RESUMEN
The acoustical properties of two rooms that are one-way connected electroacoustically, e.g., in a telephone/video conference, can be analyzed through the total impulse response from a source in one room to the receiver in the other room. The total impulse response is a convolution of the two involved room impulse responses, and such a model is analyzed in this paper. The room impulse response model used here facilitates convolution analysis as the model is quite simple and composed of two terms only, a direct sound term and an exponentially decaying random Gaussian noise term. Analytical expressions have been derived for the energy decay function, leading to estimates of room acoustical parameters like clarity and the modulation transfer functions for such convolved impulse responses. Background noise expressions are also introduced to allow signal-to-noise ratio studies. Estimates of acoustic parameter values have been compared with measurements to evaluate the model used and verify the results achieved.
RESUMEN
The aim of the study was to investigate the expression of angio- and lymphangiogenic molecules (vascular endothelial growth factors VEGF and VEGF-C and their receptors Flt-1, KDR, and Flt-4) in non-Hodgkin lymphomas (NHL) treated in the pre-rituximab era. Pre-therapeutic lymph-node biopsies from 155 patients with NHL (64 follicular lymphomas (FLs), 47 de novo diffuse large B-cell lymphomas (DLBCL) and 44 peripheral T-cell lymphomas (PTCL)) were stained by in situ hybridization and immunohistochemistry. Tumor cell expression of VEGF, VEGF-C and their receptors was detected in most of the analyzed biopsies. In FL, diffuse intratumoral VEGF staining correlated with shorter overall survival (OS) (p = 0.008) and diffuse KDR staining was associated with a higher risk of histologic transformation (p = 0.05). In DLBCL, high KDR expression predicted poor treatment response (p = 0.03) and had a significant adverse impact on OS (p < 0.001). In PTCL, diffuse tissue distribution of VEGF mRNA correlated with an unfavorable 5-year OS (p = 0.004).
Asunto(s)
Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células T Periférico/genética , Proteínas de Neoplasias/análisis , Factor A de Crecimiento Endotelial Vascular/análisis , Factor C de Crecimiento Endotelial Vascular/análisis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/análisis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/análisis , Anciano , Núcleo Celular/química , Citoplasma/química , Femenino , Perfilación de la Expresión Génica , Humanos , Ganglios Linfáticos/química , Ganglios Linfáticos/patología , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neovascularización Patológica/etiología , Neovascularización Patológica/genética , Pronóstico , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Neoplásico/análisis , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Estudios Retrospectivos , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética , Factor C de Crecimiento Endotelial Vascular/biosíntesis , Factor C de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy. METHODS: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events. RESULTS: The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events. CONCLUSIONS: After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/sangre , Humanos , Mesilato de Imatinib , Interferón-alfa/administración & dosificación , Estimación de Kaplan-Meier , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Piperazinas/efectos adversos , Pirimidinas/efectos adversos , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
In the present study we combined interferon (IFN) and hydroxyurea (HU) treatment, intensive chemotherapy and autologous stem cell transplantation (SCT) in newly diagnosed chronic myelogenous leukemia patients aged below 56 years, not eligible for allogeneic SCT. Patients who had an HLA-identical sibling donor and no contraindication went for an allogeneic SCT (related donor, RD). After diagnosis, patients not allotransplanted received HU and IFN to keep WBC and platelet counts low. After 6 months patients with Ph-positive cells still present in the bone marrow received 1-3 courses of intensive chemotherapy. Those who became Ph-negative after IFN + HU or after 1-3 chemotherapy courses underwent autologous SCT. Some patients with poor cytogenetic response were allotransplanted with an unrelated donor (URD). IFN + HU reduced the percentage of Ph-positive metaphases in 56% of patients, and 1 patient became Ph-negative. After one or two intensive cytotherapies 86 and 88% had a Ph reduction, and 34 and 40% became Ph-negative, respectively. In patients receiving a third intensive chemotherapy 92% achieved a Ph reduction and 8% became Ph-negative. The median survival after auto-SCT (n = 46) was 7.5 years. The chance of remaining Ph-negative for up to 10 years after autologous SCT was around 20%. The overall survival for allo-SCT RD (n = 91) and URD (n = 28) was almost the same, i.e. approximately 60% at 10 years. The median survival for all 251 patients registered was 8 years (historical controls 3.5 years). The role of the treatment schedule presented in the imatinib era is discussed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adolescente , Adulto , Antineoplásicos/administración & dosificación , Dinamarca , Femenino , Estudios de Seguimiento , Humanos , Hidroxiurea/administración & dosificación , Interferones/administración & dosificación , Leucaféresis , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Análisis de Supervivencia , Suecia , Trasplante Autólogo , Trasplante HomólogoRESUMEN
BACKGROUND: Imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase, produces high response rates in patients with chronic-phase chronic myeloid leukemia (CML) who have had no response to interferon alfa. We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML. METHODS: We randomly assigned 1106 patients to receive imatinib (553 patients) or interferon alfa plus low-dose cytarabine (553 patients). Crossover to the alternative group was allowed if stringent criteria defining treatment failure or intolerance were met. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression. RESULTS: After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1 percent (95 percent confidence interval, 84.1 to 90.0) in the imatinib group and 34.7 percent (95 percent confidence interval, 29.3 to 40.0) in the group given interferon alfa plus cytarabine (P<0.001). The estimated rates of complete cytogenetic response were 76.2 percent (95 percent confidence interval, 72.5 to 79.9) and 14.5 percent (95 percent confidence interval, 10.5 to 18.5), respectively (P<0.001). At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7 percent in the imatinib group and 91.5 percent in the combination-therapy group (P<0.001). Imatinib was better tolerated than combination therapy. CONCLUSIONS: In terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Benzamidas , Citarabina/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Mesilato de Imatinib , Interferón-alfa/administración & dosificación , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Evaluation of myocardial iron during iron chelation therapy is not feasible by repeated endomyocardial biopsies owing to the heterogeneity of iron distribution and the risk of complications. Recently, we described a noninvasive method based on magnetic resonance imaging. Here, the method was used for repeated estimation of the myocardial iron content during iron chelation with deferrioxamine in 14 adult nonthalassemic patients with transfusional iron overload. We investigated the repeatability of the method and the relationship between the myocardial iron estimates and iron status. The repeatability coefficient (2sD) was 2.8 micromol/g in the controls (day-to-day) and 4.0 micromol/g in the patients (within-day). Myocardial iron estimates were elevated in 10 of all 14 patients at first examination, but normalized in 6 patients after 6 to 18 months of treatment. If liver iron declined below 350 micromol/g all but one of the myocardial iron estimates were normal or nearly normal. At start (R2 = 0.69, P =.0014) and still after 6 months of iron chelation (R2 = 0.76, P =.001), the estimates were significantly and more closely related to the urinary iron excretion than to liver iron or serum ferritin levels. In conclusion, our preliminary data, which may only pertain to patients with acquired anemias, suggest the existence of a critical liver iron concentration, above which elevated myocardial iron is present, but its extent seems related to the size of the chelatable iron pool, as reflected by the urinary iron excretion. This further supports the concept of the labile iron pool as the compartment directly involved in transfusional iron toxicity.
Asunto(s)
Terapia por Quelación , Deferoxamina/uso terapéutico , Quelantes del Hierro/uso terapéutico , Hierro/análisis , Imagen por Resonancia Magnética , Miocardio/química , Adulto , Anciano , Anemia/tratamiento farmacológico , Estudios de Casos y Controles , Deferoxamina/farmacocinética , Ferritinas/sangre , Estudios de Seguimiento , Cardiopatías , Humanos , Hierro/orina , Quelantes del Hierro/farmacocinética , Sobrecarga de Hierro/tratamiento farmacológico , Hígado/química , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
Increased osteoclastic bone resorption is the major causal factor of bone disease in multiple myeloma. Recently, non-invasive methods have been developed for the estimation of bone resorptive activity. To evaluate the biological sensitivity and clinical usefulness of five biochemical assays for measuring the C-terminal telopeptide of collagen I (ICTP) in serum (beta-Crosslaps ELISA and ICTP radioimmunoassay) and urinary creatinine-adjusted excretions of pyridinoline (PYR), deoxypyridinoline (DPD) and N-terminal telopeptide of collagen I (Ntx), we performed a study of 34 consecutive newly diagnosed myeloma patients. Serum and morning-fasting, second-void urine samples were taken before the start of treatment. In total, 40 age- and sex-adjusted healthy individuals served as controls. Results were expressed as Z-scores. All test variables were highly significantly elevated in the patients (P < 0.001). Serum (S)-ICTP was elevated (Z-score > 2) in most patients (85%) and showed significantly higher Z-score values than the other markers. S-ICTP remained more sensitive than the urinary assays when patients with impaired renal function were excluded from analysis. S-ICTP and the urinary metabolites correlated significantly with skeletal morbidity. S-beta-Crosslaps correlated with the bone morbidity only when patients with renal insufficiency were excluded from the analysis. High levels of S-ICTP and urinary (U)-Ntx correlated with an increased risk for early progression of bone lesions during standard melphalan-prednisolone treatment. U-Ntx and S-ICTP are sensitive tools for estimating the increased bone resorption in multiple myeloma and are clinically useful for identifying patients with increased risk of early progression of bone disease.
Asunto(s)
Resorción Ósea , Colágeno/orina , Mieloma Múltiple/metabolismo , Osteoclastos/metabolismo , Fragmentos de Péptidos/sangre , Péptidos/orina , Procolágeno/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Biomarcadores/orina , Colágeno Tipo I , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
The role of iron overload as cause of liver dysfunction has never been studied in detail in patients without concomitant hepatotropic infections who receive multiple transfusions. We therefore investigated the relationship between the extent of hepatocellular injury as reflected by serum levels of aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and several iron status indices in 39 anti-hepatitis C virus-negative (HCV(-)) nonthalassemic patients with transfusional iron overload owing to acquired anemias. In 12 patients, we monitored aminotransferase levels and indices of iron status during iron chelation treatment. Before treatment, elevated aminotransferase activity was seen only at liver iron concentrations more than 300 microM/g. During treatment all aminotransferase values were normal if the liver iron concentration returned below 350 microM/g. At the start of treatment, ALT (R(2) = 0.64, P =.006) and AST activity (R(2) = 0.57, P =.01) were closely related to urinary iron excretion, reflecting the size of the chelatable or the labile iron pool. During treatment, a comparable pattern was seen and the urinary iron excretion was also directly related to the liver iron concentration at concentrations above approximately 400 microM/g. All elevated ALT values were associated with a urinary iron excretion more than 15 mg/24 h. In conclusion, our data suggest the existence of a critical liver iron concentration range, above which hepatocellular injury is seen. The extent of the injury seems to be determined mainly by the size of the chelatable or labile iron pool, supporting the concept of the labile iron pool as the compartment directly involved in iron toxicity. Our findings may be helpful in establishing criteria for safety from complications of transfusional iron overload.