PMC5871816_01
a Initial scan presenting axial T2 FLAIR image of the central tumor. Heterogenous, 5.1 x 3.8 x 3.4 cm ovoid mass with involvement of the left thalamus and internal capsule. Left lateral ventricle is distorted with displacement of the septum pellucidum and third ventricle. b Three-month follow-up axial T2 FLAIR image of central tumor status post treatment with chemotherapy. Concerning for tumor growth. c H&E-stained paraffin-embedded section showing moderately cellular glial neoplasm composed of relatively monomorphic round cells with clear cytoplasm and distinct cell borders (arrow), as well as arborizing capillaries (arrow heads). d From the same section as c showing calcospherites (arrow heads). e Fusion of FGFR3 with PHGDH. Top panel represents wildtype FGFR3. All exons are represented by blue or red squares while domains are represented by the gray bar (SP=signal peptide, Ig=immunoglobulin-like domain, AB=acid box, TM=transmembrane domain, TK=tyrosine kinase domain). The middle panel represents wildtype PHGDH (SB=substrate-binding domain, NAD(P)=NAD+/NADP+-binding domain, RD=regulatory domain). The lower panel represents the FGFT3-PHGDH fusion. Fusion occurs intracellularly, at the 3' end of the FGFR3. FGFR3 exons 1~17 (p.D760) fused in-frame to PHGDH exons 9~12 (p.V316). The extracellular, transmembrane, and kinase domain for FGFR3 are all intact. Standard FGF inhibitors like ponatinib should theoretically work against this fusion assuming they have sufficient ability to cross the BBB. f Copy number profile of FGFR3-PHGDH fusion
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Fig1
Peripheral edema extended to the left caudate, bilateral hypothalami, bilateral temporal cortices, and right thalamus (Fig. 1a). ACNS0831 and underwent multi-agent induction chemotherapy with carboplatin, vincristine, cyclophosphamide, and etoposide. A follow-up MRI 3 months later showed interval progression in the size of the thalamic tumor (Fig. 1b). Pathology showed fragments of densely cellular glial neoplasm composed of relatively uniform, regularly distributed, ovoid cells with round, centrally located nuclei, stippled chromatin, and clear-to-eosinophilic cytoplasm (Fig. 1c). No necrosis was seen (Fig. 1d). The fusion occurs at the very 3' end of FGFR3, with the extracellular domain, transmembrane domain and kinase domains intact (Fig. 1e, f). Sequencing also revealed homozygous deletion of cyclin-dependent kinase (CDK) 11A and CDK11B, as well as a number of other copy gains and copy losses (Fig. 1f).
Axial T2 FLAIR image of the thalamic tumor pre-radiation (left), post-radiation (November 2016, center) and after two cycles of ponatinib (March 2017, right). Dimensions of the post-radiation tumor are 45.6 mm x 28.6 mm x 35.0 mm compared to 40.3 mm x 26.6 mm 36.0 mm after two cycles on ponatinib. This represents a 15% reduction in volume
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Fig2
After two cycles, the patient had demonstrated a partial response (15% reduction compared to initial post-radiation scans, Fig. 2).