Purpose
Oncogenic fusions consisting of FGFR and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency, molecular features of FGFR-TACC fusions, and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade-II–III glioma.
Experimental Design
Overall, 795 gliomas (584 GBM, 85 grade-II–III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response.
Results
Three of 85 IDH1/2 wild type (3.5%) but none of 126 IDH1/2 mutant grade-II–III glioma harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification whereas co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively.
Conclusions
RT-PCR-sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intra-tumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with a FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.
Lesions of the brain, meninges, facial bones, and orbits are frequently observed and should be systematically sought on the brain MR and CT images obtained in patients with ECD, even if these patients are asymptomatic. Careful attention should be directed to the periarterial environment.
Our study improved the description of an unclassified, clinico-radiologic entity, which could be described by the proposed acronym: TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome.
Objectives
To assess the influence of gray-level discretization on inter- and intra-observer reproducibility of texture radiomics features on clinical MR images.
Materials and methods
We studied two independent MRI datasets of 74 lacrymal gland tumors and 30 breast lesions from two different centers. Two pairs of readers performed three two-dimensional delineations for each dataset. Texture features were extracted using two radiomics softwares (Pyradiomics and an in-house software). Reproducible features were selected using a combination of intra-class correlation coefficient (ICC) and concordance and coherence coefficient (CCC) with 0.8 and 0.9 as thresholds, respectively. We tested six absolute and eight relative gray-level discretization methods and analyzed the distribution and highest number of reproducible features obtained for each discretization. We also analyzed the number of reproducible features extracted from computer simulated delineations representative of inter-observer variability.
Results
The gray-level discretization method had a direct impact on texture feature reproducibility, independent of observers, software or method of delineation (simulated vs. human). The absolute discretization consistently provided statistically significantly more reproducible features than the relative discretization. Varying the bin number of relative discretization led to statistically significantly more variable results than varying the bin size of absolute discretization.
Conclusions
When considering inter-observer reproducible results of MRI texture radiomics features, an absolute discretization should be favored to allow the extraction of the highest number of potential candidates for new imaging biomarkers. Whichever the chosen method, it should be systematically documented to allow replicability of results.
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