RESUMO
Vaccine-induced thrombotic thrombocytopenia with cerebral venous thrombosis is a syndrome recently described in young adults within two weeks from the first dose of the ChAdOx1 nCoV-19 vaccine. Here we report two cases of malignant middle cerebral artery (MCA) infarct and thrombocytopenia 9-10 days following ChAdOx1 nCoV-19 vaccination. The two cases arrived in our facility around the same time but from different geographical areas, potentially excluding epidemiological links; meanwhile, no abnormality was found in the respective vaccine batches. Patient 1 was a 57-year-old woman who underwent decompressive craniectomy despite two prior, successful mechanical thrombectomies. Patient 2 was a 55-year-old woman who developed a fatal bilateral malignant MCA infarct. Both patients manifested pulmonary and portal vein thrombosis and high level of antibodies to platelet factor 4-polyanion complexes. None of the patients had ever received heparin in the past before stroke onset. Our observations of rare arterial thrombosis may contribute to assessment of possible adverse effects associated with COVID-19 vaccination.
Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/imunologia , Infarto Cerebral/induzido quimicamente , Púrpura Trombocitopênica Idiopática/induzido quimicamente , SARS-CoV-2/imunologia , Trombose/induzido quimicamente , Autoanticorpos/sangue , Autoanticorpos/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Infarto Cerebral/diagnóstico por imagem , ChAdOx1 nCoV-19 , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/diagnóstico por imagem , SARS-CoV-2/fisiologia , Trombose/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Vacinação/efeitos adversos , Trombose Venosa/induzido quimicamente , Trombose Venosa/diagnóstico por imagemRESUMO
BACKGROUND: Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. RESULTS: PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. CONCLUSIONS: Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.
Assuntos
Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Autofagia/efeitos dos fármacos , Etanercepte/uso terapêutico , Metotrexato/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Etanercepte/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process.
Assuntos
Artrite Reumatoide/imunologia , Aterosclerose/imunologia , Autofagia/imunologia , Micropartículas Derivadas de Células/imunologia , Animais , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Humanos , Inflamação/imunologiaAssuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Tolerância a Medicamentos , Etanercepte , Humanos , Imunoglobulina G/efeitos adversos , Estudos Longitudinais , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate the clinical response after switching to another TNFalpha antagonist in patients with rheumatoid arthritis (RA) and provide a review of the literature on this topic. METHODS: In this ongoing, longitudinal, observational study we have prospectively collected data of patients starting biological treatments since 2000. The present analysis is restricted to RA patients who switched to another anti-TNFalpha due to lack of efficacy (LaE), loss of efficacy (LoE), or adverse events (AEs) by the end of December 2007. Disease activity score (ESR-based DAS28) was calculated and the clinical response (none, moderate, good) was evaluated according to the European League Against Rheumatism (EULAR) criteria. Clinical remission (DAS28 <2.6) and low disease activity (DAS28 =3.2) were also evaluated. RESULTS: A total of 692 anti-TNFalpha-naïve patients has been registered, of whom 395 with a diagnosis of RA. Thirtyseven RA patients switched to another TNFalpha antagonist. Three months after switching, the proportion of patients with remission, low disease activity, good and moderate/good EULAR responses grew from 0%, 2.7%, 0%, and 5.4% (baseline before switching) to 16.2%, 35.1%, 27%, and 62.2% (p<0.05, p<0.001, p<0.001, p<0.000001, respectively). Of the patients who switched because of LaE, LoE, and AEs a moderate/good EULAR response was achieved in 38.4%, 66.6%, and 88.8% of patients, respectively. Mean treatment duration with the second anti-TNFalpha was significantly longer in patients switching for LoE and AEs than in those switching for LaE (p<0.05). CONCLUSIONS: The findings of this study suggest that RA patients may be successfully treated with another TNFalpha antagonist, especially those withdrawing for LoE or AEs.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Progressão da Doença , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Infliximab , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Receptores do Fator de Necrose Tumoral/uso terapêutico , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Among the different investigated biomarkers, cell proliferation has provided valuable information on the clinical outcome of patients with malignant tumors. In the present study, we analyzed the potential relevance of fractional incorporation (FI) of a nucleotide precursor (3H-thymidine, 3H-dT) into DNA of tumor cells, determined on the primary tumor, on long-term clinical outcome of a series of patients with colorectal cancer. Determination of 3H-dT FI was carried out on fresh tumor material obtained at surgery as part of the clinical management of the primary tumor in 28 patients with colorectal cancer. Analysis of the relation between the FI and clinico-pathological characteristics of the tumor showed a trend of an inverse relation between the biomarker and Dukes' stage and no relation with tumor site. At 6 year follow-up, alive patients had a statistically significant higher median FI value (2.4%; range: 1.1-6.5%) than dead patients (1%; range: 0.3-4.5%) (p=0.02). Owing to the simplicity of this inexpensive methodology, the preliminary results of our study would indicate the potential of FI, a metabolic-kinetic parameter, to give prognostic information in colorectal cancer patients.
Assuntos
Neoplasias Colorretais/metabolismo , DNA de Neoplasias/biossíntese , Timidina/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Terapia Combinada , Replicação do DNA , Humanos , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento , TrítioRESUMO
In this study we tested the hypothesis that colorectal cancers containing adenoma (CCA) could be a different entity from colon cancers without adenoma (CSA). Clinical data, histologic preparations of operative specimens and survival of 210 patients who underwent resective surgery for colorectal cancer were studied. Adenomatous tissue within the cancer was found in 62 of 210 carcinomas (CCA), the other 148 cancers were lacking adenomatous features (CSA). CCA occurred more frequently in female patients (p = 0.003). Synchronous adenomas were detected in the resected colon of 19 out 62 CCA and of 24 out 148 CSA (p = 0.04). CCA showed the extent of intraparietal spread (p = 0.001), grade (p = 0.007) and stage (p = 0.004) lower than CSA. These characteristics also appeared statistically related to size of the cancers. The adenomatous tissue within CCA was tubular in 4 cases, tubulo-villous in 34 and villous in 24 cases. The villous histotype was statistically related to the older age of patients (p < 0.0001), larger cancer size (p = 0.01), presence of synchronous adenomas in the resected colon (p = 0.02) and higher histologic grade of the cancer (p < 0.05). Patients with CCA evidenced a higher 5-year survival rate (p = 0.02). Our results evidence epidemiologic, clinical and pathologic differences between CCA and CSA and suggest a possible double histogenesis of colon cancer.