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BACKGROUND: A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis. PATIENTS AND METHODS: A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2-4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2-3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy. RESULTS: Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2-5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P < 0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P < 0.24). Adverse events incidence was not significantly different between the two treatments. CONCLUSIONS: In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity. CLINICALTRIALSGOV NUMBER: NCT00869310.
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Antieméticos/administración & dosificación , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Dexametasona/administración & dosificación , Metoclopramida/administración & dosificación , Morfolinas/administración & dosificación , Náusea/prevención & control , Vómitos/prevención & control , Actividades Cotidianas , Administración Intravenosa , Administración Oral , Adolescente , Adulto , Anciano , Antieméticos/efectos adversos , Aprepitant , Dexametasona/efectos adversos , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Isoquinolinas/administración & dosificación , Italia , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Náusea/inducido químicamente , Náusea/psicología , Palonosetrón , Calidad de Vida , Quinuclidinas/administración & dosificación , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Vómitos/inducido químicamente , Vómitos/psicología , Adulto JovenRESUMEN
Mycophenolate mofetil is a widely prescribed immunosuppressive agent for transplant patients and autoimmune diseases. Potential teratogenic effects after in utero exposure to mycophenolate mofetil has been described in human clinical observations. The complete clinical pattern is still being delineated. We present four newborns with esophageal atresia and other congenital anomalies, prenatally exposed to mycophenolate mofetil during the first trimester. Two of the cases had other defects related to the embryopathy: microtia, eye abnormalities and oral clefts. Two cases did not show major craniofacial anomalies. We propose that esophageal atresia with or without tracheoesophageal fistula is a feature of mycophenolate embryopathy even without the presence of other major craniofacial anomalies. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed.
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Atresia Esofágica/inducido químicamente , Inmunosupresores/efectos adversos , Ácido Micofenólico/análogos & derivados , Adulto , Femenino , Humanos , Ácido Micofenólico/efectos adversosRESUMEN
Abnormal thickening of the Endometrial Subendometrial Myometrium Unit (ESEMy Unit, including basal endometrium and inner myometrium) has been detected on imaging and referred to as "diffuse adenomyosis" in infertile patients with proven endometriosis. However, no robust relationship exists between enlargement of the ESEMy Unit and adenomyosis proven on hysterectomy specimen examination; moreover, if any correlation exists, it lacks histological validation in women wishing to preserve fertility. While adenomyosis effects on fertility, if any, remain elusive, thickening of the ESEMy Unit have been consistently linked to fertility impairment in both experimental and clinical models. The hypothesis tested herein is that a novel condition exists, called "ESEMy Unit disruption disease"; it is epidemiologically different from adenomyosis, diagnosable on imaging and bears a clear impact on human fertility through various mechanisms. A new wave of good quality studies may be elicited by a clear distinction between adenomyosis and the "ESEMy Unit disruption disease".
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Endometrio/diagnóstico por imagen , Miometrio/diagnóstico por imagen , Femenino , Humanos , UltrasonografíaRESUMEN
The extraction of the salient characteristics from brain connectivity patterns is an open challenging topic since often the estimated cerebral networks have a relative large size and complex structure. Since a graph is a mathematical representation of a network, which is essentially reduced to nodes and connections between them, the use of a theoretical graph approach would extract significant information from the functional brain networks estimated through different neuroimaging techniques. The present work intends to support the development of the "brain network analysis:" a mathematical tool consisting in a body of indexes based on the graph theory able to improve the comprehension of the complex interactions within the brain. In the present work, we applied for demonstrative purpose some graph indexes to the time-varying networks estimated from a set of high-resolution EEG data in a group of healthy subjects during the performance of a motor task. The comparison with a random benchmark allowed extracting the significant properties of the estimated networks in the representative Alpha (7-12 Hz) band. Altogether, our findings aim at proving how the brain network analysis could reveal important information about the time-frequency dynamics of the functional cortical networks.
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Algoritmos , Mapeo Encefálico/métodos , Electroencefalografía/métodos , Potenciales Evocados Motores/fisiología , Corteza Motora/fisiología , Red Nerviosa/fisiología , Vías Nerviosas/fisiología , Humanos , Sensibilidad y EspecificidadRESUMEN
The directed transfer function (DTF) and the partial directed coherence (PDC) are frequency-domain estimators that are able to describe interactions between cortical areas in terms of the concept of Granger causality. However, the classical estimation of these methods is based on the multivariate autoregressive modelling (MVAR) of time series, which requires the stationarity of the signals. In this way, transient pathways of information transfer remains hidden. The objective of this study is to test a time-varying multivariate method for the estimation of rapidly changing connectivity relationships between cortical areas of the human brain, based on DTF/PDC and on the use of adaptive MVAR modelling (AMVAR) and to apply it to a set of real high resolution EEG data. This approach will allow the observation of rapidly changing influences between the cortical areas during the execution of a task. The simulation results indicated that time-varying DTF and PDC are able to estimate correctly the imposed connectivity patterns under reasonable operative conditions of signal-to-noise ratio (SNR) ad number of trials. An SNR of five and a number of trials of at least 20 provide a good accuracy in the estimation. After testing the method by the simulation study, we provide an application to the cortical estimations obtained from high resolution EEG data recorded from a group of healthy subject during a combined foot-lips movement and present the time-varying connectivity patterns resulting from the application of both DTF and PDC. Two different cortical networks were detected with the proposed methods, one constant across the task and the other evolving during the preparation of the joint movement.
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Mapeo Encefálico/métodos , Electroencefalografía/métodos , Potenciales Evocados/fisiología , Corteza Motora/fisiología , Movimiento/fisiología , Vías Nerviosas/fisiología , Reconocimiento de Normas Patrones Automatizadas/métodos , Adulto , Algoritmos , Femenino , Humanos , Masculino , Análisis Multivariante , Red Nerviosa/fisiologíaRESUMEN
We investigated brain activity during the observation of TV commercials by tracking the cortical activity and the functional connectivity changes in normal subjects. The aim was to elucidate if the TV commercials that were remembered by the subjects several days after their first observation elicited particular brain activity and connectivity compared with those generated during the observation of TV commercials that were quickly forgotten. High-resolution electroencephalogram (EEG) recordings were performed in a group of healthy subjects and the cortical activity during the observation of TV commercials was evaluated in several regions of interest coincident with the Brodmann areas (BAs). The patterns of cortical connectivity were obtained in the four principal frequency bands, Theta (3-7 Hz), Alpha (8-12 Hz), Beta (13-30 Hz), Gamma (30-40 Hz) and the directed influences between any given pair of the estimated cortical signals were evaluated by use of a multivariate spectral technique known as partial directed coherence. The topology of the cortical networks has been identified with tools derived from graph theory. Results suggest that the cortical activity and connectivity elicited by the viewing of the TV commercials that were remembered by the experimental subjects are markedly different from the brain activity elicited during the observation of the TV commercials that were forgotten. In particular, during the observation of the TV commercials that were remembered, the amount of cortical spectral activity from the frontal areas (BA 8 and 9) and from the parietal areas (BA 5, 7, and 40) is higher compared with the activity elicited by the observation of TV commercials that were forgotten. In addition, network analysis suggests a clear role of the parietal areas as a target of the incoming flow of information from all the other parts of the cortex during the observation of TV commercials that have been remembered. The techniques presented here shed new light on all the cortical networks and their behavior during the memorization of TV commercials. Such techniques could also be relevant in neuroeconomics and neuromarketing for the investigation of the neural substrates subserving other decision-making and recognition tasks.
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Corteza Cerebral/fisiología , Comercio , Electroencefalografía/métodos , Potenciales Evocados Visuales/fisiología , Memoria a Corto Plazo/fisiología , Recuerdo Mental/fisiología , Televisión , Percepción Visual/fisiología , Adulto , Mapeo Encefálico/métodos , Humanos , Masculino , Red Nerviosa/fisiologíaRESUMEN
A major limitation of the approaches used in most of the studies performed so far for the characterization of the brain responses during social interaction is that only one of the participating brains is measured each time. The "interaction" between cooperating, competing or communicating brains is thus not measured directly, but inferred by independent observations aggregated by cognitive models and assumptions that link behavior and neural activation. In this paper, we use the simultaneous neuroelectric recording of several subjects engaged in cooperative games (EEG hyperscanning). This EEG hyperscanning allow us to observe and model directly the neural signature of human interactions in order to understand the cerebral processes generating and generated by social cooperation or competition. We used a paradigm called Prisoner's dilemma derived from the game theory. Results collected in a population of 22 subjects suggested that the most consistently activated structure in social interaction paradigms is the medial prefrontal cortex, which is found to be active in all the conflict situations analyzed. The role of the anterior cingulated cortex (ACC) assumes a main character being a discriminant factor for the "defect" attitude of the entire population examined. This observation is compatible with the role that the Theory of Mind assigns to the ACC.
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Mapeo Encefálico/métodos , Encéfalo/fisiología , Corteza Cerebral/fisiología , Electroencefalografía/métodos , Teoría del Juego , Análisis de Varianza , Giro del Cíngulo/fisiología , Humanos , Modelos NeurológicosRESUMEN
In order to study the concurrent activity in subjects interacting in cooperation or competition activities, the issue of the simultaneous recording of their brain activity became mandatory. The simultaneous recording of neuroelectric activity of the brain is called "EEG hyperscanning". We would like present results obtained by EEG hyperscannings performed on a group of subjects engaged in a card game. The EEG hyperscannings have been performed with the simultaneous use of high resolution EEG devices on groups of four subjects while they were playing a card game. We estimated the concurrent activity in multiple brains of the group and we depicted the causal connections between regions of different brains. Results obtained in a study of several groups recorded by the EEG hyperscanning reveal larger activity in prefrontal and anterior cingulated cortex in different frequency bands for the player that start the game when compared to other players. EEG hyperscannings will open a different area for the study of neuroscience, in which the activity of multiple brains during social cooperation could be investigated.
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Mapeo Encefálico , Encéfalo/fisiología , Electroencefalografía/métodos , Teoría del Juego , Juego e Implementos de Juego , Humanos , Modelos Neurológicos , Recreación , Sensibilidad y EspecificidadRESUMEN
In this work, a novel approach is proposed in order to capture relevant features related to the structure and organization of the functional brain networks estimated in the time-frequency domain. To achieve this, we used a cascade of computational tools able to estimate first the electrical activity of the cortical surface by using high resolution EEG techniques. Then, on the cortical signals from different regions of interests we estimated the time-varying functional connectivity patterns by means of the adaptive Partial Directed Coherence. Such time-varying connectivity estimation returns a series of causality patterns evolving during the examined task which can be summarized and interpreted with the aid of mathematical indexes based on the graph theory. The combination of all these methods is demonstrated on a set of high resolution EEG data recorded from a healthy subject performing a simple foot movement.
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Inteligencia Artificial , Mapeo Encefálico/métodos , Corteza Cerebral/fisiología , Diagnóstico por Computador/métodos , Electroencefalografía/métodos , Red Nerviosa/fisiología , Reconocimiento de Normas Patrones Automatizadas/métodos , Algoritmos , Interpretación Estadística de Datos , Humanos , Análisis Multivariante , Plasticidad Neuronal/fisiología , Análisis de RegresiónRESUMEN
In order to analyze whether the use of the cortical activity, estimated from noninvasive EEG recordings, could be useful to detect mental states related to the imagination of limb movements, we estimate cortical activity from high-resolution EEG recordings in a group of healthy subjects by using realistic head models. Such cortical activity was estimated in region of interest associated with the subject's Brodmann areas by using a depth-weighted minimum norm technique. Results showed that the use of the cortical-estimated activity instead of the unprocessed EEG improves the recognition of the mental states associated to the limb movement imagination in the group of normal subjects. The BCI methodology presented here has been used in a group of disabled patients in order to give them a suitable control of several electronic devices disposed in a three-room environment devoted to the neurorehabilitation. Four of six patients were able to control several electronic devices in this domotic context with the BCI system.
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BACKGROUND: The Tension-free Vaginal Tape (TVT) represents the most recent technique for the treatment of genuine stress urinary incontinence (GSUI). The various number of surgical procedures proposed for the treatment of GSI very often do not lead to a complete remission of this pathology. The data from the literature show how TVT is a effective procedure for the treatment of female urinary incontinence. METHODS: Twenty-nine women with diagnosis of urinary incontinence underwent application of polypropilene band (TVT: tension-free vaginal tape) underneath the uretra, in order to treat this disorder. The procedure has been carried out in peripheral anesthesia. RESULTS: A complete remission of the urinary incontinence was obtained in 24 patients. In the remaining cases there was an improvement of the symptoms in two patients, whereas in two patients remained a secondary detrusor instability. In one case the external iliac vein was perforated thus requiring a surgical repair. CONCLUSION: The short surgical time, the feasibility of the procedure and the following short hospitalization made this technique well accepted either by the surgeons ang the patients. Moreover the possibility to carry out the procedure in peripheral anesthesia allows to have the collaboration of the patient. However this technique is not free of risks, how the serious complication we had can demonstrate.
Asunto(s)
Incontinencia Urinaria de Esfuerzo/terapia , Femenino , Humanos , Incontinencia Urinaria de Esfuerzo/prevención & controlRESUMEN
In human adult hematopoiesis, the TAL-1 gene is up- and down-modulated in erythropoiesis and granulopoiesis, respectively [G. L. Condorelli et al., Blood, 86: 164-175, 19951. Here, it is shown that, in a hematopoietic progenitor cell (HPC) unilineage differentiation culture, tal-1 is induced and then expressed, in a sustained manner, in the megakaryopoietic lineage, whereas it is barely or not detected in the monocytopoietic series. We have investigated the role of enforced tal-1 expression by retroviral transfer into HPCs [erythroid burst-forming units and megakaryocytic and granulomonocytic colony-forming units (CFUs)], primitive HPCs (high proliferative potential colony-forming cells), and putative hematopoietic stem cells (HSCs), assayed as long-term culture initiating cells. TAL-1 overexpression induces an increase of erythroid burst-forming unit colony number and size and megakaryocytic CFU colony number and an inhibition of granulomonocytic CFU and granulocytic CFU (CFU-G) but not monocytic CFU colony number; conversely, TAL-1 mutants with defective heterodimerizing or DNA-binding domains do not exert these effects at a significant level. Although it does not affect long-term culture initiating cells, exogenous TAL-1 causes a significant proliferative stimulus on primary and secondary high proliferative potential colony-forming cells. In conclusion, exogenous tal-1 exerts differential and stage- and lineage-specific effects on the HPC/HSC differentiation/proliferation gene programs. Thus, it induces a stimulatory effect at the level of erythroid and megakaryocytic HPCs, while exerting a selective proliferative action on downstream erythropoiesis. Furthermore, it induces differential effects on the myeloid series: the partial blockade of CFU-G differentiation is possibly linked to the sharp down-modulation of endogenous TAL-1 expression at the level of the CFU-G-to-granulopoietic precursor differentiation step; in contrast, no significant effect is observed on monocytic CFU colony formation. Finally, the stimulatory effect on primitive HPCs but not putative stem cells suggests subtle differences in the effects exerted by tal-1 overexpression on primitive HPC/HSC subsets in adult life.
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Proteínas de Unión al ADN/fisiología , Hematopoyesis , Células Madre Hematopoyéticas/citología , Proteínas Proto-Oncogénicas , Factores de Transcripción , Adulto , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Medios de Cultivo , Técnicas de Cultivo/métodos , Proteínas de Unión al ADN/genética , Células Precursoras Eritroides/citología , Células Precursoras Eritroides/efectos de los fármacos , Eritropoyesis/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/farmacología , Vectores Genéticos/genética , Granulocitos/citología , Granulocitos/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Factores de Crecimiento de Célula Hematopoyética/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Interleucinas/farmacología , Megacariocitos/citología , Megacariocitos/efectos de los fármacos , Proteínas Recombinantes de Fusión/fisiología , Proteínas Recombinantes/farmacología , Retroviridae/genética , Proteína 1 de la Leucemia Linfocítica T Aguda , TransfecciónRESUMEN
Murine hematopoietic tissues contain cells which, upon injection into lethally irradiated mice, produce nodules on the surface of their spleen (colony-forming unit--spleen; CFU-S). The exact hierarchical level of the hematopoietic progenitors which give rise to CFU-S is not fully established; however, cell populations highly enriched for repopulating stem cells appear to contain a high percentage of CFU-S. The experiments reported here involved the injection of human fetal liver cells into mice, under conditions similar to those of the CFU-S test. These data demonstrate that human fetal liver cells are able to induce spleen colonies (tentatively called human CFU-S) when injected into lethally irradiated mice. The number of CFU-S was increased by prior purification of human fetal liver cells. When mice were injected with human fetal liver cells inactivated by irradiation, no human CFU-S were observed. Positive staining of cells found in spleen colonies, using monoclonal antibodies specific for various human determinants, indicated the human origin of part of them. The presence of human cells within the colonies was further confirmed by in situ hybridization using a probe specific for human DNA. A mean of 30-40% of analyzed colonies was thus shown to contain some patches of human cells. These data confirm that human hematopoietic cells are able to seed, proliferate, and differentiate in a murine microenvironment.
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Hematopoyesis/inmunología , Trasplante de Células Madre Hematopoyéticas , Hígado/citología , Quimera por Radiación/inmunología , Bazo/citología , Animales , Recuento de Células/efectos de la radiación , Separación Celular , Ensayo de Unidades Formadoras de Colonias , Feto , Secciones por Congelación , Hematopoyesis/efectos de la radiación , Células Madre Hematopoyéticas/citología , Humanos , Inyecciones Intravenosas , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Adhesión en Parafina , Bazo/efectos de la radiaciónRESUMEN
The TAL-1 gene specifies a basic helix-loop-helix domain (bHLH) transcription factor, which heterodimerizes with E2A gene family proteins. tal-1 protein is abnormally expressed in the majority of T-cell acute lymphoblastic leukemias (T-ALLs). tal-1 is expressed and plays a significant role in normal erythropoietic differentiation and maturation, while its expression in early myeloid differentiation is abruptly shut off at the level of late progenitors/early differentiated precursors (G. L. Condorelli, L. Vitelli, M. Valtieri, I. Marta, E. Montesoro, V. Lulli, R. Baer, and C. Peschle, Blood 86:164-175, 1995). We show that in late myeloid progenitors (the phenotypically normal murine 32D cell line) and early leukemic precursors (the human HL-60 promyelocytic leukemia cell line) ectopic tal-1 expression induces (i) a proliferative effect under suboptimal culture conditions (i.e., low growth factor and serum concentrations respectively), via an antiapoptotic effect in 32D cells or increased DNA synthesis in HL-60 cells, and (ii) a total or marked inhibitory effect on differentiation, respectively, on granulocyte colony-stimulating factor-induced granulopoiesis in 32D cells or retinoic acid- and vitamin D3-induced granulo- and monocytopoiesis in HL-60 cells. Furthermore, experiments with 32D temperature-sensitive p53 cells indicate that aberrant tal-1 expression at the permissive temperature does not exert a proliferative effect but causes p53-mediated apoptosis, i.e., the tal-1 proliferative effect depends on the integrity of the cell cycle checkpoints of the host cell, as observed for c-myc and other oncogenes. tal-1 mutant experiments indicate that ectopic tal-1 effects are mediated by both the DNA-binding and the heterodimerization domains, while the N-terminally truncated tal-1 variant (M3) expressed in T-ALL malignant cells mimics the effects of the wild-type protein. Altogether, our results (i) indicate proliferative and antidifferentiative effects of ectopic tal-1 expression, (ii) shed light on the underlying mechanisms (i.e., requirement for the integrity of the tal-1 bHLH domain and cell cycle checkpoints in the host cell, particularly p53), and (iii) provide new experimental models to further investigate these mechanisms.
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Apoptosis , Proteínas de Unión al ADN/biosíntesis , Secuencias Hélice-Asa-Hélice , Proteínas Proto-Oncogénicas/biosíntesis , Factores de Transcripción/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular/efectos de los fármacos , División Celular , Colecalciferol/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Células HL-60 , Humanos , Interleucina-3/farmacología , Leucemia Mieloide/metabolismo , Fenotipo , Proteína 1 de la Leucemia Linfocítica T Aguda , Tretinoina/farmacologíaRESUMEN
BACKGROUND AND OBJECTIVE: Hepatic toxicity directly related to the drugs administered in cyclic chemotherapy (CT), although sometimes serious, does not limit the treatment of non-Hodgkin's lymphoma (NHL). Nevertheless, reports of reactivation of viral hepatitis in NHL patients with B virus (HBV) infection are becoming more frequent. The recent observation of two cases of severe liver toxicity directly correlated to CT and a case of fatal hepatic failure due to HBV replication prompted us to evaluate the hepatic toxicity of CT in 98 consecutive B-cell NHL patients treated with relatively homogeneous cyclic CT. METHODS: Acute hepatic toxicity was retrospectively evaluated in 98 consecutive B-cell NHL patients who received induction CT. HBV and HCV markers were checked at presentation. All patients were tested for ALT and bilirubin before every CT course, while tests for HBV-DNA and/or for HCV-RNA were performed with PCR only when hepatitis occurred. RESULTS: At presentation 22 patients (22.4%) were positive for HBsAg, and 11 (15.9%) were positive for anti-HCV. Acute hepatitis developed in 12 (12.2%) NHL patients: 8 (out of 22) in HBsAg-positive and anti-HCV-negative patients, 3 (out of 76) in HBsAg-negative patients, and 1 (out of 11) in anti-HCV-positive patients. Hepatitis was attributed to reactivation of chronic B hepatitis in 3 patients and to drug toxicity in 3 others; hepatitis was undefined in 6 cases. INTERPRETATION AND CONCLUSIONS: Drug-related liver toxicity is not a rare occurrence in NHL patients. Reactivation of HBV replication is responsible for a relevant number of the hepatitis cases observed. We did not detect acute hepatitis due to the reactivation of HCV replication (in chronic C hepatitis carriers).
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hepacivirus/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/fisiopatología , Hepatitis C/fisiopatología , Linfoma de Células B/tratamiento farmacológico , Activación Viral/efectos de los fármacos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Hepacivirus/crecimiento & desarrollo , Hepatitis B/complicaciones , Virus de la Hepatitis B/crecimiento & desarrollo , Hepatitis C/complicaciones , Humanos , Cirrosis Hepática/complicaciones , Pruebas de Función Hepática , Linfoma de Células B/complicaciones , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Reacción en Cadena de la Polimerasa , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prevalencia , Recurrencia , Estudios Retrospectivos , Vincristina/administración & dosificación , Vincristina/efectos adversos , Viremia/etiología , Viremia/virologíaRESUMEN
In preliminary studies, we have analyzed the hematopoietic growth factor (HGF) requirement of hematopoietic progenitor cells (HPCs) purified from embryonic-fetal liver (FL) and grown in fetal calf serum-supplemented (FCS+) clonogenic culture. The key role of erythropoietin (Epo) for colony formation by early erythroid progenitors (burst-forming units-erythroid [BFU-E]) has been confirmed. Furthermore, in the absence of exogenous HGFs, FL monocytic progenitors (colony-forming unit monocyte [CFU-M]) generate large colonies exclusively composed of monocytes-macrophages; these colonies are absent in FCS- clonogenic culture. On this basis, we have investigated the role of all-trans retinoic acid (ATRA) and its isomer 9-cis RA in FL hematopoiesis. Both compounds modulate the growth of purified FL HPCs, which show a dose-dependent shift from mixed/erythroid/ monocytic to granulocytic colony formation. Studies on unicellular and paired daughter cell culture unequivocally indicate that the shift is mediated by modulation of the HPC differentiation program to the granulopoietic pathway (rather than RA-induced down-modulation of multipotent/ erythroid/monocytic HPC growth coupled with recruitment of granulocytic HPCs). ATRA and 9-cis RA also exert their effect on the proliferation of primitive HPCs (high-proliferative potential colony-forming cells [HPP-CFCs]) and putative hematopoietic stem cells (HSCs; assayed in Dexter-type long-term culture). High concentrations of either compound (1) drastically reduced the number of primary HPP-CFC colonies and totally abolished their recloning capacity and (2) inhibited HSC proliferation. It is crucial that these results mirror recent observations indicating that murine adult HPCs transduced with dominant negative ATRA receptor (RAR) gene are immortalized and show a selective blockade of granulocytic differentiation. Altogether, these results suggest that ATRA/9-cis RA may play a key role in FL hematopoiesis via a dual effect hypothetically mediated by interaction with the RAR/RXR heterodimer, ie, inhibition of HSC/ primitive HPC proliferation and induction of CFU-GEMM/ BFU-E/CFU-M shift from the multipotent/erythroid/monocytic to the granulocytic-neutrophilic differentiation program.
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Granulocitos/citología , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Sistema Hematopoyético/embriología , Tretinoina/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Eritropoyetina/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Sistema Hematopoyético/citología , Humanos , Interleucina-3/farmacología , Receptores de Ácido Retinoico/efectos de los fármacos , Receptores de Ácido Retinoico/fisiología , Proteínas Recombinantes/farmacología , Factor de Células Madre/farmacologíaRESUMEN
An ecographic study of the liver in a 55-year-old female, with a history of mastectomy for a breast ductal cancer, showed multiple focal lesions. On computer tomography, we interpreted these lesions as metastatic disease. 99m Tc-labeled RBC showed non-homogeneous flow distribution in the right lobe of the liver. Fine needle aspiration biopsy under ecographic guidance showed no metastatic disease, and suggested a vascular lesion. The presence of spindle-shaped cells, reactive for CD 34 and for factor VIII, enabled definitive diagnosis of angiomatous lesion. Cytological confirmation of each hepatic mass is a mandatory prerequisite for any therapy.
RESUMEN
AIM: The occurrence of unilateral involvement in bilateral bone marrow trephine biopsies in non-Hodgkin's lymphomas (NHL) at disease onset (10-20% of cases) has been reported since the early 70s. Therefore, although these studies were based on small series, the use of bilateral bone marrow biopsies has become the rule. However, the clinical value of this procedure has never been clearly established. The aim of the present study was to ascertain the true value of bilateral bone marrow biopsy in the staging of NHL. STUDY DESIGN: We examined 368 cases of NHL (A-H according to the Working Formulation) (WF), without leukemic involvement of the peripheral blood, in order to evaluate: 1) the incidence of unilateral bone marrow involvement; 2) the percentage of patients who, as a result of unilateral bone marrow involvement, changed from stages I-II to stage IV; 3) assessment of response to therapy for patients with both bilateral or unilateral bone marrow involvement. RESULTS: In the A-C NHL groups of WF there was a unilateral bone marrow involvement of 8.8%. Overall, bone marrow involvement induced a change from clinical stages I-II to stage IV in 5.6% of cases, a figure which would correspond to a false negative rate of 2.8%, if unilateral bone marrow biopsy was performed. In the D-F and G, H groups of WF, unilateral involvement was 10.1% and 8.5% respectively; the change in stage from I-II to IV by unilateral bone marrow involvement respectively amounted to 1.4% and 2.8%, which correspond to respective false negative rates of 0.7% and 1.4%. CONCLUSIONS: On the basis of these results and of the present therapeutic strategies, we propose: bilateral bone marrow biopsy for clinical stages I-II of all NHL; no bone marrow biopsy at disease onset for clinical stages III and IV of A to H histologic subtypes of the WF; unilateral bone marrow biopsy (A-C subtypes of the WF) or bilateral (D-H of the WF), after the regression of extramedullary localizations.
Asunto(s)
Biopsia/métodos , Médula Ósea/patología , Linfoma no Hodgkin/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Estadificación de Neoplasias , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We have demonstrated that 0.2% to 11% of cells from the fetal liver (FL) reacted specifically with high concentrations of anti-CD4 monoclonal antibody (MoAb). CD4+ cells from FL were similar in surface phenotype and fluorescence characteristics to the CD4+ population found previously in adult bone marrow (BM). FL and BM cells were seeded in cultures that allow differentiation to primitive precursors. FL cells released many low CD4+ and low Thy+ cells in the supernatant, while BM cells seeded under the same conditions did not. We studied the nonadherent cells harvested from 10-day FL cultures (greater than 90% low CD4+). In methylcellulose, they were able to produce more colonies that appear to be characteristic of earlier stages in the hierarchy of hematopoietic precursors (especially erythroid bursts and colonies composed of both myeloid and erythroid elements) in comparison with CD4- cells from 10-day BM cultures. CD4+ cells harvested from FL cultures initiated secondary cultures containing both a stromal layer and large hematopoietic colonies when replated under conditions similar to those of primary cultures. Furthermore, a limited number of CD4+ cells from 10-day FL cultures were able to repopulate lethally irradiated mice. Although we cannot formally exclude the possibility that the low CD4 cells produced in FL cultures were derived exclusively from the proliferation of the few CD4 cells found in fresh FL, the dynamic analysis of the development of these cells in culture favors the generation of this important population from a CD4- subset of hematopoietic stem cells (HSCs). We speculate that FL contains a prevalent population of very primitive cells not expressing the CD4 antigen, tentatively called "pre-low CD4 precursors." These primitive cells can differentiate into low CD4+ cells that share many characteristics with pluripotent HSCs of the adult type. These data indicate the possibility of using hematopoietic progenitors obtained by the expansion/differentiation of fetal stem cells in culture for transplantation purposes.
Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Células Madre Hematopoyéticas/fisiología , Hígado/citología , Animales , Secuencia de Bases , Células de la Médula Ósea , Antígenos CD4/análisis , Células Cultivadas , Feto , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Datos de Secuencia Molecular , Células del Estroma/fisiologíaRESUMEN
This study reports a case of granulocytic sarcoma that developed in the epidural zone 25 days before clinical evidence of an acute promyelocytic leukemia. The case presented the diagnostic difficulties that are common to all aleukemic granulocytic sarcomas. Moreover, it highlights the very rare association between granulocytic sarcoma and acute promyelocytic leukemia, which is far from being explained.