RESUMO
INTRODUCTION AND OBJECTIVES: Obtaining CCTA images with optimal injection location such as the arm or leg is important to avoid the artifacts caused by the CM. This study compares the computed tomography (CT) numbers and visualization scores of the three-dimensional (3D) images of the lumens of the blood vessels in the arm or leg during cardiac computed tomography angiography (CCTA) in neonatal and infant patients. PATIENTS OR MATERIALS AND METHODS: Between January 2017 and January 2020, 253 consecutive patients were considered for inclusion. We used the estimated propensity scores as a function of the demographic data, including age, body weight, and injection location (right or left side) in the arm (nâ¯=â¯58) and leg (nâ¯=â¯58) of neonatal and infant patients. We compared the mean CT numbers of the pulmonary artery, ascending aorta, and left superior vena cava; contrast-noise ratios (CNR); and visualization scores between the arm and leg as the injection locations. RESULTS: The mean CT numbers during CCTA for the arm and leg were 479.4 and 461.3 HU in the ascending aorta, 464.2 and 448.1 HU in the pulmonary artery, and 232.8 and 220.1 HU in the left superior vena cava, respectively. The mean image noise (SD) and CNR values, respectively, were 38.9 HU and 12.1 for the arm as the injection location and 39.1 HU and 12.3 for the leg as the injection location. The median visualization scores of volume rendering of the 3D images were 3.0 and 3.0 for the arm and leg injection sites, respectively. There were no significant differences in the mean CT numbers of the ascending aorta, pulmonary artery, and left superior vena cava; SD value; CNR; and visualization scores between the arm and leg injection locations. CONCLUSIONS: The CT numbers of the lumen of the blood vessel and visualization scores of the 3D images of the arm and leg injection locations are equal during CCTA in neonatal and infant patients with congenital heart disease.
Assuntos
Meios de Contraste , Veia Cava Superior , Humanos , Lactente , Recém-Nascido , Braço/diagnóstico por imagem , Perna (Membro) , Tomografia Computadorizada por Raios X/métodosRESUMO
Introducción y objetivos: En la obtención de imágenes de angiografía por cardiotomografía (ACT) es importante escoger una ubicación adecuada para inyectar el medio de contraste (p. ej., el brazo o la pierna) a fin de evitar la formación de artefactos que este provoca. En este estudio se comparan los valores de tomografía computarizada (TC) y las puntuaciones de visualización de las imágenes tridimensionales (3D) de los lúmenes de los vasos sanguíneos del brazo y la pierna durante la ACT en pacientes neonatos y lactantes. Pacientes o materiales y métodos: Entre los meses de enero de 2017 y enero de 2020 se evaluaron 253 pacientes de forma consecutiva para determinar su inclusión en el estudio. Se utilizaron las puntuaciones de propensión estimadas en función de los datos demográficos, incluidos la edad, el peso corporal y la ubicación de la inyección (lado derecho o izquierdo) en el brazo (n=58) y la pierna (n=58) de los pacientes neonatos y lactantes. A continuación, se compararon los valores medios de TC de la arteria pulmonar, la aorta ascendente y la vena cava superior izquierda; las relaciones contraste-ruido (RCR); y las puntuaciones de visualización del brazo y la pierna como lugares de inyección. Resultados: Los valores medios de TC durante la ACT para el brazo y la pierna fueron de 479,4 y 461,3 UH en la aorta ascendente, de 464,2 y 448,1 UH en la arteria pulmonar y de 232,8 y 220,1 UH en la vena cava superior izquierda, respectivamente. Los valores medios de ruido de la imagen (DE) y de RCR fueron, respectivamente, de 38,9 y 12,1 UH para el brazo y de 39,1 y 12,3 UH para la pierna. Las puntuaciones medias de visualización de la representación del volumen de las imágenes 3D fueron de 3,0 y 3,0 para los lugares de inyección del brazo y la pierna, respectivamente.(AU)
Introduction and Objectives: Obtaining CCTA images with optimal injection location such as the arm or leg is important to avoid the artifacts caused by the CM. This study compares the computed tomography (CT) numbers and visualization scores of the three-dimensional (3D) images of the lumens of the blood vessels in the arm or leg during cardiac computed tomography angiography (CCTA) in neonatal and infant patients. Patients or Materials and Methods: Between January 2017 and January 2020, 253 consecutive patients were considered for inclusion. We used the estimated propensity scores as a function of the demographic data, including age, body weight, and injection location (right or left side) in the arm (n=58) and leg (n=58) of neonatal and infant patients. We compared the mean CT numbers of the pulmonary artery, ascending aorta, and left superior vena cava; contrastnoise ratios (CNR); and visualization scores between the arm and leg as the injection locations. Results: The mean CT numbers during CCTA for the arm and leg were 479.4 and 461.3 HU in the ascending aorta, 464.2 and 448.1 HU in the pulmonary artery, and 232.8 and 220.1 HU in the left superior vena cava, respectively. The mean image noise (SD) and CNR values, respectively, were 38.9 HU and 12.1 for the arm as the injection location and 39.1 HU and 12.3 for the leg as the injection location. The median visualization scores of volume rendering of the 3D images were 3.0 and 3.0 for the arm and leg injection sites, respectively. There were no significant differences in the mean CT numbers of the ascending aorta, pulmonary artery, and left superior vena cava; SD value; CNR; and visualization scores between the arm and leg injection locations. Conclusions: The CT numbers of the lumen of the blood vessel and visualization scores of the 3D images of the arm and leg injection locations are equal during CCTA in neonatal and infant patients with congenital heart disease.(AU)
Assuntos
Humanos , Recém-Nascido , Meios de Contraste/administração & dosagem , Angiografia , Cardiotocografia , Pediatria , Cardiopatias Congênitas , Pontuação de Propensão , Radiologia , Serviço Hospitalar de Radiologia , Diagnóstico por Imagem , Estudos RetrospectivosRESUMO
INTRODUCTION: To investigate how changing the injection duration at cardiac computed tomography angiography (CCTA) affects contrast enhancement in newborns and infants. METHODS: Included were 142 newborns and infants with confirmed congenital heart disease who underwent CCTA between January 2015 and December 2018. In group 1 (n = 71 patients), the injection duration was 8 s; in group 2 (n = 71) it was 16 s. Our findings were assessed by one-to-one matching analysis to estimate the propensity score of each patient. We compare the CT number for the pulmonary artery (PA), ascending aorta (AAO), left superior vena cava (SVC), AAO and PA enhancement ratio, and the scores for visualization between the two groups. RESULTS: In group 1, median CT number and ranges was 345 (211-591) HU in the AAO, 324 (213-567) HU in the PA, and 62 (1-70) HU in the SVC. These values were 465 (308-669) HU, 467 (295-638) HU, and 234 (67-443) HU, respectively, in group 2 (p < 0.05). The median score for volume-rendering visualization on 3D images of the CCTA was 2 in group 1 and 3 in group 2; the score for visualization of the left SVC of the maximum intensity projection images was 2 in group 1 and 3 in group 2 (p < 0.05). The CT number for the AAO and PA enhancement ratio was 15.2 in group 1 and 9.2 in group 2 (p < 0.05). CONCLUSION: The 16-sec injection protocol yielded significantly higher CT numbers for the AAO, PA, and the SVC than the 8-sec injection protocol; the visualization scores were also significantly higher in group 2. IMPLICATIONS FOR PRACTICE: In newborns and infants, the longer injection time for CCTA yields stable and higher contrast enhancement at identical CM concentrations.
Assuntos
Angiografia por Tomografia Computadorizada , Veia Cava Superior , Angiografia por Tomografia Computadorizada/métodos , Meios de Contraste , Humanos , Lactente , Recém-Nascido , Artéria Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Veia Cava Superior/diagnóstico por imagemRESUMO
INTRODUCTION: To compare the computed tomography (CT) number for paediatric cardiac computed tomography angiography (CCTA) and visualisation score of the three-dimensional (3D) images using the conventional T-shaped extended tube (T-tube) and spiral flow-generating extended tube (spiral-tube) connected between the contrast injector and cannula. METHODS: In total, 108 patients suspected to have congenital heart disease (CHD) were considered for inclusion. We utilised the T-tube for intravenous contrast and spiral-tube in 54 patients each. Observers individually inspected randomized volume rendering images of the internal thoracic artery, each acquired from the with or without spiral-tube groups, using a four-point scale. We compared the mean CT number of the ascending aorta (AAO) and pulmonary artery (PA), contrast noise ratio (CNR), CT number for the AAO and PA enhancement ratio, and the visualisation scores between the groups. RESULTS: There were no significant differences in patient characteristics between the with or without spiral-tube groups (p > 0.05). The mean CT number ±standard deviation for the AAO and PA, and the CNR without or with spiral-tube groups were 441.2 ± 89.2 and 489.8 ± 86.1 HU for the AAO, 436.3 ± 100.6 and 475.3 ± 85.2 HU for the PA, and 9.5 ± 2.2 and 10.8 ± 2.4 for the CNR, respectively (p < 0.05). In the spiral-tube group, the CT number, CNR, and visualisations score of the 3D images were significantly higher for the AAO and PA than those in the T-tube group (p < 0.05). CONCLUSION: The spiral-tube proved to be beneficial in improving the CT number for the AAO and PA, CNR, and visualisation score compared with the conventional T-tube during paediatric CCTA. IMPLICATIONS FOR PRACTICE: The spiral-tube may allow the visualisation of smaller blood vessels than those visualised by the conventional T-tube for paediatric patients in CCTA.
Assuntos
Angiografia por Tomografia Computadorizada , Tomografia Computadorizada por Raios X , Criança , Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Coração , Humanos , Doses de Radiação , Tomografia Computadorizada por Raios X/métodosRESUMO
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Seguimentos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Oncologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapiaRESUMO
BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de Cabeça e Pescoço , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
Transposable element (TE) marker system was developed considering the useful properties of the transposable elements such as their large number in the animal and plant genomes, high rate of insertion polymorphism, and ease of detection. Various methods have been employed for developing a large number of TE markers in several crop plants for genomics studies. Here we describe some of these methods including the recent whole genome search. We also review the application of TE markers in molecular breeding.
Assuntos
Produtos Agrícolas/genética , Embaralhamento de DNA/métodos , Elementos de DNA Transponíveis , Marcadores Genéticos , Melhoramento Vegetal/métodos , Polimorfismo GenéticoRESUMO
Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. Patients and methods: Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients. Results: Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. Conclusions: The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. Registered clinical trial number: UMIN000010507.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metástase Neoplásica , Paclitaxel/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
BACKGROUND: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. PATIENTS AND METHODS: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. RESULTS: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). CONCLUSIONS: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. CLINICAL TRIAL REGISTRATION: NCT01345682.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Metotrexato/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Quinazolinas/administração & dosagem , Administração Intravenosa , Administração Oral , Afatinib , Antimetabólitos Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/sangue , Biópsia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). METHODS: Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. RESULTS: From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. CONCLUSIONS: The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. TRIAL REGISTRATION: ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).
Assuntos
Alanina/análogos & derivados , Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quinolonas/administração & dosagem , Estomatite/tratamento farmacológico , Adulto , Idoso , Alanina/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estomatite/induzido quimicamente , Estomatite/patologiaRESUMO
Various transcription factors are also known to enhance or suppress T helper type 17 (Th17) differentiation. We have shown previously that the development of collagen-induced arthritis was suppressed in T-bet transgenic (T-bet Tg) mice, and T-bet seemed to suppress Th17 differentiation through an interferon (IFN)-γ-independent pathway, although the precise mechanism remains to be clarified. The present study was designed to investigate further the mechanisms involved in the regulation of Th17 differentiation by T-bet over-expression, and we found the new relationship between T-bet and aryl hydrocarbon receptor (AHR). Both T-bet Tg mice and IFN-γ-/- -over-expressing T-bet (T-bet Tg/IFN-γ-/- ) mice showed inhibition of retinoic acid-related orphan receptor (ROR)γt expression and IL-17 production by CD4+ T cells cultured under conditions that promote Th-17 differentiation, and decreased IL-6 receptor (IL-6R) expression and signal transducer and activator of transcription-3 (STAT-3) phosphorylation in CD4+ T cells. The mRNA expression of ahr and rorc were suppressed in CD4+ T cells cultured under Th-17 conditions from T-bet Tg mice and T-bet Tg/IFN-γ-/- mice. CD4+ T cells of wild-type (WT) and IFN-γ-/- mice transduced with T-bet-expressing retrovirus also showed inhibition of IL-17 production, whereas T-bet transduction had no effect on IL-6R expression and STAT-3 phosphorylation. Interestingly, the mRNA expression of ahr and rorc were suppressed in CD4+ T cells with T-bet transduction cultured under Th17 conditions. The enhancement of interleukin (IL)-17 production from CD4+ T cells by the addition of AHR ligand with Th17 conditions was cancelled by T-bet over-expression. Our findings suggest that T-bet over-expression-induced suppression of Th17 differentiation is mediated through IFN-γ-independent AHR suppression.
Assuntos
Diferenciação Celular , Expressão Gênica , Interferon gama/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Proteínas com Domínio T/genética , Células Th17/citologia , Células Th17/metabolismo , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Diferenciação Celular/genética , Células Cultivadas , Modelos Animais de Doenças , Imunomodulação , Imunofenotipagem , Interferon gama/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Biológicos , Fator de Transcrição STAT3/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/imunologia , Transdução GenéticaRESUMO
We showed recently that M3 muscarinic acetylcholine receptor (M3R)-reactive CD3+ T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid-related orphan receptor-gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R-/- ) mice immunized with murine M3R peptide mixture were inoculated into recombination-activating gene 1 knockout (Rag-1-/- ) mice (M3R-/- âRag-1-/- ) with MIS. Immunized M3R-/- mice (pretransfer treatment) and M3R-/- âRag-1-/- mice (post-transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide-stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme-linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4+ T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)-γ and interleukin (IL)-17 production significantly compared with phosphate-buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4+ T cells rather than CD11c+ cells. Post-transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN-γ and IL-17 production (P < 0·05). In vitro, A213 suppressed IFN-γ and IL-17 production from M3R-stimulated splenocytes and CD4+ T cells of immunized M3R-/- mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL-17 production from Th17 differentiated CD4+ T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS-like sialadenitis through suppression of IL-17 and IFN-γ production by M3R-specific T cells.
Assuntos
Aminopiridinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Receptor Muscarínico M3/metabolismo , Sialadenite/tratamento farmacológico , Síndrome de Sjogren/tratamento farmacológico , Sulfonamidas/uso terapêutico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Transferência Adotiva , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos/imunologia , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/imunologia , Sialadenite/induzido quimicamente , Células Th1/imunologia , Células Th17/imunologiaRESUMO
BACKGROUND: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years. PATIENTS AND METHODS: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. RESULTS: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. CONCLUSIONS: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. CLINICAL TRIAL REGISTRATION: NCT01345682 (ClinicalTrials.gov).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metotrexato/administração & dosagem , Quinazolinas/administração & dosagem , Afatinib , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Metotrexato/efeitos adversos , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Platina/administração & dosagem , Platina/efeitos adversos , Quinazolinas/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do TratamentoRESUMO
Programmed cell death-1 (PD-1) plays an important role in peripheral T cell tolerance, but whether or not it affects the differentiation of helper T cell subsets remains elusive. Here we describe the importance of PD-1 in the control of T helper type 1 (Th1) cell activation and development of forkhead box protein 3 (FoxP3(+)) regulatory T cells (Tr(egs)). PD-1-deficient T cell-specific T-bet transgenic (P/T) mice showed growth retardation, and the majority died within 10 weeks. P/T mice showed T-bet over-expression, increased interferon (IFN)-γ production by CD4(+) T cells and significantly low FoxP3(+) T(reg) cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3(+) T(reg) count. The study identified a unique, previously undescribed role for PD-1 in Th1 and T(reg) differentiation, with potential implication in the development of Th1 cell-targeted therapy.
Assuntos
Diferenciação Celular/imunologia , Fatores de Transcrição Forkhead/imunologia , Receptor de Morte Celular Programada 1/imunologia , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Animais , Diferenciação Celular/genética , Fatores de Transcrição Forkhead/genética , Interferon gama/genética , Interferon gama/imunologia , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Proteínas com Domínio T/genética , Linfócitos T Reguladores/citologia , Células Th1/citologiaRESUMO
OBJECTIVE: 1,4-Dioxane is a toxic by-product formed during the synthesis of surfactants used in finished cosmetic products. There are no set permissible levels of toxic impurities in finished cosmetic products in Japan. In this study, we have established a simple and sufficiently precise analytical method to determine the activity of 1,4-dioxane in finished cosmetic cleansing products. METHODS: This method involves the standard addition approach and headspace-gas chromatography/mass spectrometry without pre-conditioning. RESULTS: Fifteen cleansing products that are sold in the Japanese market, such as shampoo, hand soap, and dishwashing liquid, were analyzed, and 1,4-dioxane was detected at a concentration of a few micrograms per gram of the product in almost all of them. The concentration of 1,4-dioxane in two dishwashing liquid products was high. The maximum concentration of 1,4-dioxane in all of the cleansing products was below 10 µg g(-1) , which is a limit that is thought to be safe and technically achievable through the application of good manufacturing practices. Since 1,4-dioxane is formed during the synthesis of polyoxyethylene ether sulfate, it was detected at high concentrations in cleansing products that contained a lot of polyoxyethylene ether sulfate. CONCLUSION: Control of the synthesis of polyoxyethylene ether sulfate can be effective in reducing the concentration of 1,4-dioxane in cleansing products.
Assuntos
Cosméticos/química , Dioxanos/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , JapãoRESUMO
BACKGROUND: KRAS mutations are predictive markers for the efficacy of anti-EGFR antibody therapies in patients with metastatic colorectal cancer. Although the mutational status of KRAS is reportedly highly concordant between primary and metastatic lesions, it is not yet clear whether genotoxic chemotherapies might induce additional mutations. METHODS: A total of 63 lesions (23 baseline primary, 18 metastatic and 24 post-treatment metastatic) from 21 patients who were treated with FOLFOX as adjuvant therapy for stage III/IV colorectal cancer following curative resection were examined. The DNA samples were obtained from formalin-fixed paraffin-embedded specimens, and KRAS, NRAS, BRAF and PIK3CA mutations were evaluated. RESULTS: The numbers of primary lesions with wild-type and mutant KRAS codons 12 and 13 were 8 and 13, respectively. The mutational status of KRAS remained concordant between the primary tumours and the post-FOLFOX metastatic lesions, irrespective of patient background, treatment duration and disease-free survival. Furthermore, the mutational statuses of the other genes evaluated were also concordant between the primary and metastatic lesions. CONCLUSION: Because the mutational statuses of predictive biomarker genes were not altered by FOLFOX therapy, specimens from both primary tumours and post-FOLFOX tumour metastases might serve as valid sources of DNA for known genomic biomarker testing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Fluoruracila/uso terapêutico , Genes ras , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)RESUMO
BACKGROUND: We aimed to compare the sensitive and quality-controlled KRAS testing with direct sequencing and to assess the impact on decision making of treatment. PATIENTS AND METHODS: We analysed genomic DNA isolated from macrodissected formalin-fixed paraffin-embedded specimens by direct sequencing and an amplification refractory mutation system-Scorpion assay (ARMS/S) method. Cetuximab was administered to patients identified as having wild-type (WT) KRAS using direct sequencing. Therapeutic effects were evaluated according to their KRAS status as determined by ARMS/S. RESULTS: Among the 159 patients, the overall mutation rate was determined to be 37.0% by direct sequencing and 44.0% by ARMS/S. For the patients diagnosed as WT by direct sequencing and treated with cetuximab (n=47), a response rate of 16.0% was observed for 38 ARMS/S WT patients, whereas 9 ARMS/S mutant (MUT) patients failed to respond. The ARMS/S WT patients showed significant improvement in progression-free survival (PFS) and overall survival (OS) compared with ARMS/S MUT patients (PFS median 5.0 vs 1.7 months, hazards ratio (HR)=0.29, P=0.001; OS median 12.1 vs 3.8 months, HR=0.26, P=0.001). CONCLUSION: Sensitive and quality-controlled KRAS testing may provide improved predictive power to determine the efficacy of anti-epidermal growth factor antibodies.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Análise Mutacional de DNA/métodos , Genes ras , Mutação , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Cetuximab , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Análise de Sequência de DNA/métodosRESUMO
PURPOSE: To evaluate the efficacy and safety of weekly paclitaxel in patients with recurrent or metastatic head and neck cancer (HNC) by combined analysis of early and late phase II trials. METHODS: Eligibility criteria included histologically proven HNC with recurrent or metastatic disease, measurable disease, PS 0-2, and one or no prior chemotherapy regimens. Treatment consisted of a 1-h infusion of paclitaxel at a dose of 100 mg/m(2) weekly for 6 weeks of a 7-week cycle. A total of 74 patients were enrolled: 37 between February and November 2004 in an early phase II trial and 37 between October 2005 and July 2006 in a late phase II trial. RESULTS: The median number of treatment cycles was two, and median dose intensity was 84.2 mg/m(2)/week. The most common grade 3-4 adverse events were leukopenia (37.5%), neutropenia (30.6%), anemia (12.5%), constipation (8.3%), peripheral neuropathy (5.6%), anorexia (5.6%), and pneumonitis (5.6%). Overall response rate was 29.0% according to RECIST. The median duration of response, median time to progression, and median survival time were 7.4, 3.4, and 14.3 months, respectively. CONCLUSIONS: This study demonstrates that weekly paclitaxel has promising activity with acceptable toxicity in the treatment of recurrent or metastatic HNC.