RESUMO
BACKGROUND: Hyperhaemolysis is a rare and life-threatening delayed haemolytic transfusion reaction characterised by complement-mediated destruction of both host and transfused red cells. It is well recognised as a complication of transfusion in patients with haemoglobinopathies and has occasionally been described in haematological malignancy and anaemia of chronic disease. Anti-HI antibodies are usually clinically insignificant but have rarely been associated with haemolytic transfusion reactions, including cases of hyperhaemolysis in sickle cell disease. METHODS AND MATERIALS: Here, we describe a novel case of a patient with myelodysplastic syndrome developing hyperhaemolysis as a result of an anti-HI alloantibody following their first-ever transfusion. The patient required multiple lines of treatment, including erythropoietin, haematinic supplementation, corticosteroids, intravenous immunoglobulin and rituximab. RESULTS: Following treatment, steady-state haemoglobin was achieved with quiescent haemolysis, and complement inhibition with eculizumab was considered but ultimately not required. CONCLUSION: This is the first known report of hyperhaemolysis with an anti-HI antibody in a non-haemoglobinopathy patient. The treatment of hyperhaemolysis is evolving, and future commissioning needs to consider the role of complement inhibition in non-haemoglobinopathy patients.
Assuntos
Anemia Falciforme , Síndromes Mielodisplásicas , Humanos , Anemia Falciforme/terapia , Anemia Falciforme/complicações , Hemólise , Eritrócitos , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/complicações , Imunoglobulinas IntravenosasAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Imunossupressores/uso terapêutico , Interleucina-6/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Pneumonia Viral/complicações , COVID-19 , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , SARS-CoV-2 , Tomografia Computadorizada por Raios XRESUMO
Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)ß/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)ß/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers.
Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Mieloma Múltiplo , NF-kappa B/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Estudo de Prova de ConceitoRESUMO
PURPOSE: To identify factors that determine patients' intentions to use point-of-care medical devices, ie, portable coagulometer devices for self-testing of the international normalized ratio (INR) required for ongoing monitoring of blood-coagulation intensity among patients on long-term oral anticoagulation therapy with vitamin K antagonists, eg, warfarin. METHODS: A cross-sectional study that applied the technology-acceptance model through a self-completed questionnaire, which was administered to a convenience sample of 125 outpatients attending outpatient anticoagulation services at a district general hospital in London, UK. Data were analyzed using descriptive statistics, factor analyses, and structural equation modeling. RESULTS: The participants were mainly male (64%) and aged ≥ 71 years (60%). All these patients were attending the hospital outpatient anticoagulation clinic for INR testing; only two patients were currently using INR self-testing, 84% of patients had no knowledge about INR self-testing using a portable coagulometer device, and 96% of patients were never offered the option of the INR self-testing. A significant structural equation model explaining 79% of the variance in patients' intentions to use INR self-testing was observed. The significant predictors that directly affected patients' intention to use INR self-testing were the perception of technology (ß = 0.92, P < 0.001), trust in doctor (ß = -0.24, P = 0.028), and affordability (ß = 0.15, P = 0.016). In addition, the perception of technology was significantly affected by trust in doctor (ß = 0.43, P = 0.002), age (ß = -0.32, P < 0.001), and affordability (ß = 0.23, P = 0.013); thereby, the intention to use INR self-testing was indirectly affected by trust in doctor (ß = 0.40), age (ß = -0.29), and affordability (ß = 0.21) via the perception of technology. CONCLUSION: Patients' intentions to use portable coagulometers for INR self-testing are affected by patients' perceptions about the INR testing device, the cost of device, trust in doctors/clinicians, and the age of the patient, which need to be considered prior to any intervention involving INR self-testing by patients. Manufacturers should focus on increasing the affordability of INR testing devices for patients' self-testing and on the potential role of medical practitioners in supporting use of these medical devices as patients move from hospital to home testing.
Assuntos
Benzoatos/administração & dosagem , Hidrazinas/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoatos/efeitos adversos , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Hidrazinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/imunologia , Pirazóis/efeitos adversosRESUMO
The authors present a case where the simultaneous administration of 6-mercaptopurine (6-MP) and cow's milk during maintenance treatment for acute lymphoblastic leukemia led to elevated full blood counts resistant to increasing doses of chemotherapy. The blood counts returned to the expected range after milk intake with chemotherapy was discontinued.
Assuntos
Mercaptopurina/administração & dosagem , Mercaptopurina/farmacocinética , Leite , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Pré-Escolar , Humanos , Contagem de Leucócitos , Masculino , Metotrexato/uso terapêutico , Neutrófilos/citologiaAssuntos
Mieloma Múltiplo/complicações , Fraturas da Coluna Vertebral/etiologia , Idoso , Humanos , Masculino , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Cervicalgia/etiologia , Compressão da Medula Espinal/etiologia , Fraturas da Coluna Vertebral/complicações , Vertigem/etiologiaRESUMO
Early, low-risk International Prognostic Scoring System (IPSS) myelodysplastic syndrome (MDS) is a heterogeneous disorder where the molecular and cellular hematopoietic defects are poorly understood. To gain insight into this condition, we analyzed gene expression profiles of marrow CD34+ progenitor cells from normal-karyotype, low-blast-count MDS patients, age-matched controls, and patients with non-MDS anemia. Given the heterogeneity of early MDS, a surprisingly consistent finding was decreased expression of B-cell lineage-affiliated genes in MDS patients compared with healthy controls and 3 of 5 samples with non-MDS anemia. Both patients with non-MDS anemia with reduced B-cell gene expression were on chemotherapy. In 25 of 27 of the original samples and 9 further MDS samples, Taqman real-time polymerase chain reaction (PCR) confirmed these data. Flow cytometry on unfractionated marrow from independent samples also demonstrated reduced B-cell progenitors in MDS patients compared with healthy controls. These novel findings suggest a common perturbation in early MDS hematopoiesis. They also provide the rationale for a larger study to evaluate the diagnostic utility of reduced B-cell progenitor number as a diagnostic biomarker of early low-risk MDS, which can pose a diagnostic challenge.
Assuntos
Linfócitos B/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Linfócitos B/metabolismo , Biologia Computacional , DNA Complementar/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/análise , RNA Mensageiro/genética , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Células-Tronco/patologia , Fatores de TempoAssuntos
Sistema Nervoso Central/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Infiltração Leucêmica , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Antineoplásicos/uso terapêutico , Benzamidas , Crise Blástica , Cegueira/etiologia , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 6/genética , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Cromossomo Filadélfia , Retina/patologia , TrissomiaAssuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos , Feminino , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Rituximab , Neoplasias Testiculares/tratamento farmacológicoAssuntos
Glucose-6-Fosfato/deficiência , Hemoglobinúria/induzido quimicamente , Hemólise , Vitaminas/efeitos adversos , Transfusão de Sangue , Feminino , Hemoglobinúria/complicações , Hemoglobinúria/terapia , Humanos , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/complicações , Esclerose Múltipla/terapiaRESUMO
Chronic lymphocytic leukaemia (CLL) is a B-cell disorder, which has a median survival of over 10 years from diagnosis for stage A disease. The natural history of stage A disease is generally indolent or only slowly progressive. It is less well known that CLL may undergo spontaneous regression. We report a series of 10 such cases (eight stage A and two stage B) followed at our institutions.