المؤلفون: Girolami, Ilaria, Mancini, Irene, Simoni, Antonella, Baldi, Giacomo Giulio, Simi, Lisa, Campanacci, Domenico, Beltrami, Giovanni, Scoccianti, Guido, D'Arienzo, Antonio, CAPANNA, RODOLFO, FRANCHI, ALESSANDRO

المساهمون: Girolami, Ilaria, Mancini, Irene, Simoni, Antonella, Baldi, Giacomo Giulio, Simi, Lisa, Campanacci, Domenico, Beltrami, Giovanni, Scoccianti, Guido, D'Arienzo, Antonio, Capanna, Rodolfo, Franchi, Alessandro

مصطلحات موضوعية: BONE TUMOURS, CANCER GENETICS, IMMUNOCYTOCHEMISTRY, Adolescent, Adult, Aged, Angiogenesis Inhibitor, Bone Density Conservation Agent, Bone Neoplasm, Cell Proliferation, Core Binding Factor Alpha 1 Subunit, Denosumab, Female, Giant Cell Tumor of Bone, Histone, Human, Male, Matrix Attachment Region Binding Protein, Middle Aged, Mutation, Neovascularization, Pathologic, Predictive Value of Test, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Transcription Factor, Treatment Outcome, Young Adult, Biomarkers, Tumor

الوقت: 2734

الوصف: Aims: Denosumab, a fully human monoclonal antibody directed against RANKL, has recently been introduced in the treatment strategy of giant cell tumour of bone (GCTB). Aim of this study was to investigate the phenotypical modifications induced by denosumab treatment in a series of 15 GCTB. Methods: The tumours were characterised for histone 3.3 mutations, and studied immunohistochemically for the modifications of RANKL, RANK, SATB2 and RUNX2 expression, as well as of tumour proliferative activity and angiogenesis. Results: Nine of 11 tumours investigated presented a histone 3.3 mutation in H3F3A, and 2 of these for which the analysis was carried out in pretreatment and post-treatment specimens showed the same mutation in both. Denosumab induced the disappearance of osteoclast-like giant cells, leaving residual spindle neoplastic cells arranged in a storiform pattern, with deposition of trabecular collagen matrix and osteoid, which tended to maturation in the peripheral portions of the lesion. RANK and RANKL expression was variable, with no significant variation after treatment. Moreover, we did not observe any significant modification of the expression of the osteoblastic markers SATB2 and RUNX2. Denosumab treatment determined a significant reduction of the proliferative index and of tumour angiogenesis (p=0.001, Wilcoxon rank-sum test). Conclusions: These results indicate that denosumab induces a partial maturation towards the osteoblastic phenotype of the neoplastic cells of GCTB, with production of fibrous and osteoid matrix, but with minor immunophenotypical changes. Finally, we first report an antiangiogenic activity of denosumab in GCTB, possibly mediated by a RANKL-dependent pathway.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/26338802; info:eu-repo/semantics/altIdentifier/wos/WOS:000370829100008; volume:69; issue:3; firstpage:240; lastpage:247; numberofpages:8; journal:JOURNAL OF CLINICAL PATHOLOGY; http://hdl.handle.net/11568/804508Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84959345838; https://jcp.bmj.com/content/69/3/240lTest

الإتاحة: https://doi.org/10.1136/jclinpath-2015-203248Test
http://hdl.handle.net/11568/804508Test
https://jcp.bmj.com/content/69/3/240lTest

المؤلفون: PETRINI, IACOPO, Meltzer, P. S., Zucali, P. A., Luo, J., Lee, C., Santoro, A., Lee, H. S., Killian, K. J., Wang, Y., Tsokos, M., Roncalli, M., Steinberg, S. M., Giaccone, G.

المساهمون: Petrini, Iacopo, Meltzer, P. S., Zucali, P. A., Luo, J., Lee, C., Santoro, A., Lee, H. S., Killian, K. J., Wang, Y., Tsokos, M., Roncalli, M., Steinberg, S. M., Giaccone, G.

مصطلحات موضوعية: BCL2 anti-apoptotic family member, CDKN2A, comparative genomic hybridization, target therapy, thymic epithelial tumor, Adult, Aged, 80 and over, Algorithm, Aniline Compound, Animal, Apoptosis Regulatory Protein, Autophagy, Benzenesulfonate, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variation, Female, Human, Male, Mice, Nude, Middle Aged, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Glandular and Epithelial, Niacinamide

الوصف: The molecular pathology of thymic epithelial tumors (TETs) is largely unknown. Using array comparative genomic hybridization (CGH), we evaluated 59 TETs and identified recurrent patterns of copy number (CN) aberrations in different histotypes. GISTIC algorithm revealed the presence of 126 significant peaks of CN aberration, which included 13 cancer-related genes. Among these peaks, CN gain of BCL2 and CN loss of CDKN2A/B were the only genes in the respective regions of CN aberration and were associated with poor outcome. TET cell lines were sensitive to siRNA knockdown of the anti-apoptotic molecules BCL2 and MCL1. Gx15-070, a pan-BCL2 inhibitor, induced autophagy-dependent necroptosis in TET cells via a mechanism involving mTOR pathways, and inhibited TET xenograft growth. ABT263, an inhibitor of BCL2/BCL-XL/BCL-W, reduced proliferation in TET cells when administered in combination with sorafenib, a tyrosine kinase inhibitor able to downregulate MCL1. Immunohistochemistry on 132 TETs demonstrated that CN loss of CDKN2A correlated with lack of expression of its related protein p16(INK4) and identified tumors with poor prognosis. The molecular markers BCL2 and CDKN2A may be of potential value in diagnosis and prognosis of TETs. Our study provides the first preclinical evidence that deregulated anti-apoptotic BCL2 family proteins may represent suitable targets for TET treatment.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/22825469; info:eu-repo/semantics/altIdentifier/wos/WOS:000306786400014; volume:3; issue:7; firstpage:e351; journal:CELL DEATH & DISEASE; http://hdl.handle.net/11568/757337Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84864882707

الإتاحة: https://doi.org/10.1038/cddis.2012.92Test
http://hdl.handle.net/11568/757337Test