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BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).
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Antígenos CD19 , Imunoterapia Adotiva , Lúpus Eritematoso Sistêmico , Agonistas Mieloablativos , Miosite , Escleroderma Sistêmico , Humanos , Antígenos CD19/administração & dosagem , Síndrome da Liberação de Citocina/etiologia , Seguimentos , Lúpus Eritematoso Sistêmico/terapia , Miosite/terapia , Escleroderma Sistêmico/terapia , Agonistas Mieloablativos/administração & dosagem , Ciclofosfamida/administração & dosagem , Infecções/etiologia , Resultado do TratamentoRESUMO
In patients receiving anticoagulant therapy for venous thromboembolism (VTE), the important issue of anemia influence on the risk of bleeding has not been consistently studied. We used the large registry data RIETE (Registro Informatizado Enfermedad Tromboembólica) to compare the rate of major bleeding in patients receiving anticoagulant therapy for VTE according to the presence or absence of anemia at baseline. Patients with or without cancer were separately studied. Until August 2016, 63492 patients had been enrolled. Of these, 21652 (34%) had anemia and 14312 (23%) had cancer. Anemia was found in 57% of the patients with cancer and in 28% without (odds ratio 3.46; 95% CI 3.33-3.60). During the course of anticoagulant therapy, 680 patients with cancer had a major bleeding event (gastrointestinal tract 43%, intracranial 14%, hematoma 12%). Cancer patients with anemia had a higher rate of major bleeding (rate ratio [RR]: 2.52; 95% CI 2.14-2.97) and fatal bleeding (RR 2.73; 95% CI 1.95-3.86) than those without anemia. During the course of anticoagulation, 1133 patients without cancer had major bleeding (gastrointestinal tract 32%, hematoma 24%, intracranial 21%). Patients with anemia had a higher rate of major bleeding (RR 2.84; 95% CI 2.52-2.39) and fatal bleeding (RR 2.76; 95% CI 2.07-3.67) than those without. On a multivariable analysis, anemia independently predicted the risk for major bleeding in patients with and without cancer (hazard ratios: 1.66; 95% CI 1.40-1.96 and 1.95; 95% CI 1.72-2.20, respectively). During anticoagulation for VTE, both cancer- and non-cancer anemic patients had a higher risk for major bleeding than those without anemia. In anemic patients (with or without cancer), the rate of major bleeding during the course of anticoagulant therapy exceeded the rate of VTE recurrences. In patients without anemia the rate of major bleeding was lower than the rate of VTE recurrences.
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Anemia/complicações , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Neoplasias/complicações , Tromboembolia Venosa/complicações , Anticoagulantes/uso terapêutico , Humanos , Sistema de Registros , Risco , Tromboembolia Venosa/tratamento farmacológicoRESUMO
There is a lack of comprehensive data on the prevalence, predictors and prognostic significance of right heart thrombi (RHT) in pulmonary embolism.In this study of patients with pulmonary embolism from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry, we assessed the prevalence and predictors of RHT, and the association between the presence of RHT and the outcomes of all-cause mortality, pulmonary embolism-related mortality, recurrences, and major bleeding through 30â days after initiation of pulmonary embolism treatment.Of 12â441 patients with pulmonary embolism and baseline echocardiographic data, 2.6% had RHT. The following increased the risk of RHT: younger age, previous bleeding, congestive heart failure, cancer, syncope, systolic blood pressure <100â mmHg, and arterial oxyhaemoglobin saturation <90%. Patients with RHT were significantly more likely to die from any cause (adjusted OR 2.50 (95% CI 1.62-3.84); p<0.001) and from pulmonary embolism (adjusted OR 4.29 (95% CI 2.45-7.48); p<0.001) during follow-up. RHT was associated with an increased risk of recurrence during follow-up (1.8% versus 0.7%; p=0.04). Major bleeding was similar in patients with and without RHT.In patients presenting with pulmonary embolism, RHT is relatively infrequent. Patients with RHT had a worse outcome when compared with those without RHT.
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Anticoagulantes/uso terapêutico , Embolia Pulmonar/complicações , Trombose/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Ecocardiografia , Feminino , Coração/fisiologia , Insuficiência Cardíaca , Hemorragia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Razão de Chances , Oxiemoglobinas/metabolismo , Prevalência , Prognóstico , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/mortalidade , Sistema de Registros , Estudos Retrospectivos , Risco , Sístole , Trombose/epidemiologia , Trombose/mortalidade , Resultado do TratamentoRESUMO
OBJECTIVE: To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc). METHODS: Randomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20â mg or placebo, three times daily for 12â weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05). RESULTS: Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12). CONCLUSIONS: The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit. TRIAL REGISTRATION NUMBER: NCT01295736.
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Dedos/irrigação sanguínea , Isquemia/tratamento farmacológico , Escleroderma Sistêmico/complicações , Citrato de Sildenafila/administração & dosagem , Úlcera Cutânea/tratamento farmacológico , Vasodilatadores/administração & dosagem , Adulto , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Isquemia/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Úlcera Cutânea/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 13th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures in September 2022 in Lille, France. The aim of this workshop is to update the mobilization and conditioning protocols for autologous hematopoietic stem cell transplantation for autoimmune diseases, and to specify contraindications for transplant, conditioning regimen selection, immunosuppressive treatment discontinuation before mobilization and disease-specific surveillance.
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Doenças Autoimunes , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante Autólogo , Transplante de Medula Óssea , Doenças Autoimunes/terapia , Imunossupressores/uso terapêutico , França , Sociedades Médicas , Condicionamento Pré-TransplanteRESUMO
Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research.
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Doenças Autoimunes do Sistema Nervoso/imunologia , Transtornos Globais do Desenvolvimento Infantil/imunologia , Animais , Anticorpos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Criança , Humanos , Inflamação/imunologiaRESUMO
Background: Venous thromboembolism (VTE) is a frequent complication in patients with cancer and a leading cause of morbidity and death. Objectives: The objective of the RIETECAT study was to compare the long-term effectiveness and safety of enoxaparin versus dalteparin or tinzaparin for the secondary prevention of VTE in adults with active cancer. Methods: We used the data from the multicenter, multinational RIETE registry to compare the rates of VTE recurrences, major bleeding, or death over 6 months in patients with active cancer and acute VTE using full doses of enoxaparin versus dalteparin or tinzaparin, and a multivariable Cox proportional hazard model was used to analyze the primary end point. Results: From January 2009 to June 2018, 4451 patients with active cancer received full doses of the study drugs: enoxaparin, 3526 patients; and dalteparin or tinzaparin, 925 (754 + 171) patients. There was limited difference in VTE recurrences (2.0% vs 2.5%) and mortality rate (19% vs 17%) between the enoxaparin and dalteparin or tinzaparin subgroups. However, there was a slight numerical increase in major bleeding (3.1% vs 1.9%). Propensity score matching confirmed that there were no differences in the risk for VTE recurrences (adjusted hazard ratio [aHR], 0.81; 95% confidence interval [CI], 0.48-1.38), major bleeding (aHR, 1.40; 95% CI, 0.80-2.46), or death (aHR, 1.07; 95% CI, 0.88-1.30) between subgroups. Conclusions: In RIETECAT, in patients with cancer and VTE receiving full-dose enoxaparin or dalteparin or tinzaparin, no statistically significant differences were observed regarding effectiveness and safety outcomes over a 6-month period.
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BACKGROUND: The natural history of patients with hematologic cancer and venous thromboembolism (VTE) has not been consistently evaluated. We aimed to compare the rates of symptomatic recurrent VTE, major bleeding, or death during anticoagulant therapy in patients with VTE associated with hematologic versus solid cancers. METHODS: Consecutive patients with active cancer recruited in RIETE were evaluated. Their baseline characteristics, treatments, and outcomes during the course of anticoagulation were compared. Univariate and multivariate competing-risk analyses were performed. RESULTS: As of December 2020, 16,694 patients with cancer and VTE were recruited. Of these, 1,062 (6.4%) had hematologic cancers. Hematologic patients were less likely to initially present with pulmonary embolism (46 vs. 55%) and more likely with upper extremity deep vein thrombosis (25 vs. 18%). They also were more likely to have severe thrombocytopenia at baseline (5.6 vs. 0.7%) or to receive chemotherapy (67 vs. 41%). During the course of anticoagulation (median, 150 vs. 127 days), 1,071 patients (6.4%) developed VTE recurrences, 806 (4.8%) suffered major bleeding, and 4,136 (24.8%) died. Patients with hematologic cancers had lower rates of recurrent VTE (rate ratio [RR]: 0.73; 95% confidence interval [CI]: 0.56-0.95), major bleeding (RR: 0.72; 95% CI: 0.53-0.98), or all-cause death (RR: 0.49; 95% CI: 0.41-0.57) than those with solid cancers. Patients with multiple myeloma showed the best outcomes. CONCLUSION: Patients with hematologic cancers, particularly multiple myeloma, and VTE had better outcomes than those with solid cancers. These findings are relevant for the interpretation of previous clinical trials and the design of future studies.
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Neoplasias Hematológicas , Mieloma Múltiplo , Neoplasias , Embolia Pulmonar , Tromboembolia Venosa , Anticoagulantes , Hemorragia , Humanos , Neoplasias/complicações , Tromboembolia Venosa/etiologiaRESUMO
OBJECTIVES: To obtain experiences and expert opinion on treatment of SSc patients with TNF-α antagonists. METHODS: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-α antagonists. Assessment forms on the frequency of TNF-α inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-α inhibitors in SSc. RESULTS: Seventy-nine centres returned information on use of TNF-α antagonists in SSc patients. A total of 65 patients were treated with TNF-α inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-α inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-α antagonists in SSc. Arthritis was suggested as an indication for TNF-α antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-α antagonists decreased and 59% recommended that TNF-α antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-α antagonists for arthritis associated with SSc. CONCLUSIONS: Most of the experts do not recommend the routine use of TNF-α antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-α antagonists are needed before general recommendations can be given.
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Artrite/tratamento farmacológico , Artrite/patologia , Técnica Delphi , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Artrite/etiologia , Artrite/imunologia , Consenso , Progressão da Doença , Fibrose , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Inflamação , Uso Off-Label , Escleroderma Sistêmico/complicações , Resultado do TratamentoRESUMO
This report describes activity in Europe for the years 2016 and 2017 in the area of cellular and tissue-engineered therapies, excluding hematopoietic stem cell treatments for the reconstitution of hematopoiesis. It is the eighth of its kind and is supported by five established scientific organizations. In 2016 and 2017, a combined 234 teams from 29 countries responded to the cellular and engineered tissue therapy survey; 227 teams reported treating 8236 patients in these 2 years. Indications were categorized in hematology/oncology (40%; predominantly prevention or treatment of graft vs. host disease and hematopoietic graft enhancement), musculoskeletal/rheumatological disorders (29%), cardiovascular disorders (6%), neurological disorders (4%), gastrointestinal disorders (<1%), as well as miscellaneous disorders (20%), which were not assigned to the previous indications. The predominantly used cells were autologous (61%). The majority of autologous cells were used to treat musculoskeletal/rheumatological (44%) disorders, whereas allogeneic cells were mainly used for hematology/oncology (78%). The reported cell types were mesenchymal stem/stromal cells (MSCs) (56%), hematopoietic cells (21%), keratinocytes (7%), chondrocytes (6%) dermal fibroblasts (4%), dendritic cells (2%), and other cell types (4%). Cells were expanded in vitro in 62% of the treatments, sorted in 11% of the cases, and rarely transduced (2%). The processing of cells was outsourced to external facilities in 30% of the cases. Cells were delivered predominantly intravenously or intra-arterially [47%], as suspension [36%], or using a membrane/scaffold (16%). The data are compared with those from previous years to identify trends in a rapidly evolving field. In this edition, the report includes a critical discussion of data collected in the space of orthopedics and the use of MSCs.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Terapia Baseada em Transplante de Células e Tecidos , Europa (Continente) , Humanos , Engenharia TecidualRESUMO
Introduction We previously reported that during the course of anticoagulation for venous thromboembolism (VTE) patients using statins were at a lower risk to die than nonusers. Methods We used the R egistro I nformatizado E nfermedad T rombo E mbólica (RIETE) registry to validate our previous findings in a subsequent cohort of patients and to compare the risk of death according to the use of different types of statins. Results From January 2018 to December 2019, 19,557 patients with VTE were recruited in RIETE. Of them, 4,065 (21%) were using statins (simvastatin, 1,406; atorvastatin, 1,328; rosuvastatin, 246; and others, 1,085). During anticoagulation (192 vs.182 days, for statin and no statin users respectively), 500 patients developed a VTE recurrence, 519 suffered major bleeding, and 1,632 died (fatal pulmonary embolism [PE], 88 and fatal bleeding, 78). On multivariable analysis, statin users were at a lower risk to die (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.59-0.79) than nonusers. When separately analyzing the drugs, on multivariable analysis, patients using simvastatin (HR = 0.64; 95% CI: 0.52-0.80), atorvastatin (HR 0.72; 95% CI: 0.58-0.89), or other statins (HR = 0.67; 95% CI: 0.52-0.87) were at a lower risk to die than nonusers. For those using rosuvastatin, difference was not statistically significant (HR = 0.77; 95% CI: 0.50-1.19), maybe due to the sample size. Conclusion Our data validate previous findings and confirm that VTE patients using statins at baseline are at a lower risk to die than nonusers. No statistically differences were found according to type of statins.
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Systemic lupus erythematosus (SLE) is an autoimmune disease with a broad range of clinical manifestations and a heterogeneous disease course. There is no cure for SLE, but current standard pharmacotherapies can improve disease prognosis in most patients. However, some patients are refractory to conventional treatments and require alternative treatment options. The present study is aimed at identifying predictors of clinical response to allogeneic bone marrow-derived or umbilical cord-derived mesenchymal stem cell (BM-/UC-MSC) transplant in SLE. All adult patients identified in the Nanjing database with an SLE Disease Activity Index (SLEDAI) score ≥ 8 at baseline that had undergone MSC transplant and who had at least 1 year of follow-up after one or two successive intravenous injections of allogeneic BM-/UC-MSCs (1 million/kg) were analyzed. SLE symptoms and SLEDAI were assessed at baseline and during follow-up to determine low disease activity (LDA) and clinical remission (CR) at 1, 3, 6, and 12 months. Sixty-nine patients were included in the study, with a median (range) SLEDAI of 13 (8-34) at baseline. Among the 69 patients, 40 (58%) achieved LDA and 16 (23%) achieved CR with a SLEDAI of 9 (4-20), 8 (0-16), 6 (0-18), and 5 (0-18) after 1, 3, 6, and 12 months, respectively. Older age (p = 0.006) and no arthralgia/arthritis at baseline (p = 0.03) were associated with a higher rate of LDA. Achieving CR was associated with older age (p = 0.033), no arthralgia/arthritis at baseline (p = 0.001), and no prior use of cyclophosphamide (p = 0.003) or hydroxychloroquine (p = 0.016). Future studies using unique immunosuppressive regimens and allogeneic MSC sources will further elucidate determinants of clinical response to MSC transplant in SLE.
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BACKGROUND: Proper risk stratification of patients for early mortality after cancer-associated thrombosis may lead to personalized anticoagulation protocols. Therefore, we aimed to derive and validate a scoring system to predict early mortality in this population. To this end, we selected patients with active cancer and thrombosis from the Computerized Registry of Patients with Venous Thromboembolism database. METHODS: The main outcome was all cause mortality within the month following a thrombotic event. We used a simple random selection to split are data in a derivation and a validation cohort. In the derivation cohort, we used recursive partitioning and binary logistic regression to identify groups at risk and to determine the likelihood of the primary outcome. The risk score was developed based on odds ratios from the final multivariate model, and then tested in the validation cohort. RESULTS: In 10,025 eligible patients, we identified 6 predictors of 30-day mortality: leukocytosis ≥11.5x109/L; platelet count ≤160x109/L, metastasis, recent immobility, initial presentation as pulmonary embolism and Body Mass Index <18.5. The model divided the population into 3 risk categories: low (score 0-3), moderate (score 4-6), and high (score ≥7). The AUC for the overall score was 0.74, and using a cutoff ≥7 points, the model had a negative predictive value of 94.4%, a positive predictive value of 23.1%, a sensitivity of 73.3%, and a specificity of 64.6% in the validation cohort. CONCLUSIONS: Our validated risk model may assist physicians in the selection of patients for outpatient management, and perhaps anticoagulant, considering expanding anticoagulation options.
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Neoplasias/complicações , Medição de Risco , Trombose/diagnóstico , Tromboembolia Venosa/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Internacionalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/mortalidade , Valor Preditivo dos Testes , Sistema de Registros , Fatores de Risco , Trombose/mortalidade , Tromboembolia Venosa/mortalidade , Adulto JovemRESUMO
The Standards, Options: Recommendations (SOR) project has been undertaken by the French National Federation of Cancer Centers (FNCLCC) is now part of the French National Cancer Institute. The project involves the development and updating of evidence-based Clinical Practice Guidelines (CPG) in oncology. In order to answer questions related to venous thromboembolic events(VTE) treatment and to central venous catheter thrombosis (CVCT) management in cancer patients, the SOR elaborated national guidelines, here presented in a short report. It results of a collaborative work with members from three learned societies("société nationale française de médicine interne": SNFMI, "société française de médicine vasculaire": SFMV and "société française dEanesthésie-réanimation:SFAR).
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Cateterismo Venoso Central/efeitos adversos , Neoplasias/complicações , Neoplasias/terapia , Tromboembolia Venosa/terapia , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Cateterismo Venoso Central/métodos , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Infusões Intravenosas , Insuficiência Renal/complicações , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologiaRESUMO
Women with scleroderma (SSc) maintain significantly higher quantities of persisting fetal microchimerism (FMc) from complete or incomplete pregnancies in their peripheral blood compared to healthy women. The non-classical class-I human leukocyte antigen (HLA) molecule HLA-G plays a pivotal role for the implantation and maintenance of pregnancy and has often been investigated in offspring from women with pregnancy complications. However data show that maternal HLA-G polymorphisms as well as maternal soluble HLA-G (sHLA-G) expression could influence pregnancy outcome. Here, we aimed to investigate the underlying role of maternal sHLA-G expression and HLA-G polymorphisms on the persistence of FMc. We measured sHLA-G levels by enzyme linked immunosorbent assay in plasma samples from 88 healthy women and 74 women with SSc. Male Mc was quantified by DYS14 real-time PCR in blood samples from 58 women who had previously given birth to at least one male child. Furthermore, eight HLA-G 5'URR/3'UTR polymorphisms, previously described as influencing HLA-G expression, were performed on DNA samples from 96 healthy women and 106 women with SSc. Peripheral sHLA-G was at lower concentration in plasma from SSc (76.2 ± 48.3 IU/mL) compared to healthy women (117.5 ± 60.1 IU/mL, p < 0.0001), independently of clinical subtypes, autoantibody profiles, disease duration, or treatments. Moreover, sHLA-G levels were inversely correlated to FMc quantities (Spearman correlation, p < 0.01). Finally, women with SSc had lower sHLA-G independently of the eight HLA-G 5'URR/3'UTR polymorphisms, although they were statistically more often homozygous than heterozygous for HLA-G polymorphism genotypes -716 (G/T), -201 (G/A), 14 bp (ins/del), and +3,142 (G/A) than healthy women. In conclusion, women with SSc display less sHLA-G expression independently of the eight HLA-G polymorphisms tested. This decreased production correlates with higher quantities of persisting FMc commonly observed in blood from SSc women. These results shed some lights on the contribution of the maternal HLA-G protein to long-term persistent fetal Mc and initiate new perspectives in this field.
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Quimerismo , Desenvolvimento Fetal/genética , Desenvolvimento Fetal/imunologia , Expressão Gênica , Antígenos HLA-G/genética , Antígenos HLA-G/imunologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Alelos , Autoanticorpos/imunologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Antígenos HLA-G/sangue , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Gravidez , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapia , Regiões não TraduzidasRESUMO
OBJECTIVE: The ERAMS study addressed the value of arterial stiffness in predicting the severity of systemic sclerosis. METHODS: ERAMS was a prospective multicentre cohort study including patients with definite systemic sclerosis. Arterial stiffness was measured by the standardized non-invasive QKd 100-60 method. Clinical evaluation, biological measurements, functional respiratory tests and cardiac Doppler echography were performed at inclusion then each year until 3 years' follow-up was completed. Progression was defined as mild (articulations, muscle, oesophagus or skin involvement) or severe (lung, heart or kidney involvement) by a critical event committee. The prediction of severe progression was studied for QKd 100-60 as well as clinical and biological data at baseline by univariate and multivariate analysis. RESULTS: Ninety-nine patients were included (81 women, 18 men, mean age 57 years, standard deviation 12.5). Although their blood pressure profile was normal, half the patients had increased arterial stiffness (QKd 100-60<200 ms). There was a significant relationship between age-adjusted arterial stiffness and decrease in carbon dioxide diffusion (P<0.03) or haemoglobin rate (P<0.01). By univariate analysis, severe progression after 3 years was predicted by age (P=0.04), lung involvement (P=0.04), diffusion of lung carbon oxide (DLCO) (P<0.01), skin score (P=0.02), haemoglobin (P<0.01) and baseline Qkd 100-60 divided into two classes according to the median (P<0.01). By multivariate analysis, only haemoglobin rate [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2-0.9] and QKd 100-60 (OR 19.6, 95% CI 1.2-308.2) predicted severe progression of systemic sclerosis. CONCLUSION: The measurement of arterial stiffness by the QKd method is a useful objective method for assessing the prognosis of systemic sclerosis independently from other data.
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Artérias/fisiopatologia , Complacência (Medida de Distensibilidade) , Escleroderma Sistêmico/fisiopatologia , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Calcinose/patologia , Escleroderma Sistêmico/patologia , Doenças da Coluna Vertebral/patologia , Calcinose/complicações , Calcinose/diagnóstico por imagem , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Síndromes de Compressão Nervosa/complicações , Síndromes de Compressão Nervosa/diagnóstico por imagem , Síndromes de Compressão Nervosa/patologia , Radiografia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Doenças da Coluna Vertebral/diagnóstico por imagem , Nervos Espinhais/patologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologiaRESUMO
The standardized incidence of cancer in patients with venous thromboembolism (VTE) is about 5%. This risk is higher in patients diagnosed with idiopathic, bilateral or recurrent VTE. The incidence of cancer is the highest within the first year after the VTE and approximately 40% of these cases are already metastatic when diagnosed. Among malignancies presenting with VTE as their first clinical manifestation, cancers from the pancreas, the stomach, the ovary, the lung, the brain or the liver are the most commonly identified. An extensive diagnostic work-up in all patients with unexplained VTE is not cost effective in terms of survival or of quality of life. Cancer screening should be guided by the results of complete clinical examination, blood count and chest X-ray.
Assuntos
Neoplasias Primárias Desconhecidas/complicações , Embolia Pulmonar/etiologia , Neoplasias Encefálicas/complicações , Feminino , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Pulmonares/complicações , Neoplasias Ovarianas/complicações , Neoplasias Pancreáticas/complicações , Recidiva , Fatores de Risco , Neoplasias Gástricas/complicações , Tromboembolia/etiologia , Trombose Venosa/etiologiaRESUMO
BACKGROUND: In cancer patients with symptomatic venous thromboembolism (VTE) (deep-vein thrombosis (DVT) and/or pulmonary embolism (PE)), clinical factors that influence the benefit-risk balance of anticoagulation need to be identified so treatment intensity and duration can be optimally adjusted for the individual patient. METHODS: Using clinical data for cancer patients with VTE obtained from the RIETE registry, we compared how rates of fatal PE and fatal bleeding during and after anticoagulation vary depending on patients' clinical characteristics. RESULTS: Data were analysed from the 10,962 cancer patients with VTE (5,740 with PE with or without DVT; 5,222 with DVT alone) in RIETE registry as of March 2016. Fatal PE occurred in 2.18% of patients, while fatal bleedings occurred in 1.55%. During the 12 months from initial VTE, fatal PE was the most common cause of death, after disseminating cancer, and bleeding the fourth most common. In patients initially presenting with PE, fatal PE during anticoagulation was 4-fold more frequent than fatal bleeding (204 vs 51 deaths) and occurred mostly during the first month of treatment (196/223, 88%). In patients initially presenting with DVT, fatal PE was 3-fold lower than fatal bleeding during (25 vs 85 deaths) and after anticoagulation treatment (8 vs 37 deaths). During the 12-month follow-up, other characteristics of cancer patients with VTE were identified as more common in fatal cases of PE and/or bleeding than in surviving cases. INTERPRETATION: Baseline clinical characteristics may determine anticoagulation outcomes in cancer patients with VTE and should be further investigated as possible factors for guiding changes in current practices of anticoagulation, such as adjusting anticoagulation intensity and duration in selected patients.