RESUMO
BACKGROUND: Predictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors. PATIENTS AND METHODS: Expression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan-Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells. RESULTS: Four hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline-taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy. CONCLUSION: FOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.
Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fatores de Transcrição Forkhead/metabolismo , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Feminino , HumanosRESUMO
BACKGROUND: In HER2-overexpressing breast cancer, accumulating preclinical evidences suggest that some chemotherapies, like trastuzumab, but also taxanes, are able to trigger a T helper 1 (Th1) anticancer immune response that contribute to treatment success. T helper 1 immune response is characterised by the expression of the transcription factor T-bet in CD4 T lymphocytes. We hypothesised that the presence of such T cells in the tumour immune infiltrates following neoadjuvant chemotherapy would predict patient survival. METHODS: In a series of 102 consecutive HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy incorporating antracyclines or taxane and trastuzumab, we studied by immunohistochemistry the peritumoral lymphoid infiltration by T-bet+ lymphocytes before and after chemotherapy in both treatment groups. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS). RESULTS: Fifty-eight patients have been treated with trastuzumab-taxane and 44 patients with anthracyclines-based neoadjuvant chemotherapy. The presence of T-bet+ lymphocytes in peritumoral lymphoid structures after chemotherapy was significantly more frequent in patients treated with trastuzumab-taxane (P=0.0008). After a median follow-up of 40 months, the presence of T-bet+ lymphocytes after neoadjuvant chemotherapy confers significantly better RFS (log-rank test P=0.011) only in patients treated with trastuzumab-taxane. In this population, multivariate Cox regression model showed that only the presence of T-bet+ lymphocytes in peritumoral lymphoid structures after neoadjuvant chemotherapy was independently associated with improved RFS (P=0.04). CONCLUSION: These findings indicate that the tumour infiltration by T-bet+ Th1 lymphocytes following neoadjuvant trastuzumab-taxane may represent a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD4-Positivos/metabolismo , Genes erbB-2 , Tecido Linfoide/metabolismo , Proteínas com Domínio T/metabolismo , Taxoides/administração & dosagem , Antraciclinas , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Docetaxel , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , TrastuzumabRESUMO
A cornucopia of physiological and pathological circumstances including anticancer chemotherapy and radiotherapy can induce cell death. However, the immunological consequences of tumor cell demise have remained largely elusive. The paradigm opposing 'apoptosis versus necrosis' as to their respective immunogenicity does not currently hold to predict long-term immunity. Moreover, the notion that tumor cells may be 'stressed' before death to be recognized by immune cells deserves to be underlined. 'Eat-me', 'danger' and 'killing' signals released by stressed tumor under the pressure of cytotoxic compounds may serve as links between the chemotherapy-elicited response of tumor cells and subsequent immune responses. This review will summarize the state-of-the-art of cancer immunity and describe how tumor cell death dictates the links between innate and acquired immunity.
Assuntos
Morte Celular , Citocinas/metabolismo , Neoplasias/imunologia , Neoplasias/fisiopatologia , Animais , Apoptose , Autofagia , Citocinas/imunologia , Células Dendríticas/imunologia , Humanos , Imunidade Ativa , Imunidade Inata , Células Matadoras Naturais/imunologia , Modelos Biológicos , Necrose , Neoplasias/patologia , Transdução de Sinais , Linfócitos T Citotóxicos/imunologiaRESUMO
We have investigated the pH dependence of U(VI) retention in quartz/10(-4) M uranyl solution systems, under conditions favoring formation of polynuclear aqueous species and of colloids of amorphous schoepite as U(VI) solubility-limiting phases. X-ray photoelectron spectroscopy was used to gain insights into the coordination environments of sorbed/precipitated uranyl ions in the centrifuged quartz samples. The U4f XPS spectra made it possible to identify unambiguously the presence of two uranyl components. A high binding energy component, whose relative proportion increases with pH, exhibits the U4f lines characteristic of a reference synthetic metaschoepite. Such a high binding energy component is interpreted as a component having a U(VI) oxide hydrate character, either as polynuclear surface oligomers and/or as amorphous schoepite-like (surface) precipitates. Its pH dependence suggests that a binding of polynuclear species at quartz surfaces and/or a formation of amorphous schoepite-like (surface) precipitates is favored when the proportion of aqueous polynuclear species increases. A second surface component exhibits binding energies for the U4f core levels at values significantly lower (DeltaE(b)=1.2 eV) than for metaschoepite, evidencing uranyl ions in a distinct coordination environment. Such a low binding energy component may be attributed to monomeric uranyl surface complexes on the basis of published EXAFS data. Such a hypothesis is supported by a major contribution of the low binding energy component to the U4f XPS spectra of reference samples for uranyl sorbed on quartz from very acidic 10(-3) M uranyl solutions where UO(2)(2+) ions predominate.
RESUMO
Authors have listed 9 criteria for testing scientific quality of computerized drug-interactions data banks. Pair of drugs with or without interactions, have been selected for each of these criteria and have been used for interrogation of eight data banks. None of these are completely satisfactory but errors or omissions are more or less important.
Assuntos
Bases de Dados Factuais , Interações Medicamentosas , Estudos de Avaliação como Assunto , França , HumanosRESUMO
Authors look at different methodological estimations of costs induced by hospitalizations for side effects of drugs: individual, global and budgetary estimations. Only the two last ones are possible today. Results are sufficient to demonstrate the economic importance of a Pharmacovigilance Centre for the Hospitals that have got such a structure.
Assuntos
Serviços de Informação sobre Medicamentos/economia , Hospitalização/economia , Vigilância de Produtos Comercializados/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This paper presents the results of an intensive surveillance based on a network of general practitioners and following 200 patients treated by famotidine 40 mg per day during 6 to 8 weeks. Four patients with a previous experience of adverse reaction to another H2 antagonist did not relapse with famotidine. None interaction was reported with drugs such as beta-blockers, oral anticoagulants, theophylline, benzodiazepines, calcium antagonists. Twenty four clinical side effects were reported; For 5 patients (2.5%) the treatment had to be stopped. The most common side effects were neurological. The results are compared with those of previously published studies.
Assuntos
Medicina de Família e Comunidade , Famotidina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Tolerância a Medicamentos , Métodos Epidemiológicos , Famotidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamenteRESUMO
We describe 5 observations of cutaneous reactions or immediate hypersensitivity with different hypoglycemic sulfonylurea: Quincke's oedema with glibornuride, three urticaria (one was followed by bronchospasm and collapsus) with glibenclamide, one bullous dermatitis with carbutamide. With special regard to cross reactions between sulfonylurea: we observe the tolerance of glipizide after glibenclamide induced urticaria, tolerance of glicalazide after glibornuride induced Quincke's oedema and eruption, tolerance of glibornuride after chlorporpamide induced urticaria and Quincke's oedema. In the literature, cross reactions between 1st generation sulfonylurea are noted, but not cross reactions between 1st and 2nd generation.
Assuntos
Hipersensibilidade a Drogas/imunologia , Hipersensibilidade Imediata/induzido quimicamente , Hipoglicemiantes/imunologia , Compostos de Sulfonilureia/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Reações Cruzadas , Toxidermias , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The four indices for a binary outcome or therapeutic objective are: the odds ratio, the relative risk, the absolute benefit and the number of patients to treat. For a continuous outcome, the effect size is the best choice. The odds ratio approximates the relative risk. The difference may be large in some instances. The number of patients to treat is the reciprocal of the absolute benefit. Although they are built on the same two quantities, they are not interchangeable and should not be considered in the same way. Moreover, their meaning is not straightforward and they can be misused.
Assuntos
Resultado do Tratamento , Protocolos Clínicos , Humanos , Razão de Chances , RiscoRESUMO
In chronic illness, when death or a non-fatal event can occur at any time, the current efficacy indices are no longer appropriate to express the effect of the treatment on the potential therapeutic objectives. The inappropriateness is not dependent on the effect model. Clues for solutions are proposed.
Assuntos
Avaliação de Medicamentos/métodos , Tratamento Farmacológico , Resultado do Tratamento , Doença Crônica/tratamento farmacológico , Tratamento Farmacológico/normas , HumanosRESUMO
Efficacy indices do not contain the same information although they are all combinations of the same two quantities. Therefore, one should choose the proper index. Actually, none is entirely appropriate. Each more or less meets the specifications, depending on the underlying effect model for the therapy considered. However, one can say that the absolute benefit is more appropriate from the patient's point of view, the relative from the scientific point of view and the number of patients to treat from the policy maker's point of view. Nevertheless, this classification needs to be considered with caution. Finally, it emerges from the review that none is fully relevant to express the efficacy of a therapy, even in the most suitable condition, the acute illness.
Assuntos
Avaliação de Medicamentos/normas , Resultado do Tratamento , Humanos , Razão de Chances , Padrões de Referência , RiscoRESUMO
Efficacy indices measure the efficacy of therapies. They derive, by definition, from two quantities, the basal or control risk of event, Rc, observed in the control group, and the on-treatment risk, Rt, observed in the treated group. In clinical trials and meta-analyses, each is an unbiased measure of efficacy. Although they are a combination of frequencies, these indices are used in clinical practice to predict the benefit in treated patients. Their relevance to express efficacy depends on the type of clinical condition, and is better for acute diseases than for chronic diseases. In order to be useful for prescribers, they should meet certain specifications. In addition, they should be considered in the more general framework of effect models.
Assuntos
Resultado do Tratamento , Ensaios Clínicos como Assunto , Humanos , Metanálise como Assunto , Modelos Teóricos , Medição de RiscoRESUMO
In this paper, we analyse all the sentences handed out by the Assize Court of Rennes in France, in the last decade. A recent increase in the number of sexual offences has been observed. An increase in the number of cases of incest has also been noted. This paper analyses the sex ratio, the age of the victim, the association with other violence and the relationship between the victim and his or her aggressor. The outcomes of the trials are discussed.
RESUMO
Tardive dyskinesia frequently occur during neuroleptic-treatments. Prevalence and risk factors, clinical characteristics, relation to other extrapyramidal disorders are reviewed. The presumed pathophysiology is that tardive dyskinesia are caused by a neuroleptic-induced dopamine receptor hypersensitivity. Several trials of treatment are compared with respect to this hypothesis.
Assuntos
Antipsicóticos/efeitos adversos , Discinesia Induzida por Medicamentos/diagnóstico , Adulto , Idoso , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson Secundária/induzido quimicamente , Prognóstico , Receptores Colinérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Risco , Transmissão Sináptica/efeitos dos fármacosRESUMO
The problem has been considered of the action of Lithium salts on the progress of pregnancy and on the product of the conception. Lithium can bring about serious troubles in morphogenesis in invertebrate animals. The results obtained in mammals in laboratory experiments differ from species to species but it seems that these animals can be given about 8 to 9 times the levels of Lithium that are used in man without causing teratogenic effects. A statistical review of the children born to human mothers taking Lithium in pregnancy shows up an increase in the incidence of cardio-vascular abnormalities. (7.8% instead of 0.04%). The infants that have received Lithium and have not been anatomically affected show no more developmental problems later than others.
Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Embrião de Mamíferos/efeitos dos fármacos , Lítio/efeitos adversos , Anfíbios , Animais , Aves , Cães , Embrião não Mamífero/efeitos dos fármacos , Feminino , Haplorrinos , Humanos , Recém-Nascido , Rim/metabolismo , Lítio/metabolismo , Masculino , Troca Materno-Fetal , Camundongos , Leite Humano/metabolismo , Mitose/efeitos dos fármacos , Morfogênese/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Transtornos Psicóticos/tratamento farmacológico , Coelhos , Ratos , Ouriços-do-Mar , Espermatozoides/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
Liver X receptors (LXRs) have been proposed to have some anticancer properties, through molecular mechanisms that remain elusive. Here we report for the first time that LXR ligands induce caspase-1-dependent cell death of colon cancer cells. Caspase-1 activation requires Nod-like-receptor pyrin domain containing 3 (NLRP3) inflammasome and ATP-mediated P2 × 7 receptor activation. Surprisingly, LXRß is mainly located in the cytoplasm and has a non-genomic role by interacting with pannexin 1 leading to ATP secretion. Finally, LXR ligands have an antitumoral effect in a mouse colon cancer model, dependent on the presence of LXRß, pannexin 1, NLRP3 and caspase-1 within the tumor cells. Our results demonstrate that LXRß, through pannexin 1 interaction, can specifically induce caspase-1-dependent colon cancer cell death by pyroptosis.
Assuntos
Apoptose , Receptores Nucleares Órfãos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Conexinas/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transplante de Neoplasias , Proteínas do Tecido Nervoso/metabolismo , Receptores Nucleares Órfãos/agonistas , Sulfonamidas/farmacologia , Carga Tumoral/efeitos dos fármacosAssuntos
Imunidade/fisiologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Humanos , Imunidade/efeitos dos fármacos , Polimorfismo Genético/genética , Receptor 4 Toll-Like/genéticaRESUMO
FOXP3 is a transcription factor necessary and sufficient for induction of the immunosuppressive functions in regulatory T lymphocytes. Its expression was first considered as specific of this cell type, but FOXP3 can also be transiently expressed in T-cell antigen receptor-activated human nonregulatory T cells. Recent data indicate that FOXP3 is also expressed by some nonlymphoid cells, in which it can repress various oncogenes that are restored following FOXP3 deletion or mutation. This review summarizes major advances in (1) the understanding of Foxp3 functions in human regulatory T cells, (2) the prognostic significance of Foxp3-expressing T cells in human malignancies and (3) the significance of Foxp3 expression in human tumor cells.