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BACKGROUND: Irinotecan (CPT-11) is the key drug used in chemotherapy for many malignant tumors. CPT-11 has cholinergic activity and induces perspiration during intravenous administration. In this study, concentrations of CPT-11 and its active metabolite, SN-38, released during perspiration were measured and risk of exposure of these drugs was assessed. METHOD: Beads of sweat were collected using a dropper from four patients undergoing a chemotherapy regimen involving intravenous administration of CPT-11. The concentrations of CPT-11 and SN-38 in sweat were measured using liquid chromatography tandem mass spectrometry. RESULT: Chemotherapy regimens were capecitabine and irinotecan plus bevacizumab (n = 1), CPT-11 monotherapy (n = 1), and oxaliplatin-irinotecan-leucovorin-5-fluorouracil (n = 2). Uridine diphosphate-glucuronosyltransferase 1A1 phenotypes were *6 homo-type (n = 1), *6 hetero-type (n = 1), and wild type (n = 2). CPT-11 dose was 292.3 ± 75.5 mg/body weight (mean ± standard deviation). CPT-11 was detected in sweat secreted by all the four patients, and its mean (±standard deviation) concentration was 252.6 (±111.9) ng/ml. SN-38 was detected in only one of the patients who received oxaliplatin-irinotecan-leucovorin-5-fluorouracil treatment and who had the wild-type uridine diphosphate-glucuronosyltransferase 1A1 phenotype at a concentration of 74.37 ng/ml. CONCLUSION: CPT-11 and SN-38 are detected in sweat released during intravenous CPT-11 administration. Beads of sweat or linen clothes that absorb the sweat might be the source of CPT-11 and SN-38 exposure.
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Irinotecano/efeitos adversos , Suor/efeitos dos fármacos , Inibidores da Topoisomerase I/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Glucuronosiltransferase/fisiologia , Humanos , Irinotecano/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Suor/metabolismoRESUMO
BACKGROUND: Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose. METHODS: T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled. RESULTS: We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%. CONCLUSIONS: Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/secundário , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Acrilamidas , Idoso , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/líquido cefalorraquidiano , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/líquido cefalorraquidiano , Receptores ErbB/genética , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/epidemiologia , Neoplasias Pulmonares/líquido cefalorraquidiano , Neoplasias Pulmonares/genética , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/genética , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Piperazinas/efeitos adversos , Piperazinas/líquido cefalorraquidiano , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/líquido cefalorraquidiano , Resultado do TratamentoRESUMO
The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR-based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non-small cell lung cancer (NSCLC) patients previously diagnosed with EGFR-activating mutations. Twenty-five patients with NSCLC previously treated with EGFR-TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin-fixed paraffin-embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines.
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Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Reação em Cadeia da Polimerase , Adenocarcinoma/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND: The aim of this study was to detect the epidermal growth factor receptor (EGFR)-activating mutations and other oncogene alterations in patients with non-small-cell lung cancers (NSCLC) who experienced a treatment failure in response to EGFR-tyrosine kinase inhibitors (TKIs) with a next generation sequencer. METHODS: Fifteen patients with advanced NSCLC previously treated with EGFR-TKIs were examined between August 2005 and October 2014. For each case, new biopsies were performed, followed by DNA sequencing on an Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel version 2. RESULTS: All 15 patients were diagnosed with NSCLC harboring EGFR-activating mutations (seven cases of exon 19 deletion, seven cases of L858R in exon 21, and one case of L861Q in exon 21). Of the 15 cases, acquired T790M resistance mutations were detected in 9 (60.0%) patients. In addition, other mutations were identified outside of EGFR, including 13 cases (86.7%) exhibiting TP53 P72R mutations, 5 cases (33.3%) of KDR Q472H, and 2 cases (13.3%) of KIT M541L. CONCLUSIONS: Here, we showed that next-generation sequencing (NGS) is able to detect EGFR T790M mutations in cases not readily diagnosed by other conventional methods. Significant differences in the degree of EGFR T790M and other EGFR-activating mutations may be indicative of the heterogeneity of disease phenotype evident within these patients. The co-existence of known oncogenic mutations within each of these patients may play a role in acquired EGFR-TKIs resistance, suggesting the need for alternative treatment strategies, with PCR-based NGS playing an important role in disease diagnosis.
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Adenocarcinoma/genética , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Adenocarcinoma/tratamento farmacológico , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: This study aimed to evaluate the association between BCL2 single-nucleotide polymorphisms and survival outcome in advanced non-small cell lung cancer (NSCLC). METHODS: One hundred and sixty-eight patients with advanced NSCLC who were treated with anti-cancer drugs and could be evaluated for therapeutic response between April 2005 and March 2010 at Kyoto University Hospital were enrolled. DNA was extracted from peripheral blood samples. The BCL2 polymorphisms -938 CâA (rs2279115) and +21 AâG (rs1801018) were genotyped using the 5'-nuclease assay. The univariate relationship between each independent clinicopathologic variable and BCL2 genotype was examined using Fisher's exact test. To evaluate risk factors associated with prognosis, a Cox proportional hazards regression model with a step-down procedure was used. RESULTS: The median survival time of patients with the -938 AA and AC genotypes were significantly shorter than those with the -938 CC genotype (p = 0.027 by log-rank test). Based on multivariate analysis, poor performance status [hazard ratio (HR) 2.424, 95% confidence interval (CI) 1.727-3.262; p < 0.0001], non-adenocarcinoma histology (HR 1.512, 95% CI 1.167-1.938; p = 0.0048) and the BCL2 -938 AA + AC genotype (HR 1.219, 95% CI, 1.024-1.456; p = 0.0256) were significant independent prognostic factors for survival. CONCLUSIONS: Polymorphisms in BCL2 may be associated with survival in advanced-stage NSCLC patients who received chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
Previous reports have shown that circulating endothelial progenitor cells (CEPs) are released in response to cytotoxic chemotherapy. We investigate the relationship between the kinetics of CEPs during one cycle of chemotherapy and the response to cytotoxic chemotherapy and prognostic impacts. Previously untreated patients (n = 38) receiving cytotoxic chemotherapy for non-small-cell lung cancer were included. Blood sampling was carried out on day 1, day 8, and just before the second cycle of chemotherapy. The mononuclear cell fraction was analyzed for CEPs by FACS analysis. We evaluated the relationship between the kinetics of CEPs, each independent clinicopathological variable, the response to chemotherapy, and the risk factors associated with prognosis. On the eighth day after chemotherapy, a significant decrease in CEPs was observed. In contrast, CEP counts before the second cycle of chemotherapy were significantly increased. The high percentage change in CEPs between day 1 and before the second cycle of chemotherapy is an independent predictive factor for response to chemotherapy. However, the change in CEP levels did not predict progression-free survival. These findings indicate that the late release of CEPs is a common phenomenon after chemotherapeutic treatment. The correlation with clinical response to chemotherapy provides further support for the biologic relevance of these cells in patients' prognosis and highlights the potential use of CEPs as therapeutic targets.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Células Endoteliais , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco , Adulto , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica , Resultado do TratamentoRESUMO
The prognosis of small-cell lung cancer remains poor and it is speculated that small-cell lung cancer patients with end-stage renal failure undergoing hemodialysis have a poorer prognosis. In this article, we present a Japanese woman with extensive small-cell lung cancer with end-stage renal failure undergoing hemodialysis who received multiple courses of chemotherapy. Although she achieved long-term survival of more than 2 years, the last-line chemotherapy, consisting of irinotecan, induced grade 4 febrile neutropenia and her performance status deteriorated even with a reduced dose according to the analysis of UDP-glucuronosyltransferase 1A1. We also conducted a pharmacokinetic analysis of irinotecan, the resulting values of which were much higher than in previous reports. Although further studies are needed, chemotherapy for small-cell lung cancer patients should not be withheld just because they are undergoing hemodialysis; however, chemotherapy should be performed more carefully because more severe toxicities can occur than expected.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Falência Renal Crônica/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neutropenia/induzido quimicamente , Diálise Renal , Idoso , Povo Asiático , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Feminino , Febre/etiologia , Humanos , Irinotecano , Neutropenia/complicações , Resultado do TratamentoRESUMO
Cancer-associated retinopathy is a rare paraneoplastic syndrome that is often associated with small-cell lung cancer. It is caused by an autoantibody to the 23 kDa photoreceptor protein, recoverin. A small number of reports have described effective treatment for the disease. We report two cases of cancer-associated retinopathy with small-cell lung cancer whose visual symptom preceded the diagnosis of cancer. Their visual acuity and visual field were slightly improved after steroid and anticancer therapy. Steroid therapy was effective, although the period from visual symptom onset to therapy was comparative longer. When cancer-associated retinopathy is suspected, a comparatively large quantity of steroids and anticancer treatment should be combined immediately.
Assuntos
Carcinoma de Células Pequenas/complicações , Carcinoma de Células Pequenas/diagnóstico , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Síndromes Paraneoplásicas/diagnóstico , Doenças Retinianas/etiologia , Transtornos da Visão/etiologia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biópsia por Agulha , Carcinoma de Células Pequenas/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Recoverina/análise , Doenças Retinianas/complicações , Acuidade Visual , Campos VisuaisRESUMO
PURPOSE: We examined patients with advanced nonsquamous, non-small cell lung cancer (NSCLC) to evaluate epidermal growth factor receptor (EGFR) mutation status and serum C-reactive protein (CRP) for their associations with response to gefitinib therapy and for prognostic impacts. METHODS: Serum levels of CRP from 79 Japanese patients with advanced nonsquamous NSCLC were measured before the start of gefitinib. We used the peptic nucleic acid-locked nucleic acid clamp method to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis. RESULTS: Having CRP-positive serum and having wild-type EGFR were both independent negative predictive factors for the response to gefitinib treatment by multivariate logistic regression model analysis. Having CRP-positive serum and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. CONCLUSIONS: Having CRP-positive serum predicted a lack of response to gefitinib therapy independent of EGFR mutational status. Both CRP-positive serum and wild-type EGFR were independent poor prognostic factors in patients with nonsquamous NSCLC who received gefitinib therapy.
Assuntos
Antineoplásicos/uso terapêutico , Proteína C-Reativa/análise , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB/genética , Neoplasias Pulmonares , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/imunologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Gefitinibe , Humanos , Japão , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , PrognósticoRESUMO
PURPOSE: The aim of our study was to evaluate the efficacy and safety of docetaxel plus ramucirumab with primary prophylactic pegylated (PEG)-granulocyte-colony stimulating factor (G-CSF) for pretreated non-small cell lung cancer (NSCLC). RESULTS: Sixty-one pretreated NSCLC patients underwent docetaxel plus ramucirumab. Primary prophylactic PEG-G-CSF was performed in 52 (85%) patients (prophylactic group). No febrile neutropenia (FN) (0%) was confirmed in 52 prophylactic group patients, whereas FN was observed in 3 (33%) of 9 non-prophylactic group patients. Among prophylactic group, median lines of prior therapy was 2 (range, 1-9). Median cycles of docetaxel plus ramucirumab was 3 (range, 1-25) (9 and 3 cases moved to ramucirumab and docetaxel monotherapies, respectively). Response rate and disease control rate were 30.8% and 73.1%, respectively. Median progression-free survival was 4.5 (95% confidence interval [CI], 3.0-6.6) months. Median overall survival was 11.4 (95% CI, 8.0-13.9) months. Six (11.5%) patients had grade 3/4 neutropenia. Observed grade 3 (incidence ≥10%) adverse event (AE) was oral mucositis (13.5%). There were no grade 4/5 non-hematological AEs. CONCLUSIONS: Our study demonstrated the efficacy and safety of docetaxel plus ramucirumab with PEG-G-CSF in clinical practice. Primary prophylactic PEG-G-CSF could markedly reduce incidence of FN. METHODS: We retrospectively reviewed medical records of pretreated NSCLC cases who had received docetaxel plus ramucirumab in our departments.
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AIM: The aim of the present study was to compare successful rate, failure reasons, and complications among procedures of histological rebiopsy. PATIENTS AND METHODS: We retrospectively reviewed medical records of histologically rebiopsied cases with non-small cell lung cancer. RESULTS: One hundred and eleven histological rebiopsies were performed in: 86 (77%) lung; 11 (10%) lymph node; 5 (5%) pleura; 4 (4%) liver; 2 (2%) muscle; 2 (2%) adrenal gland; and 1 (1%) rib. Successful rate by computed tomography-guided biopsy (CTGB), transbronchial biopsy (TBB), and ultrasound-guided biopsy were 86% (48/56), 90% (28/31), and 100% (24/24), respectively. Reasons for rebiopsy failure by CTGB were no/insufficient malignant cells (n=5) and pneumothorax (n=3), and those by TBB were no/insufficient malignant cells (n=2) and bleeding (n=1). Severe complications (≥grade 3): one grade 3 pneumothorax and one grade 4 air embolization were observed in two (2%, 2/111) cases receiving CTGB. CONCLUSION: Rebiopsy of histological samples can be highly successful and feasible by optimal procedural selection.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/efeitos adversos , Biópsia/métodos , Feminino , Humanos , Pulmão/patologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Errors in sequencing are a major obstacle in the interpretation of next-generation sequencing (NGS) results. In the present study, sequencing errors identified from analysis of single nucleotide variants (SNVs) identified during exome sequencing of human germline DNA were studied using the Thermo Fisher Ion Proton System. Two consanguineous cases were selected for sequencing using the AmpliSeq Exome capture kit, and SNVs found in both cases were validated using Sanger sequencing. A total of 98 SNVs detected by NGS were randomly selected for further analysis. Nine of the analyzed SNVs were shown to be false positives when confirmed by Sanger sequencing. All but one SNV were considered to be homopolymer regions, mainly through the insertion or deletion of nucleotides. The remaining error was considered to be related to the primer. The present results revealed that the majority of the SNV sequencing errors originated from homopolymer insertion/deletion errors, which are commonly observed when using the Ion Torrent system.
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AIM: The aim of this study was to evaluate whether irradiation induces the expression of tumor programed cell death ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventeen patients with NSCLC who received chemoradiotherapy and underwent tumor resection and six patients whose pre-treatment biopsy specimens were available, were analyzed by immunohistochemistry for PD-L1 expression between September 2011 and June 2016 at the Institute of Biomedical Research and Innovation Hospital. RESULTS: Among six patients for which pre-irradiation biopsy samples were available, the H-score for PD-L1 was reduced after irradiation following staining with two different antibody clones (SP28-8 and SP142). A PD-L1 H-score >5 with SP28-8 antibody (hazard ratio=6.46; 95% confidence interval=1.209-34.53; p=0.029) was a significant negative factor for duration of progression-free survival after curative operation or chemoradiation. CONCLUSION: We showed that tumor PD-L1 expression decreased in patients with NSCLC who received chemoradiotherapy and radiation resistance might be due to pre-treatment PD-L1 expression.
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Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Povo Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Receptores Proteína Tirosina Quinases/genéticaRESUMO
BACKGROUND: Differential biology and prognosis between T790M+ and T790M- populations imply immunological differences also. METHODS: We retrospectively analyzed programmed death-ligand 1 (PD-L1) expression and T790M status in rebiopsied samples of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). PD-L1 immunohistochemistry was performed using the SP142 antibody for tumour cell (TC) and tumour-infiltrating immune cell (IC) and the 28-8 antibody for TC. PD-L1+ was defined as TC or IC ≥1%. RESULTS: We investigated 67 available rebiopsied histologic samples in 47 patients. Using the SP142, prevalence of PD-L1 any+, moderate+, and strong+ in T790M+ vs. T790M- samples were 31% vs. 61%, 8% vs. 15%, and 0% vs. 2%, respectively, representing PD-L1+ prevalence of T790M+ samples was significantly lower than that of T790M- (p=0.0149). Prevalence of any TC+/IC+ in T790M+ vs. T790M- samples were TC: 31% vs. 51% (p=0.0997) and IC: 8% vs. 27% (p=0.0536), respectively. Using the 28-8, median percentage of PD-L1+ in T790M+ samples was 1.9 (range, 0-27.2), whereas T790M- was 4.1 (range, 0-89.8) (p=0.0801). Prevalence of PD-L1+ ≥1%, ≥5%, and ≥10% in T790M+ vs. T790M- samples were 77% vs. 83% (p=0.5476), 31% vs. 49% (p=0.1419), and 12% vs. 27% (p=0.1213), respectively. In 9 of 11 patients receiving multiple rebiopsies, T790M and/or PD-L1 expression revealed temporal dynamism. Survival curves according to PD-L1 expression/T790M status suggested better prognosis in PD-L1-/T790M+ population. CONCLUSIONS: T790M+ status was correlated to lower PD-L1 expression. PD-L1 expression might have a prognostic value and interaction with T790M mutation in EGFR-mutant NSCLC.
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Antígeno B7-H1/genética , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Expressão Gênica , Neoplasias Pulmonares/genética , Mutação , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biópsia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Current clinical trials have suggested poorer efficacies of anti-programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapies for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, implying lower PD-L1 expression in EGFR-mutant NSCLC than in EGFR-wild type. METHODS: We retrospectively analyzed correlation between PD-L1 expression and EGFR status in clinical samples of pretreated NSCLC. PD-L1 immunohistochemistry was performed using the 28-8 anti-PD-L1 antibody for tumor cell membrane staining. H-score was adopted to evaluate both percentage and intensity. We investigated H-scores ≥1, ≥5, and ≥10 as PD-L1+ cut-offs. H-score ≥10 was defined as strong PD-L1+. RESULTS: We investigated 96 available histologic samples in 77 pretreated patients with NSCLC. Median H-score in EGFR-mutant samples (n=65) was 3 (range, 0-150), whereas EGFR-wild-type (n=31) was 8 (range, 0-134) (p=0.0075). Using H-scores ≥1, ≥5, and ≥10 cut-offs, incidence of PD-L1+ in EGFR-mutant vs. EGFR-wild-type samples were: 85% (55/65) vs. 94% (29/31) (p=0.2159); 42% (27/65) vs. 74% (23/31) (p=0.0027); and 22% (14/65) vs. 48% (15/31) (p=0.0074), respectively. Patient-oriented (n=77) univariate analysis for strong PD-L1+ found age of sample (p=0.0226) and EGFR mutation status (p=0.0490) as significant factors. Multivariate analysis identified EGFR mutation status as the only significant factor (p=0.0121, odds ratio 2.99) for strong PD-L1+. H-scores of PD-L1 expression varied in all 11 cases receiving multiple rebiopsies, and categories of positivity migrated in 10 (91%) of 11 patients. CONCLUSIONS: PD-L1 expression was significantly lower in EGFR-mutant NSCLC samples than in EGFR wild-type samples. Its expression could be dynamic and affected by age of sample.
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We define specific neurophysiologic characteristics for focal cortical dysplasia, a neuronal migration disorder. We reviewed data from published reports and our patients with focal cortical dysplasia. Our patients underwent preoperative scalp video-electroencephalography (EEG), magnetic resonance imaging (MRI), magnetoencephalography, and intraoperative or extraoperative electrocorticography monitoring. Scalp EEG showed trains of rhythmic epileptiform spike or sharp waves. Positive spikes correlated with early seizure onset, MRI lesion around the rolandic fissure, hemiparesis, and a less favorable outcome. Interictal electrocorticography showed continuous epileptogenic discharges: repetitive electrographic seizures and bursting discharges or continuous or quasicontinuous rhythmic spiking. Ictal electrocorticography showed paroxysmal fast and/or repetitive spiking. Magnetoencephalography showed clustered spike sources within and extending from the lesion. Cortical stimulation gave more frequent, lower-threshold afterdischarges and higher-threshold primary motor function. Focal cortical dysplasias are highly and intrinsically epileptogenic. For surgical seizure control, EEG, electrocorticography, and magnetoencephalography must delineate the intrinsic epileptogenic zone within and extending from the focal cortical dysplasia identified by MRI.
Assuntos
Movimento Celular/fisiologia , Córtex Cerebral/anormalidades , Córtex Cerebral/fisiopatologia , Epilepsias Parciais/fisiopatologia , Neurônios/fisiologia , Mapeamento Encefálico , Criança , Estimulação Elétrica , Eletroencefalografia , Eletrofisiologia , Epilepsias Parciais/etiologia , Epilepsias Parciais/patologia , Humanos , Imageamento por Ressonância Magnética , Magnetoencefalografia , Estudos Retrospectivos , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Esclerose Tuberosa/fisiopatologia , Gravação em VídeoRESUMO
BACKGROUND: Efficacies of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) rechallenge have been demonstrated in EGFR-mutant non-small cell lung cancer (NSCLC). However, their efficacies were only moderate. Some preclinical studies suggested synergistic effects of bevacizumab to EGFR-TKI in TKI-resistant models. METHODS: We retrospectively evaluated clinical efficacy and safety of EGFR-TKI rechallenge with bevacizumab. Rebiopsy was performed on all studied cases to examine T790M-resistant mutation status. RESULTS: Between January 2010 and June 2014, a total of 24 EGFR-mutant NSCLC patients who had been previously treated with EGFR-TKIs (gefitinib, erlotinib, and/or afatinib) received EGFR-TKI rechallenge with bevacizumab. Twenty-two (92 %) patients underwent erlotinib and two (8 %) gefitinib as rechallenge EGFR-TKIs in combination with bevacizumab. Three patients achieved partial response, and 18 had stable disease, resulting in the response rate (RR) of 13 % and disease control rate (DCR) of 88 %, respectively. The median progression-free survival (PFS) was 4.1 [95 % confidence interval (CI) 2.3-4.9] months, and the median overall survival (OS) was 13.5 (95 % CI 9.7-27.4) months. The RR, DCR, median PFS, and median OS for T790M-positive versus T790M-negative were 0 versus 18 % (p = 0.530), 86 versus 88 % (p = 1.00), 3.3 versus 4.1 months (p = 0.048), and 15.1 versus 13.5 months (p = 0.996), respectively. Severe adverse events (≥grade 3): grade 3 of 1 (4 %) rash; grade 3 of 1 (4 %) paronychia; grade 3 of 1 (4 %) hypertension; and grade 3 of 1 (4 %) anemia, were observed. CONCLUSIONS: EGFR-TKI rechallenge with bevacizumab demonstrated higher DCR and modestly longer PFS than historical data on EGFR-TKI rechallenge alone. Its activity was notably higher in T790M-negative population.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Biópsia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Malignant pleural effusion (MPE) is a common complication of lung cancer with devastating consequences. Since vascular endothelial growth factor (VEGF) has been implicated in MPE, we hypothesized that bevacizumab, an anti-VEGF antibody, may be effective against MPE in patients with non-small-cell lung cancer (NSCLC). We analysed the records of 21 patients treated for NSCLC-associated MPE between February, 2010 and August, 2013 who consequently underwent bevacizumab combination chemotherapy at the Institute of Biomedical Research and Innovation Hospital. The results were retrospectively analysed using case records and radiographic imaging records. Three patients exhibited complete response of the pleural effusion to bevacizumab treatment, 8 patients achieved a partial response (PR) and 6 patients showed no response. When efficacy was assessed by the response of the measurable primary or metastatic lesions to the treatment, 5 patients achieved a PR, 13 patients had stable disease and 3 patients exhibited progressive disease. The response rate (RR) of the pleural effusion to the antibody treatment was 71.4% and the overall RR of measurable lesions was 23.8%. The median time-to-response for pleural effusion was 132 days. In conclusion, this study demonstrated a high R R to bevacizumab combination therapy for the MPE associated with non-squamous NSCLC. Therefore, bevacizumab therapy may be considered a therapeutic option for patients with non-squamous NSCLC who develop MPE.
RESUMO
BACKGROUND/AIM: Patients with malignant lung cancer often develop a solitary pulmonary nodule after treatment of the initial cancer. In those cases, it is difficult to distinguish primary lung cancer (PLC) from lung metastasis. Therefore, both local therapy for a single lung lesions and systemic therapy for micrometastases are needed. This retrospective study aimed to evaluate the safety and tolerability of concurrent stereotactic body radiation therapy (SBRT) and chemotherapy in patients with metachronous PLC. PATIENTS AND METHODS: We reviewed the records of 10 patients with metachronous PLC treated with SBRT and concurrent chemotherapy with curative intent from 2007 to 2013. The delivered radiation dose was 48 Gy in four fractions. RESULTS: All patients received SBRT with concurrent chemotherapy on schedule. Complete response rate was 90%. Safety profile of this treatment was compatible with that of traditional chemoradiotherapy. CONCLUSION: Our study showed good feasibility and safety for SBRT with concurrent chemoradiotherapy.
Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Idoso , Terapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Radiocirurgia/efeitos adversosRESUMO
BACKGROUND: Treatment for patients with advanced non-small cell lung cancer (NSCLC) is often determined by the presence of biomarkers that predict the response to agents targeting specific molecular pathways. Demands for multiplex analysis of the genes involved in the pathogenesis of NSCLC are increasing. METHODS: We validated the Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel and compared the results with those obtained using the gold standard methods, conventional PCR and Sanger sequencing. The cycleave PCR method was used to verify the results. RESULTS AND CONCLUSION: The Ion Torrent PGM resulted in a similar level of accuracy in identifying multiple genetic mutations in parallel, compared with conventional PCR and Sanger sequencing; however, the Ion Torrent PGM was superior to the other sequencing methods in terms of increased ease of use, even when taking into account the small amount of DNA that was obtained from formalin-fixed paraffin embedded (FFPE) biopsy specimens.