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1.
Blood ; 136(11): 1284-1297, 2020 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-32430507

RESUMEN

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Genes myc , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Adulto , Anciano , Fármacos Anti-VIH/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recuento de Linfocito CD4 , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , ADN Viral/sangre , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/virología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/aislamiento & purificación , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Estimación de Kaplan-Meier , Linfoma Relacionado con SIDA/complicaciones , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/virología , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/virología , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Prednisona/administración & dosificación , Prednisona/efectos adversos , Supervivencia sin Progresión , Estudios Prospectivos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversos , Carga Viral/efectos de los fármacos , Vorinostat/administración & dosificación , Vorinostat/efectos adversos
2.
BMJ Case Rep ; 12(9)2019 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-31570354

RESUMEN

Patients with AIDS have increased risk of developing lymphomas, such as anaplastic large cell lymphoma (ALCL), which generally carry a poor prognosis. The DUSP-IRF4 genetic rearrangement in ALCL confers a favourable prognosis in HIV-negative patients; it is unknown how this interacts clinically with HIV/AIDS. A man aged 53 years presented with subcutaneous nodules on the scalp and axillae, and diffuse lymphadenopathy. Biopsy of subcutaneous nodule and lymph node showed large atypical anaplastic lymphocytes which were CD30+ and anaplastic lymphoma kinase-negative, consistent with primary systemic ALCL. In addition, he was found to be HIV-positive and diagnosed with AIDS. Genetic testing of the tissue revealed a DUSP22-IRF4 rearrangement. Complete remission was achieved with HyperCVAD and subsequent brentuximab vedotin monotherapy. We report a case of AIDS-associated primary systemic ALCL with a DUSP22-IRF4 rearrangement. AIDS-associated ALCL is an aggressive lymphoma, with a poor prognosis. However, the presence of the genetic rearrangement, previously unseen in this disease, drastically altered the disease course. This case highlights the value of genetic testing and identifies DUSP22-IRF4-associated ALCL in the setting of HIV-associated lymphoproliferative disorders.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Fosfatasas de Especificidad Dual/genética , Linfoma Relacionado con SIDA/patología , Linfoma Anaplásico de Células Grandes/patología , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Neoplasias Cutáneas/patología , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/inmunología , Reordenamiento Génico/genética , Humanos , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma Relacionado con SIDA/genética , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/genética , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Resultado del Tratamiento
3.
J Acquir Immune Defic Syndr ; 81(3): 266-273, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31026237

RESUMEN

BACKGROUND: We hypothesized that carriage of presumably high Hsp70-producing gene variants on a specific human major histocompatibility complex haplotype, the 8.1 ancestral haplotype (8.1AH), may predispose HIV-infected individuals to AIDS-non-Hodgkin lymphoma (NHL). SETTING: We compared serum Hsp70 levels in the years preceding the diagnosis of AIDS-NHL in a matched case-control study (n = 151 pairs) nested in the Multicenter AIDS Cohort Study. METHODS: We tested the impact of 8.1AH-specific single-nucleotide polymorphism (SNP) and joint SNP-human leukocyte antigen extended haplotypes previously associated with AIDS-NHL in the Multicenter AIDS Cohort Study on the circulating Hsp70 levels in mixed linear models. RESULTS: We report elevated serum levels of Hsp70 in the 4 years preceding the diagnosis of AIDS-NHL in cases that carry 8.1AH, but not in noncarrier cases and not in carrier- or non-carrier-matched controls. The strongest predictor of higher serum Hsp70 was the haplotype A-G-A-C formed by SNPs rs537160(A) and rs1270942(G) in the complement factor CFB gene cluster, and rs2072633(A) and rs6467(C) in nearby RDBP and CYP21A2 located 70 Kb apart from the Hsp70 gene cluster. The association with A-G-A-C haplotype (beta = 0.718; standard error = 0.182; P = 0.0002) and with other 8.1AH-specific haplotypes including the high-producing tumor necrosis factor-alpha haplotype rs909253(G)-rs1800629(A) (beta = 0.308; standard error = 0.140; P = 0.032) were observed only with NHL identified as an AIDS-defining condition, but not as a post-AIDS condition, nor in combined AIDS and post-AIDS cases. CONCLUSION: Our combined genetic and functional approach suggests that the altered level of Hsp70 is a correlate of 8.1AH-mediated AIDS-NHL. Further investigation of the Hsp70 gene cluster and nearby loci that are tagged by A-G-A-C could better elucidate the genetic determinants of the malignancy.


Asunto(s)
Antígeno HLA-B8/genética , Antígeno HLA-DR3/genética , Proteínas HSP70 de Choque Térmico/sangre , Linfoma Relacionado con SIDA/diagnóstico , Linfoma no Hodgkin/diagnóstico , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Infecciones por VIH , Proteínas HSP70 de Choque Térmico/genética , Haplotipos , Homosexualidad Masculina , Humanos , Linfoma Relacionado con SIDA/genética , Linfoma no Hodgkin/genética , Masculino , Familia de Multigenes , Polimorfismo de Nucleótido Simple
5.
Leuk Lymphoma ; 58(12): 2939-2942, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28508728

RESUMEN

Patients with HIV are at increased risk for developing B-cell lymphomas likely due in part to chronic antigen stimulation leading to clonal immunoglobulin (Ig) gene rearrangements. Next-generation sequencing (NGS)-based identification of circulating Ig clonotypes has not been well-characterized in HIV-related lymphomas. The AIDS Malignancies Consortium (AMC) enrolled 51 untreated patients with HIV-related B-cell lymphomas and analyzed paired tumor/plasma specimens for Ig clonotypes using an NGS approach (AMC064, NCT00981097). Lymphoma-specific clonotypes (>5% frequency) were identified in 83% (33/40) of tumor specimens. Results from paired tumor/plasma specimens showed identical circulating clonotypes in the plasma from 97% (32/33) of patients. High International Prognostic Index (IPI) scores of 3-4 among patients with B-cell lymphoma correlated with higher lymphoma molecules/million diploid genomes in the plasma compared with lower IPI scores of 0-2, median 77335 vs. 6876, p = .005. Further studies are merited to determine whether plasma clonal Ig DNA is prognostic in HIV-related lymphomas.


Asunto(s)
Evolución Clonal/genética , ADN Circular , Frecuencia de los Genes , Inmunoglobulinas/genética , Linfoma Relacionado con SIDA/genética , Adulto , Anciano , Biomarcadores , Femenino , Reordenamiento Génico , Humanos , Linfoma Relacionado con SIDA/sangre , Linfoma Relacionado con SIDA/diagnóstico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Adulto Joven
6.
J Biomol Struct Dyn ; 35(7): 1547-1558, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27484103

RESUMEN

A serious challenge in cancer treatment is to reposition the activity of various already known drug candidates against cancer. There is a need to rewrite and systematically analyze the detailed mechanistic aspect of cellular networks to gain insight into the novel role played by various molecules. Most Human Immunodeficiency Virus infection-associated cancers are caused by oncogenic viruses like Human Papilloma Viruses and Epstein-Bar Virus. As the onset of AIDS-associated cancers marks the severity of AIDS, there might be possible interconnections between the targets and mechanism of both the diseases. We have explored the possibility of certain antiviral compounds to act against major AIDS-associated cancers: Kaposi's Sarcoma, Non-Hodgkin Lymphoma, and Cervical Cancer with the help of systems pharmacology approach that includes screening for targets and molecules through the construction of a series of drug-target and drug-target-diseases network. Two molecules (Calanolide A and Chaetochromin B) and the target "HRAS" were finally screened with the help of molecular docking and molecular dynamics simulation. The results provide novel antiviral molecules against HRAS target to treat AIDS defining cancers and an insight for understanding the pharmacological, therapeutic aspects of similar unexplored molecules against various cancers.


Asunto(s)
Antivirales/farmacología , Polifarmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piranocumarinas/farmacología , Piranos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Antivirales/química , Femenino , Expresión Génica , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/patología , Linfoma Relacionado con SIDA/virología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/virología , Masculino , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Papillomaviridae/efectos de los fármacos , Papillomaviridae/crecimiento & desarrollo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Piranocumarinas/química , Piranos/química , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patología , Sarcoma de Kaposi/virología , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Biología de Sistemas/métodos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología
7.
Cancer Epidemiol ; 45: 47-57, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27701053

RESUMEN

BACKGROUND: MicroRNAs, small non-coding RNAs involved in gene regulation, are implicated in lymphomagenesis. We evaluated whether genetic variations in microRNA coding regions, binding sites, or biogenesis genes (collectively referred to as miRNA-SNPs) were associated with risk of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL), and serum levels of four lymphoma-related microRNAs. METHODS: Twenty-five miRNA-SNPs were genotyped in 180 AIDS-NHL cases and 529 HIV-infected matched controls from the Multicenter AIDS Cohort Study (MACS), and real-time polymerase chain reaction was used to quantify serum microRNA levels. Adjusted odds ratios (ORs) estimated using conditional logistic regression evaluated associations between miRNA-SNPs and AIDS-NHL risk. A semi-Bayes shrinkage approach was employed to reduce likelihood of false-positive associations. Adjusted mean ratios (MR) calculated using linear regression assessed associations between miRNA-SNPs and serum microRNA levels. RESULTS: DDX20 rs197412, a non-synonymous miRNA biogenesis gene SNP, was associated with AIDS-NHL risk (OR=1.34 per minor allele; 95% CI: 1.02-1.75), and higher miRNA-222 serum levels nearing statistical significance (MR=1.21 per minor allele; 95% CI: 0.98-1.49). MiRNA-196a2 rs11614913 was associated with decreased central nervous system (CNS) AIDS-NHL (CT vs. CC OR=0.52; 95% CI: 0.27-0.99). The minor allele of HIF1A rs2057482, which creates a miRNA-196a2 binding site, was associated with systemic AIDS-NHL risk (OR=1.73 per minor allele; 95% CI: 1.12-2.67), and decreased CNS AIDS-NHL risk (OR=0.49 per minor allele; 95% CI: 0.25-0.94). CONCLUSIONS: This study suggests that a few miRNA-SNPs are associated with AIDS-NHL risk and may modulate miRNA expression. These results support a role for miRNA in AIDS-NHL and may highlight pathways to be targeted for risk stratification or therapeutics.


Asunto(s)
Predisposición Genética a la Enfermedad , Linfoma Relacionado con SIDA/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad
8.
Am J Hematol ; 91(2): 233-7, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26799611

RESUMEN

Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma with poor prognosis. Lymphoma cells are always infected with human herpesvirus-8 (HHV-8) and in most cases coinfected with Epstein-Barr virus. In classic presentation, PEL is characterized by body cavity effusions with or without mass lesions. A variant with only extracavitary localization has also been described. We report on a large single-center series of patients with PEL in the era of combined antiretroviral therapy (cART). The main objective was to compare the characteristics and the outcome of patients with classic (n = 34) and extracavitary (n = 17) variant PEL. At PEL diagnosis, no major difference was observed between the two groups in terms of demographic and HIV characteristics. Extracavitary localizations were exclusively nodal in six patients and involved various organs in 11 patients. Another HHV-8-associated disease was observed in 31 patients, Kaposi sarcoma in 25, and multicentric Castleman disease in 18 patients, without difference between the two groups. Thirty-two patients were treated with CHOP associated with high-dose methotrexate, 13 were treated with CHOP-derived regimen alone, and six patients received low-dose/no chemotherapy. Complete remission was achieved in 21 (62%) and seven (41%) patients of the classic and extracavitary groups, respectively. The median overall survival (OS) was 10.2 months. Despite a higher disease-free survival in the extracavitary group, there was no difference in OS between the two variants. Based on this series, characteristics of classic and extracavitary variants were very close. Although prognosis of PEL remains very severe in cART era, the median survival compares favorably with earlier series.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma de Efusión Primaria/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Infecciones por VIH/genética , Infecciones por VIH/mortalidad , Infecciones por VIH/virología , Humanos , Estimación de Kaplan-Meier , Cariotipificación , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/mortalidad , Linfoma Relacionado con SIDA/virología , Linfoma de Efusión Primaria/genética , Linfoma de Efusión Primaria/mortalidad , Linfoma de Efusión Primaria/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento
9.
Tumour Biol ; 35(9): 8387-93, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24961346

RESUMEN

The critical role of microRNAs (miRNAs) in cell differentiation, homeostasis and cancer development has been extensively discussed in recent publications. The microRNAs with RISC enzyme complex allow it to find its complementary sequence, which is usually located in the 3'-untranslated region (UTR) of the target messenger RNA (mRNA). This is followed by inhibition of protein translation or promotion, resulting in degradation of the target gene. miR-21 has been mapped at chromosome 17q23.2, where it overlaps with the protein coding gene vacuole membrane protein 1 (VMP1), a human homologue of rat vacuole membrane protein. Recent evidence indicates that miR-21 plays a vital role in tumour cell proliferation, apoptosis and invasion. The inhibition of miR-21 may induce cell cycle arrest and increased chemosensitivity to anticancer agents, providing evidence that miR-21 functions as an oncogene in human cancer. Increased expression levels of miR-21 were observed in tumours arising from diverse tissue types. This also includes tumours of haematological origin, such as chronic lymphatic leukaemia, diffuse large B cell lymphomas (DLBCLs), acute myeloid leukaemia and Hodgkin lymphomas. Recently, it has been shown that high levels of B cell activation were induced by miR-21 in circulating B cells and are seen in HIV-infected individual. Notably, miR-21 is overexpressed in activated B cells, suggesting its assistance in maintaining B cell hyperactivation, which plays a pivotal role in HIV-infected cells. Therefore, miR-21 can be considered as a powerful biomarker in HIV-related lymphomas. The number of studies related to the role of miR-21 in HIV-related lymphomas is sparse; therefore, this mini review highlights the recent publications related to clinical impact and significance of miR-21, specifically in HIV- and non-HIV-related lymphomas.


Asunto(s)
Linfocitos B/metabolismo , Linfoma Relacionado con SIDA/genética , Linfoma/genética , MicroARNs/genética , Linfocitos B/virología , Regulación Neoplásica de la Expresión Génica , Infecciones por VIH/genética , Infecciones por VIH/virología , Humanos , Activación de Linfocitos/genética , Linfoma/patología , Linfoma Relacionado con SIDA/patología , Linfoma Relacionado con SIDA/virología
10.
APMIS ; 122(1): 5-15, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23607450

RESUMEN

Burkitt lymphoma (BL) occurs at all ages, but the patterns of Epstein-Barr virus (EBV) positivity in relation to human immunodeficiency virus (HIV), immunoprofiles and age have not been fully explored. BL tissues from residual tissue repositories, and two academic centers in the United States were examined by expert hematopathologists for morphology, immunohistochemistry, MYC rearrangement, EBV-encoded RNA (EBER), and diagnosed according to the 2008 WHO lymphoma classification. Analysis was done using frequency tables, Chi-squared statistics, and Student's t-test. Of 117 cases examined, 91 were confirmed as BL. The age distribution was 26%, 15%, 19%, and 29% for 0-19, 20-34, 35-59, 60+ years, and missing in 11%. MYC rearrangement was found in 89% and EBER positivity in 29% of 82 cases with results. EBER positivity varied with age (from 13% in age group 0-19 to 55% in age group 20-34, and fell to 25% in age group 60+ years, p = 0.08); with race (56% in Blacks/Hispanics vs 21% in Whites/Asians/Pacific Islanders, p = 0.006); and by HIV status (64% in HIV positive vs 22% in HIV negative cases, p = 0.03). EBER positivity was demonstrated in about one-third of tumors and it was strongly associated with race and HIV status, and marginally with age-group.


Asunto(s)
Linfoma de Burkitt/virología , Herpesvirus Humano 4/aislamiento & purificación , Adolescente , Adulto , Anciano , Linfoma de Burkitt/epidemiología , Linfoma de Burkitt/genética , Niño , Preescolar , Femenino , Genes bcl-2 , Genes myc , Herpesvirus Humano 4/genética , Humanos , Incidencia , Lactante , Recién Nacido , Linfoma Relacionado con SIDA/epidemiología , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/virología , Masculino , Persona de Mediana Edad , ARN Viral/genética , ARN Viral/aislamiento & purificación , Programa de VERF , Factores de Tiempo , Estados Unidos/epidemiología , Adulto Joven
11.
World J Gastroenterol ; 19(29): 4827-31, 2013 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-23922484

RESUMEN

Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the highly active anti-retroviral therapy (HAART) era. Recently, rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma. Here, we report a rare case of gastrointestinal (GI)-ARL with MYC rearrangements and coinfected with Epstein-Barr virus (EBV) infection presenting with various endoscopic findings. A 38-year-old homosexual man who presented with anemia and was diagnosed with an human immunodeficiency virus infection for the first time. GI endoscopy revealed multiple dish-like lesions, ulcerations, bloody spots, nodular masses with active bleeding in the stomach, erythematous flat lesions in the duodenum, and multiple nodular masses in the colon and rectum. Magnified endoscopy with narrow band imaging showed a honeycomb-like pattern without irregular microvessels in the dish-like lesions of the stomach. Biopsy specimens from the stomach, duodenum, colon, and rectum revealed diffuse large B-cell lymphoma concomitant with EBV infection that was detected by high tissue EBV-polymerase chain reaction levels and Epstein-Barr virus small RNAs in situ hybridization. Fluorescence in situ hybridization analysis revealed a fusion between the immunoglobulin heavy chain (IgH) and c-MYC genes, but not between the IgH and BCL2 loci. After 1-mo of treatment with HAART and R-CHOP, endoscopic appearance improved remarkably, and the histological features of the biopsy specimens revealed no evidence of lymphoma. However, he died from multiple organ failure on the 139(th) day after diagnosis. The cause of his poor outcome may be related to MYC rearrangement. The GI tract involvement in ARL is rarely reported, and its endoscopic findings are various and may be different from those in non-AIDS GI lymphoma; thus, we also conducted a literature review of GI-ARL cases.


Asunto(s)
Endoscopía Gastrointestinal , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Reordenamiento Génico , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Proteínas Proto-Oncogénicas c-myc/genética , Adulto , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Terapia Antirretroviral Altamente Activa , Biopsia , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Resultado Fatal , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/virología , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma Relacionado con SIDA/virología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/virología , Masculino , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/virología , Valor Predictivo de las Pruebas , Prednisona/administración & dosificación , Rituximab , Factores de Tiempo , Resultado del Tratamiento , Vincristina/administración & dosificación
12.
J Acquir Immune Defic Syndr ; 64(2): 204-10, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23722608

RESUMEN

BACKGROUND: AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is a common AIDS-defining cancer. Prior studies suggest that chronic B-cell activation precedes AIDS-NHL diagnosis. Activation of B cells by multiple factors, including Toll-like receptor (TLR) signaling, leads to the expression of activation-induced cytidine deaminase (AID), a DNA mutating molecule that can contribute to oncogene translocations/mutations, leading to NHL. The goal of this study was to determine whether surface markers expressed on activated and/or germinal center B cells, and AID expression, were elevated on circulating B cells preceding AIDS-NHL and to determine if TLR signaling contributes to this activated B-cell phenotype. METHODS: Stored viable peripheral blood mononuclear cell specimens, obtained before AIDS-NHL diagnosis, were assessed by multicolor flow cytometry. Additionally, B cells isolated from peripheral blood mononuclear cell were exposed to TLR ligands in vitro, after which B-cell phenotype was assessed by flow cytometry. RESULTS: An elevated fraction of B cells expressing CD10, CD71, or CD86 was seen in those who went on to develop AIDS-NHL. AID expression was detected in some who developed AIDS-NHL, but not in HIV+ or HIV- controls. TLR2-stimulated purified B cells exhibited the activated B-cell phenotype observed in HIV+ subjects before AIDS-NHL diagnosis. CONCLUSIONS: These results indicate that an elevated fraction of B cells display an activated/germinal center phenotype in those HIV+ subjects who go on to develop AIDS-NHL and suggest that TLR2-mediated activation may play a role in HIV infection-associated B-cell activation, potentially contributing to the genesis of AIDS-NHL.


Asunto(s)
Linfocitos B/inmunología , Linfocitos B/patología , Infecciones por VIH/inmunología , Activación de Linfocitos/inmunología , Linfoma Relacionado con SIDA/inmunología , Linfoma no Hodgkin/inmunología , Receptor Toll-Like 2/inmunología , Adulto , Linfocitos B/metabolismo , Estudios de Casos y Controles , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Femenino , Citometría de Flujo , Infecciones por VIH/complicaciones , Humanos , Linfoma Relacionado con SIDA/diagnóstico , Linfoma Relacionado con SIDA/genética , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/genética , Masculino , Persona de Mediana Edad , Fenotipo
13.
Int J Hematol ; 97(5): 624-33, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23605439

RESUMEN

Primary effusion lymphoma (PEL) presents as a serous lymphomatous effusion without tumor masses exclusively in body cavities and mainly occurs in human immunodeficiency virus-1 (HIV-1)-infected patients. We established a new PEL cell line, designated GTO, from the pericardial effusion of a 39-year-old Japanese patient with acquired immunodeficiency syndrome-related PEL. This cell line was infected with human herpesvirus-8, but not with Epstein-Barr virus. Southern blot hybridization demonstrated that GTO cells display monoclonal rearrangement of the IgH gene, suggesting clonal B cell proliferation. GTO cells weakly express or lack T cell-associated markers (CD3, CD5, CD8), the majority of B cell-associated markers (CD19, CD20, CD21, CD79a), the α chains of ß 2 integrins (CD11a, CD11b, CD11c), HLA-DR, CD30, and surface immunoglobulin (sIgM, sIgG sIgκ, sIgλ), TCR (α/ß, γδ), but express CD45, and post-germinal center B cell/plasma cell-associated antigens (CD38, CD138). They also express a high level of cell-surface CD4 and can be infected by HIV-1. Immunodeficient mice intraperitoneally xenografted with GTO cells developed ascites containing lymphoma cells. The establishment of GTO and a GTO xenograft mouse model may help to provide insights toward a better understanding of the pathogenesis of PEL and the relationship between HIV-1 and HHV-8.


Asunto(s)
Antígenos CD4/metabolismo , Linfoma Relacionado con SIDA/metabolismo , Linfoma Relacionado con SIDA/patología , Linfoma de Efusión Primaria/metabolismo , Linfoma de Efusión Primaria/patología , Animales , Línea Celular Tumoral , Aberraciones Cromosómicas , Bandeo Cromosómico , Ascitis Quilosa , Herpesvirus Humano 4/genética , Herpesvirus Humano 8/genética , Humanos , Inmunofenotipificación , Linfoma Relacionado con SIDA/genética , Linfoma de Efusión Primaria/genética , Ratones , Trasplante Heterólogo
14.
Pathologe ; 34(1): 34-44, 2013 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-23319007

RESUMEN

Immune suppression is a risk factor for malignant lymphoma development. Progress in medical science has increased the numbers of immunosuppressed patients due to organ transplantations or successful treatment of autoimmune diseases. Different forms of immune suppression and the respective lymphoma entities are discussed in this article. Another issue treated are gray zone lymphomas between Hodgkin's lymphoma and diffuse large B cell lymphoma. This category not only represents a diagnostic challenge but also represents more a true biological continuum.


Asunto(s)
Ganglios Linfáticos/patología , Linfoma/patología , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Biomarcadores de Tumor/genética , Biopsia , Diagnóstico Diferencial , Regulación Neoplásica de la Expresión Génica/genética , Marcadores Genéticos/genética , Enfermedad de Hodgkin/clasificación , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/patología , Humanos , Tolerancia Inmunológica/inmunología , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Ganglios Linfáticos/inmunología , Linfoma/clasificación , Linfoma/genética , Linfoma/inmunología , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/inmunología , Linfoma Relacionado con SIDA/patología , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Neoplasias del Mediastino/clasificación , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/patología , Complicaciones Posoperatorias/genética , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/patología , Pronóstico , Factores de Riesgo , Inmunología del Trasplante/genética , Inmunología del Trasplante/inmunología
15.
Int J Clin Exp Pathol ; 6(2): 148-54, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23330000

RESUMEN

RPS6KB1 encodes p70S6K/p85S6K, which plays a role in the PI3K/Akt/mTOR signal transduction pathway. CDC2 gene encodes cdc2, which is critical for G2/M cell cycle progression. We had previously shown that amplified RPS6KB1 and CDC2 are commonly detected in the EBV+ diffuse large B-cell lymphoma (DLBCL) in HIV patients. In current study, we further evaluated the amplified RPS6KB1 and CDC2 genes in 12 HIV-related aggressive B-cell lymphomas and 10 non-HIV-related DLBCL using real time quantitative PCR. The cases were divided into 4 groups: 1) HIV-/EBV-; 2) HIV-/EBV+; 3) HIV+/EBV-; and 4) HIV+/EBV+. Receiver operating characteristic (ROC) curve and the area under the curve (AUC) was used to assess the ability of each gene to distinguish non-HIV+/EBV+ cases from HIV+/EBV+ cases. The AUC was estimated to be 0.76 for RPS6KB1 and 0.74 for CDC2 by using the Mann-Whitney statistic. Amplified RPS6KB1 and CDC2 genes were more frequently detected in common variants of DLBCL associated with HIV infection. Taken together, amplified RPS6KB1 and CDC2 are potential biomarkers for the aggressive DLBCL, particularly in HIV+/EBV+ patients. This study also suggests that the HIV+/EBV+ aggressive DLBCL could be potentially treated by targeting RPS6KB1 and CDC2 genes.


Asunto(s)
Ciclina B/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por VIH/complicaciones , Linfoma Relacionado con SIDA/genética , Linfoma de Células B Grandes Difuso/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Biomarcadores de Tumor/genética , Proteína Quinasa CDC2 , División Celular/genética , Quinasas Ciclina-Dependientes , Fase G2/genética , Humanos , Linfoma Relacionado con SIDA/patología , Linfoma Relacionado con SIDA/virología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/virología , Curva ROC , Transducción de Señal/genética
16.
Hematol Oncol ; 31(1): 22-8, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22488585

RESUMEN

We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity.


Asunto(s)
Citocinas/fisiología , Metilación de ADN , Linfoma Relacionado con SIDA/genética , Trastornos Linfoproliferativos/genética , Proteínas de Neoplasias/genética , Complicaciones Posoperatorias/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Línea Celular Tumoral , Evolución Clonal , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Humanos , Huésped Inmunocomprometido , Quinasas Janus/fisiología , Linfoma Relacionado con SIDA/fisiopatología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/fisiopatología , Mutación , Proteínas de Neoplasias/fisiología , Trasplante de Órganos , Complicaciones Posoperatorias/inmunología , Complicaciones Posoperatorias/fisiopatología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/fisiología , Estudios Retrospectivos , Factores de Transcripción STAT/fisiología , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/fisiología
18.
Ann Diagn Pathol ; 16(3): 219-23, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21531157

RESUMEN

Plasmablastic lymphoma is a high-grade B-cell lymphoma that poses major diagnostic problems and carries an extremely poor prognosis. This tumor was first described in the oral cavity of HIV+ patients but has since been identified in other sites and in seronegative patients. We describe 2 cases of plasmablastic lymphoma of the urinary tract that both presented with hydronephrosis. One occurred in an HIV+ patient and harbored a MYC translocation; the other, in an HIV- patient with no translocation detected.


Asunto(s)
Linfoma/patología , Neoplasias Urológicas/patología , Adenocarcinoma/patología , Anciano , Biomarcadores de Tumor/análisis , Neoplasias del Colon/patología , Infecciones por VIH/complicaciones , Humanos , Inmunohistoquímica , Linfoma/complicaciones , Linfoma/metabolismo , Linfoma Relacionado con SIDA/genética , Linfoma Relacionado con SIDA/metabolismo , Linfoma Relacionado con SIDA/patología , Masculino , Neoplasias Primarias Secundarias/patología , Neoplasias Urológicas/complicaciones , Neoplasias Urológicas/metabolismo
19.
Oral Oncol ; 47(9): 883-7, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21783402

RESUMEN

We present common cytogenetic features in the largest cohort of plasmablastic lymphoma (PBL) of the oral cavity published to date. This cohort included 45 patients, 32 of whom had a known HIV status, of which 31 were HIV positive. Ninety eight per cent of all PBL cases were known to be EBV positive. In line with previous studies, we found that rearrangements of the MYC gene was the most common genetic abnormality seen in 60% of cases with the immunoglobulin heavy chain (IGH) locus as a partner in 51% of cases. Additional complex genetic aberrations were frequent, in particular, an increased copy number of the CCND1 gene was seen in 41% of cases with true amplification of CCND1 in 15% of cases. Aneuploidy was also observed for the BCL6 gene in 28% of cases. Interestingly, rearrangements of both IGH genes were detected in 16% of cases with t(14;18) and t(11;14) respectively involved in conjunction with a t(8;14) in two cases. These bi-allelic IGH rearrangements have not been described before in oral PBL. Our results reinforce the notion that EBV infection and MYC rearrangements are important events in the pathogenesis of oral PBL. The genetic diversity and complexity observed in these cases, underlines the importance to genetically characterise PBL patients at presentation as this may inform the choice of more effective treatment modalities.


Asunto(s)
Infecciones por Virus de Epstein-Barr/genética , Linfoma Relacionado con SIDA/genética , Neoplasias de la Boca/genética , Adulto , Aneuploidia , Estudios de Cohortes , Ciclina D1/genética , Proteínas de Unión al ADN/genética , Femenino , Reordenamiento Génico , Genes myc/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Hibridación Fluorescente in Situ/métodos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/virología , Proteínas Proto-Oncogénicas c-bcl-6
20.
PLoS One ; 6(6): e20781, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21698185

RESUMEN

BACKGROUND: Individuals infected by HIV are at an increased risk for developing non-Hodgkin's lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt's lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis. CONCLUSION: Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs.


Asunto(s)
Linfoma Relacionado con SIDA/genética , MicroARNs/genética , Familia de Multigenes , Secuencia de Bases , Western Blotting , Línea Celular Tumoral , Cartilla de ADN , Perfilación de la Expresión Génica , Silenciador del Gen , Humanos , Procesamiento Postranscripcional del ARN
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