RESUMEN
BACKGROUND: Altered amygdala activation to fear-related stimuli has been proposed to be a potential neural correlate of heightened threat sensitivity in anxiety- and stress-related disorders. However, the role of stimulus awareness and disorder specificity remains widely unclear. Here we investigated amygdala responses to conscious and unconscious fearful faces in patients suffering from panic disorder (PD), generalized anxiety disorder (GAD), or post-traumatic stress disorder (PTSD) and in a large sample of healthy controls (HC). METHODS: During event-related functional magnetic resonance imaging participants (n = 120; 20 PD, 20 GAD, 20 PTSD, 60 HC) were confronted with briefly presented fearful faces, neutral faces, and non-faces in a backward masking paradigm. The design allowed for the analysis of trial-by-trial face detection performance and amygdala responses to fearful v. neutral faces. RESULTS: All participants exhibited increased amygdala activation to fearful v. neutral faces during conscious trials. Specifically during unconscious face processing, the PTSD, compared with all other groups, showed higher right basolateral (BLA) amygdala activity to fearful v. neutral faces. CONCLUSIONS: The present study shows that BLA amygdala hyperactivity during unconscious, but not conscious, processing of fearful faces differentiates PTSD from the investigated disorders. This finding suggests an automatic and specific neural hyper-responsivity to general fear cues in PTSD and supports the idea of categorical differences between PTSD and other anxiety-related disorders.
Asunto(s)
Amígdala del Cerebelo/fisiopatología , Trastornos de Ansiedad/fisiopatología , Miedo/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Adolescente , Adulto , Estudios de Casos y Controles , Señales (Psicología) , Expresión Facial , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastorno de Pánico/fisiopatología , Tiempo de Reacción , Análisis de Regresión , Adulto JovenRESUMEN
BACKGROUND: There is an ongoing debate whether transdiagnostic neural mechanisms are shared by different anxiety-related disorders or whether different disorders show distinct neural correlates. To investigate this issue, studies controlling for design and stimuli across multiple anxiety-related disorders are needed. METHOD: The present functional magnetic resonance imaging study investigated neural correlates of visual disorder-related threat processing across unmedicated patients suffering from panic disorder (n = 20), social anxiety disorder (n = 20), dental phobia (n = 16) and post-traumatic stress disorder (n = 11) relative to healthy controls (HC; n = 67). Each patient group and the corresponding HC group saw a tailor-made picture set with 50 disorder-related and 50 neutral scenes. RESULTS: Across all patients, increased activation to disorder-related v. neutral scenes was found in subregions of the bilateral amygdala. In addition, activation of the lateral amygdala to disorder-related v. neutral scenes correlated positively with subjective anxiety ratings of scenes across patients. Furthermore, whole-brain analysis revealed increased responses to disorder-related threat across the four disorders in middle, medial and superior frontal regions, (para-)limbic regions, such as the insula and thalamus, as well as in the brainstem and occipital lobe. We found no disorder-specific brain responses. CONCLUSIONS: The results suggest that pathologically heightened lateral amygdala activation is linked to experienced anxiety across anxiety disorders and trauma- and stressor-related disorders. Furthermore, the transdiagnostically shared activation network points to a common neural basis of abnormal responses to disorder-related threat stimuli across the four investigated disorders.
Asunto(s)
Amígdala del Cerebelo/fisiopatología , Encéfalo/fisiopatología , Ansiedad al Tratamiento Odontológico/fisiopatología , Miedo/fisiología , Trastorno de Pánico/fisiopatología , Fobia Social/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Ansiedad al Tratamiento Odontológico/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastorno de Pánico/diagnóstico por imagen , Fobia Social/diagnóstico por imagen , Trastornos por Estrés Postraumático/diagnóstico por imagen , Percepción Visual/fisiología , Adulto JovenRESUMEN
BACKGROUND: rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. AIM: To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. METHODS: This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. RESULTS: rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported. CONCLUSIONS: rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment.
Asunto(s)
Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Neutralizantes/sangre , Área Bajo la Curva , Pruebas de Coagulación Sanguínea , Coagulantes/farmacocinética , Esquema de Medicación , Factor VIII/análisis , Factor VIII/farmacocinética , Semivida , Humanos , Masculino , Persona de Mediana Edad , Curva ROC , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
In haemophilia A patients factor VIII (FVIII) recovery and half-life can vary substantially. There are parameters known to modulate FVIII pharmacokinetics (PK), but they explain only about 34% of the variability. The aim of this study was to identify new parameters that influence FVIII PK and thus to expand the current knowledge. FVIII PK were determined in 42 haemophilia A patients (37 severe, 5 moderate) without inhibitor. Patients' characteristics and laboratory parameters were evaluated for an association with FVIII PK. We analysed plasma levels of low-density lipoprotein receptor-related protein 1 (LRP1) and protein C (PC) activity, which had been hypothesized to influence FVIII activity. Furthermore, four variations in intron 6 of the LRP1 gene, which had been shown to influence LRP1, were investigated. FVIII half-life differed widely from 6.2 to 20.7 h, with a median of 10.0 h. Patients with blood group O had shorter FVIII half-life compared to patients with non-O blood group (median FVIII half-life 9.0 h vs. 10.4 h, P = 0.018). Age was significantly associated with FVIII half-life (r = 0.32, P = 0.035). Besides age, also VWF antigen (r = 0.52, P < 0.001) and blood group (r = -0.37, P = 0.015) was associated with FVIII half-life. No correlation was found with FVIII- or LRP1-genotype, LRP1 or PC concentrations. Our data showed large differences in FVIII PK between individual patients and revealed age, blood group and VWF levels as important determining factors for FVIII half-life. FVIII genotype or levels of LRP1 or PC had no influence on FVIII PK.
Asunto(s)
Factor VIII/farmacocinética , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Proteínas Recombinantes , Sistema del Grupo Sanguíneo ABO , Adulto , Factores de Edad , Coagulación Sanguínea , Índice de Masa Corporal , Factor VIII/administración & dosificación , Semivida , Hemofilia A/sangre , Hemofilia A/diagnóstico , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Masculino , Mutación , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven , Factor de von WillebrandRESUMEN
BACKGROUND: With growing evidence on the role of inflammation in cancer biology, the systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. Recently, the derived neutrophil to lymphocyte ratio (dNLR) has been proposed as an easily determinable prognostic factor in cancer patients. Nevertheless, its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients has never been explored. METHODS: Data from 290 consecutive DLBCL patients, diagnosed between 2004 and 2013 at a single Austrian centre, were evaluated retrospectively. The prognostic influence of the dNLR and other clinico-pathological factors including age, lactate dehydrogenase, cell of origin category and Ann Arbor stage on 5-year overall- (OS) and disease-free (DFS) survival was studied by Kaplan-Meier curves. To evaluate the independent prognostic relevance of dNLR, univariate and multivariate Cox regression models were applied. RESULTS: An independent significant association between high dNLR and poor clinical outcome in multivariate analysis for OS (HR=2.02, confidence interval (CI) 95%=1.17-3.50, P=0.011), as well as DFS (HR=2.15, CI 95%=1.04-4.47, P=0.038), was identified. CONCLUSION: In the present study, we showed that a high dNLR at diagnosis of DLBCL represents an independent poor prognostic factor for clinical outcome. Our data encourage the further validation of this easily available parameter in prospective studies and as a potential stratification tool in clinical trials.
Asunto(s)
Linfocitos/patología , Linfoma de Células B Grandes Difuso/sangre , Neutrófilos/patología , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Inflamación/sangre , Inflamación/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: High levels of C-reactive protein (CRP), an acute phase protein, proofed being associated with decreased clinical outcome in small-scale studies in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to evaluate the prognostic impact of pretreatment CRP levels on overall survival (OS) and disease-free survival (DFS) in a large bicentre study of DLBCL patients. METHODS: Data from 477 DLBCL patients, diagnosed and treated between 2004 and 2013 at two Austrian centres, were evaluated retrospectively. The prognostic influence of CRP and other factors, including age, tumour stage, and revised International Prognostic Index (R-IPI) on 5-year OS and 5-year DFS, were studied by Kaplan-Meier curves as well as univariate and multivariate Cox regression models. Influence of CRP on the predictive accuracy of the R-IPI score was determined by the Harrell concordance index. RESULTS: Kaplan-Meier curves revealed elevated CRP as a factor for decreased 5-year OS and DFS in DLBCL patients (P<0.001, log-rank test). An independent significant association between high CRP levels and poor clinical outcome in multivariate analysis for 5-year OS (HR=1.51, CI 95%=1.04-2.20, P=0.031) and for DFS (HR=1.91, CI 95%=1.28-2.85, P=0.002) was found. The estimated concordance index was 0.75 using the original R-IPI score and 0.79 when CRP was added. CONCLUSIONS: In the present study, we demonstrated high CRP levels at diagnosis of DLBCL as an independent poor prognostic factor for clinical outcome. Adding CRP to the well-established prognostic models such as the R-IPI score might improve their predictive ability.
Asunto(s)
Proteína C-Reactiva/metabolismo , Linfoma de Células B Grandes Difuso/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios RetrospectivosRESUMEN
In this multicenter study, 30 patients undergoing matched related or unrelated allogeneic stem-cell transplantation for leukemia were treated with palifermin, and retrospectively compared to a matched control group. Palifermin recipients transplanted with an unrelated donor showed a significant reduction of severity, incidence and duration of oral mucositis WHO grades 2-4. In addition, in the palifermin group the use of opioid analgesics and the duration of total parenteral nutrition decreased, whether stem cells were used from matched related or unrelated donors. No beneficial influence of palifermin on the incidence and severity of acute GVHD (aGVHD) was apparent. The incidence and duration of febrile neutropenia, documented infections, hematopoietic recovery or overall survival remained unchanged. The most common adverse effects included rash or erythema, generally mild and transient in appearance. Thus, the administration of palifermin was generally well tolerated and safe, and significantly reduced oral mucositis whereas--regardless of donor status--no effect on the incidence and severity of aGVHD was seen.
Asunto(s)
Factor 7 de Crecimiento de Fibroblastos/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Estomatitis/prevención & control , Adolescente , Adulto , Femenino , Factor 7 de Crecimiento de Fibroblastos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Interpersonal violence (IPV) is one of the most frequent causes for the development of posttraumatic stress disorder (PTSD) in women. One key component in PTSD is altered processing of trauma-related cues, leading to emotional symptoms. In the everyday environment, words with trauma-associated semantic content represent typical, albeit abstract, trauma-related stimuli for patients suffering from PTSD. However, the functional neuroanatomy associated with processing single trauma-related words in IPV-PTSD is not understood. The present event-related functional magnetic resonance imaging study investigated the neural basis of trauma-related word processing in women with IPV-PTSD relative to healthy controls (HC) during a non-emotional vigilance task in which the emotional content of the words was task-irrelevant. On the behavioral level, trauma-related relative to neutral word stimuli evoked more unpleasant feelings, higher arousal as well as anxiety in IPV-PTSD patients as compared to HC. Functional imaging data showed hyperactivation to trauma-related versus neutral words in the basolateral amygdala (BLA) and cortical language-processing regions (inferior frontal gyrus, posterior cingulate cortex, angular/supramarginal gyrus) in IPV-PTSD compared to HC. These results propose a role of the BLA in hypervigilant responding to verbal trauma associated cues in IPV-PTSD. Furthermore, the particular involvement of cortical language-processing regions indicates enhanced processing of trauma-related words in brain regions associated with analysis and memory of verbal material. Taken together, our findings suggest that both subcortical and cortical mechanisms contribute to automatic responsivity to verbal trauma cues in PTSD.
Asunto(s)
Complejo Nuclear Basolateral/fisiopatología , Corteza Cerebral/fisiopatología , Neuroimagen Funcional/métodos , Violencia de Pareja , Lenguaje , Trastornos por Estrés Postraumático/fisiopatología , Adulto , Femenino , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Infectious complications are frequent events in patients undergoing high-dose cytotoxic chemotherapy with subsequent autologous peripheral blood stem cell transplantation (PBSCT). To evaluate whether a single subcutaneous injection of pegfilgrastim (6 mg) is as safe and effective as daily filgrastim (5 mug/kg/day), 60 consecutive autologous stem cell transplantations performed for various haematological malignancies have been analysed. In total, 24 patients undergoing 30 consecutive PBSCT received a single subcutaneous injection of 6 mg pegfilgrastim on day 5 after transplantation and were compared retrospectively with 30 patients receiving 5 mug/kg/day of filgrastim starting from day 7 post transplantation. The mean duration of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 8.3 and 9.5 days, respectively (P=0.047). The results of the two groups were not significantly different for incidence of febrile neutropenia and toxicity profile. However, duration of febrile neutropenia (1.6 vs 3.0 days) and total days of fever (1.73 vs 4.1) were different (P=0.017 and 0.003, respectively), favouring the pegfilgrastim arm. Consequently, a higher incidence of transplants with documented infectious complications associated with the filgrastim group could be observed (56 vs 26%) (P=0.02). A single injection of pegfilgrastim administered at day 5 post transplant shows comparable safety and efficacy profiles to daily injections of filgrastim.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias Hematológicas/terapia , Trastornos Linfoproliferativos/terapia , Neutropenia/tratamiento farmacológico , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Femenino , Filgrastim , Neoplasias Hematológicas/complicaciones , Humanos , Inyecciones Subcutáneas , Trastornos Linfoproliferativos/complicaciones , Masculino , Persona de Mediana Edad , Neutropenia/etiología , Polietilenglicoles , Proteínas Recombinantes , Trasplante AutólogoRESUMEN
From 1987 to 1999 35 patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent allogeneic stem cell transplantation (SCT) at the University Hospitals of Vienna and Graz. Initial biopsy specimens were reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). All patients surviving 28 days engrafted. Twenty-eight of them (93%) attained clinical remission. At the last follow-up 14 patients were alive and disease-free at a median of 5.0 (range, 2.3-12.9) years after allogeneic SCT. The actuarial overall survival is 35%. Five patients relapsed 1.8 to 27.6 months after transplant, the probability of relapse is 23%. Of the 21 deaths following SCT, seven were due to relapse/refractory disease and 14 due to transplant-related causes. The probability of treatment-related mortality is 48%. After SCT, minimal residual disease (MRD) was monitored by polymerase chain reaction (PCR) in seven patients with a BCL-2/IgH translocation and in 13 with a clonal immunoglobulin heavy chain (IgH) rearrangement. All 20 patients attained clinical remission rapidly and converted to PCR negativity. In the follow-up nine of these patients are in long-term clinical and molecular remission, six PCR-negative patients died of transplant-related causes and five patients relapsed. In summary, allogeneic stem cell transplantation has a curative potential for patients with refractory and recurrent non-Hodgkin's lymphoma. In our series long-term disease-free survival was associated with molecular disease eradication after SCT. Treatment-related mortality rate was high, thus earlier referral of selected patients to allogeneic SCT should be considered.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin/terapia , Adulto , Femenino , Reordenamiento Génico , Genes de Inmunoglobulinas , Genes bcl-2 , Enfermedad Injerto contra Huésped/etiología , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/mortalidad , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Trasplante HomólogoRESUMEN
Chronic myeloid leukaemia (CML) inevitably terminates in blast crisis (BC) which is of myeloid phenotype in approximately two-thirds and B-lymphoid in one-third of patients. T cell BC is rare and associated with poor prognosis. We describe the case of a 48-year-old woman with extramedullary T cell lymphoblastic transformation. After treatment with combination chemotherapy she achieved a second chronic phase and underwent an allogeneic BMT from an HLA-matched unrelated donor. At 30 months follow-up she is still in complete molecular remission and in good clinical condition. We conclude that unrelated donor BMT should be considered as a therapeutic option for patients with extramedullary BC.
Asunto(s)
Crisis Blástica/terapia , Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Linfocitos T/patología , Femenino , Prueba de Histocompatibilidad , Humanos , Persona de Mediana EdadRESUMEN
A 67-year-old patient with large granular lymphocyte (LGL) leukemia is described. At fluorescence-activated cell sorting (FACS) analysis of the peripheral blood, the lymphocytes were positive for CD3, CD4, CD5, CD29, CD45RA, CD57, and TCR alpha/beta and negative for CD7, CD8, CD16, CD56, CD19, CD22, and TCR gamma/delta. Bone marrow histology and immunohistochemistry did not reveal any lymphocyte infiltration. Cytogenetic examination of peripheral blood cultures showed a clone with the karyotype 46,XY,t(3;5)(p26;q13). Molecular analysis revealed rearrangement of the gamma-T-cell-receptor chain. The region 3p25-3p26 which harbors the von Hippel-Lindau tumor suppressor gene and the RAF1 oncogene has been rearranged in a few cases of T-cell leukemia. The translocation in this case has not yet been described and may reflect an alternative mechanism in the pathogenesis of these disorders.
Asunto(s)
Cromosomas Humanos Par 3 , Cromosomas Humanos Par 5 , Leucemia Linfoide/genética , Translocación Genética , Anciano , Antígenos CD/inmunología , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Linfoide/inmunología , MasculinoRESUMEN
Ineffective hematopoiesis leading to profound cytopenias represents a major clinical problem in the management of patients with myelodysplastic syndrome (MDS). The aminothiol amifostine has shown to promote multilineage hematopoiesis both in vivo and in vitro in patients with MDS. We have treated 10 patients with 250 mg/m2 amifostine thrice weekly in combination with erythropoietin for 4 consecutive weeks followed by 2 weeks observation. Responding patients received the same 6 week schedule, while nonresponder received G-CSF in addition to erythropoietin and amifostine during the second treatment course. All patients experienced single or multilineage hematologic improvement, but only 2 reached transfusion independency. Moreover, response was durable only in a minority of patients and thus additional studies are warranted to further define the potential interaction of amifostine and growth factors.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Hematopoyesis/efectos de los fármacos , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Amifostina/administración & dosificación , Amifostina/farmacología , Amifostina/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Recuento de Células Sanguíneas , Linaje de la Célula , Eritropoyetina/administración & dosificación , Eritropoyetina/farmacología , Eritropoyetina/toxicidad , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos/toxicidad , Humanos , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/complicaciones , Resultado del TratamientoRESUMEN
Thrombotic complications are observed in patients undergoing bone marrow transplantation despite thrombocytopenia and impaired coagulation due to liver function disturbances. Endothelial cell damage which is involved in the pathogenesis of major transplant related complications like graft-versus-host disease, veno-occlusive disease, sepsis or microangiopathy may be a contributing factor. Little is known about platelet function in bone marrow transplant recipients. In order to study functional alterations in circulating platelets we investigated unstimulated and ADP-stimulated platelets of 10 bone marrow transplant recipients ex vivo by flow cytometry in a pilot study using a panel of monoclonal antibodies to characterize changes in membrane glycoproteins. Samples were collected before and during conditioning and at three timepoints after engraftment. 10 healthy volunteers served as controls. Platelets of bone marrow transplant recipients showed partly a significant, higher expression of surface bound fibrinogen, activated fibrinogen receptor, and glycoprotein Ib as compared to controls. P-selectin, a marker of platelet degranulation was significantly elevated after ADP-induced stimulation at all timepoints compared to controls. Only marginal differences were found for GP IIb/IIIa surface expression. The data point to an increased platelet activation state in bone marrow transplant recipients which might contribute to the thrombotic phenomena observed in these patients.
Asunto(s)
Trasplante de Médula Ósea/fisiología , Glicoproteínas de Membrana Plaquetaria/metabolismo , Adenosina Difosfato/farmacología , Adulto , Anticuerpos Monoclonales , Trasplante de Médula Ósea/efectos adversos , Estudios de Casos y Controles , Femenino , Fibrinógeno/metabolismo , Citometría de Flujo , Colorantes Fluorescentes , Supervivencia de Injerto/fisiología , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Selectina-P/sangre , Activación Plaquetaria/efectos de los fármacos , Activación Plaquetaria/fisiología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Quinacrina , Trombosis/sangre , Trombosis/etiología , Acondicionamiento PretrasplanteRESUMEN
BACKGROUND: Veno-occlusive disease (VOD) leads to obliteration of small intrahepatic venules and is one of three most important complications with fatal outcome after bone marrow transplantation (BMT). The etiology of VOD is not completely understood. Endothelial cell injury induced by the conditioning myeloablative radiochemotherapy with subsequent activation of the coagulation cascade seems to be a crucial step in the pathogenesis of the disease. PATIENTS AND METHODS: We investigated tissue plasminogen activator (tPA), its main inhibitor (PAI-1) and the natural anticoagulants protein C and S by enzymimmunoassay prospectively in 32 bone marrow transplant recipients. RESULTS: VOD developed in four patients. They presented with extremely elevated levels of PAI-1 after BMT whereas tPA levels remained low. Additionally a transient decrease of protein S was found one week after BMT which was more pronounced in VOD patients. No protein C deficiency was observed. CONCLUSION: Our data suggest that hypofibrinolysis due to an excess of PAI-1 may be involved in the pathogenesis of VOD. The determination of PAI-1 may be useful to recognize the development of VOD and facilitate the decision for thrombolytic therapy with rtPA. A decrease of protein S may play a role as a cofactor in the early phase after BMT.
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Trasplante de Médula Ósea/fisiología , Fibrinólisis/fisiología , Venas Hepáticas , Trombosis/sangre , Femenino , Humanos , Masculino , Neoplasias/sangre , Neoplasias/terapia , Inhibidor 1 de Activador Plasminogénico/sangre , Estudios Prospectivos , Proteína C/metabolismo , Proteína S/líquido cefalorraquídeoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Neoplasias del Bazo/tratamiento farmacológico , Adulto , Alemtuzumab , Anemia Hemolítica/etiología , Anemia Hemolítica/terapia , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino , Anticuerpos Antineoplásicos/administración & dosificación , Antígenos CD/análisis , Biomarcadores de Tumor/análisis , Transfusión Sanguínea , Cladribina/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Linfoma de Células T/complicaciones , Neutropenia/etiología , Prednisolona/administración & dosificación , Receptores de Antígenos de Linfocitos T gamma-delta/análisis , Recurrencia , Inducción de Remisión , Rituximab , Vincristina/administración & dosificaciónRESUMEN
Blastic plasmacytoid DC neoplasm (BPDCN) is a rare haematopoietic malignancy with an aggressive behaviour. We evaluated five patients allografted as consolidative treatment with an unrelated donor in first or subsequent remission. Four patients received a reduced intensity-conditioning regimen because of age or co-morbidities. As the stem cell sources, two umbilical cord blood-(UCB), two PBSC- and one BM graft were used. No GVHD was observed in the patients who received a UCB graft. However, both developed a post-transplant-associated lymphoproliferative disease. So far, only one patient has experienced relapse and was consecutively treated by escalated donor lymphocyte infusions (DLI). A potent graft-versus-leukaemia (GVL) effect was induced leading to a 17-month-long CR. Four patients are still in ongoing CR with median disease-free and overall survivals of 17 and 21 months. Thus, allogeneic SCT in BPDCN offers a potential curative option for patients with a compatible donor. UCB is an attractive alternative as a stem cell source. For relapsing patients, DLI can exert a powerful GVL effect.
Asunto(s)
Efecto Injerto vs Leucemia , Trastornos Linfoproliferativos/terapia , Neoplasias de Células Plasmáticas/terapia , Trasplante de Células Madre , Acondicionamiento Pretrasplante , Adulto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias de Células Plasmáticas/mortalidad , Tasa de Supervivencia , Factores de Tiempo , Donante no EmparentadoRESUMEN
Chemokine receptors mediate migration and activation of lymphocytes through binding of their ligands. Recent studies have revealed important contributions of chemokine receptors to the development, progression, and dissemination of haematopoietic neoplasms. Because the chemokine receptor expression profile in extragastric MALT lymphoma is unknown, we performed a comprehensive study on tissue samples of parotid glands, parotid glands affected by Sjögren syndrome, extragastric MALT lymphoma, and extranodal diffuse large B-cell lymphoma (eDLBCL) originating from MALT lymphoma (transformed MALT lymphoma). By investigating the expression of 19 chemokine receptors by real-time PCR using a semi-quantitative approach and of four chemokine receptors (CCR1, CCR5, CXCR6, and XCR1) by immunohistochemistry, we show that the chemokine receptor expression profiles of extragastric MALT lymphomas differ substantially from those of extranodal DBLCL, with lower expression of CCR1, CCR8, and CXCR3, and the absence of expression of CX3CR1 and XCR1 in eDLBCL. Expression of CCR6, CCR7, CXCR3, CXCR4, and CXCR5, responsible for B-cell homing to secondary lymphoid tissue, was detected in both B-cell malignancies. Expression of CCR4 was just detected in trisomy 3-positive MALT lymphoma cases. Comparing gastric with extragastric MALT lymphomas, up-regulation of CXCR1 and CXCR2 accompanied by down-regulation of CCR8 and CX3CR1 and loss of XCR1 expression in extragastric MALT lymphomas appear to be key determinants for the site of origin of MALT lymphomagenesis. Our results support a model of stepwise progression of extragastric MALT lymphoma from a non-neoplastic event to Sjögren syndrome, to MALT lymphoma, and finally to overt eDLBCL, guided by differentially expressed B-cell homeostatic and activation-dependent chemokine receptors and their ligands.