RESUMEN
Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication that can be observed after allogeneic hematopoietic cell transplantation (HCT). Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody-drug conjugate that has demonstrated high efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) but is associated with an increased risk of SOS in HCT recipients. Here we aimed to examine the incidence and outcomes of SOS in 47 adult patients with R/R ALL who received inotuzumab therapy and subsequently underwent HCT at our institution. All patients received prophylactic therapy with ursodiol, and continuous low-dose heparin also was administered to patients receiving myeloablative conditioning (MAC). SOS occurred in 12 patients (26%) post-HCT, at a median onset of 11 days (range, 3 to 41 days). SOS was graded as very severe in 50% (n = 6), severe in 25% (n = 3), and mild in 25% (n = 3). All patients diagnosed with SOS received treatment with defibrotide for a median of 21 days (range, 3 to 34 days), with resolution of SOS occurring in 8 patients (67%). Mortality from SOS was 33% (n = 4) and occurred at a median of 10 days from diagnosis (range, 3 to 31 days) in patients graded as very severe (n = 3) or severe (n = 1). There were no significant differences between patients who developed SOS and those who did not develop SOS in the median time from the last dose of inotuzumab to transplantation (46 days versus 53 days; P = .37), use of an MAC regimen (42% versus 49%; P = .75), number of lines of therapy prior to inotuzumab (P = .79), median number of administered cycles of inotuzumab (2 versus 2; P = .14), or receipt of inotuzumab as the last therapy prior to HCT (67% versus 66%; P = 1.0). Sirolimus-based graft-versus-host disease (GVHD) prophylaxis was used more frequently in the SOS group (75% versus 29%; P < .01), but there was no between-group difference in the peak sirolimus level (P = .81) or the median time to peak sirolimus level (7 days versus 3.5 days; P = .39). In univariable analysis, only the use of sirolimus-based GVHD prophylaxis was significantly associated with an increased risk of SOS (hazard ratio [HR], 7.50; 95% confidence interval [CI], 1.7 to 33.6; P < .01). In the SOS group, the 100-day mortality rate was 33% (n = 4), and median overall survival (OS) post-HCT was 4.3 months (range, 0.2 to 57.2 months). In the group without SOS, the 100-day mortality rate was 14% (n = 5) and the median OS post-HCT was 10.7 months (range, .52 to 39.6 months). In this study cohort, SOS was prevalent in HCT recipients who had been treated with inotuzumab prior to transplantation, and sirolimus-based GVHD prophylaxis was a risk factor for SOS in inotuzumab recipients.
Asunto(s)
Linfoma de Burkitt , Enfermedad Injerto contra Huésped , Enfermedad Veno-Oclusiva Hepática , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Adulto , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/etiología , Inotuzumab Ozogamicina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Sirolimus , Linfoma de Burkitt/inducido químicamente , Linfoma de Burkitt/complicaciones , Enfermedad Injerto contra Huésped/prevención & controlRESUMEN
Although Epstein-Barr virus (EBV) infection is widely distributed, certain EBV-driven malignancies are geographically restricted. EBV-associated Burkitt's lymphoma (eBL) is endemic in children living in sub-Saharan Africa. This population is heavily exposed to food contaminated with the mycotoxin aflatoxin B1 (AFB1). Here, we show that exposure to AFB1 in in vitro and in vivo models induces activation of the EBV lytic cycle and increases EBV load, two events that are associated with an increased risk of eBL in vivo. AFB1 treatment leads to the alteration of cellular gene expression, with consequent activations of signaling pathways, e.g. PI3K, that in turn mediate reactivation of the EBV life cycle. Finally, we show that AFB1 triggers EBV-driven cellular transformation both in primary human B cells and in a humanized animal model. In summary, our data provide evidence for a role of AFB1 as a cofactor in EBV-mediated carcinogenesis.
Asunto(s)
Aflatoxina B1/toxicidad , Linfocitos B/virología , Linfoma de Burkitt/virología , Exposición a Riesgos Ambientales , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/efectos de los fármacos , Animales , Linfocitos B/patología , Linfoma de Burkitt/inducido químicamente , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Células Cultivadas , Femenino , Herpesvirus Humano 4/fisiología , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Transducción de Señal , Activación Viral , Replicación Viral/efectos de los fármacosRESUMEN
We describe the case of a boy who presented with abdominal Burkitt lymphoma; he had been regularly using tacrolimus ointment 0.1% for severe recurrent atopic dermatitis for 7 years immediately prior to developing cancer. We present his medical history and review the current knowledge regarding a link between topical tacrolimus and malignancy risk.
Asunto(s)
Linfoma de Burkitt/diagnóstico , Dermatitis Atópica/tratamiento farmacológico , Neoplasias del Íleon/diagnóstico , Válvula Ileocecal , Inmunosupresores/efectos adversos , Tacrolimus/efectos adversos , Administración Cutánea , Linfoma de Burkitt/inducido químicamente , Linfoma de Burkitt/complicaciones , Linfoma de Burkitt/cirugía , Niño , Dermatitis Atópica/complicaciones , Diagnóstico Diferencial , Humanos , Enfermedades del Íleon/complicaciones , Enfermedades del Íleon/diagnóstico , Enfermedades del Íleon/cirugía , Neoplasias del Íleon/inducido químicamente , Neoplasias del Íleon/complicaciones , Neoplasias del Íleon/cirugía , Válvula Ileocecal/cirugía , Inmunosupresores/administración & dosificación , Intususcepción/complicaciones , Intususcepción/diagnóstico , Intususcepción/cirugía , Masculino , Tacrolimus/administración & dosificación , Tomografía Computarizada por Rayos XAsunto(s)
Anticuerpos Monoclonales/efectos adversos , Linfoma de Burkitt/etiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/fisiología , Neoplasias Gástricas/etiología , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Linfoma de Burkitt/inducido químicamente , Linfoma de Burkitt/diagnóstico , Infecciones por Helicobacter/patología , Humanos , Masculino , Psoriasis/complicaciones , Psoriasis/tratamiento farmacológico , Neoplasias Gástricas/inducido químicamente , Neoplasias Gástricas/diagnósticoRESUMEN
OBJECTIVE: Reactive oxygen species (ROS), generated following benzene exposure, are considered to trigger the development of hematopoietic neoplasms, although little supporting evidence has been found. In this study, we examined whether the experimental elimination of ROS generated following benzene exposure prevents the development of benzene-induced hematopoietic disorders to clarify the mechanism underlying the development of benzene-induced hematopoietic disorders. METHODS: C57BL/6 mice, overexpressing human thioredoxin (h-Trx-Tg), were used to examine the possible nullification of ROS induction following benzene exposure. The experimental group was exposed to 300 ppm benzene 6 hours/day, 5 days/week, for 26 weeks, and lifetime observation followed by molecular and histopathological examinations were carried out. RESULTS: The present study using h-Trx-Tg mice showed a complete suppression of the development of thymic lymphoma induced by benzene inhalation (0% in h-Trx-Tg vs 30% in wild-type (Wt) mice). This was associated with a 48% decrease in the incidence of clastogenic micronucleated reticulocyte induction in the h-Trx-Tg mice compared with the Wt control after 2 weeks of inhalation. As underlying mechanisms, the attenuation of oxidative stress was accompanied by a complete abrogation of hemato-lymphoid toxicity, as shown by the upregulation of the activity of superoxide-dismutase, and a consequently stable ROS level, as determined by cell sorting using 2', 7'-dichlorodihydrofluorescein diacetate, along with a significant attenuation of the overexpression of a cell cycle-dependent kinase inhibitor, p21. CONCLUSION: The attenuation of benzene-induced oxidative stress and that of the consequent lymphomagenesis were observed for the first time, and these indicate a role of oxidative stress in benzene-induced clastogenesis and lymphomagenesis. (These attenuations were not seen in nonthymic lymphomas, and no leukemias developed in C57BL/6 used in this study.) During the constitutive overexpression of h-Trx, the expression of aryl-hydrocarbon receptor in h-Trx-Tg mice was downregulated, which may also contribute to the attenuation.
Asunto(s)
Linfoma de Burkitt/prevención & control , Enfermedades Hematológicas/prevención & control , Inmunidad Innata/genética , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismo , Tiorredoxinas/genética , Animales , Benceno/toxicidad , Linfoma de Burkitt/inducido químicamente , Linfoma de Burkitt/genética , Carcinógenos/toxicidad , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Citocromo P-450 CYP2E1/genética , Regulación hacia Abajo , Genotipo , Enfermedades Hematológicas/inducido químicamente , Enfermedades Hematológicas/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Animales , ARN Mensajero/genética , Receptores de Hidrocarburo de Aril/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Tasa de Supervivencia , Tiorredoxinas/biosíntesis , Timo/efectos de los fármacos , Timo/metabolismo , Timo/patologíaRESUMEN
INTRODUCTION: Neoplasia and lymphoproliferative disorders are sometimes reported in patients with systemic lupus erythematosus (SLE). However, the pathophysiological link between lymphoma and SLE is still a matter of debate. We report a new case of Burkitt's lymphoma occurring in a patient treated with immunosuppressive drugs for SLE. CASE REPORT: A 38-year-old woman with SLE treated for 10 years with immunosuppressive drugs was admitted for the rapid onset of multiple neuritis with cranial nerves palsy, without extra-neurological involvement. The cerebrospinal fluid was normal. A bone marrow biopsy revealed Burkitt's lymphoma. CONCLUSION: This is the third case reported of Burkitt's lymphoma occurring in SLE. Here we discuss the data of the literature and the possible pathophysiological links between Burkitt's lymphoma and SLE.
Asunto(s)
Linfoma de Burkitt/etiología , Inmunosupresores/efectos adversos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Adulto , Biopsia , Médula Ósea/patología , Linfoma de Burkitt/inducido químicamente , Linfoma de Burkitt/patología , Ciclofosfamida/efectos adversos , Ciclosporina/efectos adversos , Resultado Fatal , Femenino , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/patologíaRESUMEN
Lymphoid system tumours have been identified in two subjects who used to handle for several years mediterranean shark liver oil and squalen extracted from this oil. Moreover, scientific data, reported in 1959 by Kröning, show the induction of lymphoid tumours in C57 B1 mice after exposure of their skin to squalen. These observations rose the question of a possible mutagenic power of shark liver oil. In order to determine the genotoxicity of these oils, in vitro assays have been performed on crude hepatic oil of three species of mediterranean sharks: two benthic sharks, Centrophorus granulosus and Galeus melastomus, and one pelagic specie, Prionace glauca. Genotoxicity of oils have been assayed using a micronucleus test which can detected simultaneously clastogen and aneugen effects. The incubation of human cells with the hepatic crude oils of Centrophorus granulosus increases the rate of the binucleated micronucleated cell in a dose dependent manner. The mean micronucleated cell rate was 9.0%. +/- 1.1 in controls and increased up to 27,1%. +/- 4,0 for the highest concentrations of oil extracts. Similar results have been obtained with crude hepatic oils of Galeus melastomus and Prionace glauca. The results of this experimental study show that the crude liver oils of three species of sharks are genotoxic and confirm a high carcinogenic risk.