RESUMEN
AIMS: Kaposi sarcoma herpesvirus (KSHV) is aetiologically related to Kaposi sarcoma, classical and extracavitary primary effusion lymphoma (PEL; EC-PEL) and multicentric Castleman disease (MCD), entities preferentially occurring in HIV-infected individuals. Characterization of HIV-associated PELs/EC-PELs suggests that the KSHV-infected malignant cells originate from a pre-terminal stage of B-cell differentiation. However, only limited phenotypic studies have been performed on HIV+ MCD, including for PR domain containing 1 with zinc finger domain/B lymphocyte-induced maturation protein 1 (PRDM1/BLIMP1), a key regulator of terminal B-cell differentiation. The aim was to characterize KSHV-infected cells in 17 cases of HIV+ MCD. METHODS AND RESULTS: Double immunohistochemistry and immunohistochemistry-in situ hybridization were used to characterize the KSHV-infected cells in MCD; the results were compared with the phenotypic profiles of 39 PELs/EC-PELs and seven PEL cell lines. Whereas the immunophenotype of KSHV-infected cells in MCD and malignant KSHV+ PEL cells was similar (PAX5, Bcl-6-; PRDM1/BLIMP1, IRF4/MUM1+; Ki67+), the MCD KSHV-infected cells differed, as they expressed OCT2, cytoplasmic lambda immunoglobulin; variably expressed CD27; lacked CD138; and were Epstein-Barr virus negative. CONCLUSIONS: Although both PEL and MCD originate from KSHV-infected pre-terminally differentiated B cells, these findings, with previously reported genetic studies, indicate HIV+ MCD may arise from extrafollicular B cells, whereas PELs may originate from cells that have traversed the germinal centre.
Asunto(s)
Linfocitos B/virología , Enfermedad de Castleman/virología , Infecciones por VIH/complicaciones , Infecciones por Herpesviridae/virología , Herpesvirus Humano 8 , Linfoma de Efusión Primaria/virología , Adulto , Linfocitos B/metabolismo , Enfermedad de Castleman/inmunología , Enfermedad de Castleman/metabolismo , Diferenciación Celular , Femenino , Herpesvirus Humano 8/inmunología , Herpesvirus Humano 8/metabolismo , Humanos , Inmunohistoquímica , Inmunofenotipificación , Hibridación in Situ , Linfoma de Efusión Primaria/inmunología , Masculino , Persona de Mediana EdadRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although some patients can be cured by current therapies, novel agents are needed to further improve outcomes. We hypothesized that Src tyrosine kinase inhibition by dasatinib may have antilymphoma effects. Here, we demonstrate that dasatinib inhibits cell growth through G(1)-S blockage in five of seven DLBCL cell lines at clinically achievable concentrations. Compared to resting B cells, DLBCL has increased tyrosine phosphorylation activities. As expected, dasatinib inhibits phosphorylation of several Src family kinase members. However, this inhibition occurs in all cell lines regardless of their proliferative response to the drug. In contrast, the activity of two downstream signaling molecules, Syk and phospholipase Cgamma2 (PLCgamma2), are well correlated with cell line sensitivity to dasatinib, suggesting that these molecules are crucial in mediating the proliferation of activated lymphoma cells. Furthermore, dasatinib inhibits B-cell receptor signaling in primary lymphoma cells. Together, our findings not only show dasatinib as a potentially useful therapy for DLBCL but also provide insights into the pathogenesis of the lymphoma. The results further suggest the possibility of using Syk and PLCgamma2 as biomarkers to predict dasatinib therapeutic response in prospective clinical trials.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Tiazoles/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Dasatinib , Humanos , Interfase/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfolipasa C gamma/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Quinasa Syk , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
BACKGROUND: Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion. METHODS: We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival. RESULTS: We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS. CONCLUSION: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.
Asunto(s)
Biomarcadores de Tumor/análisis , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/terapia , Trasplante de Células Madre , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ensayos Clínicos como Asunto , Estudios de Cohortes , Terapia Combinada , Ciclofosfamida/administración & dosificación , Bases de Datos Factuales , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/radioterapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Radioterapia , Análisis de Regresión , Estudios Retrospectivos , Rituximab , Análisis de Supervivencia , Factores de Tiempo , Trasplante Autólogo , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.
Asunto(s)
Células Madre Hematopoyéticas/patología , Proteínas de Neoplasias , Neoplasias Experimentales/irrigación sanguínea , Neoplasias Experimentales/patología , Neovascularización Patológica , Proteínas Represoras , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Endotelio Vascular/patología , Trasplante de Células Madre Hematopoyéticas , Proteína 1 Inhibidora de la Diferenciación , Proteínas Inhibidoras de la Diferenciación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Mutación , Neovascularización Patológica/genética , Pruebas de Neutralización , Proteínas Proto-Oncogénicas/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores de Factores de Crecimiento/fisiología , Receptores de Factores de Crecimiento Endotelial Vascular , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Receptor 1 de Factores de Crecimiento Endotelial VascularRESUMEN
In this report, a unique case of a large unilateral orbital tumor occurring in a 5-year-old white girl is described. The lesion, which was associated with no systemic clinical symptoms, waxed and waned in size over 12 months and eventually spontaneously resolved. Multiple biopsies were performed, which showed an angiocentric and angioinvasive infiltrate composed of a monotonous population of atypical, immature-appearing, large lymphocytes. Extensive molecular and immunophenotypic studies led to the diagnosis of an Epstein-Barr virus-negative angiocentric lymphoproliferative disorder with an immature natural killer (NK) cell immunophenotype (CD16+CD56-), specifically an immunophenotype expressed by normal cord blood NK cells. HUM PATHOL 32:339-342.
Asunto(s)
Vasos Sanguíneos/patología , Células Asesinas Naturales/patología , Órbita/irrigación sanguínea , Neoplasias Orbitales/patología , Biopsia , Antígeno CD56/análisis , Preescolar , Conjuntiva/patología , Epitelio/patología , Párpados/patología , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Células Asesinas Naturales/inmunología , Neoplasias Orbitales/inmunología , Receptores de IgG/análisis , Remisión EspontáneaRESUMEN
The organization and expression of the BCL-6 gene in normal and neoplastic thymic T cells has not been fully determined. We examined 8 precursor T-cell lymphoblastic lymphomas (T-LBLs) and found significant BCL-6 expression in 4 cases. Three of the BCL-6(+) cases expressed a common thymocyte phenotype (CD4(+), CD8(+)), and one expressed a precursor thymocyte phenotype (CD4(-), CD8(-)). In 6 cases evaluated, including those expressing BCL-6, molecular analyses demonstrated a germline configuration of the BCL-6 gene and a wild-type BCL-6 gene first exon-intron boundary region. We also evaluated 12 normal prenatal and postnatal thymuses for BCL-6 protein. BCL-6 was expressed by most cortical thymocytes and by scattered medullary thymocytes. BCL-6(+) cortical and medullary thymocytes also expressed CD2, CD3, CD4, CD5, CD7, or CD8. We further analyzed the pattern of BCL-2 and BCL-X(L) expression and their coexpression with BCL-6 in normal thymus and T-LBL and compared it to that of follicle centers of reactive lymph nodes and follicular lymphoma. BCL-6(+) cortical thymocytes coexpressed BCL-X(L) but not BCL-2. All 4 BCL-6(+) T-LBLs and 4 BCL-6(-) T-LBLs coexpressed BCL-2 and BCL-X(L). Conceivably, T-LBLs may arise through clonal expansion of cortical thymocytes normally expressing the BCL-6 protein. The pattern of BCL-6, BCL-2, and BCL-X(L) expression in cortical thymocytes is highly reminiscent of germinal centers, and the abnormal coexpression of BCL-2, BCL-X(L), and BCL-6 in T-LBL is analogous to coexpression in follicle center cell lymphomas, suggesting that coexpression of these anti-apoptotic genes may contribute to the pathogenesis of T-LBL.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Timo/embriología , Factores de Transcripción/metabolismo , Adolescente , Adulto , Apoptosis/efectos de los fármacos , Niño , Preescolar , Femenino , Feto/química , Feto/citología , Humanos , Inmunofenotipificación , Lactante , Recién Nacido , Linfoma Folicular/etiología , Linfoma Folicular/metabolismo , Linfoma de Células T/etiología , Linfoma de Células T/metabolismo , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6 , Timo/química , Timo/patología , Proteína bcl-XRESUMEN
BACKGROUND: Studies have shown telomerase activity to be present in some B-cell non-Hodgkin lymphomas (B-NHLs). However, no large studies have assayed telomerase activity in a systematic and quantitative manner. Furthermore, the relation between telomerase and proliferation suggested by in vitro studies has not been adequately tested in B-NHLs in vivo. This information is necessary to understand the relation between proliferation and telomerase and to predict the efficacy of antitelomerase drugs currently in development. METHODS: Eighteen benign biopsies and 111 B-NHLs of varying types were classified according to the revised European-American classification of lymphoid neoplasms (REAL classification) and assayed for telomerase activity and proliferation index (PI). RESULTS: All B-NHLs contained telomerase activity except for low grade marginal zone B-cell lymphomas (MZBCLs) (96 of 111, 86%) (chi(2) 95.90, P < 0.001). Telomerase activity correlated with PI (r = 0.7536, r(2) = 0.5678, t = 10.51, P < 0.001) and showed a threshold whereby telomerase activity was not present below a PI of 9.2% (t = 4.875, P < 0.001). CONCLUSIONS: The level of telomerase activity fell within characteristic ranges and generally correlated with the clinical aggressiveness of each B-NHL category. Low grade MZBCLs of extranodal, nodal, and splenic types were unique among the categories of B-NHL in lacking or containing very little telomerase activity. The association between telomerase activity and PI is evidence that telomerase is controlled in vivo along with the cell cycle and is not constitutively active in B-NHL. These data provide evidence that antitelomerase drugs may be efficacious in most types of B-NHL.
Asunto(s)
Linfoma de Células B/enzimología , Telomerasa/metabolismo , División Celular/fisiología , Humanos , Linfoma de Células B/clasificación , Linfoma de Células B/patologíaRESUMEN
Emerging data suggest that VEGF receptors are expressed by endothelial cells as well as hematopoietic stem cells. Therefore, we hypothesized that functional VEGF receptors may also be expressed in malignant counterparts of hematopoietic stem cells such as leukemias. We demonstrate that certain leukemias not only produce VEGF but also express functional VEGFR-2 in vivo and in vitro, resulting in the generation of an autocrine loop that may support leukemic cell survival and proliferation. Approximately 50% of freshly isolated leukemias expressed mRNA and protein for VEGFR-2. VEGF(165) induced phosphorylation of VEGFR-2 and increased proliferation of leukemic cells, demonstrating these receptors were functional. VEGF(165) also induced the expression of MMP-9 by leukemic cells and promoted their migration through reconstituted basement membrane. The neutralizing mAb IMC-1C11, specific to human VEGFR-2, inhibited leukemic cell survival in vitro and blocked VEGF(165)-mediated proliferation of leukemic cells and VEGF-induced leukemic cell migration. Xenotransplantation of primary leukemias and leukemic cell lines into immunocompromised nonobese diabetic mice resulted in significant elevation of human, but not murine, VEGF in plasma and death of inoculated mice within 3 weeks. Injection of IMC-1C11 inhibited proliferation of xenotransplanted human leukemias and significantly increased the survival of inoculated mice. Interruption of signaling by VEGFRs, particularly VEGFR-2, may provide a novel strategy for inhibiting leukemic cell proliferation.
Asunto(s)
Leucemia/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Secuencia de Bases , División Celular/fisiología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Cartilla de ADN/genética , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Factores de Crecimiento Endotelial/farmacología , Expresión Génica , Supervivencia de Injerto , Humanos , Leucemia/genética , Leucemia/patología , Linfocinas/genética , Linfocinas/metabolismo , Linfocinas/farmacología , Metaloproteinasa 9 de la Matriz/biosíntesis , Ratones , Ratones Endogámicos NOD , Trasplante de Neoplasias , Células Neoplásicas Circulantes , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Receptores de Factores de Crecimiento Endotelial Vascular , Transducción de Señal , Trasplante Heterólogo , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: The C57BL/6J-Min/+ (Min/+) mouse bears a germline mutation in Apc and is therefore a model for familial adenomatous polyposis and sporadic colorectal cancer. Min/+ intestinal mucosa exhibits a marked tendency for spontaneous adenoma formation. Curcumin is a phenolic antioxidant known for its antitumor and immune modulatory functions in vitro. Curcumin prevents adenoma formation in Min/+ mice, through a mechanism that may be related to its immunomodulatory properties. MATERIALS AND METHODS: To study the relationship between intestinal immunity and curcumin-induced antitumor response, we used immunohistochemistry to characterize the effect of curcumin treatment on resident intestinal immune effector cells in Min/+ mice. RESULTS/CONCLUSION: These results show that mucosal CD4(+) T cells and B cells increase in animals treated with curcumin, suggesting that curcumin modulates lymphocyte-mediated immune functions.
Asunto(s)
Antineoplásicos/farmacología , Curcumina/farmacología , Sistema Inmunológico/citología , Sistema Inmunológico/efectos de los fármacos , Mucosa Intestinal/patología , Neoplasias Intestinales/prevención & control , Intestinos/citología , Intestinos/efectos de los fármacos , Proteína de la Poliposis Adenomatosa del Colon , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Recuento de Linfocito CD4/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Proteínas del Citoesqueleto/genética , Mutación de Línea Germinal , Inmunohistoquímica , Mucosa Intestinal/efectos de los fármacos , Neoplasias Intestinales/genética , Recuento de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes/genéticaRESUMEN
In this review, our knowledge concerning the structure and function of the spleen is summarized. The unique architecture of the spleen allows for interactions between the circulatory, reticuloendothelial, and immune systems. Based on these interactions in conjunction with its microanatomy, the spleen is able to maintain the integrity of the blood and respond to circulating antigens. However, this can be a double-edged sword in the case of patients suffering from autoimmune diseases such as immune thrombocytopenic purpura since the spleen can be the site of both antibody production and circulating cell destruction.
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Bazo/anatomía & histología , Animales , Humanos , Bazo/fisiologíaRESUMEN
Mantle cell lymphoma (MCL) is a tumor of intermediate-size, IgM+, IgD+ B cells derived from the mantle zone of the germinal center. Little is known about its specific immunologic features or responsiveness to T cell-derived signals. In this work, we evaluated the proliferation and cell cycle properties of freshly isolated MCL cells after CD40 ligation, in the absence and presence of interleukin 4 (IL-4). In each MCL case examined, there was a marked growth-enhancing effect of these two stimuli characterized by improved viability, augmented expression of Ki-67, and induction of the proliferating cell nuclear antigen (PCNA). Cyclin D1 was expressed throughout the cell cycle in MCL cells induced to enter S phase. From these investigations, we conclude that the biology of MCL B lymphocytes is affected by CD154 (CD40 ligand) and IL-4, two signals usually provided by CD4+ T cells. The capacity to manipulate the activation and cell cycle state of MCL cells by these specific immunological stimuli may be exploited to confer susceptibility to chemotherapy agents and develop novel therapies in this disease.
Asunto(s)
Linfocitos B/metabolismo , Antígenos CD40/metabolismo , Interleucina-4/metabolismo , Linfoma de Células del Manto/metabolismo , Linfocitos B/inmunología , División Celular , Ciclina D1/metabolismo , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunofenotipificación , Antígeno Ki-67/metabolismo , Linfoma de Células del Manto/inmunología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Unión Proteica , Fase S , Células Tumorales CultivadasRESUMEN
Haemophagocytic syndrome (HPS) is a fulminant, often fatal, systemic illness that occurs in association with infection and malignancy. We provide the first report of HPS that heralded a primary effusion lymphoma (PEL), a rare neoplasm linked to Kaposi's sarcoma-associated herpesvirus. The patient was a 38-year-old man with acquired immunodeficiency syndrome who presented with fever, sweats, lymphadenopathy, splenomegaly and refractory anaemia. Examination of the spleen demonstrated haemophagocytosis; analysis of ascites revealed PEL. Treatment with chemotherapy and ganciclovir resulted in complete remission of both conditions. This case illustrates the diagnostic challenges posed by HPS and supports the trial of antiviral agents in combination with chemotherapy in patients with PEL.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Anemia Refractaria/complicaciones , Histiocitosis de Células no Langerhans/complicaciones , Neoplasias Pulmonares/complicaciones , Linfoma de Células B Grandes Difuso/complicaciones , Sarcoma de Kaposi/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adulto , Anemia Refractaria/tratamiento farmacológico , Anemia Refractaria/virología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , Ciclofosfamida/uso terapéutico , Ganciclovir/uso terapéutico , Herpesvirus Humano 8 , Histiocitosis de Células no Langerhans/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/virología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/virología , Masculino , Metilprednisolona/uso terapéutico , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/virología , Vincristina/uso terapéuticoAsunto(s)
Enfermedad de Hodgkin/diagnóstico , Linfoma de Células B/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Neoplasias del Mediastino/diagnóstico , Diagnóstico Diferencial , Enfermedad de Hodgkin/metabolismo , Humanos , Inmunofenotipificación , Antígeno Ki-1/análisis , Linfoma de Células B/química , Linfoma de Células B Grandes Difuso/química , Neoplasias del Mediastino/química , Neoplasias del Timo/química , Neoplasias del Timo/diagnósticoRESUMEN
Intestinal carcinogenesis involves the successive accumulation of multiple genetic defects until cellular transformation to an invasive phenotype occurs. This process is modulated by many epigenetic factors. Unconjugated bile acids are tumor promoters whose presence in intestinal tissues is regulated by dietary factors. We studied the role of the unconjugated bile acid, chenodeoxycholate, in an animal model of familial adenomatous polyposis. Mice susceptible to intestinal tumors as a result of a germline mutation in Apc (Min/+ mice) were given a 10 week dietary treatment with 0.5% chenodeoxycholate. Following this, the mice were examined to determine tumor number, enterocyte proliferation, apoptosis and beta-catenin expression. Intestinal tissue prostaglandin E2 (PGE2) levels were also assessed. Administration of chenodeoxycholate in the diet increased duodenal tumor number in Min/+ mice. Promotion of duodenal tumor formation was accompanied by increased beta-catenin expression in duodenal cells, as well as increased PGE2 in duodenal tissue. These data suggest that unconjugated bile acids contribute to periampullary tumor formation in the setting of an Apc mutation.
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Ácido Quenodesoxicólico/toxicidad , Colagogos y Coleréticos/toxicidad , Neoplasias Duodenales/inducido químicamente , Transactivadores , Poliposis Adenomatosa del Colon , Proteína de la Poliposis Adenomatosa del Colon , Animales , Pruebas de Carcinogenicidad , Proteínas del Citoesqueleto/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Neoplasias Duodenales/genética , Duodeno/efectos de los fármacos , Duodeno/metabolismo , Femenino , Ratones , beta CateninaRESUMEN
Idiopathic thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy of obscure etiology. The fundamental pathologic lesion is a hyaline thrombus composed of platelets and some fibrin accompanied by endothelial cell proliferation and detachment, in the absence of an inflammatory response. We have previously demonstrated that plasmas from patients with both idiopathic TTP and a related disorder, sporadic hemolytic-uremic syndrome (HUS), induce apoptosis and expression of the apoptosis-associated molecule Fas (CD95) in vitro in those lineages of microvascular endothelial cells (MVECs) that are affected pathologically. We now demonstrate the presence of enhanced MVEC apoptosis in splenic tissues from patients with TTP, documented by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) and morphology. This is accompanied by elevated Fas expression. It contrasts with the absence of apoptosis in splenic tissues obtained after splenectomy for trauma or immune thrombocytopenic purpura. TUNEL-positive cells, identified by immunohistochemistry as MVECs or macrophages, presumably engulfing apoptotic ECs, are noted in numerous areas, including those apart from microthrombi. Thus, it is unlikely that EC apoptosis is simply a sequela of thrombus formation. Based on these data, we propose that MVEC apoptosis is of pathophysiologic significance in idiopathic TTP/sporadic HUS.
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Apoptosis , Endotelio Vascular/patología , Púrpura Trombocitopénica Trombótica/patología , Bazo/patología , Adolescente , Adulto , Niño , Endotelio Vascular/inmunología , Femenino , Humanos , Etiquetado Corte-Fin in Situ , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/inmunología , Bazo/irrigación sanguínea , Bazo/inmunología , Receptor fas/inmunologíaAsunto(s)
Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Enfermedades Linfáticas/inducido químicamente , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/inmunología , Humanos , Infección por Mycobacterium avium-intracellulare/complicacionesRESUMEN
Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus-associated lymphoid proliferations that arise in immunosuppressed transplant recipients. Some of these lesions regress after a reduction in immunosuppressive therapy, whereas some progress despite aggressive therapy. Morphological, immunophenotypic, and immunogenotypic criteria have not been useful in predicting clinical outcome. Although structural alterations in oncogenes and/or tumor suppressor genes identified in some PT-LPDs correlate with a poor clinical outcome, the presence of these alterations has not been a consistently useful predictor of lesion regression after reduction of immunosuppression. We examined 57 PT-LPD lesions obtained from 36 solid organ transplant recipients for the presence of mutations in the BCL-6 proto-oncogene using single-strand conformation polymorphism and sequence analysis, followed by correlation with histopathologic classification and clinical outcome, which was known in 33 patients. BCL-6 gene mutations were identified in 44% of the specimens and in 44% of the patients; none were identified in the cases classified as plasmacytic hyperplasia. However, mutations were present in 43% of the polymorphic lesions and 90% of the PT-LPDs diagnosed as non-Hodgkin's lymphoma or multiple myeloma. BCL-6 gene mutations predicted shorter survival and refractoriness to reduced immunosuppression and/or surgical excision. Our results suggest that the BCL-6 gene structure is a reliable indicator for the division of PT-LPDs into the biological categories of hyperplasia and malignant lymphoma, of which only the former can regress on immune reconstitution. The presence of BCL-6 gene mutations may be a useful clinical marker to determine whether reduction in immunosuppression should be attempted or more aggressive therapy should be instituted.
Asunto(s)
ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Inmunosupresores/uso terapéutico , Trastornos Linfoproliferativos/genética , Complicaciones Posoperatorias , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes , Factores de Transcripción/genética , Trasplante/efectos adversos , Transformación Celular Neoplásica/genética , Transformación Celular Viral/genética , Análisis Mutacional de ADN , Infecciones por Herpesviridae/tratamiento farmacológico , Infecciones por Herpesviridae/mortalidad , Infecciones por Herpesviridae/transmisión , Herpesvirus Humano 4/patogenicidad , Humanos , Hiperplasia , Tablas de Vida , Linfoma de Células B/etiología , Linfoma de Células B/genética , Linfoma de Células B/mortalidad , Linfoma de Células B/virología , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/virología , Polimorfismo Conformacional Retorcido-Simple , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/virología , Pronóstico , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-bcl-6 , Resultado del Tratamiento , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/mortalidad , Infecciones Tumorales por Virus/transmisiónRESUMEN
BACKGROUND: Posttransplantation lymphoproliferative disorders (PT-LPDs) are a well-known complication of immunosuppression associated with solid organ transplantation. The clinical course of PT-LPDs is unpredictable; some patients experience regression of all lesions with a reduction in immunosuppression, whereas other patients, despite chemotherapy, radiation therapy, or surgery, rapidly die of their disease. In this study, the authors attempted to establish whether the previously described morphologic and molecular genetic categories of PT-LPD--plasmacytic hyperplasia (PH), polymorphic PT-LPD (polymorphic), and malignant lymphoma/multiple myeloma (ML/MM)--are clinically relevant and helpful in predicting the clinical outcome of patients who develop these lesions. METHODS: To determine the clinical significance of the morphologic and molecular genetic categories of PT-LPDs, the clinical characteristics of 32 solid organ transplant recipients (26 heart, 5 kidney, and 1 lung), including age, time from transplantation to development of PT-LPD, stage of disease, and clinical outcome, were compared with the morphologic and molecular genetic features of the 41 PT-LPDs that they developed (15 PH in 12 patients, 19 polymorphic in 16 patients, and 7 ML/MM in 6 patients). Clinical outcome was defined by the following categories: 1) regression (after a reduction in immunosuppression) and surgical resolution (by surgical excision, with or without a reduction in immunosuppression); 2) medical resolution (by chemotherapy and/or radiation therapy); and 3) no response. RESULTS: Although there was no difference in the time from transplantation to PT-LPD development among patients belonging to the three morphologic and molecular genetic categories, there was a significant difference in patient age at the time of PT-LPD development (P < 0.0098). Younger patients developed PH (mean age of 19 years), whereas older patients developed polymorphic PT-LPD (mean age of 35 years) and ML/MM (mean age of 56 years). Patients with PH presented with lower stages of disease (Stages I-II) than patients with ML/MM (P < 0.0004). Furthermore, there was a statistically significant trend between morphologic and molecular genetic category and clinical outcome, with decreased likelihood that lesions categorized as PH, polymorphic, or ML/MM would regress with a reduction in immunosuppression or be resolved by surgery, whereas those classified as ML/MM were more likely to exhibit no response to aggressive clinical intervention (P < 0.00006). Furthermore, no patients with PH died, whereas 20% with polymorphic PT-LPD and 67% with ML/MM died as a direct result of their PT-LPDs. CONCLUSIONS: This study strongly suggests that classification of PT-LPDs into the morphologic and molecular genetic categories PH, polymorphic, PT-LPD and ML/MM is clinically relevant.
Asunto(s)
Trasplante de Corazón/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Pulmón/efectos adversos , Trastornos Linfoproliferativos/patología , Adulto , Anciano , Niño , Preescolar , Terapia Combinada , Femenino , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Hiperplasia/patología , Linfoma de Células B/patología , Trastornos Linfoproliferativos/etiología , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Polimorfismo Genético , Pruebas Serológicas , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in treating intestinal adenomas in humans with Familial Adenomatous Polyposis (FAP) and in preventing intestinal tumors in the C57Bl/6J-Min+ (Min) mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the liver and intestinal flora to a sulfone, which has no anti-inflammatory activity, and a sulfide, which is the active anti-inflammatory metabolite. In this study, we determined which of these metabolites is responsible for the anti-tumor effect of sulindac in Min mice. Min mice were treated with either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation (+/+) were used as controls. At 110 days of age, all mice were euthanized and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6 tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte apoptosis was observed in Min control mice and Min mice treated with sulindac sulfone. Sulindac sulfide restored to normal the level of apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the small intestine of treated Min animals by 59% (P < 0.001). These data suggest that the anti-tumor effect of sulindac in Apc-deficient animals is mediated by the sulfide metabolite and correlates with suppression of tissue prostaglandin synthesis.