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1.
Acta Neuropathol ; 136(2): 227-237, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30019219

RESUMO

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.


Assuntos
Variações do Número de Cópias de DNA/genética , Ependimoma/classificação , Ependimoma/genética , Neoplasias Infratentoriais/classificação , Neoplasias Infratentoriais/genética , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Metilação de DNA/genética , Ependimoma/patologia , Ependimoma/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Infratentoriais/patologia , Neoplasias Infratentoriais/cirurgia , Estimativa de Kaplan-Meier , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Adulto Jovem
2.
Blood ; 122(6): 863-71, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23770775

RESUMO

An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.


Assuntos
Doenças Cardiovasculares/complicações , Melanoma/sangue , Mieloma Múltiplo/sangue , Proteínas Musculares/metabolismo , Miocárdio/patologia , Proteínas Quinases/metabolismo , Linfócitos T/citologia , Alelos , Motivos de Aminoácidos , Antígenos de Neoplasias/metabolismo , Técnicas de Cultura de Células , Conectina , Citocinas/metabolismo , Epitopos/metabolismo , Antígenos HLA-A/metabolismo , Humanos , Imunoterapia Adotiva , Células-Tronco Pluripotentes Induzidas/citologia , Masculino , Melanoma/terapia , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Miocárdio/imunologia , Proteínas de Neoplasias/metabolismo , Peptídeos/metabolismo , Engenharia de Proteínas , Receptores de Antígenos de Linfócitos T/imunologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-26418017

RESUMO

BACKGROUND/AIMS: Transorbital approaches traditionally have focused on skull base and cavernous sinus lesions medial to the globe. Lateral orbital approaches to the temporal lobe have not been widely explored despite several theoretical advantages compared to open craniotomy. Recently, we demonstrated the feasibility of the lateral transorbital technique in cadaveric specimens with endoscopic visualization. We describe our initial clinical experience with the endoscope-assisted lateral transorbital approach to lesions in the temporal lobe. METHODS: Two patients with mesial temporal lobe pathology presenting with seizures underwent surgery. The use of a transpalpebral or Stallard-Wright eyebrow incision enabled access to the intraorbital compartment, and a lateral orbital wall 'keyhole' opening permitted visualization of the anterior temporal pole. RESULTS: This approach afforded adequate access to the surgical target and surrounding structures and was well tolerated by the patients. To the best of our knowledge, this report constitutes the first case series describing the endoscope-assisted lateral transorbital approach to the temporal lobe. We discuss the limits of exposure, the nuances of opening and closing, and comparisons to open craniotomy. CONCLUSION: Further prospective investigation of this approach is warranted for comparison to traditional approaches to the mesial temporal lobe.


Assuntos
Tonsila do Cerebelo/cirurgia , Neoplasias Encefálicas/cirurgia , Endoscopia/métodos , Córtex Entorrinal/cirurgia , Hipocampo/cirurgia , Procedimentos Neurocirúrgicos/métodos , Convulsões/cirurgia , Adulto , Tonsila do Cerebelo/patologia , Biópsia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico , Craniotomia/métodos , Córtex Entorrinal/patologia , Feminino , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Órbita , Convulsões/diagnóstico , Convulsões/etiologia
4.
Am J Pathol ; 175(3): 1292-302, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19700746

RESUMO

Proliferative breast lesions, such as simple ductal hyperplasia (SH) and atypical ductal hyperplasia (ADH), are candidate precursors to ductal carcinoma in situ (DCIS) and invasive cancer. To better understand the relationship of breast lesions to more advanced disease, we used microdissection and DNA microarrays to profile the gene expression of patient-matched histologically normal (HN), ADH, and DCIS from 12 patients with estrogen receptor positive sporadic breast cancer. SH were profiled from a subset of cases. We found 837 differentially expressed genes between DCIS-HN and 447 between ADH-HN, with >90% of the ADH-HN genes also present among the DCIS-HN genes. Only 61 genes were identified between ADH-DCIS. Expression differences were reproduced in an independent cohort of patient-matched lesions by quantitative real-time PCR. Many breast cancer-related genes and pathways were dysregulated in ADH and maintained in DCIS. Particularly, cell adhesion and extracellular matrix interactions were overrepresented. Focal adhesion was the top pathway in each gene set. We conclude that ADH and DCIS share highly similar gene expression and are distinct from HN. In contrast, SH appear more similar to HN. These data provide genetic evidence that ADH (but not SH) are often precursors to cancer and suggest cancer-related genetic changes, particularly adhesion and extracellular matrix pathways, are dysregulated before invasion and even before malignancy is apparent. These findings could lead to novel risk stratification, prevention, and treatment approaches.


Assuntos
Neoplasias da Mama/metabolismo , Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Adesão Celular/genética , Matriz Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/patologia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Hiperplasia , Pessoa de Meia-Idade , Transdução de Sinais/genética
5.
Nat Commun ; 8(1): 319, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28831036

RESUMO

Complete loss of BRCA1 or BRCA2 function is associated with sensitivity to DNA damaging agents. However, not all BRCA1 and BRCA2 germline mutation-associated tumors respond. Herein we report analyses of 160 BRCA1 and BRCA2 germline mutation-associated breast and ovarian tumors. Retention of the normal BRCA1 or BRCA2 allele (absence of locus-specific loss of heterozygosity (LOH)) is observed in 7% of BRCA1 ovarian, 16% of BRCA2 ovarian, 10% of BRCA1 breast, and 46% of BRCA2 breast tumors. These tumors have equivalent homologous recombination deficiency scores to sporadic tumors, significantly lower than scores in tumors with locus-specific LOH (ovarian, P = 0.0004; breast P < 0.0001, two-tailed Student's t-test). Absence of locus-specific LOH is associated with decreased overall survival in ovarian cancer patients treated with platinum chemotherapy (P = 0.01, log-rank test). Locus-specific LOH may be a clinically useful biomarker to predict primary resistance to DNA damaging agents in patients with germline BRCA1 and BRCA2 mutations.Most tumours associated with germline BRCA1/BRCA2 loss of function mutations respond to DNA damaging agents, however, some do not. Herein, the authors identify that a subset of breast/ovarian tumors retain a normal allele, which is associated with decreased overall survival after DNA damage-inducing platinum chemotherapy.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Neoplasias Ovarianas/genética , Adulto , Idoso , Proteína BRCA1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Metilação de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Regiões Promotoras Genéticas/genética , Modelos de Riscos Proporcionais
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