Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
J Hepatol ; 77(4): 1026-1037, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35577029

RESUMEN

BACKGROUND & AIMS: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS: We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS: Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS: Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY: We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.


Asunto(s)
Carcinoma Hepatocelular , Hepatoblastoma , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Niño , Aberraciones Cromosómicas , Hepatoblastoma/metabolismo , Humanos , Neoplasias Hepáticas/patología , Mutación , Adulto Joven
2.
Cancer ; 124(12): 2607-2620, 2018 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-29624648

RESUMEN

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.


Asunto(s)
Neoplasias Encefálicas/diagnóstico , Histiocitosis de Células de Langerhans/diagnóstico , Enfermedades Neurodegenerativas/diagnóstico , Osteopontina/líquido cefalorraquídeo , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biopsia , Encéfalo/patología , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Células Madre Hematopoyéticas/patología , Histiocitosis de Células de Langerhans/líquido cefalorraquídeo , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Humanos , Lactante , Recién Nacido , Leucocitos Mononucleares/patología , Sistema de Señalización de MAP Quinasas , Masculino , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Estudios Retrospectivos , Adulto Joven
3.
Mod Pathol ; 28(4): 575-86, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25360585

RESUMEN

The BCOR-CCNB3 fusion gene, resulting from a chromosome X paracentric inversion, was recently described in translocation-negative 'Ewing-like' sarcomas arising in bone and soft tissue. Genetic subclassification of undifferentiated unclassified sarcomas may potentially offer markers for reproducible diagnosis and substrates for therapy. Using whole transcriptome paired-end RNA sequencing (RNA-seq) we unexpectedly identified BCOR-CCNB3 fusion transcripts in an undifferentiated spindle-cell sarcoma. RNA-seq results were confirmed through direct RT-PCR of tumor RNA and cloning of the genomic breakpoints from tumor DNA. Five additional undifferentiated sarcomas with BCOR-CCNB3 fusions were identified in a series of 42 pediatric and adult unclassified sarcomas. Genomic breakpoint analysis demonstrated unique breakpoint locations in each case at the DNA level even though the resulting fusion mRNA was identical in all cases. All patients with BCOR-CCNB3 sarcoma were males diagnosed in mid childhood (7-13 years of age). Tumors were equally distributed between axial and extra-axial locations. Five of the six tumors were soft-tissue lesions with either predominant spindle-cell morphology or spindle-cell areas interspersed with ovoid to round cells. CCNB3 immunohistochemistry showed strong nuclear positivity in five tumors before oncologic therapy, but was patchy to negative in post-treatment tumor samples. An RT-PCR assay developed to detect the fusion transcript in archival formalin-fixed tissue was positive in all six cases, with high sensitivity and specificity in both pre- and post-treated samples. This study adds to recent reports on the clinicopathologic spectrum of BCOR-CCNB3 fusion-positive sarcomas, a newly emerging entity within the undifferentiated unclassified sarcoma category and describes a simple RT-PCR assay that in conjunction with CCNB3 immunohistochemistry can be useful in diagnosing these tumors.


Asunto(s)
Ciclina B/genética , Fusión de Oncogenes/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Adulto Joven
4.
J Immunol ; 184(8): 4557-67, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20220088

RESUMEN

Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions containing CD207(+) Langerhans cells (LCs) and lymphocytes that can arise in almost any tissue and cause significant morbidity and mortality. After decades of research, the cause of LCH remains speculative. A prevailing model suggests that LCH arises from malignant transformation and metastasis of epidermal LCs. In this study, CD207(+) cells and CD3(+) T cells were isolated from LCH lesions to determine cell-specific gene expression. Compared with control epidermal CD207(+) cells, the LCH CD207(+) cells yielded 2113 differentially expressed genes (false discovery rate < 0.01). Surprisingly, the expression of many genes previously associated with LCH, including cell-cycle regulators, proinflammatory cytokines, and chemokines, were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly overexpressed in LCH CD207(+) cells. Furthermore, several genes associated with immature myeloid dendritic cells were overexpressed in LCH CD207(+) cells. Compared with the peripheral CD3(+) cells from LCH patients, the LCH lesion CD3(+) cells yielded only 162 differentially regulated genes (false discovery rate < 0.01), and the expression profile of the LCH lesion CD3(+) cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4, and SPP1. Results from this study support a model of LCH pathogenesis in which lesions do not arise from epidermal LCs but from accumulation of bone marrow-derived immature myeloid dendritic cells that recruit activated lymphocytes.


Asunto(s)
Células Epidérmicas , Epidermis/inmunología , Perfilación de la Expresión Génica , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Células de Langerhans/citología , Células de Langerhans/inmunología , Adolescente , Antígenos CD/biosíntesis , Antígenos CD/genética , Biomarcadores/metabolismo , Complejo CD3/biosíntesis , Complejo CD3/genética , Niño , Preescolar , Epidermis/patología , Perfilación de la Expresión Génica/métodos , Histiocitosis de Células de Langerhans/inmunología , Humanos , Lactante , Células de Langerhans/patología , Lectinas Tipo C/biosíntesis , Lectinas Tipo C/genética , Lectinas de Unión a Manosa/biosíntesis , Lectinas de Unión a Manosa/genética , Análisis de Secuencia por Matrices de Oligonucleótidos
5.
Mol Ther ; 19(8): 1433-9, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21654633

RESUMEN

Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions including CD207(+)/CD1a(+) dendritic cells that can result in significant morbidity and mortality. The etiology of LCH remains speculative, and neoplastic and inflammatory origins have been debated for decades. A recent study identified abundant interleukin-17 (IL-17A) protein in dendritic cells in LCH lesions as well as in plasma from patients with active disease. Furthermore, it identified dendritic cells as a novel source of IL-17A expression. However, subsequent studies from our research group failed to identify any IL-17A gene expression from CD207(+) dendritic cells or CD3(+) T cells in LCH lesions. In this study, further investigation once again fails to identify any cells in LCH lesions with IL-17A gene expression. Furthermore, IL-17A antigen is undetectable in LCH lesion lysates with western blotting, immunoprecipitation, spectral analysis, and enzyme-linked immunosorbent assay (ELISA). Western blots, immunoprecipitation, and ELISA experiments also demonstrate that antibodies used in original studies that established the IL-17A hypothesis for pathogenesis of LCH recognize nonspecific proteins. We conclude that evidence for IL-17A as a significant factor in LCH remains inadequate and clinical trials targeting IL-17A remain unjustified.


Asunto(s)
Histiocitosis de Células de Langerhans/inmunología , Interleucina-17/metabolismo , ARN Mensajero/análisis , Anticuerpos Monoclonales , Antígenos CD/inmunología , Antígenos CD1/inmunología , Western Blotting , Células Dendríticas/inmunología , Ensayo de Inmunoadsorción Enzimática , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Humanos , Inmunoprecipitación , Interleucina-17/genética , Lectinas Tipo C/inmunología , Lectinas de Unión a Manosa/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
6.
J Nucl Med Technol ; 2022 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-35882586

RESUMEN

SNMMI-TS Advocacy Committee would now like to answer the following questions and cast a level of opinion on Nuclear Medicine Technologists performing theranostics-therapy clinical work: What training does a nuclear medicine technologist (NMT) need to participate and complete theranostics? What does the SNMMI-TS Advocacy Committee feel are important initiatives to have NMTs fully engaged in theranostics today and in the long-term?

7.
Oncotarget ; 8(28): 46065-46070, 2017 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-28512266

RESUMEN

Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that is usually benign and self-limiting. We present a case of atypical, aggressive JXG harboring a novel mitogen-activated protein kinase (MAPK) pathway mutation in the MAPK1 gene, which encodes mitogen-activated protein kinase 1 or extracellular signal-regulated 2 (ERK2). Our analysis revealed that the mutation results in constitutive ERK activation that is resistant to BRAF or MEK inhibitors but susceptible to an ERK inhibitor. These data highlight the importance of identifying specific MAPK pathway alterations as part of the diagnostic workup for patients with histiocytic disorders rather than initiating empiric treatment with MEK inhibitors.


Asunto(s)
Histiocitos/patología , Ganglios Linfáticos/fisiología , Proteína Quinasa 1 Activada por Mitógenos/genética , Xantogranuloma Juvenil/genética , Células Cultivadas , Niño , Quimioterapia , Humanos , Ganglios Linfáticos/patología , Masculino , Inducción de Remisión , Transducción de Señal/genética , Trasplante de Células Madre , Xantogranuloma Juvenil/diagnóstico
8.
Proteomics Clin Appl ; 5(9-10): 532-41, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21833997

RESUMEN

PURPOSE: Despite intensive treatment regimens, overall survival for high-risk neuroblastoma (HRNB) is still poor. This is in part due to an inability to cure the disease once a patient has reached clinical relapse. Identifying plasma biomarkers of active disease may provide a way of relapse monitoring in HRNB. EXPERIMENTAL DESIGN: In this study, we developed an integrated proteomic approach to identify plasma biomarkers for HRNB. RESULTS: We identified seven candidate biomarkers (SAA, APOA1, IL-6, EGF, MDC, sCD40L and Eotaxin) for HRNB. These biomarkers were then used to create a multivariate classifier of HRNB, which showed a specificity of 90% (95% confidence interval (CI), 73%, 98%), and a sensitivity of 81% (95%CI, 54%, 96%) for classifying HRNB in a training set. When evaluated on independent test samples, the classifier exhibited 86% accuracy (95% CI, 42%, 100%) of identifying diagnostic samples, and 86% accuracy (95% CI, 70%, 100%) of detecting post-diagnosis longitudinal samples that having active disease. CONCLUSION AND CLINICAL RELEVANCE: Further validation of these biomarkers may improve patients' outcomes by developing a simple blood test for the detection of relapse prior to the development of clinically evident disease. Understanding the role of these biomarkers in immune surveillance of neuroblastoma may also provide a new direction of therapeutic strategies.


Asunto(s)
Biomarcadores/sangre , Neuroblastoma/diagnóstico , Proteómica/métodos , Adolescente , Niño , Preescolar , Citocinas/metabolismo , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Estadificación de Neoplasias , Neuroblastoma/metabolismo , Neuroblastoma/prevención & control , Recurrencia , Factores de Riesgo , Sensibilidad y Especificidad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA