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1.
Pharmacogenet Genomics ; 27(2): 70-77, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27977511

RESUMEN

OBJECTIVE: Rituximab in combination with chemotherapy has been proven to increase progression-free and overall survival in follicular lymphoma (FL), but there is considerable interindividual variability in the response. Extrinsic pathway apoptosis triggered by death receptors seems to be involved in the mechanism of action of monoclonal antibodies. This study aimed to assess the association between TRAILR1/TRAIL polymorphisms (rs20575, rs20576, rs2230229, rs12488654) and rituximab response and the relationship with FASL rs763110, previously found to be associated with rituximab response. PATIENTS AND METHODS: Polymorphisms were determined in a study cohort of 125 FL patients treated with rituximab as first-line treatment and correlated with response, which was scored according to the International Working Group Consensus Revised as complete response, partial response, stable disease, and progressive disease. RESULTS: No significant association with response was found for rs20576, rs2230229, and rs12488654 polymorphisms. In contrast, rs20575 GC/GG carriers were more partial/nonresponders (88.2%) than complete responders (72.5%), showing a trend toward statistical significance (P=0.064). In a multivariable setting, we found that female sex [odds ratio=0.355, 95% confidence interval (CI): 0.137-0.922, P=0.033] and the TRAILR1 rs20575 CC genotype (odds ratio=0.162, 95% CI: 0.035-0.757, P=0.021) were independent positive predictive factors of complete clinical response to rituximab, constructing a parsimonious model with good calibration [χ of 5.719 (d.f.=6, P=0.455)] and discrimination (C-statistic=0.739, 95% CI: 0.636-0.842). CONCLUSION: After studying the pharmacogenetic role of TRAILR1/TRAIL polymorphisms in rituximab-treated FL patients, we found that the rs20575 CC genotype is an independent predictive factor of better rituximab response, indicating the possible involvement of death receptors in anti-CD20 mechanisms of action.


Asunto(s)
Antineoplásicos/administración & dosificación , Proteína Ligando Fas/genética , Linfoma Folicular/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Rituximab/administración & dosificación , Adulto , Anciano , Antineoplásicos/farmacocinética , Apoptosis , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma Folicular/genética , Masculino , Persona de Mediana Edad , Variantes Farmacogenómicas , Rituximab/farmacocinética , Análisis de Supervivencia , Resultado del Tratamiento
2.
Br J Haematol ; 174(6): 859-67, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27185197

RESUMEN

The management of recurrent/refractory (R/R) Hodgkin lymphoma (HL) remains challenging. Previously published data have shown some efficacy of rituximab in this setting. The purpose of this phase II trial was to investigate the activity of ofatumumab in combination with etoposide, steroids, cytarabine and cisplatin (O-ESHAP) in 62 patients with R/R classical HL. Treatment consisted of ESHAP plus ofatumumab 1000 mg on days 1 and 8 of the first cycle and day 1 of the second and third cycles. O-ESHAP was well tolerated with only 3% of patients requiring treatment discontinuation because of adverse events. Overall response rate was 73% (44% complete metabolic response). In multivariate analysis, early relapse (P < 0·001), bulky disease (P < 0·001) and B symptoms (P < 0·001) were the most important prognostic factors for response. No failures of stem cell mobilization were observed. The high response rate, particularly the complete metabolic response rate, the low toxicity profile, and the high mobilizing potential of the O-ESHAP regimen suggest that patients with R/R HL may benefit from this salvage regimen. However, with the encouraging results observed with other new therapeutic agents in HL, the O-ESHAP regimen could be restricted to patients failing these agents or to those with R/R nodular lymphocyte-predominant HL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Terapia Combinada , Citarabina/efectos adversos , Citarabina/uso terapéutico , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Etopósido/efectos adversos , Etopósido/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Prednisona/efectos adversos , Prednisona/uso terapéutico , Recurrencia , Retratamiento , Terapia Recuperativa , Análisis de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Adulto Joven
3.
Eur J Haematol ; 96(5): 532-40, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26179864

RESUMEN

Bendamustine is an increasingly used hybrid alkylating agent that is active in lymphoid neoplasias via a novel mechanism of action. There are some pending questions about its use in clinical practice because of its developmental features. A consensus panel of several leading Spanish hematologists with broad experience in the clinical use of bendamustine has established recommendations for the management and treatment of hematological patients with bendamustine based on available clinical data and the experience of the participants. These recommendations address the dose and treatment regimen for different clinical indications, the management of toxicity, and support therapy. This article contains the conclusions of this consensus panel, which are intended to serve as guidelines for the use of bendamustine.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Síndrome Linfoproliferativo Autoinmune/tratamiento farmacológico , Clorhidrato de Bendamustina/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Conferencias de Consenso como Asunto , Manejo de la Enfermedad , Humanos , Mieloma Múltiple/diagnóstico , Guías de Práctica Clínica como Asunto
4.
Am J Hematol ; 90(8): 686-90, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25925613

RESUMEN

Bone marrow infiltration (BMI), categorized as an extra-nodal site, affects stage and is associated with poor prognosis in newly diagnosed lymphoma patients. We have evaluated the accuracy of PET/CT and bone marrow biopsy (BMB) to assess BMI in 372 lymphoma patients [140 Hodgkin Lymphoma (HL) and 232 High Grade B-cell non-Hodgkin Lymphoma (HG B-NHL), among them 155 Diffuse Large B-Cell Lymphoma (DLCL)]. For HL cases, and taking into account PET/CT, sensitivity, negative predictive value (NPV) and accuracy were 96.7, 99.3, and 99.3% while those of BMB were 32.3, 83.8, and 85%, respectively. For HG B-NHL and considering PET/CT, sensitivity, NPV, and accuracy were 52.7, 81.7, and 84.1%, while those of BMB were 77.6, 90.2, and 90.7%, respectively. In the HG B-NHL group, 25 patients would have been under-staged without BMB. These results lead us to recommend PET/CT and the avoidance of BMB to assess BMI in HL. In the case of HG B-NHL, bone marrow status should be assessed firstly by means of PET/CT; only in either focal or diffuse PET/CT with low borderline SUV max values or in negative cases, should BMB be carried out afterwards. In the HG B-NHL setting and at the present moment, both techniques are complementary.


Asunto(s)
Médula Ósea/patología , Enfermedad de Hodgkin/diagnóstico , Linfoma no Hodgkin/diagnóstico , Adolescente , Adulto , Anciano , Biopsia , Femenino , Fluorodesoxiglucosa F18/metabolismo , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Humanos , Linfoma no Hodgkin/clasificación , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Clasificación del Tumor , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X
5.
Br J Haematol ; 167(3): 327-36, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25066542

RESUMEN

We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk-adapted therapy in high-risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)-PET after three courses of R-MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET-positive patients received two courses of R-IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem-cell transplantation. The primary endpoint was progression-free survival (PFS). 71 patients (median age 55 years, range 25-69) were enrolled. With a median follow-up of 42·8 months (range 7·2-58·4), the estimated 4-year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N = 36) had significantly better 3-year PFS than those with partial response (N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02-6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3-year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35-20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89-97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carmustina/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/terapia , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica , Prednisona/administración & dosificación , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Rituximab , Trasplante Autólogo , Resultado del Tratamiento , Vincristina/administración & dosificación
6.
Ann Hematol ; 93(2): 243-7, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23959437

RESUMEN

The TRAILR1/TRAIL system is implicated in the induction of the extrinsic apoptotic pathway and constitutes an emerging target in cancer therapeutics. The objective of this study is to assess lymphoma risk associated with certain polymorphisms in TRAILR1 and TRAIL1 genes. DNA was extracted from 381 subjects (190 lymphoma cases and 191 matched controls) and genotyped for polymorphisms rs20576, rs2230229 and rs20575 in TRAILR1 and rs12488654 in TRAIL gene. In contrast to TRAILR1 polymorphisms, the genotype distribution of rs12488654 in TRAIL gene was different between cases and controls, A allele carriers (CA/AA) being much more common in the cases with different lymphoma types (follicular, 45 %; diffuse large B cell, 45.2 % and Hodgkin lymphomas, 40 %) than in controls (15.7 %) (odds ratio (OR), 3.5; CI, 2.1­5.9; p<0.001; OR, 3.5; CI, 1.6­7.9; p=0.001; OR, 2.9; CI, 1.1­7.5; p=0.027, respectively). This effect was consistently independent of the association with the TRAILR1 polymorphisms studied, as demonstrated by linkage disequilibrium and haplotype analyses. This study is the first one to report an association between a TRAIL polymorphism and lymphoma risk and suggests a possible role of TRAIL in B cell lymphomagenesis.


Asunto(s)
Alelos , Predisposición Genética a la Enfermedad , Linfoma/genética , Polimorfismo Genético , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Adulto , Anciano , Femenino , Humanos , Linfoma/metabolismo , Masculino , Persona de Mediana Edad , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo
7.
BMC Cancer ; 13: 228, 2013 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-23651475

RESUMEN

BACKGROUND: The interplay between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. EPHX1, NQO1 and PON1 are three genes encoding proteins directly involved in the detoxification of potential carcinogens. METHODS: We have studied the prevalence of three functional polymorphisms affecting these genes rs1051740 EPHX1, rs1800566 NQO1 and rs662 PON1 in 215 patients with lymphoma and 214 healthy controls. RESULTS: Genotype frequencies for EPHX and NQO1 polymorphisms did not show any correlation with disease. In contrast, the GG genotype in the PON1 polymorphism was found to be strongly associated with the disease (15.3% vs. 4.7%; OR = 3.7 CI (95%): 1.8-7.7; p < 0.001). According to the pathological diagnosis this association was related to follicular (p = 0.004) and diffuse large B-cell (p = 0.016) lymphomas. CONCLUSIONS: Despite the fact that further confirmation is needed, this study shows that the PON1 GG genotype in rs662 polymorphism could be a risk factor for B-cell lymphomas.


Asunto(s)
Arildialquilfosfatasa/genética , Epóxido Hidrolasas/genética , Predisposición Genética a la Enfermedad , Linfoma/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Adulto , Anciano , Estudios de Casos y Controles , Intervalos de Confianza , Femenino , Genotipo , Humanos , Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/genética , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple
8.
Cancer Med ; 12(6): 6536-6546, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36373169

RESUMEN

BACKGOUND: In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques. METHODS: The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens. RESULTS: In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age > 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24. CONCLUSION: Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.


Asunto(s)
Linfoma Folicular , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18 , Linfoma Folicular/diagnóstico por imagen , Linfoma Folicular/patología , Médula Ósea/diagnóstico por imagen , Médula Ósea/patología , Pronóstico , Estudios de Cohortes , Estudios Retrospectivos , Tomografía de Emisión de Positrones/métodos , Biopsia
9.
Mol Carcinog ; 51(6): 508-13, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21681823

RESUMEN

The interrelationship between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. Both factors need to be considered to enable assessment of disease risk associated with a given individual under certain environmental conditions. GSTT1 and GSTM1 are two genes whose proteins are involved in the detoxification of potential carcinogens. We have studied the prevalence of GSTT1 and GSTM1 null polymorphisms using a novel PCR multiplex protocol in a group of 158 patients with B-cell lymphoma (BCL, 138 with non-Hodgkin lymphoma and 20 with Hodgkin lymphoma) and 214 healthy controls. A questionnaire regarding occupational exposure and lifestyle factors was also completed by both groups. GSTM1 null genotype showed no significant differences between patients and controls (46.9% and 55.6%, respectively). In contrast, GSTT1 null genotype was observed in 25.3% of patients and 15.4% of controls (P=0.013; OR=1.85; CI (95%):1.11-3.09), suggesting a role for the GSTT1 null genotype in the development of BCL. This effect was even more evident in females (27.5% vs. 14%: P=0.014). No significant association was observed between GST genotypes and disease risk in relation to smoking or occupational exposure.


Asunto(s)
Genotipo , Glutatión Transferasa/genética , Linfoma de Células B/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Linfoma de Células B/epidemiología , Masculino , Persona de Mediana Edad , Exposición Profesional , Factores de Riesgo , España/epidemiología
10.
Int J Hematol ; 116(3): 381-392, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35551632

RESUMEN

This retrospective study evaluated 66 patients diagnosed with relapsed and/or refractory mantle cell lymphoma (R/R MCL) treated with ibrutinib in Spain in routine clinical practice. At diagnosis, patients had a median age of 64.5 years, 63.6% presented with intermediate/high sMIPI (simplified prognostic index for advanced-stage mantle cell lymphoma), 24.5% had the blastoid variant, and 55.6% had a Ki67 > 30%. Patients had received a median of 2 prior lines of therapy (range 1-2; min-max 1-7). Overall response rate was 63.5%, with 38.1% of patients achieving complete response (CR). With a median duration of ibrutinib exposure of 10.7 months (range 5.2-19.6; min-max 0.3-36), the median progression-free survival (PFS) and overall survival (OS) were 20 months [95% confidence interval (CI) 8.8-31.1] and 32 months (95% CI 22.6-41.3), respectively, and were not reached in patients achieving CR. No grade ≥ 3 cardiovascular toxicity or bleeding was reported. This study supports that treatment with ibrutinib leads to high response rates and favorable survival outcomes in patients with R/R MCL.


Asunto(s)
Linfoma de Células del Manto , Adenina/análogos & derivados , Adulto , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piperidinas , Pirazoles/efectos adversos , Pirimidinas , Estudios Retrospectivos
12.
Cancers (Basel) ; 13(10)2021 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-34067616

RESUMEN

The optimal strategy for early surveillance after first complete response is unclear in Hodgkin lymphoma. Thus, we compared the various follow-up strategies in a multicenter study. All the included patients had a negative positron emission tomography/computed tomography at the end of induction therapy. From January 2007 to January 2018, we recruited 640 patients from 15 centers in Spain. Comparing the groups in which serial imaging were performed, the clinical/analytical follow-up group was exposed to significantly fewer imaging tests and less radiation. With a median follow-up of 127 months, progression-free survival at 60 months of the entire series was 88% and the overall survival was 97%. No significant differences in survival or progression-free survival were found among the various surveillance strategies. This study suggests that follow-up approaches with imaging in Hodgkin lymphoma provide no benefits for patient survival, and we believe that clinical/analytical surveillance for this group of patients could be the best course of action.

13.
Eur J Haematol ; 85(4): 321-8, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20528905

RESUMEN

BACKGROUND AND AIM: Flow cytometry (FCM) analysis of cerebrospinal fluid (CSF) is more sensitive than conventional cytology (CC) for diagnosis of lymphomatous meningeosis, but the clinical significance of occult central nervous system (CNS) disease (positive FCM with negative CC) remains unknown. PATIENTS AND METHODS: CSF samples from 105 patients with newly diagnosed aggressive lymphomas at high risk of CNS involvement were prospectively studied by both CC and FCM, and results were correlated with cumulative incidence of CNS relapse and overall survival (OS). Patients were divided into three groups: 1) patients without CNS involvement (CC-/FCM-; n=83); 2) individuals with occult CNS disease (FCM+/CC-; n=15); and 3) cases with CNS disease (CC+/FCM+; n=7). RESULTS: Six cases showed CNS relapse or progression: two in Group 1 (2.4%), two in Group 2 (13%) and two in Group 3 (28.5%) (Group 2 vs. 1, P=0.04; Group 3 vs. 1, P<0.001). Patients from Groups 2 (P=0.05) and 3 (P<0.001) also showed a higher cumulative incidence of CNS relapse than those from Group 1. Significant differences were observed in OS between FCM-/CC- and FCM+/CC+ cases (P=0.02), while patients with occult CNS disease (FCM+/CC-) displayed intermediate OS rates, although differences did not reach statistical significance. CONCLUSIONS: The presence of occult CNS involvement at diagnosis in patients with NHL at high risk of CNS disease is associated with a higher probability of CNS relapse.


Asunto(s)
Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/diagnóstico , Citometría de Flujo/métodos , Linfoma no Hodgkin/líquido cefalorraquídeo , Linfoma no Hodgkin/diagnóstico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/complicaciones , Enfermedades del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/complicaciones , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/patología , Masculino , Microscopía/métodos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recurrencia , Factores de Riesgo , Rituximab
14.
Gastroenterol Hepatol ; 33(5): 377-81, 2010 May.
Artículo en Español | MEDLINE | ID: mdl-20363054

RESUMEN

Reactivation of hepatitis B virus infection in patients with resolved infection is rare and is usually associated with immunosuppressive therapy. Morbidity and mortality are high. Some cases of hepatitis B reactivation associated with the use of rituximab have previously been published. We present the case of a patient with B-cell non-Hodgkin lymphoma receiving combination chemotherapy with rituximab who showed hepatitis B reactivation followed by liver failure. The most recent literature on this topic is reviewed and discussed.


Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos contra la Hepatitis B/sangre , Antígenos del Núcleo de la Hepatitis B/inmunología , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/complicaciones , Factores Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Linfoma de Células B de la Zona Marginal/complicaciones , Activación Viral/efectos de los fármacos , Activación Viral/inmunología , Adenina/análogos & derivados , Adenina/uso terapéutico , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Especificidad de Anticuerpos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Comorbilidad , Ciclofosfamida/administración & dosificación , Resultado Fatal , Anticuerpos contra la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Humanos , Factores Inmunológicos/administración & dosificación , Fallo Hepático/etiología , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Masculino , Organofosfonatos/uso terapéutico , Prednisona/administración & dosificación , Recurrencia , Rituximab , Tenofovir , Vincristina/administración & dosificación
15.
Clin Cancer Res ; 14(1): 155-61, 2008 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-18172266

RESUMEN

PURPOSE: Fludarabine, cyclophosphamide, and mitoxantrone (FCM) results in a high response rate in previously treated patients with chronic lymphocytic leukemia (CLL). The aim of this study was to investigate FCM as frontline therapy in CLL. EXPERIMENTAL DESIGN: Sixty-nine patients under the age of 65 years with active CLL were treated. Patients received six cycles of fludarabine 25 mg/m(2) i.v. x 3 days, cyclophosphamide 200 mg/m(2) i.v. x 3 days, and mitoxantrone 6 mg/m(2) i.v. x 1 day. Treatment outcome was correlated with clinical and biological variables. The clinical significance of eradicating minimal residual disease (MRD) was also analyzed. RESULTS: The overall response, MRD-negative complete response (CR), MRD-positive CR, nodular partial response (PR), and PR rates were 90%, 26%, 38%, 14%, and 12%, respectively. Severe (grades 3 or 4) neutropenia developed in 10% of the patients. Major and minor infections were reported in 1% and 8% of cases, respectively. Median response duration was 37 months. Patients with del(17p) failed to attain CR. Patients achieving MRD-negative CR had a longer response duration and overall survival than patients with an inferior response. Low serum lactate dehydrogenase levels, low ZAP-70 expression, and mutated IgV(H) genes predicted longer response duration. Finally, both low ZAP-70 and CD38 expression in leukemic cells correlated with MRD-negativity achievement. CONCLUSION: FCM induces a high response rate, including MRD-negative CRs in untreated patients with active CLL. Treatment toxicity is acceptable. Both high ZAP-70 and increased CD38 expression predict failure to obtain MRD-negative response. Patients in whom MRD can be eradicated have longer response duration and overall survival than those with inferior response. These results indicate that FCM can be an ideal companion for chemoimmunotherapy of patients with CLL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/biosíntesis , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/sangre , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Neoplasia Residual/metabolismo , Neoplasia Residual/patología , Inducción de Remisión , Análisis de Supervivencia , Resultado del Tratamiento , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Proteína Tirosina Quinasa ZAP-70/biosíntesis
16.
Lab Invest ; 88(3): 306-17, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18195690

RESUMEN

Conformational diseases include heterogeneous disorders sharing a similar pathological mechanism, leading to intracellular aggregation of proteins with toxic effects. Serpins are commonly involved in these diseases. These are structurally sensitive molecules that modify their folding under even minor genetic or environmental variations. Indeed, under normal conditions, the rate of misfolding of serpins is high and unfolded serpins must be degraded by the proteasome system. Our aim was to study the effects of bortezomib, a proteasome inhibitor, on conformationally sensitive serpins. The effects of bortezomib were analysed in patients with multiple myeloma, HepG2 cells, and Swiss mice, as well as in vitro. Levels, anti-FXa activity, heparin affinity, and conformational features of antithrombin, a relevant anticoagulant serpin, were analysed. Histological, ultrastructural features and immunohistological distribution of antithrombin and alpha1-antitrypsin (another hepatic serpin) were evaluated. We also studied the intracellular accumulation of conformationally sensitive (fibrinogen) or non-sensitive (prothrombin) hepatic proteins. The inhibition of the proteasome caused intracellular accumulation and aggregation of serpins within the endoplasmic reticulum that was associated with confronting cisternae and Mallory body formation. These effects were accompanied by a heat stress response. Bortezomib also increased the levels of intracellular fibrinogen, but has no significant effect on prothrombin. Finally, bortezomib had only minor effects on the mature circulating antithrombin, with increased amounts of latent antithrombin in plasma. These results suggest that the impairment of proteasomal activities leads to an intracellular accumulation of conformationally sensitive proteins and might facilitate the release of misfolded serpins into circulation where they adopt more stable conformations.


Asunto(s)
Antineoplásicos/farmacología , Antitrombinas/metabolismo , Ácidos Borónicos/farmacología , Hígado/metabolismo , Inhibidores de Proteasoma , Pirazinas/farmacología , Serpinas/metabolismo , Alelos , Animales , Antitrombinas/genética , Antitrombinas/ultraestructura , Ácidos Borónicos/administración & dosificación , Bortezomib , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Retículo Endoplásmico/metabolismo , Inhibidores del Factor Xa , Fibrinógeno/biosíntesis , Humanos , Inmunohistoquímica , Inyecciones Intravenosas , Elastasa de Leucocito/efectos adversos , Elastasa de Leucocito/sangre , Elastasa de Leucocito/genética , Elastasa de Leucocito/inmunología , Elastasa de Leucocito/metabolismo , Elastasa de Leucocito/ultraestructura , Hígado/patología , Hígado/ultraestructura , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Ratones , Chaperonas Moleculares/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Proteínas/metabolismo , Pirazinas/administración & dosificación , Serpinas/biosíntesis , Serpinas/genética , Ubiquitina/metabolismo , alfa 1-Antitripsina/efectos adversos , alfa 1-Antitripsina/sangre , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/inmunología , alfa 1-Antitripsina/metabolismo , alfa 1-Antitripsina/ultraestructura
17.
Transfus Apher Sci ; 36(3): 235-42, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17556020

RESUMEN

INTRODUCTION: Predonation hemoglobin measurement is a problematic requirement in mobile donation settings, where accurate determination of venous hemoglobin by hematology analyzers is not available. OBJECTIVE: We have evaluated hemoglobin screening in prospective donors by the semiquantitative copper sulphate test and by capillary blood samples analyzed by three portable photometers, HemoCue, STAT-Site MHgb, and the CompoLab HB system. METHODS: Capillary blood samples were obtained from 380 donors and tested by the copper sulphate test and by at least one of the named portable photometers. Predonation venous hemoglobin was also determined in all donors using a Coulter Max-M analyzer. RESULTS: The three photometers provided acceptable reproducibility (CV below 5%), and displayed a significant correlation between the capillary blood samples and the venous hemoglobin (R2 0.5-0.8). HemoCue showed the best agreement with venous hemoglobin determination, followed by STAT-Site MHgb, and the CompoLab HB system. The copper sulphate test provided the highest rate of donors acceptance (83%) despite unacceptable hemoglobin levels, and the lowest rate for donor deferral (1%) despite acceptable hemoglobin levels. The percentage of donors correctly categorized for blood donation by the portable hemoglobinometers was 85%, 82%, and 76% for CompoLab HB system, HemoCue and STAT-Site, respectively. CONCLUSION: Our data suggest that hemoglobin determination remains a conflictive issue in donor selection in the mobile setting. Without appropriate performance control, capillary hemoglobin screening by either the copper sulphate method or by the novel portable hemoglobinometers could be inaccurate, thus potentially affecting both donor safety and the blood supply.


Asunto(s)
Almacenamiento de Sangre/métodos , Hemoglobinometría/instrumentación , Hemoglobinas/análisis , Bancos de Sangre/normas , Sulfato de Cobre , Hemoglobinometría/métodos , Humanos , Métodos , Fotometría , Donantes de Tejidos
18.
Cancer Med ; 6(11): 2507-2514, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28960797

RESUMEN

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.


Asunto(s)
Médula Ósea/diagnóstico por imagen , Médula Ósea/patología , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Femenino , Estudios de Seguimiento , Estado de Salud , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Prednisona/uso terapéutico , Estudios Retrospectivos , Rituximab/administración & dosificación , Tasa de Supervivencia , Vincristina/uso terapéutico , Adulto Joven , Microglobulina beta-2/sangre
19.
Oncotarget ; 7(9): 10174-81, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26840087

RESUMEN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.


Asunto(s)
Neoplasias del Sistema Nervioso Central/secundario , Neoplasias del Sistema Nervioso Central/terapia , Sistema Nervioso Central/patología , Células Dendríticas/patología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Adolescente , Adulto , Anciano , Niño , Femenino , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Prospectivos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
20.
Blood ; 109(10): 4258-63, 2007 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-17244682

RESUMEN

The antithrombin A384S mutation has a relatively high frequency in the British population but has not been identified in other populations. This variant has been associated with cases of thrombotic disease, but its clinical relevance in venous thrombosis remained unclear. We have conducted a secondary analysis of the prevalence of the mutation in a large case-control study, including 1018 consecutive Spanish patients with venous thromboembolism. In addition, we evaluated its functional consequences in 20 carriers (4 homozygous). This mutation, even in the homozygous state, did not affect anti-Xa activity or antigen levels, and it only slightly impaired anti-IIa activity. Thus, routine clinical methods cannot detect this anomaly, and, accordingly, this alteration could have been underestimated. We identified this mutation in 0.2% of Spanish controls. Among patients, this variant represented the first cause of antithrombin anomalies. Indeed, 1.7% patients carried the A384S mutation, but 0.6% had any other antithrombin deficiency. The mutated allele was associated with an increased risk of venous thrombosis with an adjusted OR of 9.75 (95% CI, 2.2-42.5). This is the first study supporting that antithrombin A384S mutation is a prevalent genetic risk factor for venous thrombosis and is the most frequent cause of antithrombin deficiency in white populations.


Asunto(s)
Antitrombina III/genética , Predisposición Genética a la Enfermedad , Trombosis de la Vena/genética , Adulto , Alanina/genética , Antitrombina III/análisis , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mutación Missense , Linaje , Factores de Riesgo , Serina/genética
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