RESUMO
BACKGROUND: We assessed the efficacy and safety of bevacizumab and S-1 chemotherapy for patients with previously treated advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: This was a prospective single-arm study, including patients with non-squamous NSCLC who had received at least one chemotherapy regimen along with a platinum-based regimen. Bevacizumab 15 mg/kg was intravenously administered every 3 weeks, and S-1 40 mg/m2 was orally administered twice daily from day 1 (evening) through day 15 (morning). The treatment continued for 3 weeks/cycle until disease progression or until unacceptable toxicities occurred. During the lead-in part, six patients were evaluated for dose-limiting toxicity (DLT) rate. In phase II, the primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: In the lead-in part, we evaluated the safety in the first six patients and observed no DLT. In phase II, a total of 46 patients were enrolled from September 2012 to December 2018. The median follow-up duration was 13.7 months [95% confidence interval (CI) 1.4-72.0]. The ORR was 28.3%. The median PFS and OS were 4.3 (95% CI 2.9-5.9) and 15.0 months (95% CI 9.8-30.3), respectively. The most common adverse events were hypertension (65.2%), diarrhea (47.8%), mucositis oral (45.7%), and proteinuria (43.5%), and the most common grade 3 adverse events were hypertension (23.9%) and proteinuria (6.5%). Grade 4/5 adverse events were not observed. CONCLUSION: Bevacizumab and S-1 combination chemotherapy showed high activity and were well tolerated in patients with previously treated advanced non-squamous NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Estudos ProspectivosRESUMO
The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs 1.2 months). In conclusion, resistance to ALK-TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.
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Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Aminopiridinas , Povo Asiático , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Humanos , Lactamas , Lactamas Macrocíclicas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação/genética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis , Pirimidinas/uso terapêutico , Proteínas Recombinantes/genética , Sulfonas/uso terapêuticoRESUMO
Most patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) will inevitably develop acquired resistance induced by treatment with EGFR tyrosine kinase inhibitors (EGFR-TKI). The mechanisms of resistance to EGFR-TKI are multifactorial, and the detection of these mechanisms is critical for treatment choices in patients who have progressed after EGFR-TKI therapy. We evaluated the feasibility of a molecular barcode method using next-generation sequencing to detect multifactorial resistance mechanisms in circulating tumor DNA and compared the results with those obtained using other technologies. Plasma samples were collected from 25 EGFR mutation-positive NSCLC patients after the development of EGFR-TKI resistance. Somatic mutation profiles of these samples were assessed using two methods of next-generation sequencing and droplet digital PCR (ddPCR). The positive rate for EGFR-sensitizing mutations was 18/25 (72.0%) using ddPCR, 17/25 (68.0%) using amplicon sequencing, and 19/25 (76.0%) using molecular barcode sequencing. Rate of the EGFR T790M resistance mutation among patients with EGFR-sensitizing mutations was shown to be 7/18 (38.9%) using ddPCR, 6/17 (35.3%) using amplicon sequencing, and 8/19 (42.1%) using molecular barcode sequencing. Copy number gain in the MET gene was detected in three cases using ddPCR. PIK3CA, KRAS and TP53 mutations were detected using amplicon sequencing. Molecular barcode sequencing detected PIK3CA, TP53, KRAS, and MAP2K1 mutations. Results of the three assays were comparable; however, in cell-free DNA, molecular barcode sequencing detected mutations causing multifactorial resistance more sensitively than did the other assays.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Variações do Número de Cópias de DNA , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Análise de Sequência de DNARESUMO
In patients with non-small-cell lung cancer harboring an epithelial growth factor receptor (EGFR) active mutation, central nervous system progression after a response to EGFR tyrosine kinase inhibitors is frequent. Central nervous system metastasis, especially leptomeningeal carcinomatosis (LMC), is a serious complication and no standard treatment has been established for LMC. Here, we report two cases in which the addition of bevacizumab to erlotinib enhanced the efficacy against LMC; as a result, radiographic abnormalities decreased markedly and symptoms were well controlled. This combination treatment may be useful to treat LMC in patients with EGFR-positive non-small-cell lung cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Cloridrato de Erlotinib/administração & dosagem , Humanos , Neoplasias Pulmonares/patologia , Masculino , Carcinomatose Meníngea/patologia , Pessoa de Meia-Idade , Falha de TratamentoRESUMO
BACKGROUND: We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch. METHODS: Healthy never-smokers (21 men, 20 women; mean 22.3 ± 3.7 years) participated. None had a >3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects' ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects' tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV1) decreased to <90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined. RESULTS: The number of coughs was 11.1 ± 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity. CONCLUSIONS: Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects.
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Hiper-Reatividade Brônquica/induzido quimicamente , Broncoconstrição/efeitos dos fármacos , Tosse/tratamento farmacológico , Cloreto de Metacolina/administração & dosagem , Administração por Inalação , Adulto , Resistência das Vias Respiratórias/efeitos dos fármacos , Asma/induzido quimicamente , Testes de Provocação Brônquica/métodos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Masculino , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors.
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Carbazóis/uso terapêutico , Granuloma de Células Plasmáticas/tratamento farmacológico , Granuloma de Células Plasmáticas/genética , Inflamação/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Piperidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Adulto , Quinase do Linfoma Anaplásico , Granuloma de Células Plasmáticas/diagnóstico por imagem , Granuloma de Células Plasmáticas/patologia , Humanos , Inflamação/diagnóstico por imagem , Inflamação/patologia , MasculinoRESUMO
Epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors' (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The aims of this study are to develop a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients, using PointMan™ EGFR DNA Enrichment Kit which is a novel method for selective amplification of genotype specific sequences.Pairs of blood samples and tumor tissues were collected from NSCLC patients with an EGFR activating mutation and who were resistant to EGFR-TKI treatment. EGFR T790M mutation in plasma DNA were detected using the PointMan™ EGFR DNA Enrichment Kit. The concentrations of plasma DNA were determined using quantitative real-time PCR.Of the 52 patients enrolled in this study, 41 of the patients' plasma samples were collected at post EGFR-TKIs. Nineteen (46.3 %) of the 41 patients had an EGFR T790M mutation in their plasma DNA as detected using the PointMan™ EGFR DNA Enrichment Kit after disease progression to EFGR-TKI. Of 11 cases with a detected T790M mutation from tumor tissues, 10 (90.9 %) also had a detectable T790M mutation in the plasma DNA. There was no difference in the progression-free survival between patients with T790M and those without T790M.The PointMan™ proved to be a useful method for determining plasma EGFR T790M mutation status.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação de Sentido Incorreto , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , DNA de Neoplasias/sangue , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited. PATIENTS AND METHODS: This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases. RESULTS: The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS. CONCLUSIONS: The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos RetrospectivosRESUMO
Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.
Assuntos
Pulmão/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Intensificação de Imagem Radiográfica/métodos , Radiografia Torácica/métodos , Idoso , Asma/diagnóstico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Combinação de Medicamentos , Fluticasona/uso terapêutico , Fumarato de Formoterol/uso terapêutico , Glicopirrolato/análogos & derivados , Glicopirrolato/uso terapêutico , Humanos , Indanos/uso terapêutico , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Espirometria , Brometo de Tiotrópio/uso terapêutico , Resultado do TratamentoRESUMO
Objectives: Cancer cells usually escape tumor-reactive T-cell responses using immune checkpoint proteins, such as programmed death protein-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1). These proteins can be blocked by immune checkpoint inhibitors (ICIs); the decision on ICI-based first-line treatment for advanced lung cancers depends on the PD-L1 levels in tumor specimens. Determining the PD-L1 expression conventionally requires histological specimens from resected tumors and core biopsy specimens. Non-small cell lung cancer (NSCLC) is usually diagnosed at stage III or IV; therefore, only small biopsy specimens, such as those obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are available. However, the suitability of EBUS-TBNA specimens determining the PD-L1 expression levels in advanced lung cancers remains unclear. Materials and Methods: Here, we investigated the concordance rate of PD-L1 expression between EBUS-TBNA and matched transbronchial biopsy (TBB) specimens. Using the 22C3 anti-PD-L1 antibody (immunohistochemistry), we determined the PD-L1 expression levels in paired specimens obtained from 69 patients (50 with advanced NSCLC and 19 with small cell lung cancer [SCLC]), as well as the efficacy of ICIs in these patients. Results: The concordance rate of PD-L1 expression between the EBUS-TBNA and TBB specimens was 78.3%. The κ values referent to the PD-L1-positive expression rate between EBUS-TBNA and TBB specimens were 0.707 and 0.676 at cutoff limits of ≥1% and ≥50%, respectively. Among the 19 SCLC patients, 16 (84.2%) exhibited no PD-L1 expression in both EBUS-TBNA and TBB specimens. Notably, the progression-free survival of patients with ≥50% PD-L1 expression in the paired specimens who received ICI treatment was 8.3 months. Conclusion: Collectively, our results validate the use of EBUS-TBNA specimens for the determination of the PD-L1 expression levels in the context of NSCLC and SCLC.
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BACKGROUND: In clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent. PATIENTS AND METHODS: Ninety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics. RESULTS: The objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease. CONCLUSION: The outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.
Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND/AIM: Clusters of circulating tumor cells (CTCs) increase metastatic potential compared to single CTC. However, conventional technologies have been unable to generate an accurate analysis of single and cluster CTCs in the peripheral blood. We propose an effective strategy to detect and isolate both single and cluster CTCs using two size-selective microfilters. MATERIALS AND METHODS: Five ml of whole blood were collected from 10 patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer. Single and cluster CTCs were identified using precision microfiltration membranes with two distinct pore sizes together with anti-EpCAM antibody labeling. RESULTS: Single and cluster CTCs were detected by simultaneously using two size-selective microfilters. The EGFR-L858R mutation was detected in the DNA from cells captured using both microfilters. CONCLUSION: Our method can be used to detect and isolate single and cluster CTCs in the whole blood and may facilitate the development of a liquid biopsy strategy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , DNA Tumoral Circulante/sangue , Molécula de Adesão da Célula Epitelial/sangue , Células Neoplásicas Circulantes/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Separação Celular , Feminino , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Mutação/genética , Células Neoplásicas Circulantes/patologiaRESUMO
OBJECTIVE: Serum adenosine deaminase (ADA) activity is a marker of immune reaction to several diseases. We evaluated changes in serum ADA in patients with lung cancer undergoing chemotherapy or anti-programmed cell death-1 (PD-1) therapy to examine the correlation between serum ADA and the therapy efficacy. MATERIALS AND METHODS: We assessed 50 patients with advanced lung cancer receiving chemotherapy or anti-PD-1 therapy. Serum ADA was measured before and on day 7 of the first treatment cycle and day 0 of subsequent cycles. Correlations between ADA change and efficacy of treatment were evaluated. RESULTS: Of the 50 patients, 20 were treated with chemotherapy and 30 were treated with anti-PD-1 therapy. Serum ADA decreased significantly between baseline and day 7 of the first cycle in patients undergoing chemotherapy, regardless of response (partial response [PR] or stable disease [SD]: -23% [-38 to +32; p = 0.002]; progressive disease [PD]: -12% [-42 to +6; p = 0.500]). Conversely, in patients undergoing anti-PD-1 therapy, serum ADA increased significantly between baseline and 7 days after the first dose and before subsequent doses in patients who had PR or SD. (day 7 of first cycle: +6% [-10 to +34; p = 0.034], day 0 of second cycle: 8% [-5 to +37; p = 0.002], day 0 of third cycle: 9% [-3 to +55; p = 0.002]). However, serum ADA did not significant change in PD patients undergoing anti-PD-1 therapy. Furthermore, early increases in serum ADA were associated with longer progression-free survival in patients receiving anti-PD-1 therapy (p = 0.006). CONCLUSION: Changes in serum ADA could be used to predict clinical benefit from anti-PD-1 therapy in patients with lung cancer. The association between changes in serum ADA and the efficacy of ant-PD-1 therapy thus remains inconclusive and requires further study.
Assuntos
Adenocarcinoma de Pulmão/terapia , Adenosina Desaminase/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Nivolumabe/uso terapêutico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de SobrevidaRESUMO
Lynch syndrome is caused by mutations in mismatch repair genes that lead to microsatellite instability (MSI). An increased number of mutation-associated neoantigens have been observed in patients with high-frequency MSI (MSI-H) cancer; in addition, membranous programmed death ligand-1 (PD-L1) tends to be expressed at higher levels in MSI-H cancers than in microsatellite-stable cancers. MSI-H cancer patients are therefore considered to be susceptible to immune checkpoint blockade. We herein report for the first time a case of lung adenocarcinoma with Lynch syndrome and the response to nivolumab.
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Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Idoso , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Recent studies have suggested a correlation between immune-related thyroid dysfunction (irTD) and the superior efficacy of anti-programmed cell death protein-1 (anti-PD-1) treatment in non-small cell lung cancer (NSCLC). Embryologically, the lung and thyroid are similar in origin, and thyroid transcription factor-1 (TTF-1) expresses in both organs, including NSCLC. We explored our hypothesis that TTF-1 expression in NSCLC might correlate with irTD incidence and anti-PD-1 treatment efficacy. METHODS: We identified 132 patients with NSCLC treated with anti-PD-1 antibody at our hospital between December 2015 and June 2017. We evaluated TTF-1 expression in tumor by immunohistochemistry using a mouse monoclonal antibody (clone 8G7G3/1, 1:100, Dako). IrTD was defined as two or more successive abnormal levels of thyroid-stimulating hormone (TSH) during anti-PD-1 treatment. We retrospectively assessed correlations between TTF-1 expression in tumor, irTD incidence, and anti-PD-1 treatment efficacy. RESULTS: Of 132 patients, 67 (51%) and 65 (49%) were positive and negative for TTF-1, respectively. We observed irTD in 19 patients (6 positives and 13 negatives for TTF-1). The incidence of irTD was 9% and 20% in TTF-1-positive and TTF-1-negative NSCLCs, respectively (P=0.086). Particularly, in non-squamous (NSQ) cell carcinomas, the irTD incidence was significantly higher in patients negative for TTF-1 (30%) than in those positive for TTF-1 (9%; P=0.010), and TTF-1 expression was identified as a significant risk factor for irTD on multivariate logistic regression analysis [odds ratio (OR), 0.18; 95% confidence interval (CI), 0.05-0.59; P=0.005]. Furthermore, longer median progression-free survival (10.3 months) was observed in patients with TTF-1-negative NSCLC with irTD compared to those with TTF-1-positive NSCLC with irTD, TTF-1-positive NSCLC without irTD, and TTF-1-negative NSCLC without irTD (4.2, 1.4, and 2.4 months, respectively). CONCLUSIONS: TTF-1 expression in NSCLC might correlate with irTD and anti-PD-1 treatment efficacy.
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OBJECTIVES: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice. MATERIALS AND METHODS: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation. RESULTS: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E. CONCLUSION: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Japão/epidemiologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sobrevida , Adulto JovemRESUMO
Background Asthma-COPD overlap (ACO) is a disease that shares clinical features of both asthma and COPD. The purpose of this study is to investigate the prevalence and clinical features of ACO. Methods We retrospectively reviewed data for 170 patients with persistent airflow limitation and diagnosed them according to "The Japanese Respiratory Society Guidelines for the Management of ACO 2018". Results Of the 170 patients, 111 were diagnosed as follows : COPD (74 patients, 66.6%), ACO (34 patients, 30.6%), and asthma (3 patients, 2.8%). There was no significant difference in clinical features between ACO and COPD patients. The following pulmonary function tests were significantly lower in ACO than in COPD patients : forced expiratory volume in 1 second/forced vital capacity, peak expiratory flow, maximal mid-expiratory flow, and the maximum expiratory flow at 50%and75%. The following respiratory impedance parameters were significantly higher in ACO than in COPD patients : respiratory resistance (Rrs) at 5 Hz (R5), Rrsat 20 Hz (R20), R5-R20, and low-frequency reactance area. Conclusions About 30% of patients with persistent airflow limitation were diagnosed with ACO. ACO patients had lower lung function and higher respiratory impedance compared with COPD patients. J. Med. Invest. 66 : 157-164, February, 2019.
Assuntos
Asma/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/diagnóstico , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Prevalência , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Estudos RetrospectivosRESUMO
OBJECTIVES: Pulmonary carcinosarcoma is a rare lung malignancy and little analysis has been performed to identify associated genomic alterations. We used next-generation sequencing (NGS) to analyze a pulmonary carcinosarcoma harboring an epidermal growth factor receptor (EGFR) mutation. MATERIALS AND METHODS: The lung carcinosarcoma used for this study contained components of adenocarcinoma and chondrosarcoma and originated from a 73-year-old female. Both components carried deletion mutations in exon 19 of EGFR and both had equally strong EGFR protein expression. This study analyzed the biological and genetic characteristics of both components, using NGS and immunohistochemical (IHC) staining. RESULTS AND CONCLUSION: IHC staining revealed that both total EGFR and deletion mutation specific EGFR proteins were equally expressed in both components. Intriguingly, identification of genomic alterations with NGS found five identical alterations in four genes (EGFR, CBLB, TP53, and MEN1) that were shared by the two components, and that each component had a large number of individual alterations. Additionally, we focused on an alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation which was only present in the sarcoma component. ATRX protein expression was also only detected in the sarcoma component. This is the first report of the exhaustive genomic alterations in a pulmonary carcinosarcoma harboring an EGFR mutation. The results show that our case had the same EGFR status in both components. The EGFR mutation is the driver mutation in both components. In our case, we found that TP53 may be a common alteration and ATRX may be a specific alteration in the sarcoma component.
Assuntos
Carcinossarcoma/diagnóstico , Neoplasias Pulmonares/diagnóstico , Deleção de Sequência/genética , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X/genética , Idoso , Receptores ErbB/genética , Feminino , Genoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-HistoquímicaRESUMO
In non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation, 50%-65% of cases acquire resistance after treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) because of an EGFR T790M point mutation and 3%-14% of these cases transformed to small cell lung cancer (SCLC). Generally, the EGFR T790M secondary mutation develops with ongoing ATP competitive inhibition. We present a case of a 76-year-old woman with lung adenocarcinoma harboring an EGFR-L858R mutation who received first-line gefitinib and developed SCLC transformation. She was administered several chemotherapy agents, including a platinum doublet. The primary lesion that showed SCLC transformation had reconverted to adenocarcinoma with EGFR L858R and T790M mutations at the time of a second re-biopsy. Therefore, she was administered osimertinib, which resulted in clinical remission. This case suggested that serial biopsies are necessary even after SCLC transformation.
RESUMO
BACKGROUND: The epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, tissues for the genotyping of the EGFR T790M mutation can be difficult to obtain in a clinical setting. The aims of this study were to evaluate a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients using the PointMan™ EGFR DNA enrichment kit, which is a novel method for the selective amplification of specific genotype sequences. METHODS: Blood samples were collected from NSCLC patients who had activating EGFR mutations and who were resistant to EGFR-TKI treatment. Using cell-free DNA (cfDNA) from plasma, EGFR T790M mutations were amplified using the PointMan™ enrichment kit, and all the reaction products were confirmed using direct sequencing. The concentrations of plasma DNA were then determined using quantitative real-time PCR. RESULTS: Nineteen patients were enrolled, and 12 patients (63.2%) were found to contain EGFR T790M mutations in their cfDNA, as detected by the kit. T790M mutations were detected in tumor tissues in 12 cases, and 11 of these cases (91.7%) also exhibited the T790M mutation in cfDNA samples. The concentrations of cfDNA were similar between patients with the T790M mutation and those without the mutation. CONCLUSIONS: The PointMan™ kit provides a useful method for determining the EGFR T790M mutation status in cfDNA.