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1.
Lancet Oncol ; 13(5): 459-65, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22456429

RESUMO

BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Neoplasias Encefálicas/secundário , Feminino , Humanos , Ipilimumab , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Cutâneas/patologia , Resultado do Tratamento
2.
J Exp Med ; 203(4): 805-8, 2006 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-16549599

RESUMO

CD4+ T cells are classically thought to orchestrate adaptive immune responses. But recent studies demonstrate that they can also kill infected cells directly. A new paper shows that highly efficient processing of Epstein Barr virus (EBV) glycoproteins for presentation on MHC class II makes virus-transformed B cells susceptible to lysis by CD4+ T cells. Thus, antiviral vaccines should aim to stimulate both helper and cytolytic CD4+ T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Citotoxicidade Imunológica/imunologia , Animais , Humanos , Imunidade Celular
3.
Int J Cancer ; 124(7): 1721-6, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19089927

RESUMO

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in equatorial Africa and is linked to Epstein-Barr virus (EBV) and Plasmodium falciparum coinfections early in life. Epstein-Barr nuclear antigen 1 (EBNA1) is the sole viral latent antigen expressed in BL tumors. Loss of EBNA1-specific immune surveillance could allow eBL emergence. Therefore, EBNA1-specific T cell responses were analyzed by IFN-gamma ELISPOT in Kenyan children with eBL and compared to healthy children with divergent malaria exposure. Significantly fewer children with eBL, 16% (7/44) had EBNA1-specific IFN-gamma responses in contrast to healthy children living in a malaria holoendemic area or in an area with sporadic malaria transmission, 67% (40/60) and 72% (43/60) responders, respectively (p < 0.003). Children with eBL maintained IgG(1) dominated antibody responses to EBNA1 similar to healthy children suggesting a selective loss of IFN-gamma secreting EBNA1-specific T cells in the presence of intact humoral immunity. CD8(+) T cell responses to EBV lytic and latent antigens not expressed in the tumors were similarly robust in eBL patients compared to healthy children. In addition, CD4(+) T cell responses to a malaria protein, merozoite surface protein 1, were present in lymphoma patients. This study demonstrates a selective loss of EBNA1-specific T cell responses in children with eBL and suggests a potential immunotherapeutic target for this EBV-associated lymphoma.


Assuntos
Linfoma de Burkitt/epidemiologia , Linfoma de Burkitt/imunologia , Doenças Endêmicas , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Interferon gama/imunologia , Linfócitos T/imunologia , Linfoma de Burkitt/virologia , Criança , Ensaio de Imunoadsorção Enzimática , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Quênia , Carga Viral
4.
Int J Cancer ; 123(12): 2824-31, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18781564

RESUMO

Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4(+) T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4(+) T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN-gamma expression and proliferation by CD4(+) T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8(+) T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4(+) T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteínas de Transporte/imunologia , Herpesvirus Humano 4/imunologia , Linfoma/imunologia , Linfoma/virologia , Adolescente , Adulto , Idoso , Antígenos Nucleares/imunologia , Proliferação de Células , Criança , Citocinas/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Hibridização In Situ , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA , Adulto Jovem
5.
Eur Thyroid J ; 5(3): 187-194, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27843809

RESUMO

OBJECTIVES: Effective management of adverse events (AEs) following vandetanib treatment is important to maximize clinical benefits. We examined whether more frequent contact with vandetanib-treated patients reduced AEs of CTCAE grade 2 or higher. STUDY DESIGN: In this open-label, multicentre, phase III study, patients with locally advanced or metastatic medullary thyroid cancer were randomized to a patient outreach programme (outreach) or a standard AE monitoring schedule (vandetanib control) for 52 weeks. In addition to standard AE monitoring, patients in the outreach arm were contacted every 2 weeks by telephone/during their clinic visit for specific AE questioning related to diarrhoea, nausea, vomiting, fatigue, headache and rash. Patients received vandetanib at 200 or 300 mg/day, depending on the creatinine levels at screening. RESULTS: Altogether, 205 patients were randomized (outreach, n = 103; vandetanib control, n = 102). This study did not meet its primary objective; the mean percentage of time patients experienced at least one AE of grade 2 or higher was higher for the outreach group (51.65%) than for the vandetanib control group (45.19%); the difference was not statistically significant (t statistic: 1.29; 95% CI -3.44 to 16.37%; p = 0.199). The most frequently reported AEs were diarrhoea (56.9% for the outreach group vs. 46.6% for the vandetanib controls), hypertension (36.3 vs. 31.1%), rash (25.5 vs. 24.3%) and nausea (25.5% vs. 18.4%), and the most frequently reported AEs of grade 2 or higher were hypertension (33.3 vs. 23.3%), diarrhoea (26.5 vs. 24.3%) and dermatitis acneiform (11.8 vs. 9.7%). CONCLUSIONS: Additional outreach to patients treated with vandetanib had no impact on the rate or severity of AEs compared to the standard AE monitoring schedule. AEs were consistent with the known safety profile of vandetanib.

6.
J Clin Pharmacol ; 52(9): 1350-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22031621

RESUMO

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS-690514. Two open-label, randomized, single-dose, 2-treatment, 2-period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a high-fat meal, and in study 2 (N = 17), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)), area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-690514 increased by 55%, 33%, and 34%, respectively, following a high-fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS-690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS-690514 was increased when given along with a meal, probably through inhibition of intestinal first-pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS-690514 in the absence and presence of food.


Assuntos
Interações Alimento-Droga , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética , Triazinas/administração & dosagem , Triazinas/farmacocinética , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Receptores ErbB/antagonistas & inibidores , Feminino , Alimentos , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/sangue , Pirróis/sangue , Receptor ErbB-2/antagonistas & inibidores , Triazinas/sangue , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
7.
Blood ; 109(3): 1138-46, 2007 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16985171

RESUMO

CD4+ T cells, specific for transforming latent infection with the Epstein Barr virus (EBV), consistently recognize the nuclear antigen 1 of EBV (EBNA1). EBNA1-specific effector CD4+ T cells are primarily T-helper 1 (TH1) polarized. Here we show that most healthy EBV carriers have such IFN-secreting EBNA1-specific CD4+ T cells at a frequency of 0.03% of circulating CD4+ T cells. In addition, healthy carriers have a large pool of CD4+ T cells that proliferated in response to EBNA1 and consisted of distinct memory-cell subsets. Despite continuous antigen presence due to persistent EBV infection, half of the proliferating EBNA1-specific CD4+ T cells belonged to the central-memory compartment (TCM). The remaining EBNA1-specific CD4+ T cells displayed an effector-memory phenotype (TEM), of which a minority rapidly secreted IFN upon stimulation with EBNA1. Based on chemokine receptor analysis, all EBNA1-specific TCM CD4+ T cells were TH1 committed. Our results suggest that protective immune control of chronic infections, like EBV, includes a substantial reservoir of TCM CD4+ TH1 precursors, which continuously fuels TH1-polarized effector cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Memória Imunológica , Antígenos Virais/imunologia , Células Cultivadas , Humanos , Interferons/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia
9.
J Pediatr Hematol Oncol ; 26(2): 104-7, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14767197

RESUMO

The authors report a case of follicular lymphoma of the testis in a 3-year-old boy. Follicular lymphoma of childhood is rare, accounting for less than 5% of all non-Hodgkin lymphomas in the pediatric population. Children with follicular NHL have typically been described as presenting with localized disease, with a preponderance of male patients. The authors conducted a comprehensive review of the literature and found that this patient is the only child reported to have localized follicular lymphoma of the testis successfully treated without systemic chemotherapy. In all previously reported cases, a favorable outcome was seen following surgical resection and chemotherapy. This patient has remained disease-free for more than 2 years after surgical resection alone. The successful outcome in this case following surgical resection, without postoperative adjuvant chemotherapy, suggests that localized follicular non-Hodgkin lymphoma in children may not be associated with occult systemic disease and that subsequent chemotherapy may not be necessary for cure.


Assuntos
Linfoma Folicular/cirurgia , Neoplasias Testiculares/cirurgia , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Pré-Escolar , Humanos , Imunofenotipagem , Linfoma Folicular/química , Linfoma Folicular/patologia , Masculino , Orquiectomia , Neoplasias Testiculares/química , Neoplasias Testiculares/patologia , Resultado do Tratamento
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