RESUMEN
BACKGROUND: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. PATIENTS AND METHODS: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. RESULTS: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). CONCLUSIONS: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. CLINICAL TRIAL NUMBER: NCT00144755.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Pronóstico , Factores de Riesgo , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
BACKGROUND: Treatment with escalated BEACOPP achieved a superior time to treatment failure over ABVD in patients with disseminated Hodgkin lymphoma. However, recent clinical trials have failed to confirm BEACOPP overall survival (OS) superiority over ABVD. In addition, the gain in low-risk patients is still a matter of debate. PATIENTS AND METHODS: We randomly compared ABVD (8 cycles) with BEACOPP (escalated 4 cycles ≥ baseline 4 cycles) in low-risk patients with an International Prognostic Score (IPS) of 0-2. The primary end point was event-free survival (EFS). This parallel group, open-label phase 3 trial was registered under #RECF0219 at French National Cancer Institute. RESULTS: One hundred and fifty patients were randomized in this trial (ABVD 80, BEACOPP 70): 28 years was the median age, 50% were male and IPS was 0-1 for 64%. Complete remission rate was 85% for ABVD and 90% for BEACOPP. Progression or relapses were more frequent in the ABVD patients than in the BEACOPP patients (17 versus 5 patients). With a median follow-up period of 5.5 years, seven patients died: six in the ABVD arm and one in the BEACOPP arm (HL 3 and 0, 2nd cancer 2 and 1, accident 1 and 0). The EFS at 5 years was estimated at 62% for ABVD versus 77%, for BEACOPP [hazards ratio (HR) = 0.6, P = 0.07]. The progression-free survival (PFS) at 5 years was 75% versus 93% (HR = 0.3, P = 0.007). The OS at 5 years was 92% versus 99% (HR = 0.18, P = 0.06). CONCLUSION: Fewer progressions/relapses were observed with BEACOPP, demonstrating the high efficacy of the more intensive regimen, even in low-risk patients. However, additional considerations, balancing treatment-related toxicity and late morbidity due to salvage may help with decision-making with regard to treatment with ABVD or BEACOPP.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Bleomicina/uso terapéutico , Ciclofosfamida/uso terapéutico , Dacarbazina/uso terapéutico , Relación Dosis-Respuesta a Droga , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Femenino , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/uso terapéutico , Procarbazina/uso terapéutico , Análisis de Supervivencia , Resultado del Tratamiento , Vinblastina/uso terapéutico , Vincristina/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVES: Interleukin-2 (IL-2) therapy increased CD4 cell counts and delayed antiretroviral therapy (ART) initiation in HIV-infected patients in the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) 119 trial. However, four cases of lymphoma were reported. Epstein-Barr virus (EBV) replication is associated with an increased risk of lymphoma in immunocompromised patients. We assessed whether IL-2 had an impact on EBV replication and the development of lymphoma. METHODS: A total of 130 ART-naïve patients were randomized to receive IL-2 therapy (n = 66) or no treatment (n = 64). Clinical data for patients with lymphomas were reviewed and tumours assessed for evidence of EBV infection and CD25 (the IL-2 receptor) expression. EBV DNA levels were measured in whole blood and plasma in both arms using real-time polymerase chain reaction (PCR), up to 48 weeks after baseline (BL). RESULTS: Four lymphomas occurred, a median of 61 weeks [range 40-94 weeks] after randomization at a median CD4 cell count of 396 cells/µL (IQR 234-536 cells/µL). In the IL-2 arm, two patients developed EBV-positive Hodgkin's lymphoma, and one developed EBV-negative Burkitt-type lymphoma. One patient in the control group developed EBV-positive non-Hodgkin's lymphoma. CD25 was negative in all cases. Among the 41 of 55 (control arm) and 44 of 58 (IL-2 arm) patients with detectable EBV DNA in whole blood at both BL and week 48, the median change in EBV DNA between BL and week 48 was +0.04 log10 copies/ml in both arms (P = 0.7). In plasma, EBV was detected at least once in 22 of 52 controls and 21 of 54 IL-2-treated patients (P = 0.8). CONCLUSIONS: IL-2 therapy had no significant effect on EBV replication over 48 weeks in these ART-naïve patients. The occurrence of lymphomas did not seem to be associated with IL-2 therapy.
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Fármacos Anti-VIH/uso terapéutico , Linfoma de Burkitt/virología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Herpesvirus Humano 4/genética , Enfermedad de Hodgkin/virología , Interleucina-2/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Linfoma de Burkitt/sangre , Recuento de Linfocito CD4 , ADN Viral/sangre , ADN Viral/efectos de los fármacos , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virología , Femenino , Infecciones por VIH/complicaciones , Herpesvirus Humano 4/aislamiento & purificación , Enfermedad de Hodgkin/sangre , Humanos , Incidencia , Interleucina-2/efectos adversos , Masculino , Persona de Mediana Edad , Carga Viral/efectos de los fármacosRESUMEN
An organocatalysed and chemoselective one-pot oxa-Michael-cyclocondensation reaction of N-BocNHOH to unsaturated α-ketoesters is reported which affords an original entry to enantioenriched 3-isoxazoline carboxylate derivatives as biorelevant heterocyclic frameworks.
RESUMEN
BACKGROUND: The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. PATIENTS AND METHODS: Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. RESULTS: A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). CONCLUSION: In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone.
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Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Prednisona/efectos adversos , Rituximab , Resultado del Tratamiento , Vindesina/administración & dosificación , Vindesina/efectos adversosRESUMEN
BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression-free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart.
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Linfoma de Células B Grandes Difuso/patología , Neoplasias Faríngeas/patología , Antraciclinas/uso terapéutico , Linfocitos B/metabolismo , Linfocitos B/patología , Proteínas de Unión al ADN/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Factores Reguladores del Interferón/metabolismo , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias Faríngeas/tratamiento farmacológico , Neoplasias Faríngeas/mortalidad , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6 , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
BACKGROUND: Patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD) are at substantial risk of atherothrombotic events. The COMPASS trial showed that patients with stable CAD or PAD experienced significant benefits after treatment with rivaroxaban in combination with acetylsalicylic acid (ASA) compared with ASA alone. This paper aims to provide insight into the clinical and economic consequences of treatment with rivaroxaban from a Dutch societal perspective. METHODS: The clinical and economic implications of rivaroxaban in terms of the number of events prevented, costs, the incremental cost per life-years gained (LYG), and incremental cost per quality-adjusted life-years (QALYs) were determined based on a cost-effectiveness model for patients with stable CAD or PAD and in high-risk subgroups (i.e. patients with CAD and PAD, CAD and prior myocardial infarction and renal impairment, CAD and heart failure) using results from the Cardiovascular OutcoMes for People Using Anticoagulation Strategies (COMPASS) trial. RESULTS: Patients treated with rivaroxaban have an expected increased discounted life expectancy of 0.67 years. In high-risk groups discounted incremental life expectancy ranged from 1.33 to 1.90 years. The incremental cost-effectiveness ratio for the full COMPASS population was 9,760/LYG and 12,033/QALY, whereas, for high-risk subgroups of patients with underlying conditions, incremental cost-effectiveness ratios ranged from 2,966/LYG to 5,052/LYG and from 3,940/QALY to 6,815/QALY. Results from the sensitivity analyses revealed that the model results were robust to variations in single or multiple input parameters at once. CONCLUSIONS: The cost-effectiveness analysis showed that rivaroxaban in combination with ASA is a cost-effective treatment option in stable CAD or PAD patients. Rivaroxaban in combination with ASA is even more cost-effective in high-risk subgroups.
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Enfermedad de la Arteria Coronaria , Enfermedad Arterial Periférica , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Análisis Costo-Beneficio , Humanos , Países Bajos , Enfermedad Arterial Periférica/tratamiento farmacológico , Años de Vida Ajustados por Calidad de Vida , Rivaroxabán/uso terapéuticoRESUMEN
Storage and tissue handling of surgical tumor specimen have been recognized as critical steps that can potentially affect reproducibility and comparability of molecular endpoints between laboratories. In the preparation of adrenal tumor tissue banking, three different protocols that simulate warm ischemia upon tumor removal (protocol I), thawing and refreezing cycles (protocol II), as well as storage of vital tumor samples (protocol III) were applied. For the first two protocols, samples were subdivided and either snap frozen or treated with a RNA preserving agent (RPA) while in protocol III different storage media were compared. Following these procedures, recovery and integrity of DNA, RNA, and protein by means of pulsed field electrophoresis, long-range PCR, real-time PCR, immunoblot, and immunohistochemistry (protocol I and II) as well as cell viability and steroidogenic capacity (protocol III) were investigated. While DNA integrity was not influenced by different treatment modalities, expression levels of adrenal marker genes were more affected in samples after snap freezing in comparison to RPA pretreatment. Moreover, storage at room temperature before and after freezing could be demonstrated to decrease the relative amount of protein phosphorylation (ERK) and enzymatic activity (succinate cytochrome c reductase) while overall protein levels were not significantly affected. Similarly, morphological or immunohistochemical evaluation was comparable between groups. For primary cell cultures generated after storage of tumor samples similar rates of viability were observable while steroid output varied between the groups. Overall, on the basis of the presented endpoints standardized operational procedures can be defined for a proposed European adrenal tumor biobank.
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Neoplasias de las Glándulas Suprarrenales/patología , Glándulas Suprarrenales/patología , Bancos de Muestras Biológicas/organización & administración , Feocromocitoma/patología , Manejo de Especímenes/normas , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Animales , Supervivencia Celular , Criopreservación , ADN/análisis , Europa (Continente) , Humanos , Técnicas para Inmunoenzimas , Antígeno Ki-67/metabolismo , Ratones , Ratones Desnudos , Proteínas Mitocondriales/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , Control de Calidad , ARN/análisis , Conservación de Tejido , Trasplante HeterólogoRESUMEN
BACKGROUND: Bortezomib (Velcade) is a proteasome used in the treatment of myeloma. It is associated with a number of adverse cutaneous effects, often described as papulonodular rash on the upper half of the body. We report a new case characterised by the presence of CD30+ lymphocytic infiltrate in the lesions. PATIENTS AND METHODS: A 62-year-old woman receiving six courses of bortezomib for stage IIIA IgA myeloma presented a skin eruption during the second course of treatment that involved rounded papular or papulonodular elements on the upper body. Histopathological examination of a skin biopsy sample showed clinical picture reminiscent of Sweet's syndrome but including a significant number of CD30+ lymphocytes. The skin rash recurred to a greater or lesser degree during subsequent courses of therapy, but it was not necessary to discontinue the treatment. Symptoms subsided after the final course of bortezomib. DISCUSSION: Skin eruptions with bortezomib are a common occurrence but generally do not prevent continuation of treatment. While they have given rise to a variety of histopathological pictures, clinical settings such as those seen with our patient appear common. In terms of histopathology, the rash is reminiscent of Sweet's syndrome but our case differed in terms of the presence of CD30+ infiltrate. The latter may be compared with reactional infiltrates of the same type seen during use of other treatments for malignant blood diseases. The underlying mechanism is poorly understood.
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Antineoplásicos/efectos adversos , Ácidos Borónicos/efectos adversos , Exantema/inducido químicamente , Antígeno Ki-1/análisis , Linfocitos/patología , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/efectos adversos , Enfermedades de la Piel/inducido químicamente , Antígenos CD/análisis , Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Bortezomib , Exantema/patología , Femenino , Humanos , Persona de Mediana Edad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Pirazinas/uso terapéutico , Enfermedades de la Piel/patologíaRESUMEN
The grafting of 5-iodoisatin heterocycle on a cyclic olefin copolymer (COC) and a gold surface was performed using a heterogeneous phase Sonogashira reaction consisting of coupling 5-iodoisatin with an arylalkyne previously introduced onto the surfaces. This optimized strategy takes advantage of the well-established methodology to functionalize COC or gold surfaces using aryldiazonium surface chemistry. Herein, we reported the first example of an isatin decorated polymeric or metallic surface. The surfaces were analyzed with a combination of techniques such as IR (Infrared spectroscopy), XPS (X-Ray photoelectron spectroscopy) and SPR (surface plasmon resonance). Docking studies showed that isatin and two derivatives interact with AmiC, a dimeric protein produced by Pseudomonas aeruginosa. Bacterial adhesion on isatin-COC platform was also observed. This general strategy for robust surface functionalization represents an easy approach for patterning surfaces with compounds of biological interest, allowing access to a large panel of original biosensors.
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Antibacterianos/química , Cicloparafinas/química , Isatina/análogos & derivados , Antibacterianos/farmacología , Adhesión Bacteriana/efectos de los fármacos , Cicloparafinas/farmacología , Compuestos de Diazonio/química , Oro/química , Isatina/química , Isatina/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Tamaño de la Partícula , Pseudomonas aeruginosa/efectos de los fármacos , Propiedades de SuperficieRESUMEN
The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.
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Células Endoteliales/fisiología , Productos del Gen vpr/farmacocinética , Integrina alfaVbeta3/metabolismo , Mitocondrias/metabolismo , Péptidos/farmacocinética , Secuencia de Aminoácidos , Animales , Apoptosis , Supervivencia Celular , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Productos del Gen vpr/farmacología , Humanos , Lisosomas/metabolismo , Ratones , Ratones Endogámicos BALB C , Membranas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Péptidos/farmacología , PermeabilidadRESUMEN
BACKGROUND: Data on factors influencing inclusion of Hodgkin's lymphoma (HL) patients in randomized clinical trials (RCT) are limited and, for the present study they were analyzed in a RCT for III/IV HL. PATIENTS AND METHODS: All patients with stage III/IV HL referred to the Saint-Louis Hospital between January 2003 and May 2007 were studied. A Groupe d'Etudes des Lymphomes de l'Adulte/European Organisation for Research and Treatment of Cancer RCT, to compare ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with increased-dose BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), was open for recruitment. Noninclusion criteria and physician's reasons for non-recruitment were prospectively recorded. The reasons for patient's refusal were collected retrospectively. Logistic regression analyses were carried out in order to identify factors predicting inclusion. RESULTS: A total of 102 patients were diagnosed, among whom 51% were included. Seven patients were ineligible, 22 refused to participate, and 21 were not enrolled due to the physician's decision. Main reasons for patients' refusal were standard treatment preference and concerns about experimental arm toxicity, mainly infertility risk. Conditions that could hamper accurate follow-up and toxicity concerns accounted for most of the physicians' reasons. Adverse prognostic factors [B symptoms (odds ratio, OR = 5.35) and international prognostic score > or =3 (OR = 2.69)] were independently associated with inclusion. CONCLUSION: Despite an attractive protocol, only 51% of patients were included. It highlights concerns about selection of patients and the difficulty to obtain informed consent with better prognostic profile patients.
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Enfermedad de Hodgkin/psicología , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Negativa del Paciente al Tratamiento , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Actitud del Personal de Salud , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Rol del Médico , Ensayos Clínicos Controlados Aleatorios como Asunto/psicologíaRESUMEN
BACKGROUND: Overexpression of B-cell lymphoma 2 (bcl-2) protein is a simple biological adverse prognostic factor that could delimit the poor prognosis population candidate for improvement with high-dose therapy and autologous stem-cell transplantation (ASCT) in diffuse large B-cell lymphoma (DLBCL). Therefore, we conducted a risk-adapted phase II study with ASCT as consolidation therapy in low-intermediate risk (LIR) International Prognostic Index patients aged < or = 60 years with bcl-2 overexpression (bcl-2+). PATIENTS AND METHODS: Induction chemotherapy consisted of four courses of adriamycin, cyclophosphamide, vindesine, bleomycin, prednisone, once every 2 weeks. Responding bcl-2+ patients received ASCT as consolidation, and those without bcl-2 overexpression (bcl-2-) conventional chemotherapy. Three hundred and sixteen LIR patients with DLBCL, aged between 18 and 60 years, were included. Of these, 177 (56%) were bcl-2+ and 139 (44%) bcl-2-. RESULTS: Complete response rates after induction chemotherapy were similar in bcl-2+ and bcl-2- patients (74% versus 78%). Estimated 2-year event-free survival and disease-free survival for the bcl-2+ subgroup were 79% and 87%, for bcl-2- 84% and 92% and for the whole series 81% and 90%, respectively. CONCLUSIONS: These results demonstrate that taking into account biological characteristics in prospective multicenter trials allow successful adjustment of treatment and indicate that ASCT may counteract the adverse prognostic value of bcl-2 overexpression in responding LIR patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Genes bcl-2/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/terapia , Trasplante de Células Madre , Adulto , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Prospectivos , Tasa de Supervivencia , Trasplante Autólogo , Vindesina/administración & dosificaciónRESUMEN
AIMS: To report 16 cases of sclerosing angiomatoid nodular transformation (SANT) of the splenic red pulp. METHODS AND RESULTS: Patients were selected in two phases. An initial group of seven patients was diagnosed with SANT based on the presence of angiomatoid nodules. Sheets of inflammatory fibrosis were found in three patients, resembling inflammatory pseudotumour (IPT); nine further cases of IPT were reviewed. Angiomatoid nodules were detected, leading to the diagnosis of SANT in all cases. The splenic mass (10-150 mm in diameter) was polycyclic, composed of multiple small nodules of loose connective tissue comprising myofibroblasts and a dense network of capillaries as well as some remnants of sinuses. Collagenous fibrosis surrounded them. Bands or large sheets of fibrosis, infiltrated by various inflammatory cells, particularly polytypic plasmacytes, resembling IPT, were present in 10 cases. CONCLUSIONS: SANT of the red pulp is a distinct benign pseudotumorous lesion of the spleen characterized by the presence of angiomatoid nodules. We observed such angiomatoid nodules in all our cases of splenic IPT, which were not follicular dendritic cell or myofibroblastic tumours. We therefore recommend careful examination for angiomatoid nodules in all suspected cases of splenic IPT.
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Granuloma de Células Plasmáticas/patología , Histiocitoma Fibroso Benigno/patología , Bazo/patología , Neoplasias del Bazo/patología , Adulto , Anciano , Anciano de 80 o más Años , Angiomatosis/metabolismo , Angiomatosis/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A widely accepted definition of resistance or intolerance to hydroxyurea (HU) in patients with essential thrombocythemia (ET) is lacking. An international working group (WG) was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET. To this aim, an analytic hierarchy process (AHP), a multiple-attribute decision-making technique, was used. The steps consisted of selecting the candidate criteria for defining resistance/intolerance; identifying the motivations that could influence the preference of the WG for any individual criterion; comparing the candidate criteria in a pair-wise manner; and grading them according their ability to fulfill the motivations. Every step in the model was derived by questionnaires or group discussion. The WG proposed that the definition of resistance/intolerance should require the fulfillment of at least one of the following criteria: platelet count greater than 600,000/micro l after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400,000/micro l and WBC less than 2500/micro l or Hb less than 10 g/dl at any dose of HU; presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU; HU-related fever.
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Hidroxiurea/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Conferencias de Consenso como Asunto , Resistencia a Medicamentos , Humanos , Hidroxiurea/efectos adversos , Selección de Paciente , Reproducibilidad de los ResultadosRESUMEN
Kikuchi-Fujimoto's disease (KFD) or histiocytic narcotising lymphadenitis is a febrile benign lymphadenopathy of unknown etiology, involving more frequently cervical lymph nodes and diagnosed on biopsy of an affected node. It is sometimes associated with auto-immune diseases such as systemic lupus erythematosus (SLE). However less frequent symptoms including involvement of extracervical nodes, hepatosplenomegaly and systemic symptoms (weight loss, night sweats) are possible and suggest an infectious disease. We report the case of a Senegalese patient with positive Ag HBs who developed SLE and KFD mimicking tuberculosis. Atypical pseudo-infectious appearance of an inflammatory systemic disease is a rare occurrence and the diagnosis can be difficult.
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Linfadenitis Necrotizante Histiocítica/complicaciones , Lupus Eritematoso Sistémico/complicaciones , Tuberculosis/diagnóstico , Biopsia , Diagnóstico Diferencial , Linfadenitis Necrotizante Histiocítica/diagnóstico por imagen , Linfadenitis Necrotizante Histiocítica/patología , Humanos , Masculino , Persona de Mediana Edad , Radiografía Torácica , Tuberculosis/complicaciones , Tuberculosis/diagnóstico por imagenRESUMEN
The classification of peripheral T-cell lymphomas (PTCL) is still a matter of debate. To establish a molecular classification of PTCL, we analysed 59 primary nodal T-cell lymphomas using cDNA microarrays, including 56 PTCL and three T-lymphoblastic lymphoma (T-LBL). The expression profiles could discriminate angioimmunoblastic lymphoma, anaplastic large-cell lymphoma and T-LBL. In contrast, cases belonging to the broad category of 'PTCL, unspecified' (PTCL-U) did not share a single molecular profile. Using a multiclass predictor, we could separate PTCL-U into three molecular subgroups called U1, U2 and U3. The U1 gene expression signature included genes known to be associated with poor outcome in other tumors, such as CCND2. The U2 subgroup was associated with overexpression of genes involved in T-cell activation and apoptosis, including NFKB1 and BCL-2. The U3 subgroup was mainly defined by overexpression of genes involved in the IFN/JAK/STAT pathway. It comprised a majority of histiocyte-rich PTCL samples. Gene Ontology annotations revealed different functional profile for each subgroup. These results suggest the existence of distinct subtypes of PTCL-U with specific molecular profiles, and thus provide a basis to improve their classification and to develop new therapeutic targets.
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Perfilación de la Expresión Génica , Ganglios Linfáticos/patología , Linfoma de Células T/genética , Linfoma de Células T/patología , Humanos , Linfoma de Células T/clasificación , Linfoma de Células T/diagnóstico , Reacción en Cadena de la Polimerasa , PronósticoRESUMEN
AIMS: Vitamin K antagonists (VKAs) are used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF), but necessitate regular monitoring of prothrombin time via international normalized ratio (INR) testing. This study explores the economic burden of VKA therapy for Russian patients with NVAF. METHOD: Cardiologists provided clinical characteristics and healthcare resource use data relating to the patient's first year of treatment. Data were used to quantify direct medical costs (INR testing, consultations, drug costs). The same patients completed a questionnaire providing data on direct non-medical costs (travel/expenses for attendance at VKA appointments) and indirect costs (opportunity cost and reduced work productivity). Mean costs per patient per year are described (US dollars). RESULTS: Cardiologists (n = 50) provided data on 400 patients (mean age = 63, 47% female), and 351 patients (88%) completed the patient questionnaire. Patients had a mean of nine INR tests. Estimated direct medical costs totaled $151.06, and 18.5% of direct medical costs were attributable to drug costs. Estimated annual direct non-medical costs were $22.89 per patient, and indirect costs were $275.59 per patient. LIMITATIONS: Included patients had been treated for 12-24 months, so are not fully representative of the broader treatment population. CONCLUSION: Although VKA drugs costs are relatively low, regular INR testing and consultations drive the economic burden for Russian NVAF patients treated with VKA.
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Anticoagulantes/uso terapéutico , Antitrombinas/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Warfarina/uso terapéutico , Anciano , Anticoagulantes/economía , Antitrombinas/economía , Comorbilidad , Dabigatrán/economía , Dabigatrán/uso terapéutico , Femenino , Conductas Relacionadas con la Salud , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Modelos Econométricos , Cooperación del Paciente/estadística & datos numéricos , Satisfacción del Paciente , Rivaroxabán/uso terapéutico , Federación de Rusia , Warfarina/economíaRESUMEN
In the CORAL study, 255 chemosensitive relapses with diffuse large B-cell lymphoma (DLBCL) were consolidated with autologous stem cell transplantation (ASCT), and 75 of them relapsed thereafter. The median time between ASCT and progression was 7.1 months. The median age was 56.1 years; tertiary International Prognosis Index (tIPI) observed at relapse was 0-2 in 71.6% of the patients and >2 in 28.4%. The overall response rate to third-line chemotherapy was 44%. The median overall survival (OS) was 10.0 months (median follow-up: 32.8 months). Thirteen patients received an allogeneic SCT, and three a second ASCT. The median OS was shorter among patients who relapsed <6 months (5.7 months) compared with those relapsing ⩾12 months after ASCT (12.6 months, P=0.0221). The median OS in patients achieving CR, PR or no response after the third-line regimen was 37.7 (P<0.0001), 10.0 (P=0.03) and 6.3 months, respectively. The median OS varied according to tIPI: 0-2: 12.6 months and >2: 5.3 months (P=0.0007). In multivariate analysis, tIPI >2, achievement of response and remission lasting <6 months predicted the OS. This report identifies the prognostic factors for DLBCL relapsing after ASCT and thus helps to select patients for experimental therapy.
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Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/terapia , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Tasa de SupervivenciaRESUMEN
BACKGROUND: Infection with human herpesvirus 8 (HHV8), also termed Kaposi's sarcoma (KS)-associated herpesvirus, is associated with all forms of KS, with primary effusion lymphoma (PEL), and with some forms of multicentric Castleman's disease (MCD), but the pathogenic role of HHV8 in these tumors and the clonal nature of KS are still unclear. The purpose of this study was to examine whether the number of terminal repeats (TRs) contained in the fused TR region of HHV8 could be used as a marker of clonality in HHV8-associated tumors. METHODS: Pulsed-field gel electrophoresis (PFGE) and multiple-probe Southern blot analysis of the HHV8 TR region were performed on high-molecular-weight DNA obtained from tumoral KS, PEL, and MCD lesions. RESULTS: These analysis showed that the fused TR region contains a large but variable number of TR units (ranging from 16 to 75) and that the viral genome is present as extrachromosomal circular DNA in these tumors in vivo, with occasional ladders of heterogeneous linear termini reflecting lytic replication. All PEL tumors and PEL-derived cell lines as well as some KS tumors contained monoclonal or oligoclonal fused TR fragments; however, the TR region appeared polyclonal in MCD tumors and in a few KS lesions. CONCLUSION: Several KS and PEL lesions are monoclonal expansions of a single infected cell, suggesting that HHV8 infection precedes tumor growth and thus supporting an etiologic role of latent HHV8 in these proliferations. Our finding that nodular KS lesions display all possible patterns of clonality supports the model according to which KS begins as a polyclonal disease with subsequent evolution to a monoclonal process.