Venous thromboprophylaxis in medical patients: an application review

OBJECTIVE: Routine thromboprophylaxis, despite its well-known effectiveness and the fact that venous thromboembolism is a potentially avoidable condition, is not fully established in clinical practice. The objectives of the present study were to determine how often thromboprophylaxis is used and the presence of thromboembolism risk factors, and to verify the appropriateness of its use in medical inpatients, assuming a long-standing national guideline as a parameter. METHODS: This was a retrospective cross-sectional study, involving inpatients with medical conditions in the adult general ward of a university hospital. The review was based on a defined guideline. RESULTS: 146 patients were included in the review. At least one risk factor for venous thromboembolism was found in 94.5%. In 130 (89%) patients, prophylactic heparin was indicated, and some kind of heparin was prescribed in 73.3%. Regarding the adequacy of prophylaxis, 53.4% of prescriptions were correct regarding prophylaxis indication and dose; 24% had incorrect dose or frequency of use; 19.2% had no prophylaxis prescription, although it was indicated; and in five cases (3.4%), the drugwas prescribed, even though itwas not indicated. CONCLUSION: Thromboprophylaxis is underused in this population, and an inappropriate dose was prescribed in 50% of cases. Therefore, future studies and interventions should include an educational program started from the emergency department care, an essential step to bring evidence closer to clinical practice.OBJETIVO: A tromboprofilaxia de rotina, a despeito de sua efetividade estar bem estabelecida e o tromboembolismo venoso ser uma condição potencialmente evitável, não se apresenta completamente consolidada na prática clínica. Os objetivos do presente estudo são: 1. Determinar a frequência da utilização da tromboprofilaxia e presença dos fatores de risco para tromboembolismo; 2. Verificar a adequação de sua utilização em pacientes clínicos internados, assumindo como parâmetro uma diretriz nacional estabelecida. MÉTODOS: Estudo retrospectivo transversal envolvendo pacientes internados por doenças clínicas em uma enfermaria geral de adultos de um hospital universitário. A análise foi baseada em diretriz definida. RESULTADOS: Foram incluídos 146 pacientes para análise. Destes, 94,5% possuíam pelo menos um fator de risco para tromboembolismo venoso. Em 130 (89%) pacientes havia indicação para uso de heparina profilática, sendo que em 73,3% dos casos estava prescrito algum tipo de heparina. Quanto à adequação da profilaxia, 53,4% das prescrições estavam corretas em relação à indicação e à dose da profilaxia; 24% apresentavam dose ou frequência incorretas; 19,2% não tinham prescrição de profilaxia, apesar de ela ser indicada; e em cinco casos (3,4%) o fármaco foi prescrito, apesar de não haver indicação. CONCLUSÃO: Existe subutilização da tromboprofilaxia nesta população, com inadequada dose prescrita em 50% dos casos. Portanto, estudos e intervenções futuros devem incluir um programa educacional que se inicie desde o atendimento em pronto-socorro, sendo essencial para aproximar a evidência à prática clínica.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Clínica MédicaHospital Sírio-Libanês Centro de Oncologia Departamento de RadioterapiaUniversidade de São Paulo Departamento de Hematologia e HemoterapiaFaculdade de Medicina de Marília Núcleo de Epidemiologia ClínicaFAMEMAUNIFESP, EPM, Depto. de Clínica MédicaSciEL

Expansion of NK cells with high anti-tumor activity: applications in adoptive immunotherapy and involving immunologic mechanisms.

Tem-se, atualmente, especial interesse pelo uso de células Natural Killer (NK) para imunoterapia celular no tratamento de pacientes com doença hematológica maligna e tumores sólidos. No entanto, a transferência adotiva de células NK apresenta limitações, como dificuldade em se obter número suficiente de células para tratamento, persistência inadequada, fraca expansão in vivo e limitada atividade antitumoral das células infundidas. Assim, um desafio nesse campo é a obtenção de células NK em quantidade e qualidade apropriadas para a imunoterapia adotiva. Aqui, apresentamos uma proposta inovadora para a produção em larga escala de células NK provenientes do sangue de cordão umbilical (CB-NK), com aumento de atividade antitumoral. Baseado no fato de que as células NK de sangue periférico apresentam propriedade de memória com aumento de resposta antineoplásica quando estimuladas previamente por uma combinação de citocinas, nós estudamos esse efeito em CB-NK com a intenção de se desenvolver um produto alogênico facilmente disponível para o uso clínico. CB-NK foram submetidas a um breve período de pré-ativação com uma combinação de interleucina-12 (IL-12), IL-15 e IL-18, seguido de expansão usando células feeder K562, expressando IL-21 e CD137 na presença de IL-2 exógena. Células NK pré-ativadas e expandidas (P+E CB-NK) apresentaram aumento da citotoxicidade contra linhagens tumorais mieloides, blastos de pacientes com leucemia mieloide aguda e linfoide após 14 dias de expansão. Por meio de sequenciamento de RNA, observou-se que as células P+E CB-NK apresentaram perfil transcriptômico compatível com ativação de vias de sinalização relacionadas ao aumento da função efetora, mesmo 14 dias após a ativação com a combinação de citocinas. As células P+E CB-NK apresentaram, ainda, aumento de citotoxicidade celular dependente de anticorpos (ADCC) em relação às células somente expandidas sem a fase de pré-ativação. As células NK pré-ativadas e expandidas também exibiram aumento da atividade antitumoral com estimulação do anticorpo biespecífico chamado AFM13. Após estável ligação com AFM13, essas células exibiram resposta antitumoral aumentada contra células tumorais de linfoma CD30 + in vitro e in vivo, em modelo experimental com camundongos NSG imunodeficientes. Coletivamente, esses dados identificaram a combinação de AFM13 com P+E CB-NK como uma estratégia promissora para o tratamento de doenças hematológicas CD30+.Currently there is a particular interest in using Natural Killer (NK) cells for cell immunotherapy in the treatment of patients with malignant hematologic disease and solid tumors. However, the adoptive transfer of NK cells has limitations such as difficulty in obtaining a sufficient number of cells for treatment, inadequate persistence, poor in vivo expansion, and limited antitumor activity of the infused cells. Thus, a challenge in this field is to obtain NK cells in adequate quantity and quality for adoptive immunotherapy. Here, we present an innovative proposal for the large-scale production of NK cells from umbilical cord blood (CB-NK) with increased anti-tumor activity. Based on the fact that peripheral blood NK cells have memory properties as an increased anti-neoplastic response when previously stimulated by a combination of cytokines, we studied this effect on CB-NK to develop a readily available allogeneic product for clinical use. CB-NK were pre-activated with a combination of interleukin-12 (IL-12), IL-15 and IL-18 for 16 hours, followed by expansion using K562 feeder cells expressing IL-21 and CD137 in the presence of exogenous IL-2. Pre-activated and expanded NK cells (P+E CB-NK) showed increased cytotoxicity against myeloid tumor lines, primary blasts from patients with acute myeloid leukemia and lymphoid cell line after 14 days of expansion. The P+E CB-BK cells displayed a transcriptomic profile compatible with activation of signaling pathways related to increased effector function, even 14 days after activation with the combination of cytokines in the RNA sequencing analysis. The P+E CB-NK cells also showed an increase in antibody-dependent cellular cytotoxicity (ADCC) comparing to cells that were only expanded without the pre-activation phase. Pre-activated and expanded NK cells also exhibited increased anti-tumor activity when stimulated with a bispecific antibody called AFM13. After stable binding to AFM13, these cells showed increased anti-tumor response against CD30 + lymphoma cell line in vitro and in vivo in an xenogenic model with immunodeficient NSG mice. Collectively, these data identify the combination of AFM13 with P+E CB-NK as a promising strategy for treating CD30+ hematologic diseases

Hematological approaches to multiple myeloma: trends from a Brazilian subset of hematologists. A cross-sectional study

ABSTRACT CONTEXT AND OBJECTIVE: For the last nine years, hematologists and oncologists have gathered annually at an educational symposium organized by a Brazilian and an American hospital. During the 2015 Board Review, a survey among the attendees evaluated the differences in management and treatment methods for multiple myeloma (MM). DESIGN AND SETTING: Cross-sectional study during an educational hematology symposium in São Paulo, Brazil. METHODS: Hematologists present at the symposium gave responses to an electronic survey by means of mobile phone. RESULTS: Among the 350 attendees, 217 answered the questionnaire. Most of the participants believed that immunotargeting agents (iTA) might be effective for slowing MM progression in heavily pretreated patients (67%) and that continued exposure to therapy might lead to emergence of resistant clones in patients with MM (76%). Most of the physicians use maintenance therapy after hematopoietic stem cell transplantation (95%) and 45% of them would further restrict it to post-transplantation patients with underlying high-risk disease. The first-line drugs used for transplantation-ineligible patients (TI-MM) were bortezomib-thalidomide-dexamethasone (31%), bortezomib-dexamethasone (28%), lenalidomide-dexamethasone (Rd; 17%) and melphalan-based therapy (10%). Lenalidomide was the drug of choice for post-transplantation maintenance for half of the participants. No significant differences were observed regarding age or length of experience. CONCLUSION: The treatment choices for TI-MM patients were highly heterogenous and the melphalan-based regimen represented only 10% of the first-line options. Use of maintenance therapy after transplantation was a common choice. Some results from the survey were divergent from the evidence in the literature

Guidelines on cell therapy

The Brazilian Society for Blood and Marrow Transplantation (SBTMO) presents the Brazilian Guidelines on Hematopoietic Stem Cell Transplantatio

The CXCR4–STAT3–IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide

Chronic lymphocytic leukemia (CLL) cells possess regulatory functions comparable to those of normal B10 cells, a regulatory B cell subset that suppresses effector T-cell function through STAT3-mediated IL-10 production. However, the mechanisms governing IL-10 production by CLL cells are not fully understood. Here, we show that the CXC chemokine ligand 12 (CXCL12)–CXCR4–STAT3 axis regulates IL-10 production by CLL cells and their ability to suppress T-cell effector function through an IL-10 mediated mechanism. Knockdown of STAT3 significantly impaired the ability of CLL cells to produce IL-10. Furthermore, experiments to assess the role of lenalidomide, an immunomodulatory agent with direct antitumor effect as well as pleiotropic activity on the immune system, showed that this agent prevents a CXCL12-induced increase in p-S727-STAT3 and the IL-10 response by CLL cells. Lenalidomide also suppressed IL-10-induced Y705-STAT3 phosphorylation in healthy T cells, thus reversing CLL-induced T-cell dysfunction. We conclude that the capacity of CLL cells to produce IL-10 is mediated by the CXCL12–CXCR4–STAT3 pathway and likely contributes to immunodeficiency in patients. Lenalidomide appears to be able to reverse CLL-induced immunosuppression through including abrogation of the CXCL12–CXCR4–S727–STAT3-mediated IL-10 response by CLL cells and prevention of IL-10-induced phosphorylation of Y705-STAT3 in T cells