RESUMEN
The landscape of additional chromosomal alterations (ACAs) and their impact in chronic myeloid leukemia, blast phase (CML-BP) treated with tyrosine kinase inhibitors (TKIs) have not been well studied. Here, we investigated a cohort of 354 CML-BP patients treated with TKIs. We identified +8, an extra Philadelphia chromosome (Ph), 3q26.2 rearrangement, -7 and isochromosome 17q (i(17q)) as the major-route changes with a frequency of over 10%. In addition, +21 and +19 had a frequency of over 5%. These ACAs demonstrated lineage specificity: +8, 3q26.2 rearrangement, i(17q) and +19 were significantly more common in myeloid BP, and -7 more common in lymphoid BP; +Ph and +21 were equally distributed between two groups. Pearson correlation analysis revealed clustering of common ACAs into two groups: 3q26.2 rearrangement, -7 and i(17q) formed one group, and other ACAs formed another group. The grouping correlated with risk stratification of ACAs in CML, chronic phase. Despite the overall negative prognostic impact of ACAs, stratification of ACAs into major vs minor-route changes provided no prognostic relevance in CML-BP. The emergence of 3q26.2 rearrangement as a major-route change in the TKI era correlated with a high frequency of ABL1 mutations, supporting a role for TKI resistance in the changing cytogenetic landscape in CML-BP.
Asunto(s)
Crisis Blástica/diagnóstico , Crisis Blástica/genética , Aberraciones Cromosómicas , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Crisis Blástica/tratamiento farmacológico , Crisis Blástica/mortalidad , Médula Ósea/patología , Cromosomas Humanos Par 3 , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Mutación , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Transcripción Genética , Translocación Genética , Resultado del Tratamiento , Adulto JovenRESUMEN
Lymphoproliferative disorders are known to complicate immunosuppressive therapy and two cases of primary lymphoma of CNS (PCNSL) have previously been described in association with mycophenolate mofetil (MMF) treatment. We report the third case of PCNSL in a patient with lupus nephropathy while on MMF treatment. PCNSL may be seen more frequently considering the increased use of MMF in immunosuppressant responsive conditions.
Asunto(s)
Neoplasias del Sistema Nervioso Central/inducido químicamente , Inmunosupresores/efectos adversos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Linfoma/inducido químicamente , Ácido Micofenólico/análogos & derivados , Adulto , Neoplasias del Sistema Nervioso Central/patología , Imagen de Difusión por Resonancia Magnética , Resultado Fatal , Femenino , Humanos , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/administración & dosificación , Linfoma/patología , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversosRESUMEN
BACKGROUND: Epstein-Barr virus (EBV) positive Hodgkin disease (HD), as defined by the presence of EBV genes or gene products in the malignant cells, differs epidemiologically from EBV negative HD. However, survival patterns for EBV-defined HD have not been well studied. To determine if EBV status influenced survival time after HD, the authors investigated a large, population-based series of female patients. METHODS: For 311 female patients living in the Greater San Francisco Bay Area who were aged 19-79 years with HD diagnosed between mid-1988 and 1994, histopathologically rereviewed archived biopsy specimens were assayed for EBV with immunohistochemistry and in situ hybridization. The 53 subjects with EBV positive and the 258 with EBV negative HD were observed for vital status through 1998; overall survival was analyzed with Kaplan-Meier and Cox proportional hazards regression methods. RESULTS: Epstein-Barr virus positive HD patients were older, received diagnosis at a later stage, and were less likely to have nodular sclerosis histology than EBV negative patients. Deaths were reported for 21 (40%) EBV positive and 37 (14%) EBV negative patients. No survival differences were observed between EBV positive and negative women aged 19-44 years, but survival was significantly poorer in women aged 45-79 years with EBV positive HD. Regression analysis confirmed this strong negative effect of EBV positive status on survival (hazard ratio for death, 3.0; 95% confidence interval, 1.5-6.2) as unrelated to age, stage at diagnosis, or tumor histology. CONCLUSIONS: This study found a marked survival disadvantage for EBV positive HD in older but not young adult women. These findings suggest influences of both EBV status and age on HD survival, as well as pathogenesis.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Enfermedad de Hodgkin/virología , Adulto , Edad de Inicio , Anciano , Estudios Epidemiológicos , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/patogenicidad , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
We compared surface immunoglobulin heavy chain isotype expression with a number of laboratory, morphologic, and immunophenotypic features in a series of 76 cases of B-cell chronic lymphocytic leukemia (B-CLL). Fifty-five cases were IgM+/IgD+, a phenotype associated with antigenically naïve B cells; 16 cases expressed IgD without IgM, a phenotype seen in a subset of normal B cells with extensive somatic immunoglobulin variable region (IgV) gene mutations; and 5 cases were IgD-, a phenotype associated with memory B cells. WBC count, atypical morphologic features, atypical immunophenotypic characteristics, and CD38 expression were nonrandomly distributed among the 3 categories of heavy chain isotype expression. Moreover, a WBC count more than 30,000/microL (30 x 10(9)/L), atypical morphologic features, and CD38 expression in more than 30% of neoplastic cells (all adverse prognostic factors in B-CLL) were less common among IgD-only cases than among IgM+/IgD+ and IgD- cases. These data demonstrate that surface immunoglobulin heavy chain isotype expression is associated with several laboratory, morphologic, and immunophenotypic features in B-CLL. The subset of B-CLL with the IgD-only phenotype is associated with several favorable prognostic factors, suggesting the possibility that IgD-only B-CLL may be associated with a favorable prognosis.
Asunto(s)
Antígenos CD , Cadenas Pesadas de Inmunoglobulina/metabolismo , Isotipos de Inmunoglobulinas/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Receptores de Antígenos de Linfocitos B/metabolismo , ADP-Ribosil Ciclasa , ADP-Ribosil Ciclasa 1 , Antígenos de Diferenciación/metabolismo , Linfocitos B/metabolismo , Linfocitos B/patología , Citometría de Flujo , Humanos , Inmunoglobulina D/análisis , Inmunoglobulina M/análisis , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Recuento de Leucocitos , Glicoproteínas de Membrana , NAD+ Nucleosidasa/metabolismoRESUMEN
We report a case of a 35-year-old male with a history of recurrent thromboembolic events, who presented to the emergency room with right sided weakness and difficulty with speech. The patient's past medical history included two myocardial infarctions, two deep vein thromboses, and a pulmonary embolism. Subsequent laboratory evaluation indicated that the patient was heterozygous for both the factor V Leiden and prothrombin G20210A mutations. This case report emphasizes the importance of evaluating patients with suspected hereditary thrombophilia for both of these mutations.
Asunto(s)
Factor V/genética , Protrombina/genética , Trombofilia/diagnóstico , Trombofilia/genética , Trombosis/genética , Adulto , Secuencia de Bases , Enfermedades Genéticas Congénitas/diagnóstico , Humanos , Masculino , Mutación Puntual , Reacción en Cadena de la Polimerasa , Recurrencia , Trombosis/diagnósticoRESUMEN
Gamma/delta T cell lymphomas (gamma/delta TCL) represent rare, often aggressive types of T cell malignancy that are clinically and pathologically diverse. Most gamma/delta TCL occur as a hepatosplenic or subcutaneous type. To date, analysis of the T cell receptor delta (TCRS) gene repertoire of hepatosplenic gamma/delta TCL (gamma/delta HSTCL) and subcutaneous panniculitis-like gamma/delta TCL (gamma/delta SPTCL) has been reported only in a limited number of cases. In this study we analyzed 11 gamma/delta HSTCL and 4 gamma/delta SPTCL by polymerase chain reaction and immunostaining to determine their usage of the Vdelta subtypes (Vdelta1-6). It is noteworthy that 10 of 11 gamma/delta HSTCL expressed the Vdelta1 gene. The remaining case also expressed T cell receptor delta (TCRS) as determined by flow cytometry and TCRdelta rearrangement in Southern blot. However, the Vdelta gene expressed by this lymphoma could not be determined, which suggests usage of an as yet unidentified Vdelta gene. In striking contrast to the gamma/delta HSTCL, all 4 gamma/delta SPTCL expressed the Vdelta2 gene. Our data demonstrate that gamma/delta HSTCL are preferentially derived from the Vdelta1 subset of gamma/delta T lymphocytes, whereas gamma/delta SPTCL are preferentially derived from the Vdelta2 subset. The pattern of Vdelta gene expression in HSTCL and SPTCL corresponds to the respective, predominant gamma/delta T cell subsets normally found in the spleen and skin. This finding suggests that gamma/delta TCL are derived from normal gamma/delta T lymphocytes which reside in the affected tissues. Furthermore, the selective, lymphoma type-specific Vdelta gene segment usage may provide a molecular tool to distinguish better among various types of gamma/delta TCL lymphoma particularly in the clinically advanced, widely disseminated cases.
Asunto(s)
Linfoma de Células T/genética , Linfoma de Células T/inmunología , Paniculitis/genética , Paniculitis/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Subgrupos de Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Secuencia de Bases , Cartilla de ADN/genética , Femenino , Reordenamiento Génico de la Cadena delta de los Receptores de Antígenos de los Linfocitos T , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Humanos , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Paniculitis/patología , Reacción en Cadena de la Polimerasa , Neoplasias del Bazo/genética , Neoplasias del Bazo/inmunología , Neoplasias del Bazo/patología , Subgrupos de Linfocitos T/patologíaRESUMEN
The aromatic fatty acid phenylbutyrate (PB) induces cytostasis, differentiation, and apoptosis in primary myeloid leukemic cells at clinically achievable concentrations. In the present study, we have investigated the structural and cellular basis for PB-induced cytostasis, using the ML-1 human myeloid leukemia cell line as a model system. PB induced a dose-dependent increase in cells in G1 with a corresponding decrease in cells in S-phase of the cell cycle. At comparable doses, PB induced expression of CD11b, indicating myeloid differentiation. At higher doses, the drug induced apoptosis. The antitumor activity was independent of the aromatic ring, as butyric acid (BA) was of equal or greater potency at producing these biological changes. In contrast, shortening of the fatty acid carbon chain length, as demonstrated with phenylacetate (PA), significantly diminished drug potency. Consistent with their effects on cell cycle, PB and BA, but not PA, induced the cyclin-dependent kinase inhibitor, p21(WAF1/CIP1), and led to the appearance of hypophosphorylated Rb, suggesting a role for p21(WAF1/CIP1) in PB-induced cytostasis. Therefore, it appears that the fatty acid moiety of PB, rather than its aromatic ring, is critical for its activity in myeloid leukemic cells. These data provide a potential mechanistic basis for the increased potency of PB over PA previously demonstrated in primary leukemic samples, and support the further clinical development of PB in the treatment of hematologic malignancies.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Fase G1/efectos de los fármacos , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/patología , Fenilbutiratos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Fenilbutiratos/química , Fenilbutiratos/uso terapéutico , Relación Estructura-Actividad , Células Tumorales CultivadasAsunto(s)
Células Asesinas Naturales/patología , Leucemia Linfoide/patología , Antígenos CD/metabolismo , Médula Ósea/patología , Humanos , Células Asesinas Naturales/clasificación , Células Asesinas Naturales/metabolismo , Leucemia Linfoide/clasificación , Leucemia Linfoide/metabolismo , Ganglios Linfáticos/patología , Piel/patologíaRESUMEN
In order to characterize the expression of the viral interleukin-6 (vIL-6) homologue in various human herpesvirus 8 (HHV-8)-associated diseases, in situ hybridization and immunohistochemistry were applied to formalin-fixed specimens. These assays showed consistent expression of vIL-6 in primary effusion lymphomas and in a case of human immunodeficiency virus (HIV)-associated lymphadenopathy with a Castleman's disease-like appearance. In contrast, Kaposi's sarcoma specimens showed marked differences among specimens. In a consecutive series of specimens from the Johns Hopkins archives, vIL-6 expression was demonstrated in one of 13 cases. However, among 7 specimens selected from the AIDS Malignancy Bank because of their high levels of the T1.1 lytic transcript and virion production, vIL-6 expression was consistently demonstrated in infiltrating mononuclear cells and occasional spindle-shaped cells. Thus vIL-6 expression in clinical specimens correlates with other measures of the lytic viral cycle. Both assays generally give congruent results and are consistent with the possibility that vIL-6 expression plays a role in the pathogenesis of a variety of HHV-8-associated diseases.
Asunto(s)
Herpesvirus Humano 8/inmunología , Interleucina-6/genética , Linfoma Relacionado con SIDA/virología , Sarcoma de Kaposi/virología , Proteínas Virales/genética , Adulto , Anciano , ADN Viral/análisis , Femenino , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/aislamiento & purificación , Humanos , Inmunohistoquímica , Hibridación in Situ , Interleucina-6/análisis , Linfoma , Linfoma Relacionado con SIDA/inmunología , Linfoma Relacionado con SIDA/patología , Masculino , Persona de Mediana Edad , Sistemas de Lectura Abierta , Estudios Retrospectivos , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/patología , Células Tumorales Cultivadas , Proteínas Virales/análisisRESUMEN
BACKGROUND: Hematopoietic growth factors (HGF) can suppress chemotherapy-induced programmed cell death (apoptosis) in hematopoietic cells. Although HGF can modulate the expression of apoptosis-regulatory genes, including bcl-2, bax, and p21WAF1/CIP1 in cell lines, few data address whether HGF regulate the expression of these proteins in primary acute myeloid leukemia (AML). MATERIALS AND METHODS: We evaluated the expression of bcl-2, bax, and p21WAF1/CIP1 in primary samples from patients with AML in the presence and absence of HGF. The potential association of HGF-induced changes in the levels of these proteins with inhibition of chemotherapy-induced apoptosis was further investigated. RESULTS: While a combination of steel factor (SF) and PIXY321 inhibited etoposide-induced apoptosis in 8/11 primary AML samples studied, Bcl-2 and bax protein levels were unaffected by exposure to HGF and/or etoposide. In contrast, HGF enhanced basal and etoposide-induced p21WAF1/CIP1 protein levels in 9/11 and 7/11 of the cases, respectively. In several cases, inhibition of apoptosis by HGF was seen without up-regulation of p21WAF1/CIP1 levels, suggesting that modulation of p21WAF1/CIP1 is not required for HGF-mediated inhibition of apoptosis. CONCLUSIONS: These data indicate that HGF-mediated inhibition of chemotherapy-induced apoptosis in primary AML samples is not mediated through changes in Bcl-2, bax, and p21WAF1/CIP1 protein levels.
Asunto(s)
Apoptosis , Ciclinas/metabolismo , Factores de Crecimiento de Célula Hematopoyética/metabolismo , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mielomonocítica Aguda/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/farmacología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Etopósido/farmacología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Factores de Crecimiento de Célula Hematopoyética/farmacología , Humanos , Interleucina-3/farmacología , Leucemia Eritroblástica Aguda/sangre , Leucemia Mieloide Aguda/sangre , Leucemia Mielomonocítica Aguda/sangre , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/farmacología , Factor de Células Madre/farmacología , Células Tumorales Cultivadas , Proteína X Asociada a bcl-2RESUMEN
Pharmacological inhibitors of the anabolic enzyme, fatty acid synthase (FAS), including the natural product cerulenin and the novel compound c75, are selectively cytotoxic to cancer cells via induction of apoptosis, apparently related to the tumor cell phenotype of abnormally elevated fatty acid synthetic metabolism. As part of a larger effort to understand the immediate downstream effect of FAS inhibition that leads to apoptosis, the effects of these inhibitors on cell cycle progression were examined. Both FAS inhibitors produce rapid, profound inhibition of DNA replication and S phase progression in human cancer cells. The dose responses for fatty acid synthesis inhibition and DNA synthesis inhibition are similar. The kinetics of both effects are rapid, with fatty acid synthesis inhibition occurring within 30 min and DNA synthesis inhibition occurring within 90 min of drug exposure. Meanwhile, apoptotic changes are not detected until 6 h or later after inhibitor exposure. Fatty acid synthetic pathway activity and the magnitude of DNA synthesis inhibition by FAS inhibitors are increased in parallel by withdrawal of lipid-containing serum from the cultures. The mechanism of DNA synthesis inhibition by cerulenin is indirect, because expression of certain viral oncogenes rescues DNA synthesis/S phase progression in cerulenin-exposed cells. The data suggest a direct linkage at a regulatory level, between fatty acid synthesis and DNA synthesis in proliferating tumor cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Cerulenina/farmacología , Replicación del ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Ácido Graso Sintasas/antagonistas & inhibidores , ADN/biosíntesis , Ácidos Grasos/biosíntesis , Humanos , Células Tumorales CultivadasRESUMEN
The chronic lymphoid leukemias comprise a number of biologically distinct neoplasms of mature lymphocytes. The availability of specific therapies for certain of these tumors makes accurate diagnosis imperative. In most cases, detailed immunophenotypic analysis of the chronic lymphoid leukemias permits specific classification and initiation of the most appropriate therapy. For example, the characteristic immunophenotype of B-cell chronic lymphocytic leukemia (CLL): CD5+, CD23+, FMC7-, CD20 dim+, clonal surface immunoglobulin (sIg) dim+, distinguishes it from another CD5+ B-cell lymphoproliferative disorder, mantle cell lymphoma, which typically displays the composite phenotype: CD5+, CD23-, FMC7+, CD20 bright+, clonal sIg bright+. Likewise, hairy cell leukemia has a characteristic immunophenotype: CD5-, CD11c bright+, CD25+, CD103+, which distinguishes it from other CD5- B-cell lymphoproliferative disorders, including the morphologically similar splenic lymphoma with circulating villous lymphocytes. Immunophenotypic analysis by flow cytometry may also identify clinically relevant subsets of patients within a diagnostic category of leukemia. Thus, in patients with CLL, deviation from the typical immunophenotype is associated with trisomy 12 and mixed-cell morphology. In summary, careful immunophenotyping by flow cytometry facilitates accurate diagnosis in the chronic lymphoid leukemias, and in some settings, may also offer additional therapeutically relevant information.
Asunto(s)
Citometría de Flujo , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/inmunología , Humanos , Leucemia de Células Pilosas/inmunologíaRESUMEN
Epstein-Barr virus (EBV), a ubiquitous herpesvirus associated with certain lymphomas and carcinomas, has been identified within the malignant cells of a small proportion of breast tumors. As breast cancer is a very common malignancy in women, a pathogenetic role of EBV for even a subgroup of patients could have important implications for etiology and prevention. Therefore, we attempted to confirm the EBV-breast cancer association by exploring it in a representative case series stratified by characteristics that modify breast cancer risk. We studied a sample of 97 female and 28 male patients identified from a US population-based cancer registry. Patients were selected randomly within age, sex, ethnicity and tumor estrogen-receptor status groups. With their archived tumor tissues, we examined EBV presence using in situ hybridization for the EBER-1 transcript. In the 107 technically adequate specimens, we did not detect this viral transcript in any tumors, including one from a woman who also had an EBER-positive nasopharyngeal carcinoma. Our uniformly negative findings are extremely unlikely to have occurred by chance and cannot be attributed to selective sampling, as our study group included persons at diverse risk for breast cancer. We conclude that the EBV EBER-1 transcript is not commonly expressed in breast cancer, based on a broadly representative case series, though we cannot exclude an association of EBV within a particular population subgroup.
Asunto(s)
Neoplasias de la Mama Masculina/virología , Neoplasias de la Mama/virología , ARN Viral/genética , Adulto , Factores de Edad , Anciano , Neoplasias de la Mama/genética , Etnicidad , Femenino , Humanos , Hibridación in Situ , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
The classification of natural killer (NK)-cell and NK-like T-cell malignancies has undergone significant evolution in recent years. Although examples of NK-cell tumors resembling acute leukemia have been described anecdotally as blastic, blastoid, or monomorphic NK-cell leukemia/lymphoma (NKL/L), the clinical and pathologic features of these tumors have not been systematically defined. We report four patients with blastic NKL/L and describe the clinical, pathologic, and immunophenotypic findings in these cases. All patients were elderly (58-82 years) and presented with cutaneous plaques. Two patients also had adenopathy, and three patients had marrow involvement at presentation. Biopsy of cutaneous lesions showed atypical superficial and deep dermal lymphoid infiltrates. Involved lymph nodes were architecturally effaced by an interfollicular infiltrate with blastic cytologic features. In Wright-Giemsa-stained blood or marrow smears, tumor cells had finely distributed nuclear chromatin, many with nucleoli, and variable amounts of cytoplasm. In contrast to many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent or inconspicuous. The tumor cells were immunophenotypically distinctive. They expressed intermediate density CD45, as is characteristic of blasts; in addition, the cells were positive for HLA-DR, CD2, CD4, and the NK-associated antigen CD56. Surface CD3, cytoplasmic CD3, and CD5 were negative in all cases tested, whereas CD7 was expressed in two cases. In formalin-fixed tissue, tumor cells marked with antibodies to CD43, but not with other T- or B-lineage-related antibodies. All three cases studied for Epstein-Barr viral RNA by in situ hybridization were negative. Although treatments varied, all three patients with clinical follow-up died within months of the diagnosis. The clinical course in two patients culminated in an overtly leukemic phase. These findings suggest that blastic NKL/L represents a distinct clinicopathologic entity, characterized by cutaneous, nodal, and marrow involvement by blastic cells with immunophenotypic characteristics of true NK cells. The disease afflicts elderly patients, pursues an aggressive course, and may culminate in overt leukemia.
Asunto(s)
Células Asesinas Naturales/patología , Leucemia Linfoide/patología , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Biopsia , Médula Ósea/patología , Aberraciones Cromosómicas , Trastornos de los Cromosomas , Resultado Fatal , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Células Asesinas Naturales/química , Leucemia Linfoide/genética , Ganglios Linfáticos/química , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Piel/patologíaRESUMEN
The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Infecciones por VIH/virología , VIH-1/fisiología , Ganglios Linfáticos/virología , Carga Viral , Latencia del Virus , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Técnicas de Cocultivo , ADN Viral/análisis , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Memoria Inmunológica , Antígenos Comunes de Leucocito/análisis , Activación de Linfocitos , Macrófagos/virología , Reacción en Cadena de la Polimerasa , Provirus/fisiología , Integración Viral , Replicación ViralAsunto(s)
Apoptosis , Neoplasias Hematológicas/patología , Apoptosis/genética , Apoptosis/fisiología , Proteínas de Fusión bcr-abl/fisiología , Genes bcl-2/fisiología , Genes p53/fisiología , Neoplasias Hematológicas/genética , Factores de Crecimiento de Célula Hematopoyética/fisiología , Humanos , Síndromes Mielodisplásicos/patología , Receptor fas/fisiologíaRESUMEN
Residual cancer in radical prostatectomy specimens from men with biopsy-proven adenocarcinoma occasionally may be difficult, or even impossible, to identify. Although this finding was recently described as "minimal residual cancer" or the "vanishing cancer phenomenon," there are no data on the incidence of this phenomenon in surgical pathology practice. We evaluated 3,038 consecutive radical prostatectomies performed at the Johns Hopkins Hospital between 1988 and 1995, excluding cases with a history of transurethral resection, prior therapy with a luteinizing hormone-releasing hormone agonist, focal Gleason grade 4 or 5, capsular penetration, or a positive surgical margin. Of this group, 84 cases with minimal or no residual cancer were identified. In 60 of these cases, residual cancer was "difficult to find" (mean total volume, 0.03 cc; range, 0.01-0.08 cc); in 20 cases, residual cancers were classified as "minute" (mean total volume, 0.07 cc; range, 0.03-0.13 cc). In four cases, no residual cancer could be identified, including two cases in which the diagnosis of cancer on needle biopsy was confirmed, one case in which review of the diagnostic needle biopsy revealed only high-grade prostatic intraepithelial neoplasia, and one case in which molecular analysis demonstrated mislabeling of the needle biopsy specimen. The annual incidence of minimal residual cancer increased from 0.5% in 1988 to 4% in 1993 and has begun to plateau at 3 to 4% since 1993 (p = 0.0016 for increasing trend). These data confirm the general impression that with more vigilant screening of men for prostate cancer, there has been an associated increase in cancer with little or no residual cancer at radical prostatectomy.
Asunto(s)
Adenocarcinoma/patología , Neoplasia Residual/epidemiología , Prostatectomía , Neoplasias de la Próstata/patología , Adenocarcinoma/cirugía , Humanos , Masculino , Neoplasia Residual/diagnóstico , Neoplasias de la Próstata/cirugía , Estudios RetrospectivosRESUMEN
Intravascular lymphomatosis (IVL) is an extremely rare variant of aggressive non-Hodgkin's lymphoma characterized by confinement of neoplastic lymphocytes within vascular spaces. Although IVL is potentially curable with combination chemotherapy, diagnosis is often delayed, in part owing to the negative bone marrow biopsy specimens that are typical of this disorder. We hypothesized that use of a more sensitive method of analysis might identify small clonal B-cell populations in histologically negative bone marrow biopsy specimens from patients with IVL. With use of a recently described assay for immunoglobulin heavy chain gene rearrangement based on the polymerase chain reaction, we demonstrated clonal B-cell populations in histologically negative marrow specimens from five (100%) of five patients with IVL. None of these specimens demonstrated molecular evidence of the t(14;18) associated with follicular lymphoma, providing no evidence for a common derivation of IVL and follicular lymphoma. In summary, molecular analysis of routine bone marrow biopsy sepcimens from patients in whom the diagnosis of IVL is entertained may facilitate prompt recognition of a lympho-proliferative disorder and thereby permit timely therapeutic intervention. Moreover, these findings suggest that despite histologically negative staging bone marrow biopsy specimens, IVL typically disseminates early in its course, thus arguing against the use of localized therapy in this disorder.
Asunto(s)
Médula Ósea/patología , Linfoma de Células B Grandes Difuso/patología , Neoplasias Vasculares/patología , Anciano , Reordenamiento Génico de Linfocito B/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/análisis , Linfoma de Células B Grandes Difuso/diagnóstico , Masculino , Reacción en Cadena de la Polimerasa , Neoplasias Vasculares/diagnósticoRESUMEN
Apoptosis (programmed cell death) is an important regulatory mechanism in hematopoiesis, and is thought to be a principal mechanism of action of cytotoxic chemotherapy. Proteins that modulate apoptosis include bcl-2, which inhibits apoptosis, and Fas (CD95, also known as APO-1), which induces apoptosis in susceptible cells bound by Fas ligand (FasL). To characterize precisely the expression of these apoptosis-regulatory proteins in normal and neoplastic hematopoiesis, the authors have performed multiparameter flow cytometric (FCM) analysis in a series of normal and abnormal marrow specimens. Among normal hematopoietic elements, bcl-2 expression was highest in myeloblasts (29 [+/- 9] x 10(3) molecules of equivalent soluble fluorochrome [MESF]), and lymphocytes (28[+/- 7] x 10(3) MESF). bcl-2 was essentially undetectable in granulocytes and nucleated red blood cells, whereas monocytes and B-cell precursors expressed intermediate levels of bcl-2 (11[+/- 4] x 10(3) and 7[+/- 1] x 10(3) MESF, respectively). Fas expression increased with granulocytic and monocytic differentiation; myeloblasts expressed 8(+/- 2) x 10(3) MESF, whereas granulocytes (15 [+/- 2] x 10(3) MESF) and monocytes (28[+/- 5] x 10(3) MESF) displayed relatively greater intensity of staining for Fas. Among lymphoid cells, Fas expression was heterogeneous. B cells expressed lower intensity Fas staining than both CD4+ and CD8+ T cells. Myeloblasts in 30 cases of myeloid leukemia and myelodysplasia studied for bcl-2 and/or Fas expression manifested variable levels of these molecules (range 9-105 x 10(3) MESF for bcl-2 and 3-33 x 10(3) MESF for Fas). In addition, intraclonal heterogeneity of bcl-2 and Fas expression was seen in certain cases of AML, which correlated with extent of differentiation. Among 28 cases of B-precursor ALL studied for bcl-2 and/or Fas expression, bcl-2 ranged from 22 to 60 x 10(3) MESF (P < .001 versus normal marrow B-cell precursors), and Fas varied between essentially undetectable levels and 6 x 10(3) MESF. In summary, normal marrow subsets display characteristic levels of the apoptosis-regulatory molecules, bcl-2 and Fas. In hematopoietic neoplasms, expression of bcl-2 and Fas varies among cases, and in some instances, within leukemic blast populations. Further study is required to understand the potential significance of this heterogeneous expression of bcl-2 and Fas in hematologic neoplasia.
Asunto(s)
Médula Ósea/metabolismo , Leucemia/metabolismo , Síndromes Mielodisplásicos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor fas/metabolismo , Apoptosis/fisiología , Citometría de Flujo , Humanos , Subgrupos de Linfocitos T/metabolismoRESUMEN
Lymphoid infiltrates of the salivary glands are common to a variety of pathologic conditions including autoimmune disorders, malignant lymphomas, and immunoregulatory responses to parenchymal neoplasms. Clearly, the correct identification of these salivary gland lymphoid infiltrates has important implications regarding patient prognosis and management. Immunophenotypic and molecular analyses have demonstrated that many lesions formerly regarded as myoepithelial sialadentis or benign lymphoepithelial lesion in fact represent neoplastic lymphoid proliferations with the potential for extrasalivary dissemination. In the most recent classification scheme of non-Hodgkin's lymphomas, these neoplasms fall within the spectrum of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. In the early stages of HIV infection, patients may develop salivary gland enlargement resulting from cystic lymphoepithelial lesions. These lesions are thought to reflect a localized manifestation of persistent generalized lymphadenopathy. Although HIV-associated salivary gland disease is regarded as a benign condition, malignant lymphoma has been described in association with some of these lesions, and further work is required to define more precisely the risk of salivary gland lymphoma in HIV-infected patients. Tumor-associated lymphoid proliferation refers to a prominent lymphoid reaction accompanying certain epithelial tumors of the salivary glands. Although tumor-associated lymphoid proliferation has not received as much attention as other types of salivary lymphoid infiltrates, it is a common phenomenon that is sometimes mistaken for an intraparotid lymph node harboring metastatic carcinoma.