RESUMEN
The presence of high numbers of circulating clonal plasma cells (cPCs) in patients with smoldering multiple myeloma (SMM), detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to MM. The significance of quantifying cPCs via multiparameter flow cytometry, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. This study evaluated 100 patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013. Patients with ⩾150 cPCs (N=9) were considered to have high number of cPCs based on the 97% specificity and 78% PPV of progression to MM within 2 years of cPC assessment. The median TTP of patients with ⩾150 cPCs was 9 months compared with not reached for patients with <150 cPCs (P<0.001). Thus, quantification of cPCs via multiparametric flow cytometry identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage.
Asunto(s)
Mieloma Múltiple/diagnóstico , Células Neoplásicas Circulantes/patología , Células Plasmáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Células Clonales/patología , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Citometría de Flujo/métodos , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patologíaRESUMEN
The presence of clonal circulating plasma cells (cPCs) is a marker of high-risk disease in all stages of monoclonal gammopathies. However, the prognostic utility of quantitating cPCs using multiparametric flow cytometry in multiple myeloma (MM) patients with current treatments is unknown. There were 157 consecutive patients with newly diagnosed MM seen at the Mayo Clinic, Rochester from 2009 to 2011 that had their peripheral blood evaluated for cPCs by multiparameter flow cytometry. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log-rank test. Using a receiver operating characteristics (ROC) analysis, ⩾400 cPCs were considered as the optimal cutoff for defining high-risk disease. The presence of ⩾400 cPCs was associated with higher plasma cell (PC) proliferation and adverse cytogenetics. The median time-to-next-treatment and overall survival (OS) in patients with ⩾400 cPCs (N=37, 24%) was 14 months and 32 months compared with 26 months and not reached for the rest (P<0.001). In a multivariable model, the presence of ⩾400 cPCs and older age adversely affected OS. Flow cytometry to quantify cPCs is a valuable test for risk stratifying newly diagnosed MM patients in the era of novel agents. Future studies are needed to determine its role in developing a risk-adapted treatment approach.
Asunto(s)
Citometría de Flujo/métodos , Mieloma Múltiple/sangre , Mieloma Múltiple/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular , Citogenética , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Células Plasmáticas/citología , Pronóstico , Curva ROC , Estudios Retrospectivos , Riesgo , Resultado del TratamientoRESUMEN
Smoldering multiple myeloma (SMM) carries a 50% risk of progression to multiple myeloma (MM) or related malignancy within the first 5 years following diagnosis. The goal of this study was to determine if high levels of circulating plasma cells (PCs) are predictive of SMM transformation within the first 2-3 years from diagnosis. Ninety-one patients diagnosed with SMM at Mayo Clinic from January 1994 through January 2007, who had testing for circulating PCs using an immunofluorescent assay and adequate follow-up to ascertain disease progression, were studied. High level of circulating PCs was defined as absolute peripheral blood PCs >5 × 10(6)/l and/or >5% PCs per 100 cytoplasmic immunoglobulin (Ig)-positive peripheral blood mononuclear cells. Patients with high circulating PCs (14 of 91 patients, 15%) were significantly more likely to progress to active disease within 2 years compared with patients without high circulating PCs, 71% versus 24%, respectively, P=0.001. Corresponding rates for progression within 3 years were 86% versus 34%, respectively, P<0.001. Overall survival (OS) after both SMM diagnosis and MM diagnosis was also significantly different. High levels of circulating PCs identify SMM patients with an elevated risk of progression within the first 2-3 years following diagnosis.
Asunto(s)
Mieloma Múltiple/diagnóstico , Células Neoplásicas Circulantes/patología , Células Plasmáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/etiología , Mieloma Múltiple/mortalidad , Pronóstico , Factores de Riesgo , Tasa de SupervivenciaAsunto(s)
Células Asesinas Naturales/patología , Trastornos Linfoproliferativos/patología , Antígeno CD56/metabolismo , Células Cultivadas , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Células Asesinas Naturales/metabolismo , Trastornos Linfoproliferativos/clasificación , Trastornos Linfoproliferativos/genética , Persona de Mediana Edad , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Receptores KIR/metabolismoRESUMEN
Peripheral T-cell lymphomas (PTCLs) are fatal in the majority of patients and novel treatments, such as protein tyrosine kinase (PTK) inhibition, are needed. The recent finding of SYK/ITK translocations in rare PTCLs led us to examine the expression of Syk PTK in 141 PTCLs. Syk was positive by immunohistochemistry (IHC) in 133 PTCLs (94%), whereas normal T cells were negative. Western blot on frozen tissue (n=6) and flow cytometry on cell suspensions (n=4) correlated with IHC results in paraffin. Additionally, western blot demonstrated that Syk-positive PTCLs show tyrosine (525/526) phosphorylation, known to be required for Syk activation. Fluorescence in situ hybridization showed no SYK/ITK translocation in 86 cases. Overexpression of Syk, phosphorylation of its Y525/526 residues and the availability of orally available Syk inhibitors suggest that Syk merits further evaluation as a candidate target for pharmacologic PTK inhibition in patients with PTCL.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfoma de Células T Periférico/enzimología , Proteínas Tirosina Quinasas/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Niño , Preescolar , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 9/genética , Femenino , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Inmunofenotipificación , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular/genética , Linfoma Extranodal de Células NK-T/enzimología , Linfoma Extranodal de Células NK-T/genética , Linfoma Extranodal de Células NK-T/patología , Linfoma Anaplásico de Células Grandes/enzimología , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Linfoma Cutáneo de Células T/enzimología , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/patología , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patología , Masculino , Persona de Mediana Edad , Fosforilación , Proteínas Tirosina Quinasas/genética , Quinasa Syk , Translocación Genética , Tirosina/metabolismoAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/metabolismo , Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Mieloma Múltiple/inmunología , RituximabAsunto(s)
Arterias/patología , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/diagnóstico , Riesgo , Sensibilidad y Especificidad , Accidente Cerebrovascular/diagnóstico , Trombosis/diagnósticoAsunto(s)
Células Asesinas Naturales/inmunología , Neoplasias Hepáticas/genética , Linfoma de Células T/genética , Subfamília D de Receptores Similares a Lectina de las Células NK/biosíntesis , Receptores Inmunológicos/biosíntesis , Neoplasias del Bazo/genética , Adulto , Niño , Femenino , Citometría de Flujo , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Linfoma de Células T/diagnóstico , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Subfamília D de Receptores Similares a Lectina de las Células NK/genética , Receptores Inmunológicos/genética , Receptores KIR , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/patologíaRESUMEN
Natural killer (NK) cells provide anti-infectious, anti-neoplastic, and immunomodulatory function effected by both cytokine production and direct cellular cytotoxicity that is not major histocompatibility complex-restricted. NK cells lack truly specific cell surface determinants as well as antigen-specific receptors. Recent information suggests a variety of receptor-ligand interactions that underlie recognition and treatment of target cells by NK cells. Primary NK cell disorders in humans are currently classified into NK cell lymphomas and chronic NK cell lymphocytosis (CNKL). In this review, we summarize current understanding of the biology of NK cells and describe the clinical manifestations of CNKL.
Asunto(s)
Células Asesinas Naturales/patología , Linfocitosis/patología , Animales , Enfermedad Crónica , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/fisiología , Linfocitosis/terapia , SíndromeRESUMEN
Littoral cell angioma (LCA) is a rare vascular tumor of the spleen with an unknown etiology and unclear natural history. An association with synchronous malignancy has been described. We report the case of a 54-year-old woman who had progressive splenomegaly over 3 years following resection of a colon adenocarcinoma. The splenomegaly was associated with portal hypertension and severe thrombocytopenia. Splenectomy was performed, and the histologic and immunocytochemical features of the spleen specimen were consistent with LCA. The relationship between LCA and malignancy is reviewed.
Asunto(s)
Adenocarcinoma/cirugía , Neoplasias del Colon/cirugía , Hemangioma/diagnóstico , Hipertensión Portal/diagnóstico , Neoplasias del Bazo/diagnóstico , Diagnóstico Diferencial , Femenino , Hemangioma/patología , Humanos , Hipertensión Portal/patología , Persona de Mediana Edad , Neoplasias del Bazo/irrigación sanguínea , Neoplasias del Bazo/patología , EsplenomegaliaRESUMEN
Basaloid squamous cell carcinoma (BSCC) is a recently recognized variant of squamous cell carcinoma (SCC) with a predilection to occur in the tongue base, hypopharynx, and supraglottic larynx. In smal biopsy specimens, these tumors can be difficult to distinguish from small cell undifferentiated carcinoma (SCUC) and adenoid cystic carcinoma (ACC). Monoclonal antibodies reactive with cytokeratin (AE1/AE3, 34betaE12, Cam 5.2) as well as a variety of other cellular antigens (vimentin, actin, desmin, chromogranin, synaptophysin, CD57, neuron-specific enolase [NSE], and S100) were used in an immunoperoxidase method with paraffin-embedded tissue to phenotypically characterize 23 cases of BSCC, 10 cases of SCUC, and 15 cases of ACC. The neoplastic cells in 22 of the 23 cases of BSCC reacted with the high-molecular-weight cytokeratin antibody 34betaE12, whereas no reactivity was seen in any of the 10 cases of SCUC. This pattern of 34betaE12 reactivity more consistently differentiated BSCC from SCUC than did reactivity with the neuroendocrine markers chromogranin, synaptophysin, CD57, and NSE. These findings show that immunoperoxidase stains performed on paraffin-embedded tissue are potentially useful in establishing a diagnosis of basaloid squamous cell carcinoma.
Asunto(s)
Carcinoma Adenoide Quístico/patología , Carcinoma Basoescamoso/patología , Carcinoma de Células Pequeñas/patología , Neoplasias de Oído, Nariz y Garganta/patología , Anciano , Anciano de 80 o más Años , Anticuerpos Antineoplásicos/análisis , Biomarcadores de Tumor , Carcinoma Adenoide Quístico/química , Carcinoma Basoescamoso/química , Carcinoma de Células Pequeñas/química , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Queratinas/inmunología , Masculino , Persona de Mediana Edad , Neoplasias de Oído, Nariz y Garganta/químicaRESUMEN
The immunosuppressant rapamycin (RAP) is a potent inhibitor of the entry of interleukin (IL)-2-stimulated T cells into S-phase. Earlier results indicated that RAP treatment arrested the growth of the murine IL-2-dependent T cell line CTLL-2 in late G1-phase. To explore further the interactions of RAP with the cell cycle control machinery in T cells, we examined the effects of RAP treatment on the activation of the cyclin-dependent kinases p34cdc2 and p33cdk2 in G1-phase CTLL-2 cells. Stimulation of factor-deprived cells with IL-2 led to the assembly of high molecular weight complexes containing active p34cdc2 and p33cdk2. The appearance of these complexes was explained, at least in part, by the association of both cyclin-dependent kinases with IL-2-induced cyclin A. RAP treatment profoundly inhibited both cyclin A expression and the appearance of active cyclin A-cyclin-dependent kinase complexes in IL-2-stimulated, late G1-phase CTLL-2 cells. Although p34cdc2 activation was largely dependent on association with cyclin A, a significant proportion of the active p33cdk2 pool was complexed with cyclin E. In contrast to cyclin A, the IL-2-induced accumulation of cyclin E in G1-phase cells was only partially suppressed by RAP, and cyclin E-p33cdk2 complexes were readily detected in drug-treated cells. These cyclin E-cyclin-dependent kinase complexes were nonetheless devoid of histone H1 kinase activity. The inhibitory effects of RAP on the activation of cyclin E- and cyclin A-associated cyclin-dependent kinases suggest that one or both events participate in the regulation of T cell entry into S-phase.
Asunto(s)
Proteína Quinasa CDC2/metabolismo , Quinasas CDC2-CDC28 , Quinasas Ciclina-Dependientes , Inmunosupresores/farmacología , Interleucina-2/farmacología , Polienos/farmacología , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas , Linfocitos T/efectos de los fármacos , Secuencia de Aminoácidos , Northern Blotting , División Celular/efectos de los fármacos , Línea Celular , Cromatografía en Gel , Quinasa 2 Dependiente de la Ciclina , Ciclinas/biosíntesis , Ciclinas/aislamiento & purificación , Sondas de ADN , Replicación del ADN/efectos de los fármacos , Activación Enzimática , Humanos , Cinética , Datos de Secuencia Molecular , Oligopéptidos/inmunología , Protamina Quinasa/metabolismo , Proteínas Quinasas/aislamiento & purificación , Proteínas Recombinantes/farmacología , Sirolimus , Linfocitos T/enzimologíaRESUMEN
The macrolide rapamycin (RAP) is a potent inhibitor of interleukin-2 (IL-2)-induced T-cell proliferation. Current models suggest that RAP, when complexed to its intracellular receptor, FK506-binding protein, interferes with an IL-2 receptor-coupled signaling pathway required for cell-cycle progression from G1- to S-phase. Here we show that RAP treatment inhibits the growth of an IL-2-dependent cytotoxic T-cell line, CTLL-2, in late G1-phase, just prior to entry of the cells into S-phase. In contrast, RAP-treated CTLL-2 cells retained the ability to respond to IL-2 with enhanced cytolytic activity, indicating that RAP was not a general suppressant of cellular responsiveness to IL-2. Subsequent studies revealed that IL-2 stimulation triggered a delayed activation of the p34cdc2 kinase, the timing of which correlated with the G1- to S-phase transition. The IL-2-dependent increase in p34cdc2 kinase activity was blocked by RAP. The RAP sensitivity of the p34cdc2 activation mechanism implicates this signaling pathway in the control of S-phase commitment in IL-2-stimulated T-cells.