Vivek Bhadri

Recurrent EWSR1 gene rearrangements characterise a select group of bone and soft tissue tumours. In our routine diagnostic practice with fluorescence in situ hybridisation (FISH), we have occasionally observed EWSR1 gene rearrangements in tumours not classically associated with EWSR1 translocations. This study aimed to review our institutional experience of this phenomenon and also to highlight the occurrence of unusual EWSR1 FISH signals (i.e. 5' centromeric region or 3' telomeric region signals) that do not fulfill the published diagnostic criteria for rearrangements. Using an EWSR1 break-apart probe, we performed FISH assays on formalin-fixed paraffin embedded tissue sections from 135 bone and soft tissue specimens as part of their routine diagnostic workup. EWSR1 gene rearrangements were identified in 51% of cases, 56% of which also showed an abnormal FISH signal pattern (in addition to classically rearranged signals). However, atypical FISH signals were present in 45% o...

Ewing sarcoma (EWS) is a malignant tumour of bone and soft tissue, and although many patients are cured with conventional multimodal therapy, those with recurrent or metastatic disease have a poor prognosis. Genomic instability and programmed cell death ligand-1 (PD-L1) expression have been identified in EWS, providing a rationale for treatment with agents that block the programmed cell death-1 (PD-1) receptor. In this report, we describe a heavily pre-treated patient with recurrent metastatic EWS who achieved a clinical and radiological remission with PD-1 blockade. To our knowledge, this is the first reported case demonstrating efficacy of PD-1 blockade in EWS. This warrants further investigation in particular given the poor prognosis in patients with recurrent or metastatic disease.

Glucocorticoids are critical components of combination chemotherapy regimens in pediatric acute lymphoblastic leukemia (ALL). The proapoptotic BIM protein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, whereas the antiapoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2 expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. Microarray analysis showed that KLF13 and MYB gene expression changes were significantly greater in dexamethasone-sensitive than -resistant PDXs. Chromatin immunoprecipitation (ChIP) analysis detected glucocorticoid receptor (GR) binding at the KLF13 promoter to trigger KLF13 expression only in sensitive PDXs. Next, KLF13 bound to the MYB promoter, deactivating MYB expression only in sensitive PDXs. Sustained MYB expres...

Recurrent EWSR1 gene rearrangements characterise a select group of bone and soft tissue tumours. In our routine diagnostic practice with fluorescence in situ hybridisation (FISH), we have occasionally observed EWSR1 gene rearrangements in tumours not classically associated with EWSR1 translocations. This study aimed to review our institutional experience of this phenomenon and also to highlight the occurrence of unusual EWSR1 FISH signals (i.e. 5' centromeric region or 3' telomeric region signals) that do not fulfill the published diagnostic criteria for rearrangements. Using an EWSR1 break-apart probe, we performed FISH assays on formalin-fixed paraffin embedded tissue sections from 135 bone and soft tissue specimens as part of their routine diagnostic workup. EWSR1 gene rearrangements were identified in 51% of cases, 56% of which also showed an abnormal FISH signal pattern (in addition to classically rearranged signals). However, atypical FISH signals were present in 45% o...