RESUMEN
Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0.0001). RIPA was impaired in patients receiving concomitant antiplatelet therapy or anticoagulation (14 vs 25 U, P=0.005). A gradual decline of median RIPA values was observed with increasing bleeding severity. Importantly, no CTC grade 2 or 3 bleeding were observed with RIPA values of >36 U. Sequential monitoring indicated a decrease of RIPA values from a median of 17 to 9 U within 2 weeks after initiation of treatment as well as an increase above the critical threshold of 36 U within 7 days when ibrutinib was paused. Low RIPA values were similar during treatment with another BTK inhibitor, CC292. Quantitative assessment of platelet function is a practical tool to monitor bleeding tendency under BTK-inhibitor therapy.
Asunto(s)
Hemorragia/inducido químicamente , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Agregación Plaquetaria/efectos de los fármacos , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Ristocetina/farmacología , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Monitoreo de Drogas/métodos , Femenino , Hemorragia/tratamiento farmacológico , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Masculino , Persona de Mediana Edad , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificaciónAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Humanos , Medicina de Precisión , Traumatismos por Radiación/prevención & control , Radioterapia/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Vincristina/administración & dosificaciónRESUMEN
To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.
Asunto(s)
Factores de Transcripción de Tipo Kruppel/genética , Linfoma de Células B de la Zona Marginal/genética , Mutación , Neoplasias del Bazo/genética , Biopsia , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteínas de Unión al ADN/metabolismo , Exoma , Mutación del Sistema de Lectura , Reordenamiento Génico de Cadena Pesada de Linfocito B , Variación Genética , Genotipo , Guanilato Ciclasa/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfoma/metabolismo , Linfoma de Células B de la Zona Marginal/diagnóstico , Mutación Missense , Proteínas Nucleares/metabolismo , Reacción en Cadena de la Polimerasa , Receptor Notch2/metabolismo , Recurrencia , Análisis de Secuencia de ADN , Transducción de Señal , Neoplasias del Bazo/diagnóstico , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
Primary testicular non-Hodgkin lymphoma (PTL) comprises around 9% of testicular cancers and 1-2% of all non-Hodgkin lymphomas. Its incidence is increasing and it primarily affects older men, with a median age at presentation of around 67 years. By far the most common histological subtype is diffuse large B-cell lymphoma, accounting for 80-90% of PTLs. Most patients present with a unilateral testicular mass or swelling. Up to 90% of patients have stage I or II disease at diagnosis (60 and 30%, respectively) and bilateral testicular involvement is seen in around 35% of patients. PTL demonstrates a continuous pattern of relapse and propensity for extra-nodal sites such as the central nervous system and contralateral testis. Retrospective data have emphasised the importance of prophylactic radiotherapy in reducing recurrence rates within the contralateral testis. Recent outcome data from the prospective IELSG-10 trial have shown far better progression-free and overall survival than historical outcomes. This supports the use of orchidectomy followed by Rituximab- cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), central nervous system prophylaxis and prophylactic radiotherapy to the contralateral testis with or without nodal radiotherapy in patients with limited disease. Central nervous system relapse remains a significant issue and future research should focus on identifying the best strategy to reduce its occurrence. Here we discuss the evidence supporting combination chemotherapy and radiotherapy in PTL.
Asunto(s)
Linfoma no Hodgkin/terapia , Neoplasias Testiculares/terapia , Humanos , Linfoma no Hodgkin/patología , Masculino , Estadificación de Neoplasias , Neoplasias Testiculares/patologíaRESUMEN
Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.
Asunto(s)
Antígenos CD19/genética , Cromatina/química , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 8/genética , Leucemia Mieloide Aguda/genética , Factor de Transcripción PAX5/genética , Translocación Genética/genética , Antígenos CD19/metabolismo , Linfocitos B/metabolismo , Linfocitos B/patología , Cromatina/fisiología , Inmunoprecipitación de Cromatina , Huella de ADN , Elementos de Facilitación Genéticos , Citometría de Flujo , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Regiones Promotoras Genéticas , Células Tumorales CultivadasAsunto(s)
Autoanticuerpos , Enfermedad de Hodgkin/diagnóstico , Encefalitis Límbica/diagnóstico , Receptores de N-Metil-D-Aspartato , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/metabolismo , Humanos , Encefalitis Límbica/complicaciones , Encefalitis Límbica/metabolismo , Masculino , Persona de Mediana Edad , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Ten percent to 20% of patients with Hodgkin Lymphoma (HL) are refractory to first-line therapy or relapse. Existing salvage regimens have response rates of 60-85%, considerable toxicity and frequent treatment delay or dose reduction. We report a gemcitabine, cisplatin, and dexamethasone regimen (GemCis) with intensive growth factor and platelet support and no treatment delay. Seventeen patients with relapsed or refractory biopsy proven HL were treated. Toxicity, transfusion requirement, stem cell harvesting and engraftment data were collected. Response assessment was by computed tomography and positron emission tomography. Overall and complete response rates were high (94% and 65%, respectively). There were no episodes of febrile neutropenia, treatment delays or hospital admissions. All 15 patients intended for autograft were successfully harvested. All engrafted successfully with a median time for the entire group to neutrophil engraftment of 14 days. With a median follow-up of 22 months, the median survival has not yet been reached, and the estimated 2-year survival is 88%. GemCis is a well-tolerated outpatient regimen for relapsed/ refractory Hodgkin lymphoma which does not inhibit stem cell mobilisation, gives excellent response rates and compares favourably with previously published salvage regimens using these or other chemotherapy agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Transfusión Sanguínea/economía , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/economía , Terapia Combinada , Citarabina/economía , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/economía , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Dexametasona/economía , Supervivencia sin Enfermedad , Esquema de Medicación , Evaluación de Medicamentos , Resistencia a Antineoplásicos , Etopósido/economía , Femenino , Estudios de Seguimiento , Factores de Crecimiento de Célula Hematopoyética/uso terapéutico , Enfermedad de Hodgkin/cirugía , Humanos , Masculino , Metilprednisolona/economía , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Neutropenia/prevención & control , Recurrencia , Estudios Retrospectivos , Trasplante Autólogo , Adulto Joven , GemcitabinaRESUMEN
Molecular genetic techniques have become an integral part of the diagnostic assessment for many lymphomas and other chronic lymphoid neoplasms. The demonstration of a clonal immunoglobulin or T cell receptor gene rearrangement offers a useful diagnostic tool in cases where the diagnosis is equivocal. Molecular genetic detection of other genomic rearrangements may not only assist with the diagnosis but can also provide important prognostic information. Many of these rearrangements can act as molecular markers for the detection of low levels of residual disease. In this review, we discuss the applications of molecular genetic analysis to the chronic lymphoid malignancies. The review concentrates on those disorders for which molecular genetic analysis can offer diagnostic and/or prognostic information.
Asunto(s)
Linfoma de Células B/genética , Linfoma no Hodgkin/genética , Linfoma de Células T/genética , Linfoma de Burkitt/genética , Reordenamiento Génico , Humanos , Inmunoglobulina G/genética , Leucemia de Células Pilosas/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Prolinfocítica/genética , Leucemia-Linfoma de Células T del Adulto/genética , Linfoma Folicular/genética , Linfoma de Células del Manto/genética , Técnicas de Diagnóstico Molecular , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
A 43 year old male presented with a marked eosinophilia and associated systemic symptoms. A diagnosis of myelodysplasia was made on the basis of bone marrow morphology and karyotype. Over a 12 month period the disease transformed into acute lymphoblastic leukaemia, confirmed by flow cytometry, cytochemistry, and immunohistochemistry. Karyotyping was abnormal with 5q- and -7 which persisted from diagnosis through to blastic transformation. He died following initial induction chemotherapy. Eosinophilic myelodysplasia is an uncommon condition in haematological practice and no previous report of lymphoblastic transformation has been found.
Asunto(s)
Transformación Celular Neoplásica/patología , Eosinofilia/patología , Síndromes Mielodisplásicos/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adulto , Resultado Fatal , Humanos , MasculinoRESUMEN
A 55-year-old patient developed progressive loss of vision in one eye following induction chemotherapy for acute myeloid leukaemia (AML). Aspergillus fumigatus was cultured from vitreal aspirates. The patient was treated with intravenous and intravitreal amphotericin B but suffered complete loss of vision in her right eye. We believe this is the first report of culture-proven Aspergillus fumigatus endophthalmitis in a patient treated for a haematological malignancy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Aspergilosis/inducido químicamente , Aspergillus fumigatus/aislamiento & purificación , Endoftalmitis/inducido químicamente , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Persona de Mediana EdadAsunto(s)
Nefritis Lúpica/complicaciones , Infecciones Oportunistas/complicaciones , Enfermedades Cutáneas Infecciosas/complicaciones , Infecciones Estafilocócicas/complicaciones , Adulto , Brazo , Femenino , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Infecciones Oportunistas/patología , Enfermedades Cutáneas Infecciosas/patología , Infecciones Estafilocócicas/patologíaRESUMEN
During the months of September 1993 through February 1994, an outbreak of hemorrhagic fever occurred in the city of Jayapura, the provincial capital of Irian Jaya, Indonesia. Seventy-two patients (age range = 1-41 years) with suspected dengue hemorrhagic fever (DHF) were enrolled into the outbreak investigation conducted during October-November 1993. The pediatric patient population consisted of 36 individuals ages 1-12 years of age with a similar male to female ratio. From clinical histories obtained from the children diagnosed with DHF (n = 23), the predominant complaints were fever (100%), headache (96.7%), vomiting (47.8%), abdominal pain (39.1%), back/bone pain (39.1%), cough (39.1%), sore throat (21.7%), convulsions (17.4%), and eye pain (13.0%). Clinical findings of the same pediatric patients included a positive tourniquet test result (100%), thrombocytopenia (100%), hemoconcentration (100%), skin petechiae (43.5%), epistaxis (39.1%), and maculopapular rash (26%). All four of the children diagnosed with DHF grade IV had hepatomegaly, pleural effusion, ascites, cold perspiration, and confusion. Serologic data demonstrated that a majority (46 of 70, 68.7%) of the individuals assessed did not have significant levels of IgM specific for dengue viruses at the time of their admission. However, the nine successful dengue virus isolations were only from these serononreactive cases (19.6%). From the other patients assessed, 11.4% had a primary (or first exposure) serologic response to dengue virus antigen (predominantly IgM); 17.1% had a secondary (or subsequent exposure) serologic response to the same dengue antigens (predominantly IgG response) and 5.7% (four adults) had indeterminate serologic data that could not differentiate between reactivity to dengue or Japanese encephalitis virus antigen preparations. Virus culture of blood samples produced nine dengue virus isolates: DEN- 1 (2), DEN-2 (1), and DEN-3 (6). Japanese encephalitis and influenza viruses were not isolated from blood and pharyngeal specimens, respectively, from any of the patients. Thus, this first reported outbreak of DHF in Irian Jaya, Indonesia was found to be attributed to dengue viruses types 1, 2, and 3.
Asunto(s)
Virus del Dengue/aislamiento & purificación , Dengue/epidemiología , Brotes de Enfermedades , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Niño , Preescolar , Dengue/diagnóstico , Dengue/inmunología , Dengue/virología , Virus del Dengue/clasificación , Virus del Dengue/inmunología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Indonesia/epidemiología , Lactante , Masculino , Viremia/virologíaRESUMEN
Mycobacterium tuberculosis- or group A streptococcus-activated gamma/delta T cells from normal healthy individuals were negatively sorted and restimulated in vitro from 48 h. Significant amounts of gamma interferon were detected after restimulation with M. tuberculosis, group A streptococci, or Listeria monocytogenes. In contrast, interleukin 4 was undetectable in the culture supernatants. Our findings provide indirect evidence for the involvement of gamma/delta T cells in immunity against tubercle bacilli and probably other bacteria.
Asunto(s)
Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/biosíntesis , Activación de Linfocitos , Mycobacterium tuberculosis/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/análisis , Linfocitos T/metabolismo , Células Cultivadas , Humanos , Listeria monocytogenes/inmunología , Streptococcus pyogenes/inmunología , Linfocitos T/inmunologíaRESUMEN
Immunity to intracellular bacteria including Mycobacterium tuberculosis, Mycobacterium leprae, and Listeria monocytogenes depends on specific T cells. Evidence to be described suggests that CD4 alpha/beta T cells, CD8 alpha/beta T cells and gamma/delta T cells which interact with each other and with macrophages contribute to acquired resistance against as well as pathogenesis of intracellular bacterial infections.