Clinical and economic aspects of the use of rituximab in non-Hodgkin's lymphoma

O Linfoma não-Hodgkin (LNH) consiste em um grupo de neoplasias envolvendo, principalmente, as células B e representa 90% de todos os linfomas. A terapia atual disponível é baseada em quimioterapia associada ao anticorpo monoclonal rituximabe (Mab Thera(r)), que tem como alvo a proteína CD20, presente em mais de 80% das células B maduras do LNH. Recentes relatórios clínicos mostram preferência para combinar os benefícios da quimioterapia adjuvante e imunoterapia, gerando alternativas de tratamentos seguro e eficaz. O trabalho de revisão teve por objetivo avaliar vários aspectos relacionados à aplicação do rituximabe no LNH, destacando os possíveis mecanismos inibitórios da proliferação celular, os resultados clínicos obtidos e as implicações clínicas e econômicas esperadas para o tratamento. Os resultados de testes clínicos indicam a necessidade de uma melhor compreensão dos mecanismos críticos de ação deste anticorpo, que poderão maximizar a sua eficácia terapêutica. Essa terapia não representa apenas uma opção viável para o tratamento da maioria dos tipos de LNH, principalmente quando associado à quimioterapia convencional, mas, também, oferece vantagens em termos de custo-utilidade e custo-efetividade.Non-Hodgkin's lymphoma (NHL) consists of a group of neoplasias involving mainly B cells and represents 90% of all lymphomas. The current available therapy is based on chemotherapy associated with the monoclonal antibody rituximab (Mab Thera(r)), which targets the CD20 protein, present in over 80% of NHL mature B cells. Recent clinical reports show a preference for combining the benefits of immunotherapy and adjuvant chemotherapy, thus generating safe and effective alternative treatments. The current review aimed at evaluating various aspects related to the use of rituximab for NHL, highlighting the possible inhibitory mechanisms of cell proliferation, the achieved clinical results, and the expected clinical and economic outcomes of treatments. The results from clinical tests indicate the need for a better understanding of the critical mechanisms of action of this antibody, which may maximize its therapeutic efficacy. This therapy not only represents a viable option to treat most types of NHLs, especially when associated with conventional chemotherapy, but also offers cost-utility and cost-effectiveness advantages

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Evaluation of the cellular immune responses in chagasic patients after stimulus in vitro with the Trypanaosoma cruzi recombinant antigens CRA and FRA

Made available in DSpace on 2012-05-07T14:43:59Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 000002.pdf: 934978 bytes, checksum: 6130fb3c5d45076149e34df39e1d2d14 (MD5) Previous issue date: 2006Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil.(...) nos propomos analisar a relação entre a resposta imune celular de pacientes chagásicos, após estímulo in vitro de células mononucleares de sangue periférico (PBMC) com os antígenos recombinantes CRA (Cytoplasmatic Repetitive Antigen) ou FRA (Flagellar Repetitive Antigen) de Trypanosoma cruzi, e as formas clínicas crônicas da doença de Chagas. O grupo de pacientes chagásicos consistiu de 36 indivíduos (...). Um grupo de 19 indivíduos não chagásicos (NC) foi incluído como um grupo controle. PBMC foram isoladas por centrifugação através de um gradiente de densidade de Ficoll-Paque. As células foram estimuladas com Fitohemaglutinina, Concanavalina, CRA, FRA ou com antígeno solúvel de Epimastigota (Ag-Epi) por 24h, 72h ou 6 dias. Culturas sem estímulo foram utilizadas como controles negativos. A proliferação celular foi avaliada após estímulo por 6 dias de cultivo através da quantificação de 3 H-timidina incorporada. As citocinas foram detectadas em sobrenandantes de cultura obtidos após 24h (TNF-a e IL-4), 72h (IL-10) e 6 dias (IFN-g) através de ELISA de captura. Os resultados mostraram que apesar de apresentarem índices de estimulação baixos, as células dos pacientes chagásicos estimuladas com os antígenos recombinantes apresentaram maiores respostas proliferativas quando comparados com as dos indivíduos NC. Porém, não foi possível estabelecer um padrão de resposta linfoproliferativa entre os pacientes portadores das formas clínicas FC e FI da doença. Com relação às citocinas secretadas no sobrenadante de cultura após estímulo com antígenos de T. cruzi, os resultados mostraram que CRA, bem como Ag-Epi, foram capazes de estimular a produção de TNF-a e IFN-g em pacientes chagásicos quando comparado aos indivíduos NC. Porém, os níveis dessas citocinas mostraram-se similares entre os pacientes chagásicos portadores das formas clínicas FC e FI. Apesar de não apresentarem a capacidade de diferenciar as formas clínicas da doença de Chagas através do ensaio de linfoproliferação e da detecção de citocinas de sobrenadante de cultura por ELISA, os antígenos poderiam ser utilizados em estudos sobre a imunopatogênese da doença, investigando papéis imunorregulatórios antígeno-específicos. Além disso, esses antígenos poderiam dar continuidade ao desenvolvimento de marcadores de evolução de prognóstico das formas clínicas severas da doença de Chagas através da avaliação de citocinas intracitoplasmáticas por citometria de fluxo

Spatiotemporal analysis of reported cases of acute Chagas disease in the State of Pernambuco, Brazil, from 2002 to 2013

INTRODUCTION: Control strategies to eliminate the transmission of Chagas disease by insect vectors have significantly decreased the number of reported acute cases in Brazil. However, data regarding the incidence and distribution of acute Chagas disease cases in the State of Pernambuco are unavailable in the literature. METHODS: A geographical information system was used to delineate the spatiotemporal distribution profile of the cases from 2002 to 2013 in 185 municipalities of Pernambuco based on the municipality where notification occurred. The results were presented in digital maps generated by the TerraView software (INPE). RESULTS: A total of 302 cases of acute disease were recorded in 37.8% of the municipalities, for a total of 0.13 cases per 1,000,000 inhabitants per year. Out of the 302 cases, 99.3% were reported between 2002 and 2006. The most affected municipalities were Carnaubeira da Penha, Mirandiba and Terra Nova. The risk maps showed a significant decrease in the number of notifications and a concentration of cases in the Midwest region. CONCLUSIONS: This study highlights a significant decrease in new cases of acute Chagas disease in Pernambuco starting in 2006 when Brazil received an international certification for the interruption of vectorial transmission by Triatoma infestans. However, control strategies should still be encouraged because other triatomine species can also transmit the parasite; moreover, other transmission modes must not be neglected

A comparative analysis of the suitability of different peripheral blood samples for reverse transcriptase polymerase chain reaction

Venipuncture is one of the easiest clinical procedures to obtain viable blood samples to evaluate gene expression using mRNA analysis. However, the use of this sample type in reverse transcriptase polymerase chain reaction tests (RT-PCR) without prior treatment is controversial. We therefore propose to compare the suitability of different peripheral blood samples (whole blood without treatment, whole blood with hemolysis, peripheral blood mononuclear cells and frozen whole blood) for RT-PCR analysis. The results showed that, despite the blood sample being peripheral, it is possible to extract a fair amount of RNA and perform target gene amplification. Thus, peripheral blood without prior treatment could be used to investigate the gene expression using Real Time PCR.A punção venosa representa um dos procedimentos clínicos mais simples na obtenção de amostras de sangue periférico e avaliação da expressão gênica através da análise do RNA mensageiro. Contudo, a utilização desta amostra, sem um tratamento prévio, em ensaios de Transcrição Reversa (RT-PCR) é controverso. Desta forma, propomos comparar a adequação de diferentes amostras de sangue periférico (sangue total sem tratamento, sangue total após hemólise, células mononucleares do sangue periférico e sangue total congelado) em ensaios de Transcrição Reversa Os resultados mostraram que independente da amostra de sangue periférico é possível extrair RNA em quantidade adequada e realizar a amplificação do gene alvo. Desta forma, o sangue periférico sem tratamento prévio pode ser utilizado em abordagens que envolvam a avaliação da expressão gênica por reação em cadeia da polimerase (PCR) em tempo real

Evaluation of CD4+CD25+ T lymphocyte response time kinetics in patients with chronic Chagas disease after in vitro stimulation with recombinant Trypanosoma cruzi antigens

Introduction CD4+CD25+ T lymphocytes have been implicated in the regulation of host inflammatory response against Trypanosoma cruzi, and may be involved in the clinical course of the disease. Methods Peripheral blood mononuclear cells from patients with chronic Chagas disease were cultured in the presence of T. cruzi recombinant antigens and assayed for lymphocytes at distinct time points. Results It was possible to differentiate clinical forms of chronic Chagas disease at days 3 and 5 according to presence of CD4+CD25+ T cells in cell cultures. Conclusions Longer periods of cell culture proved to be potentially valuable for prospective evaluations of CD4+CD25+ T lymphocytes in patients with chronic Chagas disease

Evaluation of CD4+CD25+ T lymphocyte response time kinetics in patients with chronic Chagas disease after in vitro stimulation with recombinant Trypanosoma cruzi antigens

Submitted by Kamylla Nascimento ([email protected]) on 2017-12-13T13:12:46Z No. of bitstreams: 1 art. Evaluation of CD4 - braz.pdf: 861951 bytes, checksum: 0541416cee2f58eceb55612e79c1c08b (MD5)Approved for entry into archive by Kamylla Nascimento ([email protected]) on 2017-12-13T13:23:11Z (GMT) No. of bitstreams: 1 art. Evaluation of CD4 - braz.pdf: 861951 bytes, checksum: 0541416cee2f58eceb55612e79c1c08b (MD5)Made available in DSpace on 2017-12-13T13:23:11Z (GMT). No. of bitstreams: 1 art. Evaluation of CD4 - braz.pdf: 861951 bytes, checksum: 0541416cee2f58eceb55612e79c1c08b (MD5) Previous issue date: 2013Esta pesquisa recebeu apoio financeiro pelo Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Edital Universal n. ° 478572 / 2009-3) e Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes). YM Gomes é um colega do CNPq (número 306427 / 2006-0). VMB Lorena é um colega pós-docente do CNPq. SCM Braz e AS Melo foram candidatos ao Mestrado em Saúde Pública (CPqAM-FIOCRUZ) e foram CNPq (número 131310 / 2009-8) e bolsistas Capes, respectivamente.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil / Fundação Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil.Universidade de Pernambuco. Pronto-socorro Cardiológico de Pernambuco. Recife, PE, Brazil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil / Fundação Oswaldo Cruz. Programa Integrado de Doença de Chagas. Rio de Janeiro, RJ, Brazil.CD4+CD25+ T lymphocytes have been implicated in the regulation of host inflammatory response against Trypanosoma cruzi, and may be involved in the clinical course of the disease

Chagas disease in the State of Pernambuco, Brazil: analysis of admissions and mortality time series Doença de Chagas no Estado de Pernambuco, Brasil: análise de séries históricas das internações e da mortalidade

INTRODUCTION: A time series study of admissions, deaths and acute cases was conducted in order to evaluate the context of Chagas disease in Pernambuco. METHODS: Data reported to the Information Technology Department of the Brazilian National Health Service between 1980 and 2008 was collected for regions and Federal Units of Brazil; and microregions and municipalities of Pernambuco. Rates (per 100,000 inhabitants) of hospitalization, mortality and acute cases were calculated using a national hospital database (SIH), a national mortality database (SIM) and the national Information System for Notifiable Diseases (SINAN), respectively. RESULTS: The national average for Chagas disease admissions was 0.99 from 1995 to 2008. Pernambuco obtained a mean of 0.39 in the same period, with the highest rates being concentrated in the interior of the state. The state obtained a mean mortality rate of 1.56 between 1980 and 2007, which was lower than the national average (3.66). The mortality rate has tended to decline nationally, while it has remained relatively unchanged in Pernambuco. Interpolating national rates of admissions and deaths, mortality rates were higher than hospitalization rates between 1995 and 2007. The same occurred in Pernambuco, except for 2003. Between 2001 and 2006, rates for acute cases were 0.56 and 0.21 for Brazil and Pernambuco, respectively. CONCLUSIONS: Although a decrease in Chagas mortality has occurred in Brazil, the disease remains a serious public health problem, especially in the Northeast region. It is thus essential that medical care, prevention and control regarding Chagas disease be maintained and improved.<br>INTRODUÇÃO: Foi realizado estudo de séries históricas de internações, óbitos e casos agudos por doenças de Chagas objetivando avaliar o contexto desta enfermidade em Pernambuco. MÉTODOS: Foram coletados dados notificados de 1980 a 2008 ao Departamento de Informática do Sistema Único de Saúde (DATASUS/MS) para regiões e unidades federativas do Brasil, microrregiões e municípios pernambucanos. As taxas (por 100.000 habitantes) de internações, mortalidade e casos agudos foram obtidas por consulta ao Sistema de Informações Hospitalares (SIH), Sistema de Informação sobre Mortalidade (SIM) e Sistema de Informações de Agravos de Notificação (SINAN), respectivamente. RESULTADOS: A média de internações nacional por doença de Chagas ficou em 0,99 no período de 1995 a 2008. Pernambuco, neste intervalo, apresentou média de 0,39, com as maiores taxas concentradas no interior do estado. Este estado obteve média de óbitos 1,56 entre 1980 e 2007, valor inferior a brasileira (3,66). O país demonstrou declínio de óbitos na análise de tendência, com Pernambuco encontrando-se em estado estacionário para esta taxa. Interpolando os dados referentes a internações e óbitos, evidenciou-se mortalidade em valores superiores as taxas de internações nacionais, entre 1995 e 2007. O mesmo fato ocorreu em Pernambuco, exceto em 2003. Entre 2001 e 2006, a taxa de casos agudos foi de 0,56 e 0,21 respectivamente para Brasil e para Pernambuco. CONCLUSÕES: Mesmo o Brasil demonstrando redução na mortalidade, a doença permanece como grave problema de saúde pública, principalmente no nordeste. Desta forma, é fundamental a manutenção e melhoria das ações de atenção médica, controle e prevenção já existentes