RESUMEN
Pluto and its satellite, Charon (discovered in 1978; ref. 1), appear to form a double planet, rather than a hierarchical planet/satellite couple. Charon is about half Pluto's size and about one-eighth its mass. The precise radii of Pluto and Charon have remained uncertain, leading to large uncertainties on their densities. Although stellar occultations by Charon are in principle a powerful way of measuring its size, they are rare, as the satellite subtends less than 0.3 microradians (0.06 arcsec) on the sky. One occultation (in 1980) yielded a lower limit of 600 km for the satellite's radius, which was later refined to 601.5 km (ref. 4). Here we report observations from a multi-station stellar occultation by Charon, which we use to derive a radius, R(C) = 603.6 +/- 1.4 km (1sigma), and a density of rho = 1.71 +/- 0.08 g cm(-3). This occultation also provides upper limits of 110 and 15 (3sigma) nanobar for an atmosphere around Charon, assuming respectively a pure nitrogen or pure methane atmosphere.
RESUMEN
The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Toma de Decisiones Clínicas , Conferencias de Consenso como Asunto , Dasatinib/uso terapéutico , Manejo de la Enfermedad , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Expresión Génica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Esperanza de Vida/tendencias , Monitoreo Fisiológico , Nitrilos/uso terapéutico , Pirimidinas/uso terapéutico , Calidad de Vida , Quinolinas/uso terapéutico , Análisis de SupervivenciaRESUMEN
Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor alpha (RARalpha) and the retinoic X receptor (RXR). In contrast to differentiation-therapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Leucemia Mieloide/tratamiento farmacológico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Retinoides/farmacología , Telomerasa/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Muerte Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Relación Estructura-Actividad , Telomerasa/genética , Telómero/efectos de los fármacos , Telómero/genética , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Crisis Blástica/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Humanos , Mesilato de Imatinib , Proyectos Piloto , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3-67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.
Asunto(s)
Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Mutación Puntual , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Benzamidas , Análisis Mutacional de ADN , Relación Dosis-Respuesta a Droga , Femenino , Francia , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Endometriosis frequently affects women with genital activity and exceptionally involves the urinary tract, and the ureter in particular. From a case report of a female consulting for renal colic pain related to an intrinsic-type pelvic ureteral endometriosis, we report the difficulty in diagnosing this pseudotumoral obstruction and finding therapeutic options with a review of the literature. Ureteral endometriosis is marked by non-specific symptoms liable to delay preoperative diagnosis with a risk of deterioration of renal function due to the obstruction. Regarding the therapeutic approach, the surgical treatment associated or not with GNRH agonists seems best.
Asunto(s)
Endometriosis/complicaciones , Obstrucción Ureteral/etiología , Endometriosis/cirugía , Femenino , Humanos , Persona de Mediana Edad , Obstrucción Ureteral/cirugíaRESUMEN
Recent data have renewed the interest for arsenic-containing compounds as anticancer agents. In particular, arsenic trioxide (As2O3) has been demonstrated to be an effective drug in the treatment of acute promyelocytic leukemia by inducing programmed cell death in leukemic cells both in vitro and in vivo. This prompted us to study the in vitro effects of As2O3 and of another arsenical derivative, the organic compound melarsoprol, on human myeloma cells and on the plasma cell differentiation of normal B cells. At pharmacological concentrations (10(-8) to 10(-6) mol/L), As2O3 and melarsoprol caused a dose- and time-dependent inhibition of survival and growth in myeloma cell lines that was, in some, similar to that of acute promyelocytic leukemia cells. Both arsenical compounds induced plasma cell apoptosis, as assessed by 4',6-diamidino-2-phenylindole staining, detection of phosphatidylserine at the cell surface using annexin V, and by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay. As2O3 and melarsoprol also inhibited viability and growth and induced apoptosis in plasma-cell enriched preparations from the bone marrow or blood of myeloma patients. In nonseparated bone marrow samples, both arsenical compounds triggered death in myeloma cells while sparing most myeloid cells, as demonstrated by double staining with annexin V and CD38 or CD15 antibodies. In primary myeloma cells as in cell lines, interleukin 6 did not prevent arsenic-induced cell death or growth inhibition, and no synergistic effect was observed with IFN-alpha. In contrast to As2O3, melarsoprol only slightly reduced the plasma cell differentiation of normal B cells induced by pokeweed mitogen. Both pokeweed mitogen-induced normal plasma cells and malignant plasma cells showed a normal nuclear distribution of PML protein, which was disrupted by As2O3 but not by melarsoprol, suggesting that the two arsenical derivatives acted by different mechanisms. These results point to the use of arsenical derivatives as investigational drugs in the treatment of multiple myeloma.
Asunto(s)
Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Intoxicación por Arsénico , Arsenicales , Melarsoprol/toxicidad , Mieloma Múltiple/inmunología , Óxidos/toxicidad , Células Plasmáticas/efectos de los fármacos , Trióxido de Arsénico , División Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Cinética , Activación de Linfocitos , Mieloma Múltiple/sangre , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/biosíntesis , Proteínas Nucleares/análisis , Células Plasmáticas/citología , Células Plasmáticas/patología , Proteína de la Leucemia Promielocítica , Factores de Transcripción/análisis , Factores de Transcripción/biosíntesis , Proteínas Supresoras de TumorRESUMEN
OBJECTIVES: The aim of this study was to assess whether global longitudinal strain (GLS) measured early during treatment with anthracycline (at a cumulative dose of 150mg/m2) can predict subsequent alterations in left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Eighty-six patients suffering from Hodgkin's disease, non-Hodgkin's lymphoma or acute leukemia and receiving anthracyclines were prospectively included. They underwent complete echocardiography on four separate occasions: baseline (V1); after reaching a cumulative dose of 150mg/m2 (V2); end of treatment (V3); one year follow-up (V4). Six patients developed cardiotoxicity defined by a decrease in LVEF by more than 10 percentage points to a value of at least less than 53% at V4. Both GLS measured at V1 and at V2 were significantly lower in the cardiotoxicity group compared with the control group (P=0.042 and P=0.01, respectively). Compared to GLS at V1, GLS obtained at V2 provided implemental predictive information and appeared to be the strongest predictor of cardiotoxicity (area under the receiver operating characteristic curve, 0.823). At a threshold of -17.45% for GLS measured at V2, the sensitivity and specificity of detecting cardiotoxicity were 67% (95%CI: [33-100%]) and 97% (95%CI: [94-100%]) respectively. CONCLUSION: GLS>-17.45%, obtained after 150mg/m2 of anthracycline therapy, is a significant predictor of future anthracycline-induced cardiotoxicity. This study should encourage physicians to perform echocardiography earlier during treatment with anthracyclines.
RESUMEN
Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation and a reciprocal t(15;17) translocation fusing the PML gene to the retinoic acid receptor alpha (RAR alpha) gene. PML was recently identified as a potential transcription factor. In non hematopoietic cells, the transfected PML-RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha. A major question raised by these observations is whether PML-RAR alpha contributes to the inhibition of myeloid differentiation. We find that in myeloid cell lines responsive to retinoic acid, PML-RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation. These findings strongly suggest that PML-RAR alpha may, by blocking normal retinoic acid dependent myeloid differentiation, participate in the leukemogenesis of APL. The fact that high doses of all-trans retinoic acid relieve the inhibitory effect of PML-RAR alpha corroborates the therapeutic effect of all-trans retinoic acid in APL patients.
Asunto(s)
Células de la Médula Ósea , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 17 , Granulocitos/citología , Proteínas de Neoplasias , Proteínas Nucleares , Receptores de Ácido Retinoico/fisiología , Proteínas Recombinantes de Fusión/fisiología , Factores de Transcripción/fisiología , Activación Transcripcional/genética , Translocación Genética/genética , Tretinoina/farmacología , Secuencia de Bases , Médula Ósea/química , Médula Ósea/ultraestructura , Diferenciación Celular/efectos de los fármacos , Línea Celular , Colecalciferol/farmacología , ADN de Neoplasias/genética , Relación Dosis-Respuesta a Droga , Humanos , Leucemia Promielocítica Aguda/genética , Datos de Secuencia Molecular , Proteína de la Leucemia Promielocítica , Receptores de Ácido Retinoico/análisis , Receptores de Ácido Retinoico/genética , Proteínas Recombinantes de Fusión/genética , Receptor alfa de Ácido Retinoico , Factores de Transcripción/genética , Transfección , Células Tumorales Cultivadas , Proteínas Supresoras de TumorRESUMEN
PURPOSE: Most studies using various reverse-transcription polymerase chain reaction (RT-PCR) techniques reported that the detection of the AML1-ETO fusion transcript was a common finding in long-term complete remission (CR) in acute myeloid leukemia (AML) with t(8;21) translocation. However, larger prospective studies with interlaboratory quality control may be important to investigate more precisely the clinical usefulness of studying minimal residual disease with RT-PCR in t(8;21) AML. PATIENTS AND METHODS: We collected 223 marrow samples from 51 patients with t(8;21) AML diagnosed in five centers and tested all samples by two different RT-PCR techniques (a nested technique and a one-step technique, with a sensitivity of 10(-6) and 10(-5), respectively) in two different laboratories. RESULTS: Samples from 14 patients in long persistent CR (median follow-up duration, 112 months) were taken at least twice, and all were PCR-negative by both techniques. Samples were prospectively taken from 37 patients after achievement of first CR and/or second CR, before intensive consolidation treatment, and every 3 to 6 months after completion of therapy. Patients who converted to PCR negativity with the one-step technique (60%) or both techniques (48%) after CR achievement had a longer CR duration than those with persistently positive PCR results (two-sided log-rank test, P =.0001). Patients who became PCR-negative with the one-step technique before intensive consolidation (23%) had a lower relapse rate (11% v 72%) and a longer CR duration than those who remained persistently PCR-positive at that point (two-sided log-rank test, P =.0015). CONCLUSION: Patients with AML with t(8;21) in long-term remission were all PCR-negative. In prospectively studied patients, a good correlation was found between negative PCR results and absence of relapse. Early negative results with the one-step RT-PCR technique, before consolidation treatment, seemed to carry an especially good prognosis, suggesting that RT-PCR analysis could help in choosing the type of consolidation therapy in patients with t(8;21) AML.
Asunto(s)
Reordenamiento Génico , Leucemia Mieloide/genética , Reacción en Cadena de la Polimerasa , Transcripción Genética , Enfermedad Aguda , Adolescente , Adulto , Fusión Artificial Génica , Células de la Médula Ósea/patología , Niño , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Estudios de Evaluación como Asunto , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide/terapia , Modelos Lineales , Masculino , Persona de Mediana Edad , Neoplasia Residual , Proteínas de Fusión Oncogénica/genética , Pronóstico , Estudios Prospectivos , Proteína 1 Compañera de Translocación de RUNX1 , Inducción de Remisión , Estudios Retrospectivos , Sensibilidad y Especificidad , Factores de Transcripción/genética , Translocación Genética/genéticaRESUMEN
Human blood dendritic cells (DC) comprise plasmacytoid DC (PDC) and myeloid DC (MDC), which both prime antitumor T-cell responses. We prospectively monitored blood DC in 30 chronic myeloid leukemia (CML) patients before and after imatinib mesylate therapy. We found a dramatic reduction in PDC and MDC prior treatment. This reduction was associated with high plasmatic vascular endothelial growth factor (VEGF), a central regulator of angiogenesis which also participates to tumor-associated immune deficiencies. Phenotypic analysis of DC revealed in some patients a deficient expression of BDCA-4/neuropilin-1 on PDC, a molecule involved in angiogenesis and DC-T-cell interactions. High VEGF correlated to an altered Th1/Th2 balance in vivo and shifted PDC-induced T-cell polarization towards Th2 in vitro. Upon imatinib treatment, plasmatic VEGF rapidly decreased and a normal BDCA-4 expression was restored. PDC and MDC increased but did not reach the levels observed in healthy individuals. We conclude that VEGF may be a key player in blood DC deficiency in CML and we show that imatinib inhibits VEGF overproduction. Incomplete recovery of blood DC under imatinib despite VEGF normalization suggests a negative impact of this drug on dendritopoiesis in vivo and may result in a sustained defect in DC-mediated anti-CML responses.
Asunto(s)
Antineoplásicos/uso terapéutico , Células Dendríticas/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Células Mieloides/inmunología , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Antígenos de Superficie/metabolismo , Benzamidas , Células Sanguíneas , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Células Mieloides/citología , Neuropilina-1/metabolismo , Estudios Prospectivos , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Using a combination of intensive chemotherapy and G-CSF, we conducted a prospective trial designed to improve the complete remission (CR) rate in patients with AML evolving from a primary documented myelodysplastic syndrome (sAML) and therapy-related AML (tAML). Thirty-four patients (median age 61 years) with sAML (25 patients) or tAML (nine patients) entered the study. Induction course consisted of idarubicin (12 mg/m2 of body-surface area per day for 3 days) and intermediate-dose (ID) cytarabine in the 24 younger patients (1 g/m2 of body-surface area as a 2 h infusion every 12 h for 5 days) or standard-dose (SD) cytarabine in the 10 older patients (100 mg/m2 of body-surface area per day as a continuous infusion for 7 days), followed by G-CSF until neutrophil recovery or treatment failure. Nineteen patients (56%, 13/24 in the ID group and 6/10 in the SD group) achieved a CR (14/25 sAML and 5/9 tAML). Early death occurred in four patients, but four additional patients died in CR from treatment-related toxicity (overall toxic death rate 24%). Initial cytogenetics was available in 33 patients. The CR rate was significantly lower in patients with unfavorable cytogenetics compared to patients with intermediate cytogenetics (37% vs 79%). Median remission duration and overall survival were 3 and 9 months, respectively and not different between ID and SD patients. Although the treatment-related toxicity is high, a high CR rate can be obtained in these poor-risk AML patients with the use of intensive chemotherapy in combination with G-CSF, although the role of the latter is still to be proven. Results remain especially poor in patients with unfavorable cytogenetics. New approaches are needed to maintain remission in these high-risk AML patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Adulto , Anciano , Anemia Refractaria con Exceso de Blastos/complicaciones , Examen de la Médula Ósea , Trasplante de Médula Ósea , Terapia Combinada , Citarabina/administración & dosificación , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/genética , Estudios Prospectivos , Inducción de RemisiónRESUMEN
FLT3 internal tandem duplications (FLT3-ITDs) are present in nearly 25% of patients with AML and have been associated with poor response to conventional therapy and poor outcome. We retrospectively evaluated the effect of reinforced courses of chemotherapy on the prognostic value of FLT3-ITDs in 159 AML patients prospectively enrolled in the ALFA-9000 trial, which randomly compared three reinforced induction regimens (standard 3+7 including high-dose daunorubicin, double induction, and timed-sequential therapy). FLT3-ITD was present in 40/159 (25%) blast samples and associated with high WBC (P = 0.002) and cytogenetics (P < 0.001) with a higher incidence (35%) in patients with a normal karyotype. There was no difference in CR rate between FLT3-wt and FLT3-ITD patients (80% vs 78%). Relapse-free survival (RFS) was similar in both groups (5-year RFS, 33% vs 32%; P = 0.41), even after adjustment for age, sex, WBC, cytogenetics, and treatment arm. A trend to a worse survival was observed in the FLT3-ITD group (estimated 5-year OS, 23% vs 37%; P = 0.09), mainly in patients with a normal karyotype. This was associated with a dramatic outcome in relapsing FLT3-ITD patients (estimated 3-year post-relapse survival, 0% vs 27%; P = 0.04). These results suggest that the bad prognosis associated with FLT3-ITDs in AML might be partly overcome using reinforced chemotherapy. Early detection of FLT3 mutations might thus be useful to intensify induction as well as post-remission therapy in FLT3-ITD patients.
Asunto(s)
Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Secuencias Repetidas en Tándem/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , ADN de Neoplasias/análisis , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Prospectivos , Receptores de Superficie Celular/genética , Estudios Retrospectivos , Factor de Células Madre/genética , Tasa de Supervivencia , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fmsRESUMEN
We previously showed that arsenic trioxide (ATO) and melarsoprol may inhibit the growth of multiple myeloma (MM) cells in vitro and in vivo. We report here the administration of arsenic derivatives in 12 relapsing or refractory secretory MM patients. A total of 10 patients received ATO (eight in a continuous schedule, two discontinuously) and two received melarsoprol. The melarsoprol arm was prematurely closed due to toxicity. In the ATO arm, median duration of treatment was 38 days (9-54). Hepatic toxicity was grade 3 and 2 in one and eight patients, respectively. Other toxicities included neuropathy (n=2, grade 2), encephalitis (n=1, grade 3) and leuconeutropenia (n=4, grade 3). At 2 weeks after treatment initiation, mean serum concentration of arsenic was 1.11+/-0.16 micromol/l. No complete or partial remission was observed. A minor response (25-49% reduction of M protein in serum) and a stabilization of the M-protein level were observed in three and four patients, respectively. After ATO discontinuation, these responses were of short duration in all cases. ATO as a single agent did not produce any significant response in advanced MM patients despite sufficient arsenic exposure. Strategies to improve biodistribution, pharmacokinetic and efficacy of the drug as well as treatment combinations are needed.
Asunto(s)
Antineoplásicos/uso terapéutico , Arsenicales/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Óxidos/uso terapéutico , Anciano , Antineoplásicos/administración & dosificación , Trióxido de Arsénico , Arsenicales/administración & dosificación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Recurrencia Local de Neoplasia/sangre , Óxidos/administración & dosificación , Terapia RecuperativaRESUMEN
The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , División Celular/efectos de los fármacos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Sinergismo Farmacológico , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Hematopoyesis/efectos de los fármacos , Humanos , Leucemia Mieloide/patología , Leucemia Mieloide/fisiopatología , Masculino , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , RecurrenciaRESUMEN
Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citidina Monofosfato/análogos & derivados , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Anciano , Arabinonucleotidos/administración & dosificación , Citidina Monofosfato/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide de Fase Crónica/mortalidad , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Recombinantes , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.
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Aberraciones Cromosómicas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Aneuploidia , Benzamidas , Cromosomas Humanos Par 7 , Cromosomas Humanos Par 8 , Células Clonales/patología , Femenino , Humanos , Mesilato de Imatinib , Incidencia , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
Traditional surgical treatment of non-melanoma skin cancer includes excision with adjacent surgical margins, such "safety" margins theoretically leading to lower recurrence rates. Thus, some authors favor a clinical excision margin of 4mm for basal cell carcinoma and 6mm for squamous cell carcinoma. However, such "safety" margins cannot be applied in all cases of eyelids tumors for anatomic and functional reasons, because such recommendations may lead to severe ocular complications, even loss of the globe. Thus, in order to mitigate these issues in oculoplastic surgery, excision with reduced margins is proposed, either with frozen sections or with traditional pathologic analysis and secondary reconstructive surgery several days later. The purpose of this article is to demonstrate that it is possible to reduce surgical margins while respecting "safety" from tumor recurrence, in order to preserve ocular integrity. The most appealing technique is frozen section of the margins, corresponding to "slow-Mohs" micrographic surgery.
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Carcinoma Basocelular/cirugía , Carcinoma de Células Escamosas/cirugía , Neoplasias de los Párpados/cirugía , Párpados/cirugía , Procedimientos Quirúrgicos Oftalmológicos/métodos , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/patología , Neoplasias de los Párpados/patología , Párpados/patología , Secciones por Congelación , Humanos , Cirugía de Mohs , Tratamientos Conservadores del Órgano/métodos , Procedimientos de Cirugía PlásticaRESUMEN
Polysialylated neuronal cell adhesion molecule (PSA-N-CAM) is a cell surface molecule associated with neurons that undergo changes in configuration or spatial translocation. In both cases, this molecule is thought to reduce the adhesivity of these cells or of their processes, which can thereby insinuate themselves into the existing parenchyma. We used a monoclonal antibody specific to PSA to offer what we believe is the first account of the distribution of PSA-N-CAM in the adult songbird brain. This antibody stained a diversity of cell classes and processes, as follows: 1) a subset of ventricular zone cells; 2) migrating cells thought to be neuroblasts; 3) a subset of differentiated neurons; 4) some brain surface astrocytes; 5) some tanycytes; 6) the neuropil of some regions; 7) some axonal fibers; and 8) possibly some synapses. Our results demonstrate also, for the first time, the wide distribution of a very numerous population of migrating cells in the telencephalon and the seasonal regulation of PSA-N-CAM expression in a part of the adult brain known to undergo seasonal changes in cell recruitment and function. However, we did not find PSA-N-CAM associated with young migrating cells in the high vocal center (HVC), nor was there PSA-N-CAM in the robust nucleus of the archistriatum (RA), which is known to receive new axonal endings from HVC. In these instances spatial translocation may occur with the assistance of other surface molecules.
Asunto(s)
Química Encefálica , Canarios/fisiología , Moléculas de Adhesión Celular Neuronal/análisis , Animales , Astrocitos/química , Axones/química , Moléculas de Adhesión Celular Neuronal/fisiología , Movimiento Celular/fisiología , Femenino , Inmunohistoquímica , Masculino , Plasticidad Neuronal/fisiología , Neuronas/química , Neuronas/ultraestructura , Estaciones del Año , Ácidos Siálicos/metabolismo , Factores de TiempoRESUMEN
Brain lipid binding protein (BLBP), a member of the fatty acid binding protein family, is expressed at high levels in the mammalian central nervous system during development, but not in adulthood. Because the brain of adult birds continues to show significant levels of neurogenesis, we thought it likely that BLBP expression would also be present. We used a polyclonal antibody against BLBP to study the presence of this protein in the adult canary brain. This antibody stained 1) fibers and perikarya of radial cells in the telencephalon; 2) Bergmann glia in the cerebellum; 3) astrocytes; 4) tanicytes in the walls of the third ventricle; 5) the neuropil of certain forebrain and brainstem regions, including nuclei of the song system; and 6) some migrating cells in the telencephalon. This anatomical distribution suggests that BLBP plays a role in the neuronal migration and synaptic reorganization of adult avian brain.