RESUMEN
This article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 × 109/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfocitosis/inducido químicamente , Linfoma/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Humanos , Masculino , Prednisona/efectos adversos , Rituximab , Vincristina/efectos adversosRESUMEN
BACKGROUND: Abnormal NK phenotype and cytotoxic functions have been described in acute myeloid leukemia, chronic lymphocytic leukemia, myeloma and myelodysplastic syndromes. Defective NK cytotoxicity is due to decreased expression of the Natural Cytotoxicity Receptors (NCRs), 2B4/CD244/p38, or NKG2D. This prompted us to test the expression of these molecules on circulating NK cells from patients with AIDS-related lymphomas (RL) in comparison with HIV + patients without lymphoma, healthy subjects and HIV-negative patients with lymphoma. METHODS: Blood samples were analyzed by flow cytometry for NCRs, 2B4/CD244/p38 and NKG2D expression on NK cells defined as CD3-/CD56+ lymphocytes. We also analyzed by quantitative PCR specific RNA for NKp30/NCR3 and NKp46/NCR1. RESULTS: We could not detect any defect in NKp46/NCR1 expression between all groups. NKp44/NCR2, NKp30/NCR3 and NKG2D had lower expression in AIDS-RL in comparison with HIV + patients without lymphoma when compared to patients with similar (>0.3 G/L) CD4+ lymphocyte levels. Expression of 2B4/CD244/p38 was lower in AIDS-RL than in HIV-negative lymphoma. Comparison of specific NKp30/NCR3 and NKp46/NCR1 RNA showed increased steady state levels, despite decreased surface expression for NKp30/NCR3, suggesting abnormal post-transcriptional regulatory mechanisms. CONCLUSIONS: We show a more pronounced defect in NK activating molecule when HIV infection is associated with lymphoma than when only one condition (HIV positivity or lymphoma) is present. Defective NK phenotype, in addition to CD4+ depletion and dysfunction, may participate to the increased incidence of lymphoma in HIV patients.
RESUMEN
In monoclonal gammopathies (MG) and multiple myeloma (MM), normal natural cytotoxicity receptors (NCR) expression (NCR1/NKp46, NCR2/NKp44, NCR3/NKp30) is observed in natural killer (NK) cells. Nonetheless, except in plasma cell leukemia, few tumor plasmocytes are present in PB, while NK studies have been performed on peripheral blood (PB). For this reason we focused our attention on NK from bone marrow (BM). Our study demonstrates that the down-regulation of NCR3/NKp30 is only detectable in NK from BM but not in PB, and shows a drastic decrease of both NKG2D and CD244/2B4/p38 expression in NK from BM in comparison with PB. In conclusion, our data more precisely describe the mechanism of immune escape of MG/MM from innate immunity since we show a drastic down regulation of 3 major activating NK receptors (NCR3/NKp30, NKG2D and CD244/2B4/p38) at the site of tumor, i.e BM, that was undetectable in PB. Further studies regarding immune regulatory drugs in MG/MM will imperiously require the assessment of immune cell status not only in PB but also in BM to obtain more relevant data regarding anti-tumor efficacy.
Asunto(s)
Médula Ósea/metabolismo , Regulación hacia Abajo , Células Asesinas Naturales/inmunología , Mieloma Múltiple/inmunología , Paraproteinemias/inmunología , Receptores de Células Asesinas Naturales/metabolismo , Anciano , Antígenos CD/metabolismo , Médula Ósea/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Receptor 3 Gatillante de la Citotoxidad Natural/metabolismo , Paraproteinemias/genética , Paraproteinemias/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Células Asesinas Naturales/sangre , Receptores de Células Asesinas Naturales/inmunología , Familia de Moléculas Señalizadoras de la Activación LinfocitariaAsunto(s)
Síndrome de Bernard-Soulier/genética , Heterocigoto , Mutación , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Trombocitopenia/genética , Adulto , Síndrome de Bernard-Soulier/sangre , Síndrome de Bernard-Soulier/patología , Femenino , Humanos , Masculino , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Trombocitopenia/sangre , Trombocitopenia/patologíaRESUMEN
Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 10(9)/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10(9)/L (interquartile range, 75-167 × 10(9)/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10(9)/L (interquartile range, 35-44 × 10(9)/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.
Asunto(s)
Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores Fc/uso terapéutico , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Plaquetas/efectos de los fármacos , Ensayos de Uso Compasivo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Proteínas Recombinantes de Fusión/efectos adversos , Estudios Retrospectivos , Trombopoyetina/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Recent advances in chronic lymphocytic leukaemia (CLL) treatment, more particularly through upfront use of anti-CD20 monoclonal antibodies, have prolonged patient progression-free survival. Nonetheless, apart from allogeneic stem cell transplantation, no curative treatment is available. One possible explanation for the lack of cure in CLL could be a defective immune anti-tumour response. As the result of abnormal HLA class I molecule expression, CLL cells escape from specific T-lymphocyte immunity but should be the target for the innate natural killer (NK) cell-mediated immune response. Defective NK cytotoxicity as the result of decreased expression of the natural cytotoxicity receptors (NCRs) NKp30/NCR3, NKp44/NCR2 and NKp46/NCR1 has been described in haematological malignancies such as acute myeloid leukaemia. This prompted us to focus our attention on NCR expression on NK cells from patients with CLL. Although we failed to detect any difference between CLL patients and healthy age-matched controls, a precise analysis of clinical data showed a correlation between decreased NCR expression and poor prognosis factors such as low haemoglobin level, high (>30×10(9) per litre) lymphocyte count or elevated C-reactive protein. Together, these observations support the rationale for restoration of normal NK cell functions in patients with CLL, putatively through the use of immune therapy protocols that already have demonstrated some benefit in acute myeloid leukaemia such as interleukin-2 plus histamine dihydrochloride.
Asunto(s)
Células Asesinas Naturales/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Receptores de Células Asesinas Naturales/biosíntesis , Anciano , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/patología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/patología , Masculino , Persona de Mediana Edad , Fenotipo , Receptores de Células Asesinas Naturales/inmunologíaRESUMEN
In order to standardize cellular hematology practices, the French-speaking Cellular Hematology Group (Groupe Francophone d'Hématologie Cellulaire, GFHC) focused on Perls' stain. A national survey was carried out, leading to the proposal of recommendations on insoluble iron detection and quantification in bone marrow. The criteria presented here met with a "strong professional agreement" and follow the suggestions of the World Health Organization's classification of hematological malignancies.
RESUMEN
Peripheral T-cell lymphomas constitute a heterogeneous group with regard to diagnosis, treatment and prognosis. Efforts have been made to combine novel techniques with cytology and immunochemistry in order to more precisely define these entities. Molecular profiling has contributed to novel insights in the biology of T-cell lymphoma. Regarding anaplastic large cell lymphoma, low expression T-cell receptor signalling and high STAT3 target signatures have been associated with the ALK-positive subgroup. Gene expression profiling differentiates angioblastic T-cell lymphoma from other T-cell malignancies, suggests that the normal counterpart of lymphoma cells are follicular helper T cells, and supports the involvement of vascular endothelial growth factor deregulation in its physiopathology. In peripheral T-cell lymphoma unspecified, gene profiling suggests the normal counterpart of tumour cells are activated CD4(+) or CD8(+) T-lymphocytes, delineates prognostic groups depending on the proliferative signature, and suggests therapeutic options aimed at regulating nuclear factor-kappaB and platelet-derived growth factor receptor-alpha phosphorylation. Gene expression profiling of primary cutaneous T cell lymphomas highlighted the importance of abnormal methylation patterns, suggested a pivotal role for JUNB/AP-1, and defined a predictive model for response to interferon-alpha. In conclusion, gene expression profiling is beginning to change the pathological classification, the prognosis profiles and the therapeutic approach in T-cell lymphomas.
Asunto(s)
Linfoma de Células T Periférico/genética , Perfilación de la Expresión Génica , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/terapia , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/terapia , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Gaucher disease (GD) is the most frequent lysosomal storage disease and corresponds to an inherited deficiency of glucocerebrosidase. Due to excessive accumulation of glucocerebroside in bone marrow, both cytopenia and bone lesions may occur. The incidence of malignant disorders has been evoked in non-neuronopathic type I GD. More particularly, many case reports have been published that describe the association between GD and multiple myeloma (MM). Here, we first deal with diagnosis criteria that allow to distinguish between bona fide Gaucher celles and the so-called pseudo or pseudo-pseudo Gaucher cells. We then analyse relevant case reports and recent articles that provide convincing data regarding GD and MM association and suggest physiopathological links between the two disorders.
Asunto(s)
Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/diagnóstico , Enfermedades por Almacenamiento Lisosomal/complicaciones , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Anciano , Diagnóstico Diferencial , Glucosilceramidasa/metabolismo , Humanos , Macrófagos/patología , Persona de Mediana EdadRESUMEN
Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB). These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK) cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2]. In this study we investigated the effect of the demethylating drug 5-azacytidine (Vidaza(®)) on NK receptors with the hypothesis that demethylation of the promoters of activating NK receptor genes induces gene reactivation and thus may increase their expression.
RESUMEN
Polycythemia vera (PV) is a disease with slow development. Nonetheless, the immune response is unable to eliminate the uncontrolled proliferating hematopoietic cells, leading to treatment of patient by phlebotomy and/or cytotoxic drugs. In addition, a higher incidence of cancers is observed in PV patients, independently of treatment. These observations argue for an impaired immune response in PV. In order to investigate this hypothesis, we studied the distribution of lymphocyte subpopulations in PV, and showed a significant decrease in T, TCR γ/δ and B cells together with an increase in natural killer (NK) cells.
Asunto(s)
Subgrupos de Linfocitos B/patología , Células Asesinas Naturales/patología , Policitemia Vera/patología , Subgrupos de Linfocitos T/patología , Anciano , Anciano de 80 o más Años , Subgrupos de Linfocitos B/inmunología , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Inmunofenotipificación , Janus Quinasa 2/genética , Janus Quinasa 2/inmunología , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana Edad , Mutación , Policitemia Vera/genética , Policitemia Vera/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
We report the case of a patient bearing a T315I-mutant chronic myeloid leukemia resistant to nilotinib, successfully treated with omacetaxine and then with dasatinib. After 9 months of nilotinib, the patient achieved a major molecular response but relapsed 3 months later due to the T315I mutation. Because third-generation tyrosine kinase inhibitor was not available and the patient refused bone marrow transplantation, he received two cycles of omacetaxine. This treatment had been stopped after two cycles because of clinical intolerance, but a major molecular response and total disappearance of the T315I clone was obtained. Treatment with dasatinib was then started and after 34-month follow-up the patient is still in major molecular response, thus suggesting that eradication of the T315I mutation could be achieved without third-generation tyrosine kinase inhibitors.
Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/farmacología , Dasatinib/farmacología , Dasatinib/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Masculino , Persona de Mediana Edad , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirimidinas/uso terapéuticoRESUMEN
Natural killer cells (NK) are pivotal cells of innate immunity. They are potent antileukemic cytotoxic effectors. A defect in their cytotoxicity has been described in some hematopoietic malignancies such as acute myeloid leukemia, multiple myeloma and myelodysplastic syndromes. This defect is at least partially linked to a decreased or absent expression of some activating NK cells molecules, more particularly the so-called natural cytotoxicity receptors. In the present study, we more particularly focused our attention on NK cells of polycythemia vera, a myeloproliferative disease characterized by the presence of mutated JAK2 tyrosine kinase. The polymerase chain reaction analysis of NK cells from patients showed that they expressed the mutated form of JAK2. In polycythemia vera the proportion of NK was increased compared to healthy donors. The proliferative and cytotoxic abilities of NK cells from patients were similar to healthy donors. Expression of activating or inhibitory receptors was comparable in patients and donors, with nonetheless an imbalance for the inhibitory form of the CD158a,h couple of receptors in patients. Finally, the transcriptomic profile analysis clearly identified a discriminant signature between NK cells from patients and donors that could putatively be the consequence of abnormal continuous activation of mutated JAK2.
Asunto(s)
Células Asesinas Naturales/inmunología , Policitemia Vera/inmunología , Anciano , Antígenos de Superficie/metabolismo , Estudios de Casos y Controles , Análisis por Conglomerados , Citotoxicidad Inmunológica , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunofenotipificación , Janus Quinasa 2/genética , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia Vera/metabolismo , Receptores de Células Asesinas Naturales/genética , Receptores de Células Asesinas Naturales/metabolismoRESUMEN
Tissue factor pathway inhibitor (TFPI) plays a crucial role in haemostasis by regulating TF-induced initiation of coagulation. Since it is expressed by endothelial and trophoblastic cells, TFPI is of particular importance at the placental level and might be involved in the occurrence of gestational vascular complications (GVC). In the present study, we investigated plasma free TFPI antigen in four groups of women: healthy non-pregnant women without history of pregnancy complications; women at the beginning (<12 weeks) and women during the third trimester of a normal pregnancy; women with late pregnancy complications (pre-eclampsia / HELLP syndrome, intra-uterine fetal death, fetal growth retardation) at the time of obstetrical event and/or at distance from pregnancy. In normal pregnancy, TFPI increased between first trimester and delivery (median 5.0 ng/ml vs. 7.1 ng/ml; p<0.0001) but remained lower than in non-pregnant controls (median 8.2 ng/ml; p<0.0001). In patients, when measured concomitantly to the obstetrical event, TFPI showed no difference with normal late pregnancy levels. In contrast, at distance from pregnancy, in the absence of any hormonal influence, TFPI was significantly lower than in non-pregnant controls (median 5.9 vs. 8.2ng/ml, p < 0.0001). After categorisation into quartiles, an inverse dose-effect relationship was demonstrated between TFPI categories recorded apart from pregnancy and GVC risk, with a crude odds ratio of 43.5 (95% confidence interval 8.2-230) for patients with TFPI values in the lowest quartile (< 5.7 ng/ml). In conclusion, low free TFPI at distance from pregnancy appears to be a strong indicator of GVC risk.
Asunto(s)
Lipoproteínas/deficiencia , Valor Predictivo de las Pruebas , Complicaciones Cardiovasculares del Embarazo/diagnóstico , Estudios de Casos y Controles , Inhibidores del Factor Xa , Femenino , Edad Gestacional , Humanos , Lipoproteínas/sangre , Oportunidad Relativa , Embarazo , Complicaciones Cardiovasculares del Embarazo/sangre , Trimestres del Embarazo , RiesgoAsunto(s)
Agranulocitosis/tratamiento farmacológico , Agranulocitosis/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Anciano , Agranulocitosis/sangre , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Ciclosporina/administración & dosificación , Resultado Fatal , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Recuento de Leucocitos , Masculino , Inducción de Remisión , RituximabRESUMEN
Quarenta e cinco leucemias linfoblásticas agudas (LAL) foram testadas imunologicamente. Quatro com as características de LAL pré-B, isto é, a presença de cadeia intracitoplasmática detectas por imunofluorescência direta, sem imunoglobulina de membrana. Estes quatro casos exprimiam o antígeno de membrana HLA-DR, e um caso com o antígeno reconhecido pelo anticorpo monoclonal J-5 (CALLA). Estes quatro pacientes, dois adultos e duas crianças, apresentavam síndrome clínica e biológica de mau prognóstico com características tumoral e hiperleucocitose