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1.
Cancers (Basel) ; 16(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38473382

RESUMO

Scarce data exist on double maintenance in transplant-eligible high-risk (HR) newly diagnosed multiple myeloma (NDMM) patients. This prospective phase 2 study enrolled 120 transplant-eligible NDMM patients. The treatment consisted of four cycles of ixazomib-lenalidomide-dexamethasone (IRD) induction plus autologous stem cell transplantation followed by IRD consolidation and cytogenetic risk-based maintenance therapy with lenalidomide + ixazomib (IR) for HR patients and lenalidomide (R) alone for NHR patients. The main endpoint of the study was undetectable minimal residual disease (MRD) with sensitivity of <10-5 by flow cytometry at any time, and other endpoints were progression-free survival (PFS) and overall survival (OS). We present the preplanned analysis after the last patient has been two years on maintenance. At any time during protocol treatment, 28% (34/120) had MRD < 10-5 at least once. At two years on maintenance, 66% of the patients in the HR group and 76% in the NHR group were progression-free (p = 0.395) and 36% (43/120) were CR or better, of which 42% (18/43) had undetectable flow MRD <10-5. Altogether 95% of the patients with sustained MRD <10-5, 82% of the patients who turned MRD-positive, and 61% of those with positive MRD had no disease progression at two years on maintenance (p < 0.001). To conclude, prolonged maintenance with all-oral ixazomib plus lenalidomide might improve PFS in HR patients.

2.
Ann Hematol ; 98(12): 2781-2792, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31673775

RESUMO

Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS.


Assuntos
Lenalidomida/administração & dosagem , Quimioterapia de Manutenção , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoenxertos , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Taxa de Sobrevida
3.
Thromb Haemost ; 99(2): 427-34, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18278195

RESUMO

Heparinization requires monitoring, but optimal methods for measuring the anticoagulant effects of heparin remain to be determined. We compared prothrombinase-induced clotting time (PiCT) and two chromogenic anti-factor Xa activity (anti-Xa) assays in monitoring high-dose heparinization during cardiopulmonary by-pass (CPB). Heparin effects were serially measured with PiCT and two anti-Xa assays in 100 patients. Antithrombin and protein C activities were measured preoperatively, and antithrombin activity was measured during CPB. Activation of coagulation was assessed with measurements of prothrombin fragment F1+2, soluble fibrin complexes, and D-dimer before, during, and after CPB. During CPB mean ranges of PiCT and of anti-Xa heparin levels measured with (anti-Xa A) and without (anti-Xa B) dextran sulfate and antithrombin supplementation were 5.0-5.2, 4.7-5.0, and 4.5-4.9 IU/ml, respectively. There was poor agreement between PiCT and anti-Xa and between the two anti-Xa assays (r = 0.32-0.65 and broad limits of agreement). Patients with low preoperative antithrombin or protein C levels had lower PiCT (p = 0.028 and p = 0.01) and anti-Xa A (both p<0.001) levels during CPB than others. Patients with the lowest heparin activities during CPB (lowest deciles of PiCT and anti-Xa A) had higher subsequent F1+2 after CPB (p = 0.002 and p = 0.02), and patients with high heparin levels required fewer transfusions of packed red blood cells than others. In conclusion, in the challenging setting of CPB there is poor agreement between anti-Xa assays and PiCT. However, coagulation-based PiCT could provide an alternative to the chromogenic anti-Xa assays. Higher heparin levels during CPB were confirmed to associate with reduced transfusion requirements.


Assuntos
Anticoagulantes/administração & dosagem , Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea/efeitos dos fármacos , Ponte Cardiopulmonar , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa , Heparina/administração & dosagem , Monitorização Intraoperatória/instrumentação , Tromboplastina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/metabolismo , Perda Sanguínea Cirúrgica/prevenção & controle , Compostos Cromogênicos , Ponte de Artéria Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Transfusão de Eritrócitos , Fator Xa/metabolismo , Feminino , Fibrina/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Estudos Prospectivos , Proteína C/metabolismo , Protrombina/metabolismo
4.
Thromb Res ; 117(3): 291-7, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-15878612

RESUMO

INTRODUCTION: In addition to mediating the final common pathway of aggregation, the glycoprotein (GP) IIb/IIIa receptor participates in the activation of coagulation on the platelet surface. High-affinity conformation of GP IIb/IIIa in response to collagen-induced inside-out signalling seems to be mediated by GP VI(-FcRgamma) and reinforced by release of soluble mediators. METHODS: We assessed the effects of the three currently available GP IIb/IIIa antagonists--abciximab, tirofiban and eptifibatide--on platelet aggregation induced by various procoagulant and GP VI-related agonists, i.e. collagen-related peptide (CRP), convulxin and collagen fibrils, in PPACK-anticoagulated platelet-rich plasma. RESULTS: At concentrations that equally inhibited 80% of ADP-induced maximal aggregation abciximab-inhibited GP VI-mediated platelet responses to CRP or convulxin significantly more than the low-molecular-weight antagonists (CRP: abciximab 75+/-18%, tirofiban 41+/-7% and eptifibatide 41+/-6%; convulxin: abciximab 90+/-6%, tirofiban 64+/-20%, eptifibatide 61+/-14%, p<0.01 for all). In contrast, aggregation induced by collagen was equally abolished with all antagonists under the similar conditions. During CRP- or convulxin-triggered platelet activation, inhibition of fibrin polymerisation with GPRP potentiated the antiaggregatory effects of tirofiban and eptifibatide to reach that of abciximab. GPRP as such did not affect platelet aggregation. CONCLUSIONS: GP IIb/IIIa antagonists exhibit distinct inhibition profiles in platelet aggregation, depending on fibrin polymerization and calcium. Specifically, the ability of procoagulant platelet agonists to expose pre-activated and ligand-bound GP IIb/IIIa from the internal pool seems important.


Assuntos
Coagulantes/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Abciximab , Difosfato de Adenosina/química , Anticorpos Monoclonais/farmacologia , Proteína C-Reativa/química , Cromatografia em Gel , Colágeno/química , Relação Dose-Resposta a Droga , Eptifibatida , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Modelos Estatísticos , Peptídeos/farmacologia , Adesividade Plaquetária , Agregação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Tirofibana , Tirosina/análogos & derivados , Tirosina/farmacologia
5.
Neurosurgery ; 57(1): 16-24; discussion 16-24, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15987536

RESUMO

OBJECTIVE: Approximately one-third of all patients with acute nontraumatic subarachnoid hemorrhage (SAH) experience complications owing to delayed ischemic deficit. We reported recently that enoxaparin 40 mg once daily for 10 days seems safe and demonstrates thromboprophylactic efficacy, but it failed to improve outcome in a randomized SAH trial. In the present study, we assessed hemostatic variables associated with clinical status and outcome of SAH. We also monitored the effect of enoxaparin on activation of coagulation and fibrinolysis after closure of the ruptured aneurysm. METHODS: Blood samples to measure activation of coagulation and fibrinolysis were collected from 42 patients participating in the enoxaparin trial for acute aneurysmal SAH at four time points: 1) at hospital admission; 2) 12 to 24 hours after aneurysm surgery but before initiation of enoxaparin therapy; 3) 3 hours after the first dose; and 4) at the conclusion of treatment. RESULTS: At admission, several variables of coagulation and fibrinolysis were elevated and correlated well with clinical status. Specifically, D-dimer levels at all four time points correlated with patients' long-term outcomes. A single dose of enoxaparin suppressed early coagulation activity, but thrombin generation was not inhibited during thromboprophylaxis. However, PAI-1 activity was suppressed. CONCLUSION: D-dimer offers a useful laboratory tool for assessing early and late clinical severity of SAH. A thromboprophylactic dose of enoxaparin inhibited PAI-1 activity but failed to down-regulate coagulation activity and D-dimer. These findings are compatible with the lack of efficacy of enoxaparin in reducing ischemic deficit after SAH.


Assuntos
Enoxaparina/uso terapêutico , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinolíticos/uso terapêutico , Hemorragia Subaracnóidea/tratamento farmacológico , Resultado do Tratamento , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea/métodos , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Masculino , Inibidor 1 de Ativador de Plasminogênio/uso terapêutico , Valor Preditivo dos Testes , Inibidores de Serina Proteinase/uso terapêutico , Hemorragia Subaracnóidea/sangue , Fatores de Tempo
6.
J Neurosurg ; 99(6): 953-9, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14705720

RESUMO

OBJECT: From the moment an intracranial aneurysm ruptures, cerebral blood flow is impaired, and this impairment mainly determines the outcome in patients who survive after the initial bleeding. The exact mechanism of impairment is unknown, but activation of coagulation and fibrinolysis correlate with clinical condition and outcome after aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to determine whether enoxaparin, a low-molecular-weight heparin, which is a well-known anticoagulating agent, has any effect on the outcome of aneurysmal SAH postoperatively. METHODS: In this randomized, double-blind, single-center clinical trial, 170 patients (85 per group) with aneurysmal SAH were randomly assigned to receive either enoxaparin (40 mg subcutaneously once daily) or a placebo, starting within 24 hours after occlusion of the aneurysm and continuing for 10 days. Analysis was done on an intention-to-treat basis. Outcome was assessed at 3 months on both the Glasgow Outcome and modified Rankin Scales. Patients were eligible for the study if surgery was performed within 48 hours post-SAH, and no intracerebral hemorrhage was larger than 20 mm in diameter on the first postoperative computerized tomography scan. At 3 months, there were no significant differences in outcome by treatment group. Of the 170 patients, 11 (6%) died, and only 95 (56%) had a good outcome. Principal causes of unfavorable outcome were poor initial condition, delayed cerebral ischemia, and surgical complications. There were four patients with additional intracranial bleeding in the group receiving enoxaparin. The bleeding was not necessarily associated with the treatment itself, nor did it require treatment, and there were no such patients in the placebo group. CONCLUSIONS: Enoxaparin seemed to have no effect on the outcome of aneurysmal SAH in patients who had already received routine nimodipine and who had received triple-H therapy when needed. Routine use of low-molecular-weight heparin should be avoided during the early postoperative period in patients with SAH, because this agent seems to increase intracranial bleeding complications slightly, with no beneficial effect on neurological outcome.


Assuntos
Aneurisma Roto/complicações , Anticoagulantes/uso terapêutico , Enoxaparina/uso terapêutico , Aneurisma Intracraniano/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/cirurgia , Aneurisma Roto/cirurgia , Terapia Combinada , Método Duplo-Cego , Feminino , Escala de Resultado de Glasgow , Humanos , Aneurisma Intracraniano/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Hemorragia Subaracnóidea/etiologia , Resultado do Tratamento
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