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1.
J Thromb Thrombolysis ; 54(1): 109-114, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34817787

RESUMEN

Bone marrow biopsies are largely used for the diagnosis and prognostic of various hematological diseases. Complications are rare but can be as serious as hemorrhage. However, little is known about management of patients deemed at high hemorrhagic risk like thrombocytopenic patients or patients receiving antithrombotic drugs. The aim of the study was to describe the management of patients regarding their laboratory profile and antithrombotic treatment prior to bone marrow biopsy and the short-term outcomes, notably hemorrhage. We conducted a retrospective observational study between February 2007 and March 2018. A standardized form was used to collect data from patients' records, blood tests results, management of antiplatelet and anticoagulant treatment before biopsy and complications including bleeding and thromboembolic events until 3 months after the biopsy. A total of 524 bone marrow biopsies were performed. No major bleeding events were reported. The incidence of clinically relevant non-major bleeding was 0.19% (CI 95% 0.00-1.20) and was linked to low platelets counts (p = 0.002) and not to abnormal coagulation profile or antithrombotic therapy, whether or not a bridging therapy has been used. Anticoagulants were temporarily stopped before biopsy in most cases without subsequent thrombotic complications. Our data suggest that thrombocytopenic patients have a non-negligible bleeding risk. Coagulation profiling seems irrelevant. We propose an algorithm to assist the management of those patients, notably when receiving antithrombotic drugs.


Asunto(s)
Médula Ósea , Fibrinolíticos , Anticoagulantes/efectos adversos , Biopsia/efectos adversos , Fibrinolíticos/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo
2.
J Clin Apher ; 37(1): 106-116, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34967023

RESUMEN

BACKGROUND: Infections are common with significant mortality and morbidity in patients with graft-versus-host disease (GvHD). Extracorporeal photopheresis (ECP) is an advantageous treatment option for patients with GvHD because it is not immunosuppressive. The objective of this study was to assess the rate of infections and to determine risk factors in patients with GvHD. MATERIALS AND METHODS: In a single-center cohort, we retrospectively collected data on infectious episodes by evaluating the clinical records of patients with GvHD treated by ECP since 2011. RESULTS: A total of 47 patients were included in this study. At ECP initiation, there were 10 patients with acute GvHD and 37 with chronic GvHD. At the final follow-up, 200 infectious episodes were diagnosed in 91.5% of patients with an average follow-up of 25.9 months (ie, 1.97 infections per patient per year). Most episodes had positive outcomes as there was no death related to infections, and only six infections required long-term treatment. Higher dose of corticosteroids at the initiation of ECP was significantly associated with a shorter onset of the first infection (hazard ratio [HR] = 2.05; 95% confidence interval [CI] [1.17, 3.57]; P = .013). Unrelated donor transplants were significantly associated with a lower rate of infection (HR = 0.61; 95% CI [0.39, 0.95]; P = .028). CONCLUSION: The results of our study suggest that ECP is associated with a low infection rate and an optimal clinical efficacy. Thus, ECP is still a suitable treatment for GvHD. Yet, a future study with a larger cohort will be necessary to deepen the identification of risk factors for infection.


Asunto(s)
Enfermedad Injerto contra Huésped/terapia , Infecciones/epidemiología , Fotoféresis , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/microbiología , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Infecciones/etiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Medición de Riesgo , Adulto Joven
3.
Oncology ; 97(1): 18-25, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31132779

RESUMEN

PURPOSE: It is usual for cancer patients to use complementary and alternative medicines (CAMs) and yet the literature evaluating their efficacy in cancer patients is very limited. The objective of the present study was to report on the nature, frequency of use, and patient-reported outcome of CAMs in a single-center study. METHODS: All the consecutive patients treated between November 2017 and June 2018 at the Lucien Neuwirth Cancer Institute (France) were screened. Their reasons for using CAMs and their usage habits were collected. Patients evaluated their benefit. RESULTS: Of the 209 patients screened, 200 patients were included. CAMs ranged from osteopathy, homeopathy, acupuncture, healing touch, magnetism, naturopathy, suction cups, Chinese medicine, reflexology, to hypnosis. CAMs were widely used (n = 166, 83%), the first being osteopathy (n = 99, 49.5%), the second homeopathy (n = 78, 39.0%), and finally acupuncture (n = 76, 38.0%). Whatever the CAM, high satisfaction rates were reported (median satisfaction: 61-81%). CAMs were mainly used to prevent/treat side effects of anticancer treatments (81.2% for healing touch), increase well-being (55.4% for naturopathy), improve the immune system (16.9% for homeopathy), and treat cancer (n = 3, 5.1% for homeopathy). Patients could easily consider using CAMs, as up to 50.8% would have accepted a consultation. CONCLUSIONS: The reasons for using CAMs differed among patients. They praised CAMs and kept asking for more information although there is limited evidence about their efficacy in the literature. Thus, prospective randomized controlled trials exploring the safety and efficacy of CAMs in cancer patients are needed.


Asunto(s)
Terapia por Acupuntura/métodos , Terapias Complementarias/métodos , Medicina Tradicional China/métodos , Neoplasias/terapia , Terapias Complementarias/psicología , Femenino , Francia/epidemiología , Homeopatía/métodos , Humanos , Hipnosis/métodos , Masculino , Masaje/métodos , Naturopatía/métodos , Neoplasias/epidemiología , Neoplasias/patología , Aceptación de la Atención de Salud/psicología , Satisfacción del Paciente , Resultado del Tratamiento
4.
Tumour Biol ; 39(7): 1010428317716629, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28718379

RESUMEN

Acute myeloid leukemia is driven by leukemic stem cells which can be identified by cross lineage expression or arrest of differentiation compared to normal hematopoietic stem cells. Self-renewal and lack of differentiation are also features of stem cells and have been associated with the expression of embryonic genes. The aim of our study was to evaluate the expression of embryonic antigens (OCT4, NANOG, SOX2, SSEA1, SSEA3) in hematopoietic stem cell subsets (CD34+CD38- and CD34+CD38+) from normal bone marrows and in samples from acute myeloid leukemia patients. We observed an upregulation of the transcription factors OCT4 and SOX2 in leukemic cells as compared to normal cells. Conversely, SSEA1 protein was downregulated in leukemic cells. The expression of OCT4, SOX2, and SSEA3 was higher in CD34+CD38- than in CD34+CD38+ subsets in leukemic cells. There was no correlation with biological characteristics of the leukemia. We evaluated the prognostic value of marker expression in 69 patients who received an intensive treatment. The rate of complete remission was not influenced by the level of expression of markers. Overall survival was significantly better for patients with high SOX2 levels, which was unexpected because of the inverse correlation with favorable genetic subtypes. These results prompt us to evaluate the potential role of these markers in leukemogenesis and to test their relevance for better leukemic stem cell identification.


Asunto(s)
Biomarcadores de Tumor/biosíntesis , Fucosiltransferasas/biosíntesis , Leucemia Mieloide Aguda/tratamiento farmacológico , Antígeno Lewis X/biosíntesis , Factor 3 de Transcripción de Unión a Octámeros/biosíntesis , Factores de Transcripción SOXB1/biosíntesis , ADP-Ribosil Ciclasa 1/genética , Adulto , Anciano , Antígenos CD34/genética , Células de la Médula Ósea/metabolismo , Diferenciación Celular/genética , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias/patología , Femenino , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Pronóstico
5.
Acta Haematol ; 136(4): 193-200, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27623172

RESUMEN

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often proposed for patients with comorbidities. To enhance engraftment and limit graft-versus-host disease (GVHD), antithymoglobulin (ATG) is usually used. However, the dose needed remains unclear unlike myeloablative conditioning. In order to clarify this point, we conducted a retrospective study on patients who received a reduced intensity conditioning allo-HSCT based on a 2-day fludarabine and busulfan treatment with either 1 or 2 days of ATG treatment. One hundred and eight patients received 2.5 mg/kg (ATG2.5) and another 60 patients 5 mg/kg (ATG5). The median follow-up was 36 months. The median overall survival was 39 months and the median disease-free survival 45 months. In multivariate analysis, overall nonrelapse mortality (NRM) was independently influenced by the acute GVHD grade III-IV (p < 0.001) and ATG dose (30 vs. 21% for ATG5; p = 0.008). Despite heterogeneity of populations, using proportional-hazard assumptions, we have been able to observe in multivariate analysis a lower NRM in the ATG5 group. This leads to a statistically higher overall survival for the ATG5 group. In conclusion, 2 days of ATG decrease NRM independently without increasing the risk of relapse or infectious disease.


Asunto(s)
Suero Antilinfocítico/uso terapéutico , Agonistas Mieloablativos/uso terapéutico , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vidarabina/uso terapéutico
7.
Respiration ; 90(3): 229-34, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26278709

RESUMEN

BACKGROUND: Neutropenia recovery (NR) has been associated with worsening preexisting lung injury in up to 50% of critically ill cancer patients. However, only limited relevant data exist in the general population of hematological patients. OBJECTIVES: To assess the incidence of acute respiratory deterioration during NR in patients with hematological malignancies. METHODS: Adult patients with neutropenia expected to last more than 7 days were included. Worsening of respiratory status (WRS) was defined as a decrease in oxygen saturation of ≥5%, the need for oxygen therapy for ≥24 h, an increase in oxygen flow of ≥50% in patients previously treated with oxygen, or the need for mechanical ventilation. NR was defined as the 3 days preceding or following a neutrophil count of >0.5 × 109/l. RESULTS: A total of 16 of 50 patients included in this pilot study experienced WRS during NR (32%), and 13 patients had WRS during neutropenia (26%). The incidence density of WRS was 0.53 (±0.79) episodes per 10 days during NR and 0.20 (±0.39) episodes per 10 days during neutropenia (p = 0.004). Sepsis, stem cell transplantation, preexisting pneumonia, or the use of granulocyte colony-stimulating factor were not associated with WRS during NR. CONCLUSION: Up to one third of noncritically ill hematological patients with expected neutropenia of more than 7 days experience WRS during NR. Clinical consequences and risk factors for WRS during NR remain to be evaluated.


Asunto(s)
Lesión Pulmonar Aguda/etiología , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/cirugía , Trasplante de Células Madre Hematopoyéticas/métodos , Neutropenia/fisiopatología , Lesión Pulmonar Aguda/fisiopatología , Adulto , Anciano , Estudios de Cohortes , Intervalos de Confianza , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Francia , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Neoplasias Hematológicas/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Proyectos Piloto , Estudios Prospectivos , Recuperación de la Función , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo
8.
Cancers (Basel) ; 15(19)2023 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-37835401

RESUMEN

BACKGROUND: Embryonic antigens (EA) regulate pluripotency, self-renewal, and differentiation in embryonic stem (ES) cells during their development. In adult somatic cells, EA expression is normally inhibited; however, EAs can be re-expressed by cancer cells and are involved in the deregulation of different signaling pathways (SPs). In the context of AML, data concerning the expression of EAs are scarce and contradictory. METHODS: We used mass cytometry to explore the expression of EAs and three SPs in myeloid cells from AML patients and normal bone marrow (NBM). Imaging flow cytometry was used for morphological assessment of cells in association with their OCT3/4 expression status (positive vs. negative). RESULTS: An overall reduction in or absence of EA expression was observed in immature myeloid cells from AML patients compared to their normal counterparts. Stage-specific embryonic antigen-3 (SSEA-3) was consistently expressed at low levels in immature myeloid cells, whereas SSEA-1 was overexpressed in hematopoietic stem cells (HSCs) and myeloblasts from AML with monocytic differentiation (AML M4/M5). Therefore, these markers are valuable for distinguishing between normal and abnormal myeloid cells. These preliminary results show that the exploration of myeloid cell intracellular SPs in the setting of AML is very informative. Deregulation of three important leukemogenic SPs was also observed in myeloid cells from AML. CONCLUSIONS: Exploring EAs and SPs in myeloid cells from AML patients by mass cytometry may help identify characteristic phenotypes and facilitate AML follow-up.

9.
Bull Cancer ; 110(12): 1251-1259, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37696744

RESUMEN

INTRODUCTION: Therapeutic approaches in Multiple Myeloma (MM) have considerably changed over the last few years, with effective oral chemotherapy and continuous treatment. In this context, the objective of this study was to examine the circuitry of an advanced practitioner nurse (APN)-led intervention that provided supportive care for MM patients treated with oral chemotherapy. METHODS: This population-based study was conducted at the hematology department - Institut de Cancérologie Lucien Neuwirth (ICLN, Saint-Priest-en-Jarez), from April 2017 to September 2020. A follow-up program was established with a specialized APN in oncology. RESULTS: All APN interventions were recorded, representing 1240 phone calls and 162 consultations for 42 MM patients. Eighty-two calls were referred to the physician with 45 consultations triggered. Most of the calls were frequent within the few first months, with a high request for information and reassurance, especially for treatment-naive or relapsed patients. In our study, the APN was able to manage multiple side effects through care organization (i.e., hospitalizations, transfusions) and a careful coordination between the primary care team and the hospital. DISCUSSION: In order to respond to the high need for care pathway and safety improvement, especially in elderly population, we have initiated an original follow-up by an APN for MM patients treated with oral chemotherapy. While the role of APN has become prominent in the oncology field in recent years, its holistic approach has to be emphasized in further studies to bring a comprehensive perspective to health care coordination in the future.


Asunto(s)
Mieloma Múltiple , Humanos , Anciano , Mieloma Múltiple/tratamiento farmacológico , Atención a la Salud
10.
Cytometry A ; 81(11): 996-1004, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22930640

RESUMEN

One of the essential parameters of targeted therapy efficiency in cancer treatment is the amount of drug reaching the therapeutic target area. Imatinib (IM) was the first specifically targeted drug to be developed and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). To evaluate cellular uptake of IM, we developed a method based on the chemical structure of the molecule and using the natural UV fluorescence that we quantified by flow cytometry. In two CML cell lines, we obtained a satisfactory relationship between intracellular IM (ICIM) levels and media concentrations, and we found a strong correlation between ICIM at 1 h and IM efficacy at 24 h, demonstrating that ICIM at 1 h might be a relevant predictive parameter of cell sensitivity. Our method was more sensitive than the standard physicochemical method. We applied our method to primary cells and found cell morphology-dependent IM accumulation. Moreover, in CML cells from patients at diagnosis, IM accumulation was heterogeneous. In all cases, ICIM at the single-cell level was much higher than in culture media arguing in favor of a predominantly active uptake process. We developed a simple method directly applicable to primary cells that has shown two major advantages: only a small number of cells are required, and cell subsets can be identified according to morphological criteria and/or the presence of particular antigenic sites. This method provides a new tool to assess CML cell sensitivity to IM, and ICIM levels in native CML cells could be used to monitor therapeutic response.


Asunto(s)
Citometría de Flujo/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Antineoplásicos/farmacocinética , Benzamidas , Forma de la Célula , Medios de Cultivo/metabolismo , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Fluorescencia , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Piperazinas/sangre , Pirimidinas/sangre , Sensibilidad y Especificidad , Rayos Ultravioleta
11.
Exp Cell Res ; 317(18): 2616-29, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-21871449

RESUMEN

Direct cell-cell contact between haematopoietic progenitor cells (HPCs) and their cellular microenvironment is essential to maintain 'stemness'. In cancer biology, focal adhesion (FA) proteins are involved in survival signal transduction in a wide variety of human tumours. To define the role of FA proteins in the haematopoietic microenvironment of myelodysplastic syndromes (MDS), CD73-positive mesenchymal stromal cells (MSCs) were immunostained for paxillin, pFAK [Y(397)], and HSP90α/ß and p130CAS, and analysed for reactivity, intensity and cellular localisation. Immunofluorescence microscopy allowed us to identify qualitative and quantitative differences, and subcellular localisation analysis revealed that in pathological MSCs, paxillin, pFAK [Y(397)], and HSP90α/ß formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y(397)], and HSP90α/ß and enhanced nuclear co-localisation of these proteins correlated with a consistent proliferative advantage in MSCs from patients with refractory anaemia with excess blasts (RAEB) and negatively impacted clonogenicity of HPCs. These results suggest that signalling via FA proteins could be implicated in HPC-MSC interactions. Further, because FAK is an HSP90α/ß client protein, these results suggest the utility of HSP90α/ß inhibition as a target for adjuvant therapy for myelodysplasia.


Asunto(s)
Adhesiones Focales/metabolismo , Mesodermo/patología , Síndromes Mielodisplásicos/metabolismo , Paxillin/metabolismo , Células del Estroma/patología , Adulto , Anciano , Anciano de 80 o más Años , Proteína Sustrato Asociada a CrK/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Adhesiones Focales/patología , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Mesodermo/metabolismo , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Células del Estroma/metabolismo
12.
Front Cardiovasc Med ; 9: 998687, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36337867

RESUMEN

Introduction: To perform Calibrated Automated Thrombography (CAT), the use of reduced plasma volumes (referred to as "MidiCAT") makes it possible to more efficiently use limited volumes of valuable biobanked plasma samples and decreases expenses for reagents. It is, however, unclear whether the MidiCAT procedure is suitable when thrombin generation (TG) is studied in the presence of added thrombomodulin (TG-TM). Moreover, a simplified centrifugation scheme would facilitate biobanking, if appropriate, for more sensitive coagulation studies. We aimed to compare the results of "MidiCAT" (halved plasma and reagent volumes) with those from regular CAT, in the absence or presence of TM, as well as to study the impact of a single-centrifugation scheme for plasma preparation before freezing. Materials and methods: Plasma samples were prepared from the citrated blood from 20 Geneva hospital diverse patients without gross coagulation abnormalities with a single- or double-centrifugation scheme. Samples were kept frozen at -80°C and thawed just before the TG assay in duplicate under two conditions: 1 pM tissue factor (TF) or 5 pM TF + TM. Results and discussion: (1) We externally validated "MidiCAT" and also extended the validation to TG-TM. Whatever the method (CAT or MidiCAT), intra-assay (assessed with duplicates) CV was below 6% (1 pM TF) or below 10% (5 pM TF + TM) for ETP. Agreement between the MidiCAT and CAT results was satisfactory; the p coefficients were above 0.95 for ETP and above 0.90 for most other parameters; biases for ETP were +10.0% (1 pM FT) and +13.5% (5 pM + TM). (2) The centrifugation scheme markedly affected the results obtained in the presence of TM, whereas the bias and limit of agreement (difference plots) were low for the no TM condition. The bias in the presence of TM was obvious, more marked with plasma samples sensitive to TM when double centrifuged: the lower the ETP-TM, the greater the relative difference between the ETP-TM of plasma samples prepared with just single centrifugation and the reference plasma samples. Thus, a single-centrifugation procedure, as is often used for plasma biobanking, is suitable for TG study only if it is not performed in the presence of TM.

13.
J Thromb Haemost ; 20(8): 1859-1867, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35557490

RESUMEN

BACKGROUND: Venous thromboembolism (VTE) is a concern for patients with newly diagnosed multiple myeloma. OBJECTIVES: We aimed to evaluate VTE incidence, risk factors, and risk score. PATIENTS/METHODS: We performed a substudy of the "Intergroupe Francophone du Myelome 2009" randomized controlled trial. RESULTS: We assessed 700 patients receiving lenalidomide/bortezomib/dexamethasone, followed or not by autologous hematopoietic stem cell transplantation. VTE incidence at 6 months was 4.8% (95% confidence interval [CI]: 3.3-6.9%) and 1.5% (95% CI: 0.8-2.9%) from 6 to 12 months. Using multivariate analysis we confirmed history of VTE (odds ratio 5.1 [1.6-16.7], P = .007) as a strong VTE-related risk factor, invalidated erythropoietin exposure (0.6 [0.2-1.7], P = .3) as risk factor, and added two new risk factors: fracture at diagnosis (2.6 [1.3-5.5], P = .01), and serum gamma globulin level > 27 g/L (2.8 [1.2-6.8,] P = .02). Moreover, we noticed that VTE occurred earlier in patients with gamma globulin levels >27 g/L, suggesting a need to revisit the thromboprophylaxis timeframe. Heparin administration was associated with a decreased risk (0.3 [0.1-0.7], P = .005) but failed to erase the risk regardless of dose. The area under the receiver operating characteristic curve of the IMPEDE VTE score was 0.67, as previously reported, confirming our cohort was well representative. CONCLUSIONS: Prospective studies are warranted in light of these results to improve VTE risk stratification and to design adapted thromboprophylaxis in terms of timing and dose.


Asunto(s)
Mieloma Múltiple , Tromboembolia Venosa , Anticoagulantes/uso terapéutico , Bortezomib/efectos adversos , Dexametasona/efectos adversos , Humanos , Lenalidomida/efectos adversos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/prevención & control , gammaglobulinas/uso terapéutico
14.
Front Cell Dev Biol ; 9: 735518, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34650981

RESUMEN

Acute myeloid leukemias (AMLs) are a group of hematologic malignancies that are heterogeneous in their molecular and immunophenotypic profiles. Identification of the immunophenotypic differences between AML blasts and normal myeloid hematopoietic precursors (myHPCs) is a prerequisite to achieving better performance in AML measurable residual disease follow-ups. In the present study, we applied high-dimensional analysis algorithms provided by the Infinicyt 2.0 and Cytobank software to evaluate the efficacy of antibody combinations of the EuroFlow AML/myelodysplastic syndrome panel to distinguish AML blasts with recurrent genetic abnormalities (n = 39 AML samples) from normal CD45low CD117+ myHPCs (n = 23 normal bone marrow samples). Two types of scores were established to evaluate the abilities of the various methods to identify the most useful parameters/markers for distinguishing between AML blasts and normal myHPCs, as well as to distinguish between different AML groups. The Infinicyt Compass database-guided analysis was found to be a more user-friendly tool than other analysis methods implemented in the Cytobank software. According to the developed scoring systems, the principal component analysis based algorithms resulted in better discrimination between AML blasts and myHPCs, as well as between blasts from different AML groups. The most informative markers for the discrimination between myHPCs and AML blasts were CD34, CD36, human leukocyte antigen-DR (HLA-DR), CD13, CD105, CD71, and SSC, which were highly rated by all evaluated analysis algorithms. The HLA-DR, CD34, CD13, CD64, CD33, CD117, CD71, CD36, CD11b, SSC, and FSC were found to be useful for the distinction between blasts from different AML groups associated with recurrent genetic abnormalities. This study identified both benefits and the drawbacks of integrating multiple high-dimensional algorithms to gain complementary insights into the flow-cytometry data.

15.
Front Oncol ; 11: 746951, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34804933

RESUMEN

Acute myeloid leukemias (AMLs) are hematologic malignancies with varied molecular and immunophenotypic profiles, making them difficult to diagnose and classify. High-dimensional analysis algorithms might increase the utility of multicolor flow cytometry for AML diagnosis and follow-up. The objective of the present study was to assess whether a Compass database-guided analysis can be used to achieve rapid and accurate diagnoses. We conducted this study to determine whether this method could be employed to pilote the genetic and molecular tests and to objectively identify different-from-normal (DfN) patterns to improve measurable residual disease follow-up in AML. Three Compass databases were built using Infinicyt 2.0 software, including normal myeloid-committed hematopoietic precursors (n = 20) and AML blasts harboring the most frequent recurrent genetic abnormalities (n = 50). The diagnostic accuracy of the Compass database-guided analysis was evaluated in a prospective validation study (125 suspected AML patients). This method excluded AML associated with the following genetic abnormalities: t(8;21), t(15;17), inv(16), and KMT2A translocation, with 92% sensitivity [95% confidence interval (CI): 78.6%-98.3%] and a 98.5% negative predictive value (95% CI: 90.6%-99.8%). Our data showed that the Compass database-guided analysis could identify phenotypic differences between AML groups, representing a useful tool for the identification of DfN patterns.

16.
Front Immunol ; 12: 665541, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33986753

RESUMEN

Natural killer (NK) cells are key innate immunity effectors that play a major role in malignant cell destruction. Based on expression patterns of CD16, CD56, CD57, and CD94, three distinct NK cell maturation stages have been described, which differ in terms of cytokine secretion, tissue migration, and the ability to kill target cells. Our study addressed NK cell maturation in bone marrow under three conditions: a normal developmental environment, during pre-leukemic state (myelodysplastic syndrome, MDS), and during leukemic transformation (acute myeloblastic leukemia, AML). In this study, we used a new tool to perform multicolor flow cytometry data analysis, based on principal component analysis, which allowed the unsupervised, accurate discrimination of immature, mature, and hypermature NK subpopulations. An impaired NK/T cell distribution was observed in the MDS bone marrow microenvironment compared with the normal and AML settings, and a phenotypic shift from the mature to the immature state was observed in NK cells under both the MDS and AML conditions. Furthermore, an impaired NK cell antitumor response, resulting in changes in NK cell receptor expression (CD159a, CD158a, CD158b, and CD158e1), was observed under MDS and AML conditions compared with the normal condition. The results of this study provide evidence for the failure of this arm of the immune response during the pathogenesis of myeloid malignancies. NK cell subpopulations display a heterogeneous and discordant dynamic on the spectrum between normal and pathological conditions. MDS does not appear to be a simple, intermediate stage but rather serves as a decisive step for the mounting of an efficient or ineffective immune response, leading to either the removal of the tumor cells or to malignancy.


Asunto(s)
Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Leucemia Mieloide Aguda/inmunología , Síndromes Mielodisplásicos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Humanos , Leucemia Mieloide Aguda/sangre , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Receptores de Células Asesinas Naturales/metabolismo , Microambiente Tumoral
17.
Sci Rep ; 11(1): 6187, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33731863

RESUMEN

Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients' response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.


Asunto(s)
Antígenos CD34/inmunología , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide de Fase Crónica , Pirimidinas/farmacología , Humanos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/inmunología , Leucemia Mieloide de Fase Crónica/patología , Células Tumorales Cultivadas
18.
Crit Rev Oncol Hematol ; 154: 103067, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32739782

RESUMEN

Chronic fatigue is the most common and severe symptom in myelodysplastic syndromes (MDS) and has a strong negative association with health-related quality of life (HRQoL). Despite anemia being the most common objective manifestation of MDS, and the associated link between anemia and fatigue, evidence on treatments which temporarily mitigate anemia is equivocal regarding the effects on fatigue. Furthermore, previous work has found weak associations between anemia and chronic fatigue in MDS. As such, given that improving HRQoL is one of the primary treatment aims in MDS, further work is required to identify other potential contributors to chronic fatigue in these patients. In addition to anemia, MDS is associated with numerous other deviations in physiological homeostasis and has negative psychological consequences with links to chronic fatigue. Accordingly, the present review provides several potential aetiologic agents relevant to chronic fatigue in MDS which can be used to guide future research in this field.


Asunto(s)
Anemia/epidemiología , Anemia/etiología , Síndrome de Fatiga Crónica , Fragilidad , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/epidemiología , Humanos , Calidad de Vida
19.
Cells ; 9(3)2020 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-32155953

RESUMEN

Emerging evidence indicates that in myelodysplastic syndromes (MDS), the bone marrow (BM) microenvironment may also contribute to the ineffective, malignant haematopoiesis in addition to the intrinsic abnormalities of haematopoietic stem precursor cells (HSPCs). The BM microenvironment influences malignant haematopoiesis through indirect mechanisms, but the processes by which the BM microenvironment directly contributes to MDS initiation and progression have not yet been elucidated. Our previous data showed that BM-derived stromal cells (BMSCs) from MDS patients have an abnormal expression of focal adhesion kinase (FAK). In this study, we characterise the morpho-phenotypic features and the functional alterations of BMSCs from MDS patients and in FAK knock-downed HS-5 cells. The decreased expression of FAK or its phosphorylated form in BMSCs from low-risk (LR) MDS directly correlates with BMSCs' functional deficiency and is associated with a reduced level of haemoglobin. The downregulation of FAK in HS-5 cells alters their morphology, proliferation, and differentiation capabilities and impairs the expression of several adhesion molecules. In addition, we examine the CD34+ healthy donor (HD)-derived HSPCs' properties when co-cultured with FAK-deficient BMSCs. Both abnormal proliferation and the impaired erythroid differentiation capacity of HD-HSPCs were observed. Together, these results demonstrate that stromal adhesion mechanisms mediated by FAK are crucial for regulating HSPCs' homeostasis.


Asunto(s)
Médula Ósea/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/deficiencia , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Anciano , Anciano de 80 o más Años , Diferenciación Celular , Proliferación Celular , Células Madre Hematopoyéticas/citología , Homeostasis , Humanos , Células Madre Mesenquimatosas/metabolismo
20.
Oncotarget ; 11(26): 2560-2570, 2020 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-32655840

RESUMEN

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of BCR-ABL1 transcript as a result of reciprocal translocation between chromosome 9 and 22. The most common transcripts subtypes are e13a2 (b2a2) and e14a2 (b3a2). The prognostic impact of the type of BCR-ABL1 transcript has been the subject of controversies over time. In the imatinib era, several studies have suggested a deeper and faster response in patients expressing e14a2. However, the impact on response after first line therapy with a second-generation tyrosine kinase inhibitor, nilotinib, is unknown. We retrospectively evaluated 118 patients newly diagnosed with chronic phase CML and treated frontline with nilotinib inside or outside clinical trial in five French centers. Only patients expressing e14a2 or e13a2 transcripts alone were analyzed. At baseline, 55.3% expressed e14a2, 44.7% expressed e13a2. The median age was 51 years and median follow-up was 49 months. Relative risks of CML at diagnosis were similar according to the ELTS score (p = .87). Complete hematological response and complete cytogenetic response rates were similar among groups. Patients expressing e14a2 transcripts compared to e13a2 transcripts had deeper and faster molecular responses, when considering MMR (100% vs 84.1%, p = .007) with a median time of 6.7 and 17.1 months or MR4.5 (100% vs 59.9%, p = .005) with a median time of 39.7 and 70.9 months, respectively. A sustained treatment free remission was observed in 10/10 patients with e14a2 versus 1/3 with e13a2 transcript (p = .04). In conclusion, even treated with nilotinib first line, patients with chronic phase CML expressing BCR-ABL1 e13a2 transcript have a lower rate of deep molecular responses.

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