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Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.
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Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Metilación de ADN , Tumores Neuroectodérmicos/genética , Tumores Neuroectodérmicos/patología , Secuencia de Aminoácidos , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/diagnóstico , Niño , Factores de Transcripción Forkhead/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Datos de Secuencia Molecular , Tumores Neuroectodérmicos/clasificación , Tumores Neuroectodérmicos/diagnóstico , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/química , Proteínas Represoras/genética , Transducción de Señal , Transactivadores , Proteínas Supresoras de Tumor/genéticaRESUMEN
PURPOSE: To present a single-center 20-year experience with operated thyrotropinomas, including prevalence, clinical, biochemical and histological characteristics, and postoperative outcomes. METHODS: Retrospective series of histopathologically-proven thyrotropinomas (1993-2013), divided in two groups: A (active, central hyperthyroidism) and B (silent, no hyperthyroidism). RESULTS: Of 1628 operated pituitary adenomas, 20 were ß-TSH-positive (1.2%). In increments of 5 years, proportion of thyrotropinomas was 1, 1, 0.04 and 1.77% respectively. Median follow-up was 10.4 months (1.2-150). Group A: 6 patients (5 men), age 41 ± 12 years presented with hyperthyroidism (3), pituitary incidentaloma (2) and acromegaly (1). Tumor diameter was 2.1 ± 1.2 cm, FT4 2.68 ± 2.73 ng/dL; TSH 6.50 ± 3.68 µIU/mL. Glycoprotein alpha subunit (GSU) was uniformly elevated. Two patients had biochemical evidence of acromegaly. Tumors were plurihormonal (5 GH-positive); none atypical. Postoperative euthyroidism was achieved in 4 of 6 patients (66%). Group B: 14 patients (7 men), age 47 ± 14 years presented with acromegaly (6), mass effect (4), incidentaloma (3) and galactorrhea (1). Tumor diameter was 2.0 ± 1.0 cm. Free T4 (1.00 ± 0.24 ng/dL) and TSH (2.02 ± 1.65 mIU/L) were lower than in group A (p < 0.01). GSU was elevated in all tested cases. Nine patients had biochemical evidence of acromegaly. Tumors were plurihormonal (12 GH-positive); none atypical. Gross total resection was achieved in 12 of 14 (86%), and 1 (7%) recurred. CONCLUSION: In our series, more thyrotropinomas were operated in recent years. These tumors were often plurihormonal with heterogenous clinical presentation and frequent GH co-secretion. Surgical outcomes were good but long-term follow up is necessary.
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Adenoma/epidemiología , Adenoma/terapia , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/terapia , Tirotropina/metabolismo , Acromegalia/complicaciones , Acromegalia/epidemiología , Adenoma/diagnóstico , Adenoma/metabolismo , Adulto , Femenino , Humanos , Hipertiroidismo/epidemiología , Hipertiroidismo/etiología , Hipertiroidismo/terapia , Hallazgos Incidentales , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/estadística & datos numéricos , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/metabolismo , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Diffuse midline gliomas are among the deadliest human cancers and have had little progress in treatment in the last 50 years. Cell cultures of these tumors have been developed recently, but the degree to which such cultures retain the characteristics of the source tumors is unknown. DNA methylation profiling offers a powerful tool to look at genome-wide epigenetic changes that are biologically meaningful and can help assess the similarity of cultured tumor cells to their in vivo progenitors. Paraffinized diagnostic tissue from three diffuse intrinsic pontine gliomas with H3 K27M mutations was compared with subsequent passages of neurosphere cell cultures from those tumors. Each cell line was passaged 3-4 times and analyzed with DNA methylation arrays and standard algorithms that provided a comparison of diagnostic classification and cluster analysis. All samples tested maintained high classifier scores and clustered within the reference group of H3 K27M-mutant diffuse midline gliomas. There was a gain of 1q in all cell lines, with two cell lines initially manifesting the gain of 1q only during culture. In vitro cell cultures of H3 K27M-mutant gliomas maintain high degrees of similarity in DNA methylation profiles to their source tumor, confirming their fidelity even with some chromosomal changes.
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GD2-targeting immunotherapies have improved survival in children with neuroblastoma, yet on-target, off-tumor toxicities can occur and a subset of patients cease to respond. The majority of neuroblastoma patients who receive immunotherapy have been previously treated with cytotoxic chemotherapy, making it paramount to identify neuroblastoma-specific antigens that remain stable throughout standard treatment. Cell surface glycoproteomics performed on human-derived neuroblastoma tumors in mice following chemotherapy treatment identified protein tyrosine kinase 7 (PTK7) to be abundantly expressed. Furthermore, PTK7 shows minimal expression on pediatric-specific normal tissues. We developed an anti-PTK7 chimeric antigen receptor (CAR) and find PTK7 CAR T cells specifically target and kill PTK7-expressing neuroblastoma in vitro. In vivo, human/murine binding PTK7 CAR T cells regress aggressive neuroblastoma metastatic mouse models and prolong survival with no toxicity. Together, these data demonstrate preclinical efficacy and tolerability for targeting PTK7 and support ongoing investigations to optimize PTK7-targeting CAR T cells for neuroblastoma.
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Neuroblastoma , Receptores Quiméricos de Antígenos , Humanos , Niño , Animales , Ratones , Neuroblastoma/terapia , Neuroblastoma/patología , Inmunoterapia , Receptores Quiméricos de Antígenos/genética , Proteínas Tirosina QuinasasRESUMEN
Sonic hedgehog (Shh)-driven medulloblastoma (Shh MB) cells are dependent on constitutive Shh signaling, but targeted treatment of Shh MB has been ineffective due to drug resistance. The purpose of this study was to address the critical role of signal transducer and activator of transcription 3 (STAT3) in Shh signaling and drug resistance in Shh MB cells. Herein, we show that STAT3 is required for Smoothened (Smo)-dependent Shh signaling and, in turn, is reciprocally regulated by Shh signaling, and demonstrate that STAT3 activity is critical for expression of HCK proto-oncogene, Src family tyrosine kinase (Hck) in Shh MB. We also demonstrate that maintained STAT3 activity suppresses p21 expression and promotes colony formation of Shh MB cells, whereas dual treatment with inhibitors of both Smo and STAT3 results in marked synergistic killing and overcomes drug resistance in vitro of Smo antagonist-resistant Shh MB cells. Finally, STAT3 inhibitor treatment significantly prevents in vivo tumor formation in genetically engineered Shh MB mice. Collectively, we show that STAT3 is necessary to maintain Shh signaling and thus is a potential therapeutic target to treat Shh MB and overcome anti-Smo drug resistance.
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Neoplasias Cerebelosas , Meduloblastoma , Animales , Carcinogénesis/genética , Neoplasias Cerebelosas/patología , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones , Factor de Transcripción STAT3/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/metabolismoRESUMEN
Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8+ T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8+ T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8+ T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8+ T cells, including bystander CD8+ T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8+ T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8+ T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.
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Neoplasias Encefálicas , Linfocitos T CD8-positivos , Neoplasias Encefálicas/metabolismo , Humanos , Receptores de Antígenos de Linfocitos T/genética , Subgrupos de Linfocitos T , Microambiente TumoralRESUMEN
Background: Pediatric gliomas comprise a diverse set of brain tumor entities that have substantial long-term ramifications for patient survival and quality of life. However, the study of these tumors is currently limited due to a lack of authentic models. Additionally, many aspects of pediatric brain tumor biology, such as tumor cell invasiveness, have been difficult to study with currently available tools. To address these issues, we developed a synthetic extracellular matrix (sECM)-based culture system to grow and study primary pediatric brain tumor cells. Methods: We developed a brain-like sECM material as a supportive scaffold for the culture of primary, patient-derived pediatric glioma cells and established patient-derived cell lines. Primary juvenile brainstem-derived murine astrocytes were used as a feeder layer to support the growth of primary human tumor cells. Results: We found that our culture system facilitated the proliferation of various primary pediatric brain tumors, including low-grade gliomas, and enabled ex vivo testing of investigational therapeutics. Additionally, we found that tuning this sECM material allowed us to assess high-grade pediatric glioma cell invasion and evaluate therapeutic interventions targeting invasive behavior. Conclusion: Our sECM culture platform provides a multipurpose tool for pediatric brain tumor researchers that enables both a wide breadth of biological assays and the cultivation of diverse tumor types.
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OBJECT: The incidence of ependymoma in patients with neurofibromatosis-2 (NF-2) is low and information regarding treatment and prognosis is lacking. We present two cases of cervicomedullary tumors in patients with NF-2 from our institution, and we provide a review of the literature in order to summarize the known clinical information about this rare occurrence. PATIENTS AND METHODS: Patient #1 had histological confirmation of ependymoma and was treated with subtotal resection followed by observation and has had no evidence of progression for 11 months. Patient #2 has been observed for 4 1/2 years without treatment for a cervicomedullary tumor, which appears to be an ependymoma by imaging. Although it has increased in size very slowly, there have been no clinical symptoms. Among the additional 21 cases of NF-2 and ependymoma from the literature, the most common location is the cervical spine (70%), and the median age at diagnosis is 15 years. Surgical resection was performed in 85% of the cases and subtotal resection in 64% of cases. Fifteen patients (75%) were reported alive at the time of the published reports, with survival ranging from 0.1 to 10 years, and the 8-year survival estimated as 51%. Survival was related to the location of the tumor. CONCLUSIONS: We conclude from our two cases and review of the existing literature that NF-2 associated spinal ependymomas have an indolent course and typically can be observed or treated by surgical excision alone.
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Ependimoma/patología , Neurofibromatosis 2/patología , Neoplasias de la Médula Espinal/patología , Adolescente , Edad de Inicio , Niño , Ependimoma/etiología , Ependimoma/cirugía , Femenino , Humanos , Masculino , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/cirugía , Pronóstico , Neoplasias de la Médula Espinal/etiología , Neoplasias de la Médula Espinal/cirugíaRESUMEN
In this patient-focused review, we present a 34-year-old previously healthy man admitted for fever and headache two weeks after a motor vehicle accident. On admission, his workup was concerning for meningoencephalitis based on elevated cerebrospinal fluid (CSF) white blood cell count and elevated CSF protein. He was admitted for management of meningoencephalitis. During his course, no causative infectious agent was identified despite an extensive workup. He additionally underwent an autoimmune and paraneoplastic workup that was negative. During his hospitalization, he developed acute transverse myelitis manifested by bilateral lower extremity paralysis. After four weeks marked by persistent clinical deterioration, brain biopsy was performed. Pathologic examination was consistent with neuromyelitis optica spectrum disorder (NMOSD). In this case report and literature review, we explore the presentations of NMOSD that mimic an infection. Clinicians should be aware of the possibility of NMOSD masquerading as infectious meningoencephalitis or acute transverse myelitis.
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Meningoencefalitis/diagnóstico , Neuromielitis Óptica/diagnóstico , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Meningoencefalitis/microbiología , Meningoencefalitis/virología , Mielitis Transversa/diagnóstico , Mielitis Transversa/diagnóstico por imagen , Mielitis Transversa/etiología , Neuromielitis Óptica/diagnóstico por imagen , Neuromielitis Óptica/etiologíaRESUMEN
We present a case of a 14-year-old male with a germline TP53 mutation who presented with synchronous primitive neuroectodermal tumor and choroid plexus carcinoma. Identification of synchronous brain tumors prompted genetic testing for predisposition to malignancy. Within 5 months of presentation, the child developed widely metastatic alveolar rhabdomyosarcoma. Patient DNA sequencing showed a TP53 allele with a premature stop codon in the oligomerization/nuclear export signal (NES) domain (R342ter). The child's parents, younger brother, paternal grandparents, and maternal grandmother, are without history of malignancy. The patient's brother tested negative for TP53 mutations. This case identifies a rare, de novo, germline TP53 mutation presenting with synchronous CNS malignancies and exhibiting a more fulminant course than typical cases of Li-Fraumeni syndrome.
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Neoplasias Encefálicas/genética , Carcinoma/genética , Neoplasias del Plexo Coroideo/genética , Codón sin Sentido , Genes p53 , Mutación de Línea Germinal , Neoplasias Primarias Múltiples/genética , Tumores Neuroectodérmicos Primitivos/genética , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/secundario , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirugía , Carcinoma/tratamiento farmacológico , Carcinoma/patología , Carcinoma/radioterapia , Neoplasias del Plexo Coroideo/tratamiento farmacológico , Neoplasias del Plexo Coroideo/patología , Neoplasias del Plexo Coroideo/radioterapia , Cisplatino/administración & dosificación , Terapia Combinada , Irradiación Craneana , Resultado Fatal , Lóbulo Frontal/patología , Lóbulo Frontal/cirugía , Humanos , Lomustina/administración & dosificación , Masculino , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/terapia , Neoplasias Primarias Desconocidas/genética , Tumores Neuroectodérmicos Primitivos/patología , Tumores Neuroectodérmicos Primitivos/cirugía , Radioterapia Adyuvante , Neoplasias de la Columna Vertebral/tratamiento farmacológico , Neoplasias de la Columna Vertebral/radioterapia , Neoplasias de la Columna Vertebral/secundario , Vincristina/administración & dosificaciónRESUMEN
Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and site-directed sequencing. Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAFV600E mutations (n = 7). Two additional cases harbored RELA rearrangements. Other cases lacked these specific genetic alterations (n = 8). By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively. In contrast, BRAFV600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA). Six additional tumors clustered with either supratentorial pilocytic astrocytoma and ganglioglioma (LGG-PA/GG-ST), normal or reactive cerebrum, or with no defined DNA methylation class. While certain histologic features favored one genetic group over another, no group could be reliably distinguished by histopathology alone. Survival analysis between genetic AB subtypes was limited by sample size, but showed that MN1-rearranged AB tumors were characterized by better overall survival compared to other genetic subtypes, in fact, significantly better than BRAFV600E-mutant tumors (P = 0.013). Our data confirm that histologically-defined ABs are molecularly heterogeneous and do not represent a single entity. They rather encompass several low- to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions. Genetic subtyping of tumors exhibiting AB histology, particularly determination of MN1 and BRAFV600E status, is necessary for important prognostic and possible treatment implications.
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Neoplasias Encefálicas/genética , Reordenamiento Génico/genética , Genómica/métodos , Neoplasias Neuroepiteliales/genética , Proteínas Proto-Oncogénicas B-raf/genética , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Neuroepiteliales/mortalidad , Neoplasias Neuroepiteliales/patología , Pronóstico , Tasa de Supervivencia/tendencias , Adulto JovenRESUMEN
The evaluation of central nervous system tumors increasingly relies on molecular genetic methods to aid in classification, offer prognostic information, and predict response to therapy. Available assays make it possible to assess genetic losses, amplifications, translocations, mutations, or the expression levels of specific gene transcripts or proteins. Current molecular diagnostics frequently use a panel-based approach and whole genome analysis, and generally rely either on DNA sequencing or on hybridization-based methodologies, such as those used in cytogenomic microarrays. In some cases, immunohistochemistry can be used as a surrogate for genetic analysis when the mutation of interest consistently results in overexpression or underexpression of a known protein product. In surgical neuropathology practice, the diagnostic workup of diffuse gliomas, medulloblastomas, low-grade circumscribed gliomas, as well as other diseases, now routinely incorporates the results of genomic studies. Here we summarize our institution's current approach to diagnostic surgical neuropathology, using these contemporary molecular diagnostic applications.
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Neoplasias del Sistema Nervioso Central/genética , Perfilación de la Expresión Génica/métodos , Neuropatología/métodos , Patología Quirúrgica/métodos , Biomarcadores de Tumor/genética , Humanos , NeurocirugiaRESUMEN
Red blood cells (RBCs) have a well-defined lifespan, indicating a mechanism by which senescent cells of a certain age are removed from circulation. However, the specifics by which senescent cells are recognized and removed are poorly understood. There are multiple competing hypotheses for this process, perhaps the most commonly cited is that senescent RBCs expose neoantigens [or senescent antigen(s)] that are then recognized by naturally occurring antibodies, which opsonize the senescent cells and result in clearance from circulation. While there are a large volume of published data to indicate that older RBCs accumulate increased levels of antibody on their surface, to the best of our knowledge, the causal role of such antibodies in clearance has not been rigorously assessed. In the current report, we demonstrate that RBC lifespan and clearance patterns are not altered in mice deficient in antibodies, in C3 protein, or missing both. These data demonstrate that neither antibody nor C3 is required for clearance of senescent RBCs, and questions if they are even involved, in a murine model of RBC lifespan.
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BACKGROUND: Astroblastomas (ABs) are rare glial tumors showing overlapping features with astrocytomas, ependymomas, and sometimes other glial neoplasms, and may be challenging to diagnose. METHODS: We examined clinical, histopathological, and molecular features in 28 archival formalin-fixed, paraffin-embedded AB cases and performed survival analyses using Cox proportional hazards and Kaplan-Meier methods. RESULTS: Unlike ependymomas and angiocentric gliomas, ABs demonstrate abundant distinctive astroblastic pseudorosettes and are usually Olig2 immunopositive. They also frequently exhibit rhabdoid cells, multinucleated cells, and eosinophilic granular material. They retain immunoreactivity to alpha thalassemia/mental retardation syndrome X-linked, are immunonegative to isocitrate dehydrogenase-1 R132H mutation, and only occasionally show MGMT promoter hypermethylation differentiating them from many diffuse gliomas. Like pleomorphic xanthoastrocytoma, ganglioglioma, supratentorial pilocytic astrocytoma, and other predominantly cortical-based glial tumors, ABs often harbor the BRAFV600E mutation, present in 38% of cases tested (n = 21), further distinguishing those tumors from ependymomas and angiocentric gliomas. Factors correlating with longer patient survival included age less than 30 years, female gender, absent BRAFV600E , and mitotic index less than 5 mitoses/10 high-power fields; however, only the latter was significant by Cox and Kaplan-Meier analyses (n = 24; P = .024 and .012, respectively). This mitotic cutoff is therefore currently the best criterion to stratify tumors into low-grade ABs and higher-grade anaplastic ABs. CONCLUSIONS: In addition to their own characteristic histological features, ABs share some molecular and histological findings with other, possibly ontologically related, cortical-based gliomas of mostly children and young adults. Importantly, the presence of BRAFV600E mutations in a subset of ABs suggests potential clinical utility of targeted anti-BRAF therapy.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Corteza Cerebral/patología , Mutación/genética , Neoplasias Neuroepiteliales/patología , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Corteza Cerebral/metabolismo , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Neuroepiteliales/genética , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Cytokines play critical roles during T cell development; however, it is unclear to what extent development is altered by the high levels of cytokines produced during immune responses. A potential mechanism to shield developing cells from cytokine influence is attenuation of cytokine signaling. Using intracellular staining and flow cytometry to detect cytokine-induced Stat phosphorylation, we analyzed the cytokine responsiveness of developmentally defined mouse T cells. We assessed CD4(-)CD8(-) (DN), CD4(+)CD8(+) (DP), CD4(+)CD8(-) (SP4), and CD4(-)CD8(+) (SP8) in the thymus, and CD4(+)CD44(lo) (naive), CD4(+)CD44(hi) (memory), CD8(+)CD44(lo) (naive), and CD8(+)CD44(hi) (memory) in the periphery for responsiveness to interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL- 10, IL-15, interferon-alpha (IFN-alpha), and IFN-gamma. SP thymocytes responded to a wider range of cytokines than did the less mature DN and DP subpopulations. DP thymocytes were nonresponsive to all cytokines tested except for modest responses to IL-4 and IFN-alpha. Peripheral naive and memory T cells also displayed differential cytokine sensitivity. Memory T cells were less responsive to the proinflammatory cytokines IL-6 and IFN-gamma when compared with naive T cells, and the memory CD4(+) subset was less responsive to IL-4. In summary, developing thymocytes and memory T cells appear to be resistant to the influences of numerous cytokines produced during immune responses.
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Citocinas/farmacología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD/análisis , Diferenciación Celular , Femenino , Memoria Inmunológica , Ratones , Ratones Endogámicos C57BL , Receptores de Citocinas/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/efectos de los fármacos , Timo/crecimiento & desarrollo , Timo/inmunologíaRESUMEN
We describe a case of a 5-year-old girl with onchocerciasis. The patient was recently adopted from Ethiopia and presented with a firm, raised nodule on the midportion of the forehead. Initially, Langerhans cell histiocytosis with bone involvement was suspected; however, histopathologic analysis of the excised nodule revealed the presence of a young-adult, female Onchocerca volvulus worm. This case exemplifies the importance of recognizing the key morphologic characteristics of adult O. volvulus worms isolated from pediatric patients in nonendemic areas to ensure adroit clinical management.
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Onchocerca/aislamiento & purificación , Oncocercosis/parasitología , Tejido Subcutáneo/parasitología , Animales , Antiparasitarios/uso terapéutico , Biopsia , Preescolar , Femenino , Frente , Humanos , Inmunohistoquímica , Ivermectina/uso terapéutico , Oncocercosis/diagnóstico , Oncocercosis/terapia , Valor Predictivo de las Pruebas , Tejido Subcutáneo/patología , Resultado del TratamientoRESUMEN
Leptomeningeal dissemination in children is typical of high-grade, and occasionally low-grade, neoplasms. Rare cases of widely disseminated oligodendroglia-like leptomeningeal tumors, sometimes with associated spinal cord lesions, have been described that respond to treatment and follow an indolent course. Whether these lesions represent an established tumor category or are a unique entity remains to be established. We present 9 pediatric cases of such diffuse leptomeningeal neuroepithelial tumors (DLNT), 8 with assessment of 2 common genetic alterations seen in oligodendrogliomas, 1p and 19q chromosomal deletions and isocitrate dehydrogenase-1 (IDH1) R132H mutations. Four patients were male and 5 female, with a mean age at presentation of 4 years (range, 2 to 7 y). All presented with signs of increased intracranial pressure and diffuse contrast enhancement of the leptomeninges by magnetic resonance imaging. Three had a cervical or upper thoracic spinal cord tumor, and another had a small cerebellar lesion. Leptomeningeal biopsies showed a thickened and fibrotic arachnoid infiltrated by monotonous cells with round nuclei and prominent perinuclear clearing. All cases were strongly immunoreactive for S100 protein, and most showed faint granular synaptophysin reactivity. Six of 8 cases showed deletions of chromosome arm 1p by fluorescence in situ hybridization, 2 of which also had loss of 19q. None of the lesions reacted with IDH1-R132H antibodies. Although the clinicopathologic features show overlap of these DLNT lesions with oligodendroglioma and extraventricular neurocytoma, they do not exactly match either one, suggesting that DLNTs are a distinct tumor entity.
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Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Deleción Cromosómica , Carcinomatosis Meníngea/patología , Neoplasias Neuroepiteliales/patología , Niño , Preescolar , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 19/genética , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Isocitrato Deshidrogenasa/análisis , Isocitrato Deshidrogenasa/biosíntesis , Masculino , Carcinomatosis Meníngea/genética , Carcinomatosis Meníngea/metabolismo , Neoplasias Neuroepiteliales/genética , Neoplasias Neuroepiteliales/metabolismoRESUMEN
Pathologic review of tumor morphology in histologic sections is the traditional method for cancer classification and grading, yet human review has limitations that can result in low reproducibility and inter-observer agreement. Computerized image analysis can partially overcome these shortcomings due to its capacity to quantitatively and reproducibly measure histologic structures on a large-scale. In this paper, we present an end-to-end image analysis and data integration pipeline for large-scale morphologic analysis of pathology images and demonstrate the ability to correlate phenotypic groups with molecular data and clinical outcomes. We demonstrate our method in the context of glioblastoma (GBM), with specific focus on the degree of the oligodendroglioma component. Over 200 million nuclei in digitized pathology slides from 117 GBMs in the Cancer Genome Atlas were quantitatively analyzed, followed by multiplatform correlation of nuclear features with molecular and clinical data. For each nucleus, a Nuclear Score (NS) was calculated based on the degree of oligodendroglioma appearance, using a regression model trained from the optimal feature set. Using the frequencies of neoplastic nuclei in low and high NS intervals, we were able to cluster patients into three well-separated disease groups that contained low, medium, or high Oligodendroglioma Component (OC). We showed that machine-based classification of GBMs with high oligodendroglioma component uncovered a set of tumors with strong associations with PDGFRA amplification, proneural transcriptional class, and expression of the oligodendrocyte signature genes MBP, HOXD1, PLP1, MOBP and PDGFRA. Quantitative morphologic features within the GBMs that correlated most strongly with oligodendrocyte gene expression were high nuclear circularity and low eccentricity. These findings highlight the potential of high throughput morphologic analysis to complement and inform human-based pathologic review.