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1.
J Thromb Haemost ; 18(2): 278-284, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31999063

RESUMO

Venous thromboembolism is a common complication of asparaginase-based chemotherapy regimens for the treatment of acute lymphoblastic leukemia. Thrombosis associated with asparaginase administration poses a number of specific and often clinically challenging management decisions. This review provides guidance on the prevention and treatment of thrombosis associated with asparaginase in adults including discussions on antithrombin repletion, pharmacologic thromboprophylaxis, cerebral venous thrombosis, and therapeutic anticoagulation.

3.
Cancer Treat Res ; 179: 179-189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317488

RESUMO

Venous thromboembolism is commonly diagnosed in patients with primary and secondary brain tumors. Anticoagulation management in the setting of brain tumors is complicated by the high background rate of spontaneous intracranial hemorrhage. Until recently, there was limited evidence to support the decision to administer therapeutic anticoagulation in the setting of brain metastases or primary brain tumors. The current evidence suggests that the safety profile of therapeutic low molecular weight heparin for the treatment of venous thromboembolism is contingent on whether the origin of brain tumor is primary (i.e., glioma) versus secondary. In patients with brain metastases, the rate of intracranial hemorrhage often exceeds 20% but is not influenced by the administration of low molecular weight heparin. In contrast, in primary brain tumors such as glioma, therapeutic anticoagulation is associated with an increased risk of intracranial hemorrhage that can negatively impact survival. This chapter reviews the underlying mechanisms contributing to thrombosis and hemorrhage in brain tumors and summarizes the current evidence and approaches in anticoagulation to treat venous thromboembolism.


Assuntos
Anticoagulantes/uso terapêutico , Neoplasias Encefálicas/complicações , Hemorragias Intracranianas/etiologia , Tromboembolia Venosa/tratamento farmacológico , Anticoagulantes/efeitos adversos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Humanos , Hemorragias Intracranianas/induzido quimicamente , Tromboembolia Venosa/etiologia
5.
JCI Insight ; 4(4)2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30652973

RESUMO

BACKGROUND: Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models, but the clinical effect of targeting extracellular PDI in humans has not been studied. METHODS: We conducted a multicenter phase II trial of sequential dosing cohorts to evaluate the efficacy of targeting PDI with isoquercetin to reduce hypercoagulability in cancer patients at high risk for thrombosis. Patients received isoquercetin at 500 mg (cohort A, n = 28) or 1000 mg (cohort B, n = 29) daily for 56 days, with laboratory assays performed at baseline and the end of the study, along with bilateral lower extremity compression ultrasound. The primary efficacy endpoint was a reduction in D-dimer, and the primary clinical endpoint included pulmonary embolism or proximal deep vein thrombosis. RESULTS: The administration of 1000 mg isoquercetin decreased D-dimer plasma concentrations by a median of -21.9% (P = 0.0002). There were no primary VTE events or major hemorrhages observed in either cohort. Isoquercetin increased PDI inhibitory activity in plasma (37.0% in cohort A, n = 25, P < 0.001; 73.3% in cohort B, n = 22, P < 0.001, respectively). Corroborating the antithrombotic efficacy, we also observed a significant decrease in platelet-dependent thrombin generation (cohort A median decrease -31.1%, P = 0.007; cohort B median decrease -57.2%, P = 0.004) and circulating soluble P selectin at the 1000 mg isoquercetin dose (median decrease -57.9%, P < 0.0001). CONCLUSIONS: Isoquercetin targets extracellular PDI and improves markers of coagulation in advanced cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02195232. FUNDING: Quercegen Pharmaceuticals; National Heart, Lung, and Blood Institute (NHLBI; U54HL112302, R35HL135775, and T32HL007917); and NHLBI Consortium Linking Oncology and Thrombosis (U01HL143365).

6.
Res Pract Thromb Haemost ; 2(4): 664-669, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30349884

RESUMO

Background: The management of anticoagulation for cancer-associated thrombosis (CAT) in patients with thrombocytopenia is controversial. Whereas some studies suggest that administration of reduced-dose low-molecular-weight heparin (LMWH) or temporary discontinuation for moderate and severe thrombocytopenia may be a safe and effective, others suggest full-dose anticoagulation with transfusion support. We sought to address this important knowledge gap and summarize the literature comparing these two common management strategies. Methods: A systematic review of the literature (PROSPERO CRD42017077127) using MEDLINE (inception to September 2017) was conducted. We included studies that reported recurrent venous thromboembolism (VTE) and major bleeding complications among patients treated with both of the two most common management strategies: therapeutic anticoagulation with platelet transfusion support and dose-modified anticoagulation for periods when the platelet count is <50 × 109/L. Results: A total of 134 article records were identified on the initial search and 10 articles underwent full text review. Two observational studies met the inclusions criteria. A total of 121 patients with CAT and thrombocytopenia were included. Forty-two of these patients had pulmonary embolism and 87 had deep vein thrombosis (DVT) including 38 upper extremity DVT. Overall, 27% of patients, regardless of their treatment strategy, experienced recurrent VTE. Thirteen percent of anticoagulated patients (15% of all patients) experienced a major bleeding episode. Meta-analysis could not be conducted. Conclusions: Our findings do not support one management strategy over another to treat CAT patients with thrombocytopenia. However, the data highlights the heightened risk of recurrent VTE in this patient population despite the thrombocytopenia.

7.
Thromb Haemost ; 118(8): 1439-1449, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30060256

RESUMO

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting.


Assuntos
Anticoagulantes/efeitos adversos , Dalteparina/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Neoplasias/complicações , Piridinas/efeitos adversos , Tiazóis/efeitos adversos , Tromboembolia Venosa/tratamento farmacológico , Idoso , Anticoagulantes/administração & dosagem , Tomada de Decisão Clínica , Dalteparina/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Feminino , Hemorragia/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Seleção de Pacientes , Piridinas/administração & dosagem , Recidiva , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Tiazóis/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/etiologia
8.
Thromb Res ; 164 Suppl 1: S130-S135, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29703471

RESUMO

The mechanisms underlying the hypercoagulability of cancer are complex and include the upregulation coagulation factors or procoagulant proteins, shedding of microparticles, and direct activation of vascular cells. Protein disulfide isomerase (PDI) is a thiol isomerase secreted from activated platelets and endothelial cells and plays a critical role in both platelet aggregation and fibrin generation. A number of potential intravascular targets of PDI have been identified including cell surface receptors (e.g. ß-integrins and glycoprotein Ib), receptor ligands (e.g. fibrinogen and von Willebrand factor), serine proteases (e.g. cathepsin G and kallekrein-14), and coagulation factors (e.g. factor XI and factor V). Recent clinical studies demonstrated that a small molecule inhibitor of PDI, isoquercetin, decreases platelet-dependent thrombin generation and PDI activity in plasma following oral administration. This review explores the mechanistic overlap between the molecular drivers of cancer associated thrombosis and the potential roles PDI plays in mediating thrombosis. These molecular insights provide rationale for clinical trials targeting PDI to prevent thrombosis in cancer patients.


Assuntos
Neoplasias/complicações , Isomerases de Dissulfetos de Proteínas/sangue , Trombose/etiologia , Humanos , Trombose/patologia
9.
N Engl J Med ; 378(7): 615-624, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29231094

RESUMO

BACKGROUND: Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. METHODS: In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration. RESULTS: Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). CONCLUSIONS: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).


Assuntos
Anticoagulantes/uso terapêutico , Dalteparina/uso terapêutico , Neoplasias/complicações , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adulto , Idoso , Anticoagulantes/efeitos adversos , Dalteparina/efeitos adversos , Seguimentos , Hemorragia/induzido quimicamente , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Recidiva , Tiazóis/efeitos adversos , Tromboembolia Venosa/etiologia
10.
Blood ; 129(25): 3379-3385, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28468796

RESUMO

Venous thromboembolism occurs in up to one-third of patients with primary brain tumors. Spontaneous intracranial hemorrhage (ICH) is also a frequent occurrence in these patients, but there is limited data on the safety of therapeutic anticoagulation. To determine the rate of ICH in patients treated with enoxaparin, we performed a matched, retrospective cohort study with blinded radiology review for 133 patients with high-grade glioma. After diagnosis of glioma, the cohort that received enoxaparin was 3 times more likely to develop a major ICH than those not treated with anticoagulation (14.7% vs 2.5%; P = .036; hazard ratio [HR], 3.37; 95% confidence interval [CI], 1.02-11.14). When enoxaparin was analyzed as a time-varying covariate, anticoagulation was associated with a >13-fold increased risk of hemorrhage (HR, 13.26; 95% CI, 3.33-52.85; P < .0001). Overall survival was significantly shorter for patients who suffered a major ICH on enoxaparin compared with patients not receiving anticoagulation (3.3 vs 10.2 months; log-rank P = .012). We applied a validated ICH prediction risk score PANWARDS (platelets, albumin, no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke), and observed that all major ICHs on enoxaparin occurred in the setting of a PANWARDS score ≥25, corresponding with a sensitivity of 100% (95% CI, 63% to 100%) and a specificity of 40% (95% CI, 25% to 56%). We conclude that caution is warranted when considering therapeutic anticoagulation in patients with high-grade gliomas given the increased risk of ICH and poor prognosis after a major hemorrhage on anticoagulation. The PANWARDS score may assist clinicians in identifying the patients at greatest risk of suffering a major intracranial hemorrhage with anticoagulation.


Assuntos
Anticoagulantes/uso terapêutico , Neoplasias Encefálicas/complicações , Enoxaparina/uso terapêutico , Glioma/complicações , Hemorragias Intracranianas/induzido quimicamente , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Estudos de Coortes , Enoxaparina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
11.
Blood ; 129(13): 1742-1743, 2017 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-28360357
12.
JCI Insight ; 2(1): e89373, 2017 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-28097231

RESUMO

BACKGROUND: Protein disulfide isomerase (PDI) is required for thrombus formation. We previously demonstrated that glycosylated quercetin flavonoids such as isoquercetin inhibit PDI activity and thrombus formation in animal models, but whether extracellular PDI represents a viable anticoagulant target in humans and how its inhibition affects blood coagulation remain unknown. METHODS: We evaluated effects of oral administration of isoquercetin on platelet-dependent thrombin generation in healthy subjects and patients with persistently elevated anti-phospholipid antibodies. RESULTS: Following oral administration of 1,000 mg isoquercetin to healthy adults, the measured peak plasma quercetin concentration (9.2 µM) exceeded its IC50 for inhibition of PDI by isoquercetin in vitro (2.5 ± 0.4 µM). Platelet-dependent thrombin generation decreased by 51% in the healthy volunteers compared with baseline (P = 0.0004) and by 64% in the anti-phospholipid antibody cohort (P = 0.015) following isoquercetin ingestion. To understand how PDI affects thrombin generation, we evaluated substrates of PDI identified using an unbiased mechanistic-based substrate trapping approach. These studies identified platelet factor V as a PDI substrate. Isoquercetin blocked both platelet factor Va and thrombin generation with an IC50 of ~5 µM. Inhibition of PDI by isoquercetin ingestion resulted in a 53% decrease in the generation of platelet factor Va (P = 0.001). Isoquercetin-mediated inhibition was reversed with addition of exogenous factor Va. CONCLUSION: These studies show that oral administration of isoquercetin inhibits PDI activity in plasma and diminishes platelet-dependent thrombin generation predominantly by blocking the generation of platelet factor Va. These pharmacodynamic and mechanistic observations represent an important step in the development of a novel class of antithrombotic agents targeting PDI. TRIAL REGISTRATION: Clinicaltrials.gov (NCT01722669) FUNDING: National Heart, Lung, and Blood Institute (U54 HL112302) and Quercegen Pharma.


Assuntos
Fatores de Coagulação Sanguínea/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/efeitos dos fármacos , Quercetina/análogos & derivados , Trombina/efeitos dos fármacos , Administração Oral , Animais , Síndrome Antifosfolipídica/imunologia , Humanos , Modelos Animais , Quercetina/administração & dosagem , Quercetina/farmacologia
13.
Sci Transl Med ; 8(368): 368ra171, 2016 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-27928025

RESUMO

We developed a personalized cancer vaccine in which patient-derived acute myeloid leukemia (AML) cells are fused with autologous dendritic cells, generating a hybridoma that potently stimulates broad antitumor responses. We report results obtained from the first 17 AML patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. Vaccination was also associated with a marked rise in circulating T cells recognizing whole AML cells and leukemia-specific antigens that persisted for more than 6 months. Twelve of 17 vaccinated patients (71%; 90% confidence interval, 52 to 89%) remain alive without recurrence at a median follow-up of 57 months. The results demonstrate that personalized vaccination of AML patients in remission induces the expansion of leukemia-specific T cells and may be protective against disease relapse.


Assuntos
Vacinas Anticâncer/imunologia , Leucemia Mieloide Aguda/imunologia , Indução de Remissão , Vacinação , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Feminino , Humanos , Sistema Imunitário , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Linfócitos T/imunologia , Linfócitos T Reguladores/citologia , Resultado do Tratamento
14.
Thromb Res ; 140 Suppl 1: S60-5, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27067980

RESUMO

Both venous thromboembolism and intracranial metastases are common complications in the setting of primary brain tumors and metastatic malignancies. Anticoagulation is indicated in the presence of cancer-associated thrombosis in order to limit the risk of pulmonary embolism; however, there is reluctance to initiate anticoagulation in the setting of intracranial metastatic disease due to potential for intracranial hemorrhage. Recent evidence suggests that therapeutic anticoagulation can be safely administered in the setting of metastatic brain tumors. This review examines the current understanding of the pathophysiology of intracranial hemorrhage in malignancy, describes the incidence of intracranial hemorrhage in the setting of brain tumors with therapeutic anticoagulation, and outlines management strategies relevant to the treatment of intracranial hemorrhage in the setting of anticoagulation.


Assuntos
Anticoagulantes/efeitos adversos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/tratamento farmacológico , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/complicações , Tromboembolia Venosa/complicações , Tromboembolia Venosa/tratamento farmacológico , Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/fisiopatologia , Humanos , Hemorragias Intracranianas/fisiopatologia , Hemorragias Intracranianas/terapia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/fisiopatologia
15.
Thromb Res ; 137: 169-173, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26585763

RESUMO

INTRODUCTION: Although epidemiologic evidence points to cardioprotective activity of red wine, the mechanistic basis for antithrombotic activity has not been established. Quercetin and related flavonoids are present in high concentrations in red but not white wine. Quercetin-glycosides were recently shown to prevent thrombosis in animal models through the inhibition of extracellular protein disulfide isomerase (PDI). We evaluated whether red or white wine inhibited PDI activity in vitro. METHODS: Quercetin levels in red and white wines were measured by HPLC analysis. Inhibition of PDI activity by red and white wines was assessed by an insulin reduction turbidity assay at various concentrations of wine. PDI inhibition was confirmed using a reduced peptide that contained a disulfide containing peptide as a substrate. The inhibition of PDI related thiol isomerases ERp5 and ERp57 was also assessed. RESULTS: We observed a dose-dependent decrease of PDI activity for a variety of red but not white wines. Red wine diluted to 3% final concentration resulted in over 80% inhibition of PDI activity by insulin reductase assay for all varieties tested. This inhibition was also observed in the peptide based assay. Red grape juice yielded similar results but ethanol alone did not affect PDI activity. Interestingly, red wine also inhibited the PDI related thiol isomerases ERp5 and ERp57, albeit to a lesser degree than PDI. CONCLUSIONS: PDI activity is inhibited by red wine and grape juice, identifying a potentially novel mechanism underlying the cardiovascular benefits attributed to wine consumption.


Assuntos
Etanol/química , Isomerases de Dissulfetos de Proteínas/química , Quercetina/química , Vitis/química , Vinho/análise , Cor , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Análise de Alimentos , França , Vinho/classificação
16.
Blood ; 126(4): 494-9, 2015 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-25987658

RESUMO

Venous thromboembolism occurs frequently in patients with cancer who have brain metastases, but there is limited evidence supporting the safety of therapeutic anticoagulation. To assess the risk for intracranial hemorrhage associated with the administration of therapeutic doses of low-molecular-weight heparin, we performed a matched, retrospective cohort study of 293 patients with cancer with brain metastases (104 with therapeutic enoxaparin and 189 controls). A blinded review of radiographic imaging was performed, and intracranial hemorrhages were categorized as trace, measurable, and significant. There were no differences observed in the cumulative incidence of intracranial hemorrhage at 1 year in the enoxaparin and control cohorts for measurable (19% vs 21%; Gray test, P = .97; hazard ratio, 1.02; 90% confidence interval [CI], 0.66-1.59), significant (21% vs 22%; P = .87), and total (44% vs 37%; P = .13) intracranial hemorrhages. The risk for intracranial hemorrhage was fourfold higher (adjusted hazard ratio, 3.98; 90% CI, 2.41-6.57; P < .001) in patients with melanoma or renal cell carcinoma (N = 60) than lung cancer (N = 153), but the risk was not influenced by the administration of enoxaparin. Overall survival was similar for the enoxaparin and control cohorts (8.4 vs 9.7 months; Log-rank, P = .65). We conclude that intracranial hemorrhage is frequently observed in patients with brain metastases, but that therapeutic anticoagulation does not increase the risk for intracranial hemorrhage.


Assuntos
Anticoagulantes/efeitos adversos , Neoplasias Encefálicas/complicações , Enoxaparina/efeitos adversos , Hemorragias Intracranianas/epidemiologia , Neoplasias/patologia , Tromboembolia Venosa/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Boston/epidemiologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Incidência , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/mortalidade , Adulto Jovem
17.
Acta Haematol ; 133(4): 347-53, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25677780

RESUMO

BACKGROUND: Not all patients with diffuse large B-cell lymphoma (DLBCL) are candidates for aggressive regimens. (90)Y ibritumomab tiuxetan ((90)Y-IT), an anti-CD20 radionuclide-conjugated antibody, has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile. METHODS: This phase II trial investigated the overall response rate (ORR), event-free survival (EFS), overall survival (OS) and toxicity of treatment with (90)Y-IT (0.4 or 0.3 mCi (90)Y/kg based on platelets) followed by rituximab maintenance therapy in patients with DLBCL not candidates for transplant. RESULTS: 25 patients were enrolled. At best response 8 patients obtained a complete response (CR) and 1 a partial response (ORR 36%). Median EFS was 2.5 months and OS 8.1 months. No patient who obtained CR later relapsed systemically. Two patients were free of disease at the 61- and 100-month follow-ups; 65% had grade 3/4 thrombocytopenia, but no significant bleeding was observed. Grade 3 nonhematologic toxicity occurred in 36%. Patients who had progressed through a rituximab-containing regimen responded poorly. CONCLUSION: The ORR of 36% with (90)Y-IT as salvage therapy for DLBCL while inferior to more aggressive regimens is significant with acceptable toxicity. For a subset of patients not candidates for salvage with autologous transplant, this treatment strategy can produce a durable, long-lasting remission.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Radioisótopos de Ítrio/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/química , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Radioimunoterapia , Indução de Remissão , Rituximab , Terapia de Salvação , Taxa de Sobrevida , Trombocitopenia/etiologia , Tomografia Computadorizada por Raios X , Radioisótopos de Ítrio/química
18.
Arterioscler Thromb Vasc Biol ; 35(1): 16-23, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25104801

RESUMO

The study of thrombus formation has increasingly applied in vivo tools such as genetically modified mice and intravital microscopy to the evaluation of molecular and cellular mechanisms of thrombosis. Among several unexpected findings of this approach was the discovery that protein disulfide isomerase serves an essential role in thrombus formation at sites of vascular injury. The observation that the commonly ingested quercetin flavonoid, quercetin-3-rutinoside, inhibits protein disulfide isomerase and blocks thrombus formation in preclinical studies has set the stage for clinical trials using protein disulfide isomerase antagonists as antithrombotics. Although the mechanisms by which protein disulfide isomerase facilitates platelet activation and fibrin formation have yet to be elucidated, protein disulfide isomerase antagonists are currently being developed as antithrombotics. This review will consider what is known about the role of protein disulfide isomerase in platelet accumulation and fibrin generation with a focus on pharmacological strategies for blocking protein disulfide isomerase activity in the context of thrombus formation. Potential indications and clinical trial design for testing the efficacy of protein disulfide isomerase inhibition to reduce the incidence of thrombosis will be considered.


Assuntos
Plaquetas/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Fibrinolíticos/uso terapêutico , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Trombose/tratamento farmacológico , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/enzimologia , Desenho de Drogas , Fibrina/metabolismo , Humanos , Ativação Plaquetária/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/sangue , Trombose/sangue , Trombose/enzimologia
19.
Transfusion ; 55(4): 719-25, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25385549

RESUMO

BACKGROUND: Human granulocytic anaplasmosis (HGA) is an acute nonspecific febrile illness caused by the bacterium Anaplasma phagocytophilum. Although usually transmitted via tick bite, HGA may rarely also be acquired through transfusion. HGA during pregnancy may pose significant gestational risks due to altered maternal immune status and the potential for perinatal transmission. CASE REPORT: A pregnant 34-year-old Massachusetts woman with ß-thalassemia trait was diagnosed at 32 weeks of gestation with transfusion-associated HGA (TAHGA) after receiving nine leukoreduced red blood cell transfusions. She was successfully treated with rifampin therapy and gave birth to a healthy child who tested negative for HGA after delivery. An implicated blood donor was subsequently identified through physician collaboration with the regional American Red Cross and Massachusetts Department of Public Health. DISCUSSION: This is the 11th reported case of HGA in pregnancy and is at least the sixth known case in which leukoreduction did not prevent TAHGA. As seen in this case, nonspecific symptomatology of variable onset can impede diagnosis and treatment. This may increase risk of poor outcomes in maternal HGA patients. Cases of TAHGA, although currently uncommon, may increase as the incidence of HGA in certain parts of the country increases. CONCLUSION: Heightened cross-institutional awareness of the potential risk of TAHGA is warranted. Clinicians need to consider transfusion-associated infections when fever occurs in a transfusion recipient. This case provides additional evidence that leukoreduction does not obviate risk of A. phagocytophilum contamination of donated blood components.


Assuntos
Anaplasma phagocytophilum/isolamento & purificação , Bacteriemia/transmissão , Ehrlichiose/transmissão , Transfusão de Eritrócitos/efeitos adversos , Complicações Hematológicas na Gravidez/terapia , Complicações Infecciosas na Gravidez/microbiologia , Talassemia beta/terapia , Anaplasma phagocytophilum/imunologia , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/sangue , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Doadores de Sangue , Segurança do Sangue , Diagnóstico Tardio , Ehrlichiose/diagnóstico , Ehrlichiose/tratamento farmacológico , Ehrlichiose/epidemiologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Recém-Nascido , Procedimentos de Redução de Leucócitos , Masculino , Massachusetts/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Rifampina/uso terapêutico , Talassemia beta/complicações
20.
J Clin Oncol ; 32(32): 3596-9, 2014 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-25267753

RESUMO

A previously healthy 41-year-old man presents with left leg pain and shortness of breath. He has a 20­packyear history of smoking but quit 2 years ago. An ultrasound of the left leg shows thrombosis of the superficial femoral and popliteal veins.Onchest computed tomography (CT) angiogram, there is a large right hilar mass and enlarged mediastinal lymph nodes but no pulmonary emboli. He is treated with therapeutic doses of low­molecular weight heparin (LMWH), with brief interruptions for invasive procedures and surgery. Transbronchial biopsy is performed, and pathology yields a diagnosis of poorly differentiated non­small cell lung cancer (NSCLC; EGFR/KRAS wild type and ALK and ROS1 negative by fluorescent in situ hybridization). After additional tests, the patient is determined to have stage IIIA NSCLC. Subsequently, he receives concurrent chemotherapy consisting of cisplatin/etoposide and chest radiotherapy, resulting in a marked decrease in the size of the right hilar mass and mediastinal lymph nodes. He then undergoes right upper lobectomy and mediastinal lymph node dissection, which demonstrate no clinical or pathologic evidence of cancer. The patient returns to clinic, having been treated for >6 months with LMWH. He reports both mild shortness of breath with exertion and minimal chronic swelling of the left lower extremity. A follow-up ultrasound shows nonocclusive intraluminal thrombus in the left superficial femoral and popliteal veins; follow-up chest CT angiogram shows no evidence of pulmonary emboli.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Heparina de Baixo Peso Molecular/uso terapêutico , Neoplasias Pulmonares/terapia , Trombose Venosa/tratamento farmacológico , Adulto , Anticoagulantes/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Quimiorradioterapia , Humanos , Perna (Membro)/irrigação sanguínea , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico , Masculino , Guias de Prática Clínica como Assunto , Literatura de Revisão como Assunto , Fatores de Tempo , Trombose Venosa/complicações
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