhanced Raman scattering (SERS)-lateral flow assay (LFA) strip for ultrasensitive detection of miR-21 and miR-196a-5p in non-small cell lung cancer (NSCLC) urine on a single test (T) line. 4-mercaptobenzoic acid or 5,5'-dithiobis-2-nitrobenzoic acid as Raman molecules was labeled and two hairpin DNA sequence was modified gold nanocages (GNCs) were designed as two SERS tags. Through target miRNA-triggered catalytic hairpin assembly (CHA), the double-stranded DNAs (H1-H2 complex) formed by SERS tags and the related hairpin-structured DNA sequence 2 (H2) were immobilized on a single T line of SERS-LFA strip. This generated abundant "hot spots" because of the formation of numerous H1-H2 complex thus facilitated the SERS measurement. Through this method, two kinds of miRNAs were analyzed, resulting in limits of detection of 2.08 pM and 3.31 pM for miR-21 in PBS buffer and human urine, 1.77 pM and 2.18 pM for miR-196a-5p in PBS buffer and human urine. Significantly, the SERS-LFA strip exhibited high specificity and good repeatability toward miRNAs. The whole detection time was only 30 min, which means that the high detection efficiency of the strip. The clinical feasibility of the proposed method was also evaluated by detecting the levels of miR-21 and miR-196a-5p in urine samples from NSCLC patients and healthy subjects. The developed SERS-LFA strip has wide application prospect in biomedical research, drug development and early clinical diagnosis.


Assuntos
Técnicas Biossensoriais , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas Metálicas , MicroRNAs , Carcinoma Pulmonar de Células não Pequenas/genética , Ouro , Humanos , Limite de Detecção , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , MicroRNAs/genética , Análise Espectral Raman
3.
World J Surg Oncol ; 19(1): 262, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470640

RESUMO

BACKGROUND: This study aimed to investigate the correlation between miRNA-216b expression in patients with non-small cell lung cancer (NSCLC) and 18F-fluorodeoxyglucose (FDG) uptake by PET/CT and to explore the clinical application value of 18F-FDG PET/CT in miRNA-216b based on therapy for NSCLC. METHODS: Eighty patients with NSCLC and 40 healthy subjects were enrolled in our study. The SUVmax of the lesion area by PET/CT imaging was calculated. SUVmax represented the highest concentration of 18F-FDG in the lesion. The expression of miRNA-216b in the plasma and fiber bronchoscopic puncture of NSCLC patients was detected by RT qPCR. Then Pearson correlation analysis was used to analyze the correlation between miRNA-216b expression and 18F-FDG uptake in patients with different types of NSCLC. RESULTS: Compared with healthy subjects, SUVmax of early adenocarcinoma and advanced adenocarcinoma were increased. Compared with healthy subjects, SUVmax of early squamous and advanced squamous were increased. And the SUVmax content of advanced adenocarcinoma and squamous cell carcinoma was higher than that of early adenocarcinoma and squamous cell carcinoma. Compared with healthy subjects, the expression of miRNA-216b in the plasma of patients with early and advanced adenocarcinoma was reduced, and the expression of miRNA-216b in the plasma of patients with early and advanced squamous cell carcinoma was reduced. Compared with adjacent tissues, the expression of miRNA-216b in early adenocarcinoma tissues and advanced adenocarcinoma tissues was reduced, and the expression in early squamous cell carcinoma and advanced squamous cell carcinoma was reduced. Pearson correlation analysis showed a negative correlation between SUVmax and miRNA-216b (plasma and tissue) in patients with four types of NSCLC. CONCLUSION: miRNA-216b expression was negatively correlated with 18F-FDG uptake in NSCLC. miRNA-216b could be used for the classification and staging of non-small cell lung cancer. 18F-FDG PET/CT may be used to evaluate the therapeutic response in application of miRNA-216b-based cancer treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Fluordesoxiglucose F18/farmacocinética , Neoplasias Pulmonares , MicroRNAs , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , MicroRNAs/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos
4.
Ann Palliat Med ; 10(8): 8818-8826, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488370

RESUMO

BACKGROUND: Roughly 30-40% of lung cancer (LC) patients develop bone metastasis during the course of disease. The genetic differences between primary LC and matched bone metastasis are not yet fully understood. METHODS: A total of 40 LC patients with bone metastasis were collected and 450 targeted cancer-related genes were sequenced for genomic-alteration (GA) identification. RESULTS: Among the 40 LC patients, 33 had adenocarcinomas and 7 had squamous cell carcinomas. The metastatic sites of the 33 lung adenocarcinomas (LUADs) were the pelvis (6 patients), spine (16 patients), and limbs (11 patients). A total of 425 and 422 GAs were detected in the primary and metastatic lesions, respectively. The most common GAs were epidermal growth factor receptor (EGFR) mutations, which had mutation rates of 85.0% and 72.5% in the primary and metastatic lesions, respectively, and tumor protein 53 (TP53) mutations, which had mutation rates of 52.5% and 67.5% in the primary and metastatic lesions, respectively. Metastases to the pelvis and spine were most commonly accompanied by factor receptor substrate 2 (FRS2), cyclin-dependent kinase 4 (CDK4), and murine double minute 2 (MDM2) amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion. The concordance between primary lung squamous cell carcinoma (LUSC) and corresponding metastasis was significantly higher than that of primary LUAD and corresponding metastasis (P=0.033). Compared to limb and pelvis metastases, the shared mutation in spine metastasis was significantly lower (P=0.016 and P=0.023, respectively). In matched primary LUSCs and bone metastasis lesions, there was no significant difference in the distribution of the tumor mutational burden (TMB) (P=0.9). Conversely, a significant difference of the TMB distribution was detected in pairs of primary LUAD and corresponding bone metastasis lesions (P=0.021). CONCLUSIONS: The consistency of mutation patterns between primary LC lesions and matched bone metastases may vary in terms of metastatic sites, but is very high in general. There was a significant difference in the TMB between primary LUAD and matched bone metastatic lesions. Our findings contribute to molecular understandings of primary LC and matched bone metastatic lesions.


Assuntos
Neoplasias Ósseas , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Metástase Neoplásica/genética
5.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445544

RESUMO

Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Citoplasma/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ácido Fólico/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Células Tumorais Cultivadas
6.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443299

RESUMO

Phycocyanin, derived from marine algae, is known to have noteworthy antineoplastic properties. However, the underlying mechanism involved in phycocyanin-mediated anti-growth function on non-small cell lung cancer (NSCLC) cells is still ambiguous. Here, we investigated the mechanism of action of phycocyanin on H1299, A549, and LTEP-a2 cells. According to the results obtained, insulin receptor substrate 1 (IRS-1) expression was reduced by phycocyanin. Cell phenotype tests showed that siRNA knockdown of IRS-1 expression significantly inhibited the growth, migration, colony formation, but promoted the apoptosis of NSCLC cells. Meanwhile, phycocyanin and IRS-1 siRNA treatment both reduced the PI3K-AKT activities in NSCLC cells. Moreover, overexpression of IRS-1 accelerated the proliferation, colony formation, and migration rate of H1299, A549, and LTEP-a2 cells, which was contradicting to the knockdown results. Overall, this study uncovered a regulatory mechanism by which phycocyanin inhibited the growth of NSCLC cells via IRS-1/AKT pathway, laying the foundation for the potential target treatment of NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Ficocianina/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
7.
World J Surg Oncol ; 19(1): 244, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399782

RESUMO

BACKGROUND: The study was done to investigate the effect of LncRNA MEG3 on the immunity and autophagy of non-small cell lung carcinoma through the IDO signaling pathway. METHODS: A total of 78 cases of early NSCLC patients (research group; RG) and 69 cases of health controls (control group; CG) during the same time were included. The contents of LncRNA MEG3 and miR-543 in peripheral blood and tissues and their diagnostic values for NSCLC were detected. The relationship between LncRNA MEG3 and miR-543 and their posttreatment contents and influence on the prognosis of NSCLC patients were tested. The expression of LncRNA MEG3, miR-543, and IDO (IDO1, IDO2, and TDO proteins) in the lung tissue of rats and the immune function in the CG and the RG were detected. The effects of LncRNA MEG3 and miR-543 on the biological behavior of NSCLC cells were determined. The role of LncRNA MEG3, miR-543, and IDO in NSCLC was verified. RESULTS: LncRNA MEG3 was low in peripheral blood and tissues, while miR-543 was high (P < 0.05); both had good diagnostic values for NSCLC (P < 0.05). LncRNA MEG3 had a negative correlation with miR-543 (P < 0.05) and influenced the prognosis of NSCLC patients (P < 0.05). LncRNA MEG3 in the lung tissue of rats using IDO inhibitor was elevated compared with that of lung carcinoma model rats (P < 0.05). The level of miR-543 was declined compared with that of lung carcinoma model rats (P < 0.05). The levels of IDO1, IDO2, and TDO proteins were evidently declined compared with those of lung carcinoma model rats (P < 0.05). Compared with lung carcinoma model rats, CD3+, CD4+, and CD4+/CD8+ of IDO inhibitor rats were elevated, while CD8+ was declined (P < 0.05). Cell proliferation and invasion ability and IDO1, IDO2, TDO, Beclin-1, and LC3-II proteins were declined in the sh-LncRNA MEG3 group (P < 0.05), while those in the mimics-miR-543 group were evidently elevated (P < 0.05). However, the double luciferase activity detection and RIP experiment confirmed that there was targeted regulation among them (P < 0.05). CONCLUSION: MEG3 has low expression in NSCLC and affects the immunity and autophagy of NSCLC cells via regulating the miR-543/IDO signaling pathway, which is effective for the treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Animais , Apoptose , Autofagia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase , Neoplasias Pulmonares/genética , MicroRNAs/genética , Prognóstico , RNA Longo não Codificante/genética , Ratos , Transdução de Sinais
8.
In Vivo ; 35(5): 2941-2945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410991

RESUMO

BACKGROUND: Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor approved for the treatment of T790M-positive non-small-cell lung cancer. More recently, osimertinib demonstrated improved disease control compared to other EGFR-TKIs. Multiple mechanisms of resistance have been described in T790M-positive patients who experienced treatment failure with osimertinib. CASE REPORT: We report the case of a 78-year-old non-smoker woman with stage IV EGFR L858R-positive lung adenocarcinoma presented with T790M mutation after five years of treatment with gefitinib. The patient was started on osimertinib, but after two and a half years of treatment experienced disease progression. The analyses of circulating tumor DNA using next-generation sequencing showed, together with the pre-existing T790M and exon 21 L858R, the presence of the EGFR C797G resistance mutation. CONCLUSION: Our case report revealed a rare EGFR-dependent acquired resistance mutation to osimertinib in circulating tumor DNA. Liquid biopsy appears to be a promising resource to understand the biology of osimertinib resistance by clonal evolution monitoring and the identification of novel resistance mechanisms.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Idoso , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Feminino , Humanos , Biópsia Líquida , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
13.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445227

RESUMO

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Receptor EphB4/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ciclo Celular/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Mutação , Proteínas de Neoplasias/genética , Receptor EphB4/genética
14.
Medicine (Baltimore) ; 100(29): e26674, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398034

RESUMO

ABSTRACT: This study aimed to explore the dynamics of circulating tumor cells (CTCs) and CD8+ T cells in stage II-III non-small cell lung cancer patients with CTCs in different programmed death-ligand 1 (PD-L1) status treated with radiotherapy and evaluate the correlation between CTCs and CD8+ T cells.This study was a retrospective study which reviewed 69 stage II-III non-small cell lung cancer patients underwent postoperative radiotherapy and peripheral blood tests of CTCs and T lymphocyte were available before radiation, 1 week after radiation and 1 month after radiation.In this study, 25 patients had PD-L1 positive CTCs and 44 patients had PD-L1 negative CTCs. The CTCs count was significantly decreased compared with baseline in patients with different PD-L1 status CTCs at 1 week and 1 month after radiotherapy. The proportion of CD8+ T cells was significantly increased at 1 month after radiotherapy compared with baseline in the total population (mean change, 7.24 ±â€Š2.12; P < .05) and patients with PD-L1 negative CTCs (mean change, 7.17 ±â€Š2.65; P < .05). One month after radiotherapy, the proportion of CD8+ T cells was negatively correlated with the CTCs count in the total population (r = -0.255, P = .034) and PD-L1 negative patients (r = -0.330, P = .029). In patients with PD-L1 negative CTCs, the CTCs count 1 week after radiotherapy (hazard ratio, 0.150 [95% confidence intervals., 0.027-0.840], P = .031) and the proportion of CD8+ T cells 1 month after radiotherapy (hazard ratio, 7.961 [95% confidence intervals, 1.028-61.68], P = .047) were independent prognostic factors for disease recurrence.After radiotherapy, only PD-L1-negative patients had a significant increase in the CD8+ T cell levels, while it was negatively correlated with CTCs count and was an independent prognostic factors of disease recurrence.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Células Neoplásicas Circulantes/metabolismo , Receptor de Morte Celular Programada 1/genética , Adolescente , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , China , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
16.
J Int Med Res ; 49(8): 3000605211035005, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34396834

RESUMO

Targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often fails because of drug resistance. Here, we report a 57-year-old male patient with stage IV small cell lung cancer (SCLC) transformation during targeted therapy. Chest computerized tomography (CT), hematoxylin and eosin histological examination, immunohistochemistry, allele refractory mutation system-based quantitative polymerase chain reaction analysis of EGFR point mutations, and next-generation sequencing were performed for diagnosis and therapeutic efficacy evaluation. A combination of chest CT, histological examination, and immunohistochemistry confirmed the initial NSCLC diagnosis. Next-generation sequencing detected only EGFR exon 19 deletion (ex19del) before treatment and later identified EGFR exon20p.T790M point mutation, EGFR amplification, myc proto-oncogene (MYC) amplification, retinoblastoma 1 (RB1) mutation, and tumor protein 53 (TP53) mutation. Histology and immunohistochemistry revealed transformation from NSCLC to SCLC during treatment, which eventually returned to NSCLC. Drug resistance to targeted therapy for patients with NSCLC frequently occurs because of EGFR exon20p.T790M point mutation, TP53 mutation, RB1 mutation, and MYC amplification. These mutations are also the major determining factors of NSCLC outcomes. Therefore, next-generation sequencing should be performed to confirm drug efficacy during targeted therapy for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
17.
Lung Cancer ; 159: 128-134, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34333203

RESUMO

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have proven to be effective treatment for lung cancer. However, a precise predictive immuno-oncology biomarker is still under development. We investigated the associations among PD-L1 expression, tumor mutational burden (TMB), and oncogenic driver alterations in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. MATERIALS AND METHODS: This multicenter cohort study included 1017 lung cancer patients. PD-L1 expression using four IHC assays (22C3, 28-8, SP263, SP142), TMB by whole-exome sequencing and oncogenic driver alterations were analyzed comprehensively. Clinical characteristics, treatment and survival data were collected. RESULTS: The results of 22C3 and 28-8 for PD-L1 expression showed acceptable concordance (k = 0.89; 95% confidence interval [CI], 0.87-0.92), and the clinical outcomes of ICIs classified according to PD-L1 expression by both assays were also approximately the same. There was slight concordance (k = 0.16; 95% CI, 0.11-0.22) between 22C3 and SP142, and high PD-L1 expression by SP142 was correspond to very high PD-L1 expressions by other assays. Patients with both high PD-L1 expression and high TMB showed a good response to ICIs with the response rate of 64% and median progression-free survival of 9.0 months despite of small population. Common EGFR or STK11 mutations showed a lower rate of high PD-L1 expression and a worse efficacy of ICIs and KRAS mutations had no negative impact on response to ICIs. CONCLUSION: Comprehensive assessment of PD-L1 expression, TMB, and oncogenic driver alterations would help to better predict the clinical outcomes of ICIs in NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Coortes , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética
18.
Sci Transl Med ; 13(606)2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380768

RESUMO

Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of Kras G12D/+;p53 -/- NSCLC, including a mismatch repair-deficient variant (Kras G12D/+;p53 -/-;Msh2 -/-) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1+ regulatory T cells (Tregs), which were more efficiently targeted by the PD-1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor-ß-rich tumor microenvironment that supported PD-1+ Tregs Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated Tregs, redirected the PD-1 antibody to CD8+ T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Antígeno B7-H1 , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Receptor de Morte Celular Programada 1 , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular
19.
Medicine (Baltimore) ; 100(30): e26680, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397694

RESUMO

RATIONALE: Approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastasis, which is related to poor survival outcomes. The ability of tyrosine kinase inhibitor drugs to penetrate the blood-brain barrier makes them a potential option for intracranial metastases. Dacomitinib, an irreversible second-generation pan-HER tyrosine kinase inhibitor, has become a standard therapy for patients with epidermal growth factor receptor mutations. However, its efficacy in patients with brain metastases (BMs) is not yet established. Here, we present 2 patients with epidermal growth factor receptor-mutant NSCLC with brain metastasis. After initiation of dacomitinib as first-line treatment, a significant clinical response was achieved, and a long-lasting complete remission was achieved in 1 patient up to this date. PATIENT CONCERN: Case 1 was a 47-year-old man who was admittedtothe hospital because of recurrent cough and expectoration for >1 year. Chest computed tomography scans revealed a high-density shadow in the left upper lobe. Cranial magnetic resonance imaging indicated an abnormal nodular enhancement in the right cerebellar hemisphere. Case 2 was a 55-year-old man with a chief complaint of intermittent cough and expectoration for >1 month. Chest computed tomography revealed a high-density mass in the left superior lobe. Magnetic resonance imaging of the central nervous system revealed 2 abnormal nodular enhancements in the left frontal lobe. DIAGNOSIS: Both patients were diagnosed with lung adenocarcinoma by bronchoscopy and lymph node biopsy. INTERVENTIONS: Both patients received dacomitinib 30 mg once daily as first-line therapy for 8 and 11 months, respectively until disease progression. OUTCOME: After treatment with dacomitinib, both patients achieved complete response in BMs. Progression-free survival was 11 and 8 months, respectively. LESSONS: Dacomitinib strongly controlled BMs in patients with advanced NSCLC, and the adverse reactions were tolerable. Dacomitinib may be considered a new treatment option for these patients. Further prospective studies are recommended to confirm this conclusion.


Assuntos
Neoplasias Encefálicas/etiologia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Genes erbB-1/genética , Neoplasias Encefálicas/genética , Broncoscopia/métodos , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Quinazolinonas/efeitos adversos , Quinazolinonas/uso terapêutico , Tomografia Computadorizada por Raios X/métodos
20.
Ann Clin Lab Sci ; 51(4): 487-493, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452886

RESUMO

OBJECTIVE: Hepatitis B X-interacting protein (HBXIP) interacts with hepatitis B virus X protein to participate in the replication of the hepatitis B virus and carcinogenesis. Cellular growth and metastasis of non-small-cell lung cancer (NSCLC) are repressed by HBXIP inhibition. However, the role and mechanism of HBXIP on NSCLC cell growth remain unknown. MATERIALS: Expression of HBXIP was assessed by qRT-PCR and Western blot. siRNA targeting HBXIP was applied to detect cell viability and proliferation by MTT and colony formation assays. In vivo tumor growth was assessed, and anti-tumor immunity was determined by flow cytometry. The downstream partners involved in HBXIP-mediated tumorigenesis were detected by Western blot. RESULTS: Expression of HBXIP and neuropilin1-1 (NRP-1) was higher in NSCLC tissues and cells than in paracancerous tissues and human lung epithelial cells. siRNA-mediated knockdown of HBXIP decreased the cell viability of NSCLC and suppressed proliferation. Protein expression of Lin28B and NRP-1 was reduced by the knockdown of HBXIP, and over-expression of Lin28B attenuated the HBXIP silence-induced decrease of NRP-1. In vivo tumor growth was suppressed by HBXIP silencing, and the knockdown of HBXIP enhanced anti-tumor immunity through the increase of CD4+ and CD8+ T lymphocytes. CONCLUSION: Down-regulation of HBXIP reduced Lin28B-mediated NRP-1 to suppress NSCLC cell growth and enhance anti-tumor immunity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Neuropilina-1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neuropilina-1/genética , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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