Resistance of B-Cell Lymphomas to CAR T-Cell Therapy Is Associated With Genomic Tumor Changes Which Can Result in Transdifferentiation.

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.

[Simple mucinous cyst of the pancreas: Case-report and literature review]. / Kyste mucineux simple du pancréas : description d'un cas et revue de la littérature.

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.

Synthesis and luminescence properties of new red-shifted absorption lanthanide(III) chelates suitable for peptide and protein labelling.

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.

Postsynthetic derivatization of fluorophores with alpha-sulfo-beta-alanine dipeptide linker. Application to the preparation of water-soluble cyanine and rhodamine dyes.

A straightforward method to enhance water solubility of fluorescent organic dyes (cyanines and rhodamines) by a postsynthetic chemical derivatization of their carboxylic acid functionality with an original disulfonated heterobifunctional linker is described. Significant water solubility enhancement is achieved without compromising either the photophysical properties (especially large molar extinction coefficients and high quantum yields) or bioconjugation efficiency of the parent non-water-soluble fluorophores. The results both demonstrate the strong potential of these new compounds as fluorescent labels for a broad range of biotechnology and biomedical applications and illustrate the utility of such an easy-to-handle water-solubizing group.