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2.
Cancer Manag Res ; 11: 2663-2675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037034

RESUMO

Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients.

3.
J Intern Med ; 286(1): 63-74, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30725503

RESUMO

BACKGROUND: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. METHODS: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs. RESULTS: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. CONCLUSIONS: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions.


Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Árvores de Decisões , Humanos , Monitorização Fisiológica , Oligopeptídeos/uso terapêutico
4.
J Hematol Oncol ; 11(1): 10, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29338789

RESUMO

Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography-computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma.


Assuntos
Plasmocitoma/diagnóstico , Plasmocitoma/terapia , Gerenciamento Clínico , Europa (Continente)/epidemiologia , Humanos , Imagem por Ressonância Magnética/métodos , Plasmocitoma/epidemiologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Resultado do Tratamento
5.
Leukemia ; 32(2): 383-390, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28761118

RESUMO

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl-1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.


Assuntos
Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Aberrações Cromossômicas/efeitos dos fármacos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Intervalo Livre de Progressão , Talidomida/uso terapêutico , Transplante Autólogo/métodos , Adulto Jovem
6.
Leukemia ; 2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29251284

RESUMO

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.

8.
Psychooncology ; 26(12): 2040-2047, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28264148

RESUMO

OBJECTIVE: To optimize personalized medicine for patients with hematological malignancies (HM), we find that knowledge on patient preferences with regard to information provision and shared decision-making (SDM) is of the utmost importance. The aim of this study was to investigate the SDM preference and the satisfaction with and need for information among newly diagnosed HM patients and their informal caregivers, in relation to sociodemographic and clinical factors, cognitive coping style, and health related quality of life. METHODS: Newly diagnosed patients and their caregivers were asked to complete the Hematology Information Needs Questionnaire, the Information Satisfaction Questionnaire, and the Threatening Medical Situations Inventory. Medical records were consulted to retrieve sociodemographic and clinical factors and comorbidity by means of the ACE-27. RESULTS: Questionnaires were completed by 138 patients and 95 caregivers. Shared decision-making was preferred by the majority of patients (75%) and caregivers (88%), especially patients treated with curative intent (OR = 2.7, P = .041), and patients (OR = 1.2, P < .001) and caregivers (OR = 1.2, P = .001) with a higher monitoring cognitive coping style (MCCS). Among patients, total need for information was related to MCCS (P = .012), and need for specific information was related to MCCS and several clinical factors. Importantly, dissatisfaction with the information they received was reported by a third of the patients and caregivers, especially patients who wanted SDM (χ2  = 7.3, P = .007), and patients with a higher MCCS (OR = 0.94, P = .038). CONCLUSION: The majority of HM patients want to be involved in SDM, but the received information is not sufficient. Patient-tailored information is urgently needed, to improve SDM.


Assuntos
Cuidadores/psicologia , Comunicação , Tomada de Decisões , Neoplasias Hematológicas/diagnóstico , Participação do Paciente , Satisfação Pessoal , Adaptação Psicológica , Adulto , Feminino , Neoplasias Hematológicas/psicologia , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Participação do Paciente/psicologia , Preferência do Paciente , Satisfação do Paciente , Relações Médico-Paciente , Qualidade de Vida , Encaminhamento e Consulta , Inquéritos e Questionários
9.
Ther Adv Hematol ; 7(6): 330-344, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27904737

RESUMO

Even though the prognosis of patients with multiple myeloma is continuing to improve, all patients eventually develop relapsed refractory disease. Several novel therapeutics have been developed in the last few years including the second-generation proteasome inhibitor carfilzomib which has been approved for patients with relapsed and refractory multiple myeloma in the United States since 2012. Recently data from several phase III studies have become available showing the promising efficacy of carfilzomib in combination with lenalidomide, which led to the renewed approval of carfilzomib in combination with lenalidomide and dexamethasone for relapsed myeloma in 2015. Furthermore carfilzomib showed superiority over bortezomib on both efficacy and toxicity profiles, especially a profoundly lower incidence in polyneuropathy. Carfilzomib has been shown to partially overcome the negative effects of high-risk cytogenetics. Promising combinations of carfilzomib with histone deacetylase (HDAC) inhibitors, pomalidomide and several other novel therapeutics have been presented in early studies. The optimal dosing regimen and sequence of treatment regimens remain important questions for the future.

10.
EJNMMI Res ; 6(1): 46, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27246327

RESUMO

BACKGROUND: Bone disease in multiple myeloma is characterized by reduced bone formation. The gold standard of bone formation is the mineral apposition rate (MAR), an invasive technique reflecting bone formation at a single site. We compared (18)F-fluoride-PET with the MAR in myeloma patients. METHODS: Bone formation was measured before and after bortezomib treatment by determination of the MAR in iliac bone marrow biopsies and the measurement of (18)F-uptake. RESULTS: The inter- and intra-individual variations in (18)F-uptake (SUVA50%) were pronounced as 33.50 (range 4.42 to 37.92) and 27.18 (range 4.00 to 31.18), respectively. A significant correlation between the MAR and (18)F-uptake was found (r = 0.80, p = 0.017). There was a heterogeneous response after treatment varying from -2.20 to 4.53. CONCLUSIONS: Iliac (18)F-uptake was associated with the local MAR in myeloma patients. Furthermore, (18)F-fluoride-PET demonstrated the heterogeneity of in vivo bone formation, enabling monitoring during treatment.

11.
Int J Lab Hematol ; 38 Suppl 1: 110-22, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27161311

RESUMO

Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant disorders. IgG and IgA MGUS are precursor conditions of multiple myeloma (MM), whereas light-chain MGUS is a precursor condition of light-chain MM. Smoldering MM (SMM) is a precursor condition with higher tumor burden and higher risk of progression to symptomatic MM compared to MGUS. Assessment of the risk of progression of patients with asymptomatic monoclonal gammopathies is based on various factors including clonal burden, as well as biological characteristics, such as cytogenetic abnormalities and light-chain production. Several models have been constructed that are useful in daily practice for predicting risk of progression of MGUS or SMM. Importantly, the plasma cell clone may occasionally be responsible for severe organ damage through the production of a M-protein which deposits in tissues or has autoantibody activity. These disorders are rare and often require therapy directed at eradication of the underlying clone. Importantly, recent studies have shown that asymptomatic patients with a bone marrow plasma cell percentage ≥60%, free light-chain ratio ≥100, or >1 focal lesion on MRI (myeloma-defining events) have a 80% risk of developing symptomatic MM within 2 years. These patients are now considered to have MM requiring therapy, similar to patients with symptomatic disease. In this review, we provide an overview of the new diagnostic criteria of the monoclonal gammopathies and discuss risk of progression to active MM. We also provide recommendations for the management of patients with MGUS and SMM including risk-adapted follow-up.


Assuntos
Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Mieloma Múltiplo/diagnóstico , Células Clonais/patologia , Gerenciamento Clínico , Progressão da Doença , Humanos , Gamopatia Monoclonal de Significância Indeterminada/complicações , Plasmócitos/patologia , Medição de Risco
12.
Bone Marrow Transplant ; 50(11): 1424-31, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26237165

RESUMO

In myelofibrosis, the introduction of reduced-intensity conditioning (RIC) preceding allogeneic stem cell transplantation (SCT) resulted in lower transplant-related mortality rates compared with myeloablative conditioning. However, lowering the intensity of conditioning may increase the risk of graft failure in myelofibrosis, although hitherto this has not been indisputably proven. We here report the outcome of 53 patients who underwent allogeneic SCT with different conditioning regimens (RIC and non-myeloablative (NMA)) in three transplantation centers in the Netherlands. The cumulative incidence of graft failure within 60 days after SCT was high (28%), and this was primarily associated with the intensity of the conditioning regimen. Cumulative neutrophil engraftment at 60 days was lower in patients who received NMA conditioning compared with those who received RIC (56% vs 84%, P=0.03). Furthermore, of six patients who received a second transplantation after graft failure, the three patients with RIC regimens subsequently engrafted, whereas the three patients who received a second NMA regimen did not. This study indicates that in myelofibrosis, NMA regimens result in high engraftment failure rates. We propose the use of more intensive conditioning regimens, incorporating busulfan or melphalan.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Sobrevivência de Enxerto , Agonistas Mieloablativos/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico , Mielofibrose Primária/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/uso terapêutico , Calreticulina/genética , Terapia Combinada , Ciclofosfamida/uso terapêutico , Progressão da Doença , Feminino , Humanos , Janus Quinase 2/genética , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Neutrófilos/transplante , Policitemia Vera/complicações , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/etiologia , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Estudos Retrospectivos , Trombocitemia Essencial/complicações , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Irradiação Corporal Total , Adulto Jovem
13.
Leukemia ; 28(8): 1573-85, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24496300

RESUMO

In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed.


Assuntos
Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Fatores Etários , Ensaios Clínicos como Assunto , Dexametasona/administração & dosagem , Esquema de Medicação , Humanos , Infecções/induzido quimicamente , Mieloma Múltiplo/genética , Mieloma Múltiplo/psicologia , Neutropenia/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Qualidade de Vida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/farmacologia , Talidomida/uso terapêutico , Tromboembolia Venosa/induzido quimicamente
14.
Bone Marrow Transplant ; 49(4): 513-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24419517

RESUMO

We studied the outcome of allo-SCT after reduced-intensity conditioning in relapsed or refractory indolent and aggressive lymphoid malignancies. All 54 patients (diagnosis: B-CLL n=13, indolent lymphoma n=12, aggressive lymphoma n=13, transformed lymphoma n=16) received conditioning with fludarabine and CY between July 2001 and November 2010. They underwent allo-SCT because of relapse after auto-SCT or because no other therapy could lead to a meaningful remission. Patients received an unmanipulated peripheral blood stem-cell graft. Median follow-up was 67 months. Thirty-two patients had received rituximab. Immediately after transplantation, remission status had improved in 21 patients, all without DLI. During the follow-up six additional patients achieved CR without further therapy. Four-year OS (EFS) was 46% (46%) for B-CLL, 83% (75%) for indolent lymphoma, 69% (55%) for aggressive lymphoma and 74% (67%) for transformed lymphoma (P=0.28 (P=0.54)). Forty two percent developed acute GVHD, 68% chronic GVHD (16% limited, 52% extensive). Previous auto-SCT did not influence OS, while acute GVHD did. Two-year non-relapse mortality was 16%. In conclusion, reduced-intensity conditioning with fludarabine-CY is feasible and effective for both indolent and aggressive lymphoid malignancies, even after previous auto-SCT. Because of the excellent anti-B-cell/lymphoma activity fludarabine-CY decreases tumor load, gaining time for the development of a graft versus lymphoma effect.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
15.
Leukemia ; 28(3): 525-42, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24253022

RESUMO

Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Humanos
16.
Bone Marrow Transplant ; 48(12): 1574-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23892332

RESUMO

Chronic GVHD (cGVHD) complicating allo-SCT commonly presents as sclerotic skin changes resembling systemic sclerosis (SSc), suggesting a common pathophysiological pathway. Damage to capillaries is considered an early event in the pathogenesis of SSc, and is associated with characteristic nailfold capillary abnormalities. Whether such nailfold capillary abnormalities occur in sclerodermatous cGVHD is unknown. Nailfold videocapillaroscopy (NVC) was used to evaluate capillary morphology, density and loop dimensions in 14 patients with sclerodermatous cGVHD, 14 sex- and age-matched SSc patients, and 14 healthy controls. It was shown that none of the cGVHD patients and controls, whereas all SSc patients showed severe capillary abnormalities. cGVHD patients and controls showed no differences in capillary density (9.05 vs 9.16 loops/mm, respectively, P=0.84), and capillary loop dimensions (total loop width 44.36 vs 45.56 µm, respectively, P=0.84). Compared with cGVHD patients, SSc patients had a reduced capillary density (9.05 vs 5.25 loops/mm, respectively, P<0.001), and an increase in capillary loop dimensions (total loop width 44.36 vs 99.97 µm, respectively, P=<0.001). In conclusion sclerodermatous cGVHD patients do not show the characteristic microvascular abnormalities seen in SSc, suggesting that capillary damage does not contribute to the pathophysiology of sclerodermatous cGVHD, and making NVC unsuitable for early identification.


Assuntos
Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Unhas/irrigação sanguínea , Escleroderma Sistêmico/patologia , Capilares/patologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Unhas/patologia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Autólogo
17.
Int J Lab Hematol ; 34(4): 432-41, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22471741

RESUMO

INTRODUCTION: Immunophenotypic detection of minimal residual disease (MRD) in bone marrow (BM) of acute myeloid leukaemia (AML) patients is of high prognostic relevance. Standard MRD percentage is assessed as a percentage of total white blood cells (WBCs) and is therefore highly dependent on WBC count. Peripheral blood (PB) contains more than five times lower MRD percentages. Therefore, PB in BM aspirates cause dilution of the MRD cells, possibly leading to false-negative results for BM MRD. The latter is avoided when relating the fraction of malignant primitive cells, identified by aberrant marker expression [aberrant primitive cells (aPC)], to the total population of primitive cells. Such a fraction may in addition reflect an important biological parameter. METHODS: As this approach is thus independent of WBC count and the total size of the primitive compartment, we investigated the role of aPC fractions on overall and relapse-free survival (RFS) in 98 patients with AML under the age of 60. RESULTS: We show that this approach identifies MRD-negative (as defined by % of WBC) but aPC-positive (as defined by % of primitive cells) patients with poor outcome after both first and second induction cycle of chemotherapy. CONCLUSION: As a result, in cases with a primitive marker present, RFS is best predicted when combining standard MRD percentage with aPC fractions.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/fisiopatologia , Neoplasia Residual/diagnóstico , Pré-Escolar , Reações Falso-Negativas , Humanos , Lactente , Pessoa de Meia-Idade , Análise Multivariada , Neoplasia Residual/patologia , Prognóstico , Padrões de Referência
18.
Leukemia ; 26(4): 757-68, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21941364

RESUMO

Proteasome inhibition is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the ß5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization of the various BTZ-resistant cells revealed upregulation of mutant ß5 subunit of the proteasome. These newly identified ß5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the ß5 subunit, that of the S1 specificity pocket in particular. Moreover, we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant ß5 subunit of the proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the α7 subunit of the proteasome can overcome this drug resistance modality.


Assuntos
Antineoplásicos/metabolismo , Ácidos Borônicos/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/genética , Pirazinas/metabolismo , Substituição de Aminoácidos , Ácidos Borônicos/uso terapêutico , Bortezomib , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma , Pirazinas/uso terapêutico
19.
Thromb Haemost ; 106(5): 885-92, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21947221

RESUMO

A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged ≥16 years were included. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Menorrhagia, defined as occurrence of ≥2 menorrhagia symptoms, was reported by 81%. Of all VWD women, 78% received any kind of treatment for menorrhagia and 20% underwent a hysterectomy predominantly because of severe menstrual bleeding. Over half of the women reported more blood loss than can be expected with a normal delivery. In 52% of reported pregnancy losses curettage was needed because of bleeding. Mean number of live births was 1.9, which is comparable with the general Dutch population. In conclusion, women with moderate or severe VWD frequently have menorrhagia in need of treatment, and 20% of the VWD women underwent a hysterectomy. Bleeding complications occurred in over 50% of the women after childbirth or pregnancy loss. Progeny seems not to be affected in women with moderate or severe VWD.


Assuntos
Menorragia/etiologia , Hemorragia Pós-Parto/etiologia , Doenças de von Willebrand/complicações , Doenças de von Willebrand/diagnóstico , Aborto Espontâneo/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Testes de Coagulação Sanguínea , Estudos Transversais , Feminino , Morte Fetal/etiologia , Inquéritos Epidemiológicos , Humanos , Histerectomia , Nascimento Vivo , Menorragia/sangue , Menorragia/diagnóstico , Menorragia/cirurgia , Pessoa de Meia-Idade , Países Baixos , Hemorragia Pós-Parto/sangue , Hemorragia Pós-Parto/diagnóstico , Hemorragia Pós-Parto/cirurgia , Gravidez , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem , Doenças de von Willebrand/sangue
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