RESUMO
Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy (CART) in B-cell non-Hodgkin lymphomas, durable responses are uncommon. The histopathologic and molecular features associated with treatment failure are still largely unknown. Therefore, we have analyzed 19 sequential tumor samples from 9 patients, prior anti-CD19 CART (pre-CART) and at relapse (post-CART), using immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, next-generation DNA and RNA sequencing, and genome-scale DNA methylation. The initial diagnosis was diffuse large B-cell lymphoma (n=6), double-hit high-grade B-cell lymphoma (n=1), and Burkitt lymphoma (n=2). Histopathologic features were mostly retained at relapse in 7/9 patients, except the frequent loss of 1 or several B-cell markers. The remaining 2 cases (1 diffuse large B-cell lymphoma and 1 Burkitt lymphoma) displayed a dramatic phenotypic shift in post-CART tumors, with the drastic downfall of B-cell markers and emergence of T-cell or histiocytic markers, despite the persistence of identical clonal immunoglobulin gene rearrangements. The post-CART tumor with aberrant T-cell phenotype showed reduced mRNA expression of most B-cell genes with increased methylation of their promoter. Fluorescence in situ hybridization and comparative genomic hybridization showed global stability of chromosomal alterations in all paired samples, including 17p/TP53 deletions. New pathogenic variants acquired in post-CART samples included mutations triggering the PI3K pathway (PIK3R1, PIK3R2, PIK3C2G) or associated with tumor aggressiveness (KRAS, INPP4B, SF3B1, SYNE1, TBL1XR1). These results indicate that CART-resistant B-cell non-Hodgkin lymphomas display genetic remodeling, which may result in profound dysregulation of B-cell differentiation. Acquired mutations in the PI3K and KRAS pathways suggest that some targeted therapies could be useful to overcome CART resistance.
Assuntos
Linfoma de Burkitt , Linfoma Difuso de Grandes Células B , Transdiferenciação Celular , Hibridização Genômica Comparativa , Genômica , Humanos , Imunoterapia Adotiva/métodos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genéticaAssuntos
Leucemia Mieloide/complicações , Mucormicose/etiologia , Antifúngicos/uso terapêutico , Feminino , Humanos , Leucemia Mieloide/diagnóstico por imagem , Pessoa de Meia-Idade , Mucormicose/diagnóstico , Mucormicose/diagnóstico por imagem , Nitrilas/uso terapêutico , Infecções Oportunistas/complicações , Infecções Oportunistas/tratamento farmacológico , Piridinas/uso terapêutico , Insuficiência Respiratória/diagnóstico por imagem , Insuficiência Respiratória/etiologia , Choque Séptico/diagnóstico por imagem , Choque Séptico/etiologia , Tomografia Computadorizada por Raios X/métodos , Triazóis/uso terapêuticoRESUMO
Simple mucinous cyst of the pancreas is an unusual pancreatic cyst, first described by Kosmahl et al. in 2002 with 5 cases. We describe a case of simple mucinous cyst of the pancreas, followed by a literature review. The physiopathology of this cyst is still unclear. It is an epithelial cyst, presenting as unilocular cystic lesion of the pancreatic body or tail, with a clear content, and no communication with the pancreatic duct. Microscopically, the cyst is lined by mucin-producing cells with mild atypia, and contains a fibrous wall without ovarian-like stroma. The prognosis is excellent, as no recurrent disease and progression to malignancy have been described. The non neoplastic origin of this lesion is debated, as cases with KRAS mutation and intra-epithelial neoplastic lesions have been recently reported. It is important to distinguish this lesion from macrocystic serous cystadenoma, mucinous cystic neoplasms and intraductal papillary mucinous neoplasms, by clinical, radiological and pathological features, as the treatment varies from simple surveillance to surgical resection.
Assuntos
Cisto Pancreático/patologia , Idoso , Cistadenoma Seroso/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Imageamento por Ressonância Magnética , Mucinas/análise , Cisto Pancreático/diagnóstico , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/diagnóstico , Pseudocisto Pancreático/diagnóstico , PrognósticoAssuntos
Adenocarcinoma/diagnóstico , Neoplasias do Colo/diagnóstico , Tumor de Células Granulares/diagnóstico , Neoplasias do Íleo/diagnóstico , Valva Ileocecal/patologia , Adenocarcinoma/complicações , Adenocarcinoma/cirurgia , Criança , Colectomia , Neoplasias do Colo/complicações , Neoplasias do Colo/cirurgia , Feminino , Tumor de Células Granulares/complicações , Tumor de Células Granulares/patologia , Humanos , Neoplasias do Íleo/complicações , Neoplasias do Íleo/patologia , Achados Incidentais , Doenças Inflamatórias Intestinais/complicações , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
The synthesis and photo-physical properties of an original bis-pyridinylpyrazine chromophore efficiently sensitising europium(III) and samarium(III) are described. The corresponding lanthanide(III) complexes display in aqueous solutions a maximum excitation wavelength which is significantly red-shifted compared to the usual terpyridine-based chelates, and a valuable luminescence brightness above 2,000 dm(3) mol(-1) cm(-1) at 345 nm was obtained with a europium(III) derivative. Further functionalisation with three different bioconjugatable handles was also investigated and their ability to efficiently label a model hexapeptide was evaluated and compared. Finally, the best bioconjugatable europium(III) chelate was used in representative labelling experiments involving monoclonal antibodies and the luminescence features of the corresponding bioconjugates remained satisfactory.