Sujet(s)
Éosinophilie/complications , Éosinophilie/génétique , Leucémie-lymphome lymphoblastique à précurseurs B et T/complications , Leucémie-lymphome lymphoblastique à précurseurs B et T/génétique , Biopsie , Moelle osseuse/métabolisme , Cellules de la moelle osseuse/métabolisme , Enfant , Aberrations des chromosomes , Humains , Hybridation fluorescente in situ , Caryotypage , MâleRÉSUMÉ
AIMS: To investigate the possibility of detecting small focal prostatic cancer by alpha-methylacyl CoA racemase (AMACR)/P504S immunohistochemistry on needle biopsy specimens that were previously interpreted as negative for carcinoma on routine haematoxylin and eosin (H&E)-stained sections. METHODS: Prostate needle biopsy specimens (n = 793) previously interpreted as benign prostatic tissue by conventional morphology from 239 patients with prostatic cancer diagnosed in other biopsy cores taken at the same biopsy session were stained with the P504S monoclonal antibody. If a biopsy specimen stained positively, two pathologists independently reviewed the original corresponding H&E-stained sections to establish the malignant diagnosis. RESULTS: Eighty-four of the 793 biopsy specimens showed AMACR immunoreactivity; nine of these (9/793, 1.1%) contained previously unrecognized small focal prostatic carcinoma (Gleason 6, N = 8; Gleason 8, N = 1). Six of nine (67%) carcinomas showed foamy/pseudohyperplastic (N = 3) or atrophic (N = 3) features. Additionally, five biopsy specimens (5/793, 0.6%) with positive AMACR staining that did not meet the criteria for prostatic cancer on the original H&E slides were considered to be atypia. CONCLUSIONS: In this study, we found a 1.1% false-negative rate for carcinoma on routine H&E-stained sections. AMACR immunohistochemical staining has shown the ability to improve detection of small focal prostatic carcinoma that could be missed by conventional histological examination.
Sujet(s)
Prostate/anatomopathologie , Tumeur intraépithéliale prostate/diagnostic , Tumeurs de la prostate/diagnostic , Racémases et épimérases/analyse , Ponction-biopsie à l'aiguille , Humains , Immunohistochimie , Mâle , Prostate/enzymologie , Tumeur intraépithéliale prostate/enzymologie , Tumeurs de la prostate/enzymologie , Tumeurs de la prostate/anatomopathologie , Sensibilité et spécificitéRÉSUMÉ
AIM: To test whether alpha-methylacyl-CoA racemase (AMACR) is a sensitive and specific marker of prostate cancer. METHODS AND RESULTS: The expression levels of AMACR mRNA were measured by real-time polymerase chain reaction. A total of 807 prostatic specimens were further examined by immunohistochemistry specific for AMACR. Quantitative immunostaining analyses were carried out by using the ChromaVision Automated Cellular Imaging System and the Ariol SL-50 Imaging System, respectively. AMACR mRNA levels measured in prostatic adenocarcinoma were 55 times higher than those in benign prostate tissue. Of 454 cases of prostatic adenocarcinoma, 441 were positive for AMACR, while 254 of 277 cases of benign prostate were negative for AMACR. The sensitivity and specificity of AMACR immunodetection of prostatic adenocarcinomas were 97% and 92%, respectively. Both positive and negative predictive values were 95%. By automatic imaging analyses, the AMACR immunostaining intensity and percentage in prostatic adenocarcinomas were also significantly higher than those in benign prostatic tissue (105.9 versus 16.1 for intensity, 45.7% versus 0.02% and 35.03% versus 4.64% for percentage, respectively). CONCLUSIONS: We have demonstrated the promising features of AMACR as a biomarker for prostate cancer in this large series and the potential to develop automated quantitative diagnostic tests.
Sujet(s)
Marqueurs biologiques tumoraux/génétique , Tumeurs de la prostate/anatomopathologie , Racémases et épimérases/génétique , Adénocarcinome/enzymologie , Adénocarcinome/génétique , Adénocarcinome/anatomopathologie , Marqueurs biologiques tumoraux/analyse , Humains , Immunohistochimie , Mâle , Tumeurs de la prostate/enzymologie , Tumeurs de la prostate/génétique , ARN messager/génétique , ARN messager/métabolisme , Racémases et épimérases/analyse , RT-PCRRÉSUMÉ
The ability to diagnose prostate carcinoma would be improved by the detection of a tumor-associated antigen. P504S, a cytoplasmic protein, was recently identified by cDNA library subtraction in conjunction with high throughput microarray screening from prostate carcinoma. The aim of this study was to establish the pattern of expression of P504S in prostate carcinoma and benign prostatic tissue. A total of 207 cases, including 137 cases of prostate carcinoma and 70 cases of benign prostate, from prostatectomies (n = 77), prostate needle biopsies (n = 112), and transurethral prostate resections (n = 18) were examined by immunocytochemistry for P504S. P504S showed strong cytoplasmic granular staining in 100% of prostate carcinomas regardless of Gleason scores and diffuse (>75% of tumor) staining in 92% of cases. In contrast, 171 of 194 (88%) of benign prostates, including 56 of 67 (84%) benign prostate cases and 115 of 127 (91%) cases of benign glands adjacent to cancers were negative for P504S. The remainders of benign prostates were focally and weakly positive for P504S. The staining pattern of these normal glands was different and easily distinguishable from that observed in prostate carcinoma. Expression of P504S was not found in basal cell hyperplasia, urothelial cells/metaplasia and small atrophic glands that may mimic prostate carcinoma. Our findings indicate that P504S is a highly sensitive and specific positive marker for prostate carcinoma.
Sujet(s)
Marqueurs biologiques tumoraux , Carcinomes/diagnostic , Tumeurs de la prostate/diagnostic , Racémases et épimérases , Anticorps monoclonaux , Technique de Western , Carcinomes/enzymologie , Carcinomes/chirurgie , Humains , Techniques immunoenzymatiques , Kératines/métabolisme , Mâle , Masse moléculaire , Prostate/enzymologie , Prostate/anatomopathologie , Prostate/chirurgie , Tumeurs de la prostate/enzymologie , Tumeurs de la prostate/chirurgie , Racémases et épimérases/métabolismeRÉSUMÉ
Second nonocular malignancies develop with increased incidence in patients with hereditary retinoblastoma. Osteosarcoma is by far the most common type with an incidence of up to 50%, followed by soft tissue sarcomas. Visceral leiomyosarcoma is extremely rare and only 2 cases have been reported in the past 2 decades, one in the liver and another one in the urinary bladder, both of which developed after cyclophosphamide therapy. Here we report a case of vesical leiomyosarcoma that was diagnosed in a 49-year-old woman 47 years after the diagnosis of a hereditary retinoblastoma. The patient's retinoblastoma was treated with unilateral enucleation without adjuvant radiation or chemotherapy. We believe that this is the first report of vesical leiomyosarcoma occurring in a patient with retinoblastoma without a prior history of radiation or chemotherapy. This report is significant not only because of the rarity of vesical leiomyosarcoma as a second nonocular tumor in retinoblastoma patients, but also because of the infrequency of vesical leiomyosarcoma in general. We also investigated the potential molecular pathogenesis of the leiomyosarcoma.
Sujet(s)
Tumeurs de l'oeil/chirurgie , Léiomyosarcome/anatomopathologie , Seconde tumeur primitive/anatomopathologie , Rétinoblastome/chirurgie , Tumeurs de la vessie urinaire/anatomopathologie , Actines/analyse , Adulte , Cycline D1/analyse , Cystectomie , Desmine/analyse , Tumeurs de l'oeil/génétique , Femelle , Hématurie/étiologie , Humains , Hystérectomie , Léiomyosarcome/imagerie diagnostique , Léiomyosarcome/chirurgie , Seconde tumeur primitive/imagerie diagnostique , Seconde tumeur primitive/chirurgie , Ovariectomie , Rétinoblastome/génétique , Protéine du rétinoblastome/analyse , Survivants , Tomodensitométrie , Protéine p53 suppresseur de tumeur/analyse , Tumeurs de la vessie urinaire/imagerie diagnostique , Tumeurs de la vessie urinaire/chirurgieRÉSUMÉ
BACKGROUND: Treatment with a donor-specific transfusion (DST) and a brief course of anti-mouse CD154 (anti-CD40-ligand) monoclonal antibody (mAb) prolongs the survival of both allografts and rat xenografts in mice. The mechanism by which allograft survival is prolonged is incompletely understood, but depends in part on the presence of CD4+ cells and the deletion of alloreactive CD8+ T cells. Less is known about the mechanism by which this protocol prolongs xenograft survival. METHODS: We measured rat islet and skin xenograft survival in euthymic and thymectomized mice treated with combinations of DST, anti-CD154 mAb, anti-CD4 mAb, and anti-CD8 mAb. Recipients included C57BL/6, C57BL/6-scid, C57BL/6-CD4null, and C57BL/6-CD8null mice. RESULTS: Pretreatment with a depleting anti-CD4 mAb markedly prolonged the survival of both skin and islet xenografts in mice given DST plus anti-CD154 mAb. Comparable prolongation of xenograft survival was obtained in C57BL/6-CD4null recipients treated with DST and anti-CD154 mAb. In contrast, anti-CD8 mAb did not prolong the survival of either islet or skin xenografts in mice treated with DST and anti-CD154 mAb. Thymectomy did not influence xenograft survival in any treatment group. Adoptive transfer of splenocytes from C57BL/6-CD4null recipients treated with DST and anti-CD154 mAb and bearing long-term skin xenografts revealed the presence of residual xenoreactive cells. CONCLUSIONS: These data suggest that treatment with DST and anti-CD154 mAb induces a state of "functional" transplantation tolerance. They also support the hypothesis that both the induction and maintenance of graft survival based on this protocol depend on different cellular mechanisms in allogeneic and xenogeneic model systems.
Sujet(s)
Transfusion sanguine , Lymphocytes T CD4+/cytologie , Ligand de CD40/immunologie , Survie du greffon/physiologie , Transplantation hétérologue/immunologie , Animaux , Anticorps/usage thérapeutique , Survie du greffon/immunologie , Déplétion lymphocytaire , Souris , Souris de lignée C57BL , Rats , Rats de lignée LEWRÉSUMÉ
Human PBMC engraft in mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation (Hu-PBL-scid mice). Hu-PBL-NOD-scid mice generate 5- to 10-fold higher levels of human cells than do Hu-PBL-C.B-17-scid mice, and Hu-PBL-NOD-scid beta2-microglobulin-null (NOD-scid-B2mnull) mice support even higher levels of engraftment, particularly CD4+ T cells. The basis for increased engraftment of human PBMC and the functional capabilities of these cells in NOD-scid and NOD-scid-B2mnull mice are unknown. We now report that human cell proliferation in NOD-scid mice increased after in vivo depletion of NK cells. Human cell engraftment depended on CD4+ cells and required CD40-CD154 interaction, but engrafted CD4+ cells rapidly became nonresponsive to anti-CD3 Ab stimulation. Depletion of human CD8+ cells led to increased human CD4+ and CD20+ cell engraftment and increased levels of human Ig. We further document that Hu-PBL-NOD-scid mice are resistant to development of human EBV-related lymphoproliferative disorders. These disorders, however, develop rapidly following depletion of human CD8+ cells and are prevented by re-engraftment of CD8+ T cells. These data demonstrate that 1) murine NK cells regulate human cell engraftment in scid recipients; 2) human CD4+ cells are required for human CD8+ cell engraftment; and 3) once engrafted, human CD8+ cells regulate human CD4+ and CD20+ cell expansion, Ig levels, and outgrowth of EBV-related lymphoproliferative disorders. We propose that the Hu-PBL-NOD-scid model is suitable for the in vivo analysis of immunoregulatory interactions between human CD4+ and CD8+ cells.
Sujet(s)
Herpèsvirus humain de type 4/immunologie , Agranulocytes/transplantation , Syndromes lymphoprolifératifs/génétique , Syndromes lymphoprolifératifs/immunologie , Immunodéficience combinée grave/génétique , Immunodéficience combinée grave/immunologie , Transfert adoptif , Animaux , Cellules présentatrices d'antigène/immunologie , Lymphocytes T CD4+/immunologie , Lymphocytes T CD4+/métabolisme , Antigènes CD40/métabolisme , Ligand de CD40 , Lymphocytes T CD8+/immunologie , Division cellulaire/génétique , Division cellulaire/immunologie , Lignée de cellules transformées , Anergie clonale/génétique , Infections à virus Epstein-Barr/génétique , Infections à virus Epstein-Barr/immunologie , Humains , Immunité innée/génétique , Immunophénotypage , Interphase/génétique , Interphase/immunologie , Cellules tueuses naturelles/immunologie , Ligands , Activation des lymphocytes/génétique , Déplétion lymphocytaire , Syndromes lymphoprolifératifs/prévention et contrôle , Syndromes lymphoprolifératifs/virologie , Glycoprotéines membranaires/métabolisme , Souris , Souris de lignée NOD , Souris SCID , Cavité péritonéale/anatomopathologie , Immunodéficience combinée grave/virologie , Lymphocytes T/immunologie , Lymphocytes T cytotoxiques/transplantationRÉSUMÉ
We describe a tolerance-based stem cell transplantation protocol that combines sublethal radiation with transient blockade of the CD40-CD154 costimulatory pathway using an anti-CD154 antibody. With this protocol, we established hematopoietic chimerism in BALB/c mice transplanted with fully allogeneic C57BL/6 bone marrow. The percentage of donor-origin mononuclear cells in recipients was more than 99%. In addition, all chimeric mice treated with anti-CD154 antibody remained free of graft-versus-host disease (GVHD) and accepted donor-origin but not third-party skin allografts. It was similarly possible to create allogeneic hematopoietic chimerism in NOD/Lt mice with spontaneous autoimmune diabetes. Pancreatic islet allografts transplanted into chimeric NOD/Lt mice were resistant not only to allorejection but also to recurrence of autoimmunity. We conclude that it is possible to establish robust allogeneic hematopoietic chimerism in sublethally irradiated mice without subsequent GVHD by blocking the CD40-CD154 costimulatory pathway using as few as 2 injections of anti-CD154 antibody. We also conclude that chimerism created in this way generates donor-specific allograft tolerance and reverses the predisposition to recurrent autoimmune diabetes in NOD/Lt mice, enabling them to accept curative islet allografts. (Blood. 2000;95:2175-2182)
Sujet(s)
Auto-immunité , Moelle osseuse/effets des radiations , Survie du greffon , Transplantation d'ilots de Langerhans , Glycoprotéines membranaires/immunologie , Chimère obtenue par transplantation , Transplantation homologue , Animaux , Ligand de CD40 , Diabète expérimental/immunologie , Diabète expérimental/radiothérapie , Femelle , Maladie du greffon contre l'hôte/prévention et contrôle , Hyperglycémie/thérapie , Tolérance immunitaire , Ilots pancréatiques/anatomie et histologie , Mâle , Souris , Souris de lignée BALB C , Souris de lignée C57BL , Souris de lignée CBA , Souris de lignée NOD , Récidive , Transplantation de peau , Facteurs temps , Conditionnement pour greffe/méthodesRÉSUMÉ
Treatment with a 2-week course of anti-CD154 antibody and a single transfusion of donor leukocytes (a donor-specific transfusion or DST) permits skin allografts to survive for >100 days in thymectomized mice. As clinical trials of this methodology in humans are contemplated, concern has been expressed that viral infection of graft recipients may disrupt tolerance to the allograft. We report that acute infection with lymphocytic choriomeningitis virus (LCMV) induced allograft rejection in mice treated with DST and anti-CD154 antibody if inoculated shortly after transplantation. Isografts resisted LCMV-induced rejection, and the interferon-inducing agent polyinosinic:polycytidylic acid did not induce allograft rejection, suggesting that the effect of LCMV is not simply a consequence of nonspecific inflammation. Administration of anti-CD8 antibody to engrafted mice delayed LCMV-induced allograft rejection. Pichinde virus also induced acute allograft rejection, but murine cytomegalovirus and vaccinia virus (VV) did not. Injection of LCMV approximately 50 days after tolerance induction and transplantation had minimal effect on subsequent allograft survival. Treatment with DST and anti-CD154 antibody did not interfere with clearance of LCMV, but a normally nonlethal high dose of VV during tolerance induction and transplantation killed graft recipients. We conclude that DST and anti-CD154 antibody induce a tolerant state that can be broken shortly after transplantation by certain viral infections. Clinical application of transplantation tolerance protocols may require patient isolation to facilitate the procedure and to protect recipients.
Sujet(s)
Anticorps monoclonaux/usage thérapeutique , Rejet du greffon/immunologie , Maladie du greffon contre l'hôte/prévention et contrôle , Tolérance immunitaire , Virus de la chorioméningite lymphocytaire , Transplantation de peau/immunologie , Animaux , Ligand de CD40/immunologie , Antigènes CD8/immunologie , Association thérapeutique , Femelle , Rejet du greffon/virologie , Inducteurs de l'interféron/usage thérapeutique , Transfusion de leucocytes , Mâle , Souris , Souris de lignée BALB C , Souris de lignée C57BL , Virus Pichinde , Poly I-C/usage thérapeutique , Transplantation de peau/méthodes , Organismes exempts d'organismes pathogènes spécifiques , Facteurs tempsRÉSUMÉ
Transition of cells from quiescence to proliferation requires an increase in the rate of protein synthesis, which is regulated in part by two key translation initiation factors, 4E and 2alpha. The expression and activity of both factors are increased transiently when normal resting cells are stimulated to proliferate. They are constitutively elevated in oncogene transformed cultured cells, and overexpression of either initiation factor in rodent cells makes them tumorigenic. In this study we investigate an association between the expression of translation initiation factors and lymphomagenesis. We have analyzed the expression of the protein synthesis initiation factors 4E and 2alpha by immunohistochemistry in reactive lymph nodes and several types of non-Hodgkin's lymphoma representing a wide range of clinical behaviors based on the Revised European-American Lymphoma behavioral classification. The study included 7 benign lymph nodes with follicular hyperplasia, 26 indolent lymphomas (6 marginal zone lymphomas, 7 small lymphocytic lymphomas, and 13 follicular lymphomas, grades 1 and 2), 16 moderately aggressive lymphomas (8 mantle cell lymphomas and 8 follicular lymphomas, grade 3), 24 aggressive lymphomas (14 large-B-cell lymphomas and 10 anaplastic large-cell lymphomas), and 15 highly aggressive lymphomas (7 lymphoblastic lymphomas and 8 Burkitt's lymphomas). Strong expression of initiation factors 4E and 2alpha was demonstrated in the germinal centers of reactive follicles. Minimal or no expression was seen in the mantle zones and surrounding paracortices, indicating that high expression of initiation factors 4E and 2alpha is associated with the active proliferation of lymphocytes. Most cases of aggressive and highly aggressive lymphomas showed strong expression of initiation factors 4E and 2alpha, in contrast to the cases of indolent and moderately aggressive lymphoma, in which their expression was intermediate between the germinal centers and the mantles of reactive follicles. A positive correlation was found between the expression of both initiation factors 4E and 2alpha and the Revised European-American Lymphoma behavior classification (P < 0.05). Thus, constitutively increased expression of initiation factors 4E and 2alpha may play an important role in the development of lymphomas and is correlated with their biological aggressiveness.
Sujet(s)
Facteur-2 d'initiation eucaryote/métabolisme , Lymphome malin non hodgkinien/métabolisme , Facteurs initiation chaîne peptidique/métabolisme , Technique de Western , Facteur-4E d'initiation eucaryote , Humains , Immunohistochimie , Noeuds lymphatiques/métabolisme , Noeuds lymphatiques/anatomopathologie , Lymphome malin non hodgkinien/anatomopathologie , Valeurs de référenceRÉSUMÉ
A protocol consisting of a single donor-specific transfusion (DST) plus a brief course of anti-CD154 monoclonal antibody (anti-CD40 ligand mAb) induces permanent islet allograft survival in chemically diabetic mice, but its efficacy in mice with autoimmune diabetes is unknown. Confirming a previous report, we first observed that treatment of young female NOD mice with anti-CD154 mAb reduced the frequency of diabetes through 1 year of age to 43%, compared with 73% in untreated controls. We also confirmed that spontaneously diabetic NOD mice transplanted with syngeneic (NOD-Prkdc(scid)/Prkdc(scid)) or allogeneic (BALB/c) islets rapidly reject their grafts. Graft survival was not prolonged, however, by pretreatment with either anti-CD154 mAb alone or anti-CD154 mAb plus DST. In addition, allograft rejection in NOD mice was not restricted to islet grafts. Anti-CD154 mAb plus DST treatment failed to prolong skin allograft survival in nondiabetic male NOD mice. The inability to induce transplantation tolerance in NOD (H2g7) mice was associated with non-major histocompatibility complex (MHC) genes. Treatment with DST and anti-CD154 mAb prolonged skin allograft survival in both C57BL/6 (H2b) and C57BL/6.NOD-H2g7 mice, but it was ineffective in NOD, NOD.SWR-H2q, and NOR (H2g7) mice. Mitogen-stimulated interleukin-1beta production by antigen-presenting cells was greater in strains susceptible to tolerance induction than in the strains resistant to tolerance induction. The results suggest the existence of a general defect in tolerance mechanisms in NOD mice. This genetic defect involves defective antigen-presenting cell maturation, leads to spontaneous autoimmune diabetes in the presence of the H2g7 MHC, and precludes the induction of transplantation tolerance irrespective of MHC haplotype. Promising islet transplantation methods based on overcoming the alloimmune response by interference with costimulation may require modification or amplification for use in the setting of autoimmune diabetes.
Sujet(s)
Diabète de type 1/immunologie , Tolérance immunitaire , Transplantation d'ilots de Langerhans , Transplantation de peau , Animaux , Anticorps monoclonaux/usage thérapeutique , Transfusion sanguine , Ligand de CD40 , Femelle , Rejet du greffon/prévention et contrôle , Mâle , Glycoprotéines membranaires/immunologie , Souris , Souris de lignée BALB C , Souris de lignée C57BL , Souris de lignée NOD , Souris SCID , Thymectomie , Donneurs de tissus , Conditionnement pour greffeRÉSUMÉ
Intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and the lymphocyte function-associated antigen (LFA-1) are cell adhesion molecules thought to play an important role in the complex process of airway inflammation and tumor cell growth. The aim of this study was to examine the distribution of ICAM-1, VCAM-1, and LFA-1 in adenocarcinoma of lung and in major cellular compartments of non-neoplastic lung tissue. We examined cellular compartments in tissue from five bronchoalveolar carcinomas, three acinar adenocarcinomas, and one colon cancer metastatic to the lung. The compartments in neoplasms included the tumor cells proper, endothelial cells within the tumor vasculature, tumor stromal cells, and tumor-infiltrating lymphocytes. The compartments in non-neoplastic lung tissue included lung endothelial cells, pulmonary lymphocytes, interstitial fibroblasts, Type II alveolar pneumocytes, and bronchial epithelial cells. ICAM-1 was expressed in tumor cells from all of the nine adenocarcinomas. In contrast, VCAM-1 expression was not identified in tumor cells from any of the nine adenocarcinomas. ICAM-1 was expressed in all cellular compartments of the non-neoplastic lung tissue, whereas VCAM-1 was expressed only in pulmonary lymphocytes and interstitial fibroblastic cells. LFA-1 was uniformly expressed in tumor-infiltrating lymphocytes from each of the nine tumors and all of the lymphocytes in non-neoplastic lung tissue. This study showed major differences in the expression of ICAM-1 and VCAM-1 in tumor cells from pulmonary adenocarcinoma and also provided evidence for a wider distribution of ICAM-1, compared with VCAM-1, in non-neoplastic cellular compartments of the lung. ICAM-1 expression was particularly noticeable in bronchial and alveolar epithelial cells. Upregulation of ICAM-1 in pulmonary adenocarcinoma might foster binding by LFA-1-bearing lymphocytes, with a possible impact on the vulnerability of tumor cells to host defense mechanisms.
Sujet(s)
Adénocarcinome/métabolisme , Molécule-1 d'adhérence intercellulaire/métabolisme , Tumeurs du poumon/métabolisme , Antigène-1 associé à la fonction du lymphocyte/métabolisme , Molécule-1 d'adhérence des cellules vasculaires/métabolisme , Adénocarcinome/anatomopathologie , Sujet âgé , Femelle , Coupes minces congelées , Humains , Techniques immunoenzymatiques , Maladies pulmonaires/métabolisme , Maladies pulmonaires/anatomopathologie , Tumeurs du poumon/anatomopathologie , Mâle , Adulte d'âge moyenRÉSUMÉ
BACKGROUND: Posttransplant lymphoproliferative disorders are generally associated with Epstein-Barr virus (EBV) and are of B cell origin. We report the case of a B-immunoblastic lymphoma that developed in a pretransplantation EBV-seronegative woman 4 months after kidney transplant from her HLA-haploidentical brother. The patient successfully underwent immunotoxin therapy for lymphoma and has been in remission for 36 months. METHODS: Latent EBV genomes were identified by polymerase chain reaction, and the purified amplification products were directly sequenced with [35S]dATP. RESULTS: Molecular analysis of the latent membrane protein (LMP)1 oncogene of EBV, which was expressed in most tumor cells, revealed a 30-base pair deletion. No wild-type LMP1 sequences were found. Analysis of peripheral blood mononuclear cells from the EBV-seropositive donor showed the presence of both the LMP1 deletion variant and the wild-type sequence. The LMP1 deletion variant and the wild-type sequence were also identified within peripheral blood mononuclear cells of the EBV-seroconverted kidney recipient 20 months after lymphoma therapy. CONCLUSION: This pattern is consistent with a natural growth advantage of B cells expressing the LMP1 deletion variant in the immunocompromised host.
Sujet(s)
Herpèsvirus humain de type 4 , Transplantation rénale , Lymphome B/virologie , Complications postopératoires , Leucémie-lymphome lymphoblastique à précurseurs B et T/virologie , Infections à virus oncogènes/anatomopathologie , Protéines de la matrice virale/génétique , Adulte , Substitution d'acide aminé , Femelle , Variation génétique , Glomérulonéphrite à dépôts d'IgA/chirurgie , Herpèsvirus humain de type 4/génétique , Herpèsvirus humain de type 4/isolement et purification , Humains , Immunotoxines/usage thérapeutique , Donneur vivant , Lymphome B/traitement médicamenteux , Lymphome B/anatomopathologie , Mutation ponctuelle , Leucémie-lymphome lymphoblastique à précurseurs B et T/traitement médicamenteux , Leucémie-lymphome lymphoblastique à précurseurs B et T/anatomopathologie , Délétion de séquence , Infections à virus oncogènes/traitement médicamenteux , Latence viraleRÉSUMÉ
Dendritic cells are immune accessory cells which are widely distributed in many tissues. Those which are present within lymphoid follicle centers are classified as follicular dendritic cells. Those which are found outside germinal centers may be referred to as interdigitating reticulum cells, or Langerhans cells when they occur in the skin. Abnormal proliferations of dendritic cells are best known as the group of disorders comprising Langerhans-cell histiocytosis, which occurs primarily in children and teenagers. There are increasing reports of malignant proliferations of both types of dendritic cells in adults. However, there is only one previous description of the cytologic features of a dendritic cell sarcoma based on imprint cytology of a resected jejunal mass. The current report provides a detailed description of the cytologic features of a fine-needle aspirate of a recurrence of an interdigitating reticulum-cell sarcoma of the cecum.
Sujet(s)
Tumeurs de l'intestin/anatomopathologie , Lymphome malin non hodgkinien/anatomopathologie , Sujet âgé , Cellules dendritiques/anatomopathologie , Femelle , Humains , Radiographie abdominale , TomodensitométrieRÉSUMÉ
The expression of bcl-2 seems to influence the biologic activity of a variety of neoplasms. In this study, we examined bcl-2 protein expression in 47 surgically resected adenocarcinomas of the lung to determine its expression in the neoplastic and adjacent non-neoplastic cells. Seven squamous cell carcinomas, six small cell carcinomas, five non-neoplastic lung lesions, and five normal lungs were also studied. The bcl-2 protein was detected after antigen retrieval with bcl-2 monoclonal antibody using archival formalin-fixed, paraffin-embedded tissue material. Fifty-one of 52 cases had bronchioles that could be evaluated and all expressed bcl-2, and of these, 12 showed basal immunostaining, 17 showed luminal immunostaining, and 22 showed immunostaining in both cellular compartments. Thirty of the 47 adenocarcinomas expressed bcl-2, whereas four of seven squamous cell carcinomas and all six small cell carcinomas were bcl-2 positive. bcl-2 immunostaining was correlated with a survival using the Fisher exact test. There were no statistically significant differences in survival between patients with bcl-2-positive and bcl-2-negative adenocarcinomas (P = 0.332). Similar results were obtained using the Kaplan-Mier product limit survival analysis method (P = 0.356). Our study also showed that expression of bcl-2 is common in pulmonary adenocarcinomas and that bcl-2 expression may be found in the basal and the luminal surfaces of normal bronchioles.
Sujet(s)
Adénocarcinome/composition chimique , Adénocarcinome/anatomopathologie , Bronches/composition chimique , Tumeurs du poumon/composition chimique , Tumeurs du poumon/anatomopathologie , Poumon/composition chimique , Protéines proto-oncogènes c-bcl-2/analyse , Sujet âgé , Sujet âgé de 80 ans ou plus , Bronches/cytologie , Bronches/immunologie , Femelle , Humains , Immunohistochimie , Poumon/cytologie , Poumon/immunologie , Mâle , Adulte d'âge moyenRÉSUMÉ
This sequencing study of 17 acquired immunodeficiency syndrome-related lymphomas (9 primary brain, 8 systemic) and 8 human immunodeficiency virus-negative atypical lymphoproliferations expressing large amounts of the latent membrane protein 1 (LMP1) of Epstein-Barr virus was performed to characterize the carboxy terminal NF-kappa B activation domain of LMP1 at the molecular level in an immunocompromised host. In-frame deletions within the NF-kappa B activation domain were identified in all but 2 primary brain lymphomas, 4 systemic lymphomas, and 4 atypical lymphoproliferations, ie, in 60% of cases. In addition, non silent point mutations (range 1 to 5, mean 3.3) were detected in all cases. Although all changes occurred within the first 100 nucleotides of the carboxy terminal NF-kappa B activation domain--a critical sequence for the protein half-life--not a single point mutation was found in the remaining 62 nucleotides, necessary for malignant transformation. Such a clustering of nonrandom sequence variations, associated with a high oncoprotein expression in immunocompromised hosts, suggests that this part of the LMP1 oncogene behaves as a hypervariable region with natural selection of growth-promoting variants through prolongation of the protein half-life.
Sujet(s)
Transformation cellulaire néoplasique/génétique , Transformation cellulaire virale/génétique , Infections à Herpesviridae/virologie , Herpèsvirus humain de type 4/génétique , Lymphome lié au SIDA/virologie , Syndromes lymphoprolifératifs/virologie , Facteur de transcription NF-kappa B/métabolisme , Infections à virus oncogènes/virologie , Protéines de la matrice virale/génétique , Séquence d'acides aminés , Séquence nucléotidique , Tumeurs du cerveau/génétique , Tumeurs du cerveau/virologie , Régulation de l'expression des gènes viraux , Séronégativité VIH , Période , Herpèsvirus humain de type 4/isolement et purification , Herpèsvirus humain de type 4/physiologie , Humains , Lymphome lié au SIDA/génétique , Syndromes lymphoprolifératifs/génétique , Données de séquences moléculaires , Mutation ponctuelle , Structure tertiaire des protéines , Sélection génétique , Alignement de séquences , Délétion de séquence , Protéines de la matrice virale/composition chimique , Protéines de la matrice virale/métabolismeRÉSUMÉ
This report examines the mechanisms involved in the down-regulation of the immune response in acute viral infection and documents the presence of apoptotic lymphocytes in situ in the spleens of mice during the resolution of the immune response to acute lymphocytic choriomeningitis virus infection. Apoptotic cells were detected by an in situ nucleotidyl transferase assay. Both T and B lymphocytes were shown to be dying in vivo, the latter in clusters. A biphasic occurrence of apoptosis during the course of the acute infection was observed, with elevated levels occurring at day 3 after infection and a second more pronounced peak at day 11 after infection, coincident with the decline of the cytotoxic T lymphocyte response and with the decrease in total splenic leukocyte number. Apoptosis in vivo was detected in lpr mice, suggesting that Fas expression is not imperative for lymphocyte apoptosis in the context of an acute viral infection. Apoptosis in situ and the decline of the T lymphocyte response to acute lymphocytic choriomeningitis virus infection was unaffected by the enforced lymphocyte-directed expression of Bcl-2, a protein that blocks growth factor deprivation-induced apoptosis of lymphocytes in vitro. These results argue that the silencing of the T cell response to acute infection may not be a result simply of growth factor deprivation. The susceptibility of activated T cells to apoptotic death, which has previously been associated with virus-induced immune deficiency, may therefore also explain the en masse elimination of the expanded lymphocyte pool subsequent to an acute viral infection.
Sujet(s)
Apoptose , Lymphocytes/physiologie , Chorioméningite lymphocytaire/immunologie , Syndromes lymphoprolifératifs/immunologie , Protéines proto-oncogènes/immunologie , Maladie aigüe , Animaux , Mort cellulaire , Cellules cultivées , Régulation négative , Cytométrie en flux , Immunohistochimie , Numération des leucocytes , Chorioméningite lymphocytaire/anatomopathologie , Virus de la chorioméningite lymphocytaire/immunologie , Syndromes lymphoprolifératifs/génétique , Syndromes lymphoprolifératifs/anatomopathologie , Mâle , Souris , Souris de lignée C57BL , Souris transgéniques , Protéines proto-oncogènes/génétique , Protéines proto-oncogènes c-bcl-2 , Rate/anatomopathologieRÉSUMÉ
Expression of the adhesion molecules LFA-1, ICAM-1, and VCAM-1 was studied in five resected colon carcinomas, one villous adenoma, and normal colon mucosa to determine whether expression of these markers is increased in response to tumor. Frozen tissue samples were stained by a labeled avidin-biotin technique using primary antibodies to LFA-1 (CD11a), CD2, CD4, CD8, CD20, CD68, HLA-DR, ICAM-1 (CD54), and VCAM-1. For each marker, the number of positive mononuclear cells was graded semiquantitatively, and stromal and endothelial cells were scored as either positive or negative. Overall grade of inflammation was increased in tumor compared with normal mucosa in five cases. Cells positive for LFA-1, CD2, CD4, CD8, and CD20 were increased in the tumors in the same cases. ICAM-1 was expressed in vessels, inflammatory cells, and stromal cells in normal mucosa. It was markedly increased in tumor stroma in all six cases. VCAM-1 was negative in normal mucosa, and focally expressed in tumor vessels and stroma. We conclude that increased expression of adhesion molecules occurs around colon neoplasms, particularly in stromal cells, and may be a mechanism for the recruitment of activated leukocytes as part of the inflammatory response to colon carcinomas.