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Research ArticleBrain Tumor Imaging

Quantification of T2-FLAIR Mismatch in Nonenhancing Diffuse Gliomas Using Digital Subtraction

Nicholas S. Cho, Francesco Sanvito, Viên Lam Le, Sonoko Oshima, Ashley Teraishi, Jingwen Yao, Donatello Telesca, Catalina Raymond, Whitney B. Pope, Phioanh L. Nghiemphu, Albert Lai, Timothy F. Cloughesy, Noriko Salamon and Benjamin M. Ellingson
American Journal of Neuroradiology February 2024, 45 (2) 188-197; DOI: https://doi.org/10.3174/ajnr.A8094
Nicholas S. Cho
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
cDepartment of Bioengineering (N.S.C., V.L.L., B.M.E.), Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California
dMedical Scientist Training Program (N.S.C.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Francesco Sanvito
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Viên Lam Le
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
cDepartment of Bioengineering (N.S.C., V.L.L., B.M.E.), Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California
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Sonoko Oshima
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Ashley Teraishi
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Jingwen Yao
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Donatello Telesca
eDepartment of Biostatistics (D.T.), Fielding School of Public Health, University of California Los Angeles, Los Angeles, California
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Catalina Raymond
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Whitney B. Pope
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Phioanh L. Nghiemphu
fUCLA Neuro-Oncology Program (P.L.N., A.L., T.F.C.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
gDepartment of Neurology (P.L.N., A.L., T.F.C.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Albert Lai
fUCLA Neuro-Oncology Program (P.L.N., A.L., T.F.C.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
gDepartment of Neurology (P.L.N., A.L., T.F.C.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Timothy F. Cloughesy
fUCLA Neuro-Oncology Program (P.L.N., A.L., T.F.C.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
gDepartment of Neurology (P.L.N., A.L., T.F.C.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Noriko Salamon
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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Benjamin M. Ellingson
aFrom the UCLA Brain Tumor Imaging Laboratory (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., B.M.E.), Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, Los Angeles, California
bDepartment of Radiological Sciences (N.S.C., F.S., V.L.L., S.O., A.T., J.Y., C.R., W.B.P., N.S., B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
cDepartment of Bioengineering (N.S.C., V.L.L., B.M.E.), Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, California
hDepartment of Neurosurgery (B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
iDepartment of Psychiatry and Biobehavioral Sciences (B.M.E.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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  • FIG 1.
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    FIG 1.

    Representative true-positive and true-negative typical cases with T2-FLAIR subtraction maps and tumor segmentations. A, Patient A is a 38-year-old woman from the TCIA cohort diagnosed with a grade 2 IDHm-A demonstrating 59.6% T2-FLAIR mismatch volume (true-positive result). B, Patient B is a 23-year-old man from the institutional cohort diagnosed with grade 2 IDHm-A demonstrating 48.0% T2-FLAIR mismatch volume (true-positive result). C, Patient C is a 35-year-old woman from the TCIA cohort diagnosed with grade 2 IDHm-O demonstrating heterogeneous T2-weighted and T2-weighted FLAIR hyperintensity and no T2-FLAIR mismatch on the subtraction map (true-negative result). D, Patient D is a 59-year-old woman from the institutional cohort diagnosed with grade 4 IDHwt glioblastoma. The relative hypointense central T2-weighted FLAIR signal with a peripheral hyperintense rim may mimic a T2FM sign at first glance, but the corresponding absence of T2FM on the subtraction map from the heterogeneous T2-weighted hyperintensity clearly shows the lack of T2FM (true-negative result). Corresponding tumor segmentation VOIs of T2FM (pink) and T2FNM (green) subregions (A–D) as well as the T2FNM subregion external borders encoded with thickness (A/C) are shown. INST indicates institutional.

  • FIG 2.
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    FIG 2.

    Representative false-negative and false-positive cases with T2-FLAIR subtraction maps and tumor segmentations. A, Patient A is a 38-year-old man from the TCIA cohort diagnosed with grade 2 IDHm-A with no T2-FLAIR mismatch on the subtraction map (false-negative result). B, Patient B is a 36-year-old woman from the institutional cohort diagnosed with grade 2 IDHm-A with no T2-FLAIR mismatch on the subtraction map excluding the cystic portion (false-negative result). C, Patient C is a 45-year-old man from the TCIA cohort diagnosed with grade 2 IDHm-O demonstrating 35.0% T2FM volume, which was assessed as a false-positive for the T2FM sign by 1 reader using subtraction maps (false-positive result). D, Patient D is a 35-year-old woman diagnosed with IDHwt glioblastoma demonstrating 12.5% T2FM volume, which was assessed as a false-positive for the T2-FLAIR mismatch sign by both readers using subtraction maps. Corresponding tumor-segmentation VOIs of T2FM (pink) and T2FNM (green) subregions are shown (A–D) (false-positive result).

  • FIG 3.
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    FIG 3.

    Tumor percentage of T2FM volume and diagnostic performance for IDHm-A classification. Results are shown for both the TCIA cohort (A and B) and the institutional cohort (C and D). IDHm-A had a higher percentage T2FM volume (% T2FM volume) compared with the other molecular signatures (A and C). ROC curves show that a specificity of 100% for the IDHm-A diagnosis could be achieved with a threshold of ≥42% T2FM volume in both cohorts (B and D), though in the validation cohort, a threshold of ≥25% T2FM volume sufficed (D). The summary results when pooling the 2 cohorts are also shown (E and F). INST indicates institutional; Spec, specificity; Sens, sensitivity; *, P < .05; ***, P < .001; ****, P < .0001.

  • FIG 4.
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    FIG 4.

    T2FNM thickness, tumor grade, and tumor volume relationships based on tumor percentage T2FM volume. In both cohorts, tumor percentage T2FM volume (% T2FM volume) was significantly negatively correlated with T2FNM subregion thickness (A and C, P < .0001). Grade 3–4 IDHm-A had significantly higher percentage T2FM volume compared to grade 2 IDHm-A (B, TCIA, P = .008; E, institutional, P = .03), and tumor volumes were significantly greater in ≥15% T2FM volume IDHm-A compared with <15% T2FM volume IDHm-A (C, TCIA, P = .01; F, institutional, P = .04). INST indicates institutional; *, P < .05, **, P < .01.

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    Table 1:

    Patient data

    CharacteristicTCIA Cohort (n = 70 Patients with n = 71 Lesions)Institutional Cohort (n = 34 Patients/Lesions)
    Age (mean) (range)43 (22–78)42 (22–79)
    Sex: male/female41/2918/16
    Diagnosis (No.) (%)
    IDHm-A46 (64.8%)19 (55.9%)
      Grade 23311
      Grade 3137
      Grade 401
    IDHm-O9 (12.7%)9 (26.5%)
     Grade 298
     Grade 301
    IDHwt glioma16 (22.5%)6 (17.6%)
    • View popup
    Table 2:

    Reader study results of T2FM sign: Sensitivity and specificity

    Classification Definition/ReaderWith Subtraction MapSensitivity (95% CI)Specificity (95% CI)
    Patel et al6
     Reader 1No35.4 (23.9–48.2)97.5 (86.8–99.9)
    Yes36.9 (25.3–49.8)92.5 (79.6–98.4)
     Reader 2No30.8 (19.9–43.5)92.5 (79.6–98.4)
    Yes38.5 (26.7–51.4)92.5 (79.6–98.4)
    Lasocki et al8
     Reader 1No50.8 (38.1–63.4)90.0 (76.3–97.2)
    Yes55.4 (42.5–67.7)85.0 (70.2–94.3)
     Reader 2No41.5 (29.4–54.4)92.5 (79.6–98.4)
    Yes49.2 (36.6–61.9)92.5 (79.6–98.4)
    • View popup
    Table 3:

    Reader study results of T2FM sign: Interreader agreement

    Classification Definition/with Subtraction MapCohen κ (95% CI)
    Patel et al6
     No0.70 (0.53–0.87)
     Yes0.78 (0.64–0.92)
    Lasocki et al8
     No0.76 (0.63–0.89)
     Yes0.78 (0.65–0.90)
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Cite this article
Nicholas S. Cho, Francesco Sanvito, Viên Lam Le, Sonoko Oshima, Ashley Teraishi, Jingwen Yao, Donatello Telesca, Catalina Raymond, Whitney B. Pope, Phioanh L. Nghiemphu, Albert Lai, Timothy F. Cloughesy, Noriko Salamon, Benjamin M. Ellingson
Quantification of T2-FLAIR Mismatch in Nonenhancing Diffuse Gliomas Using Digital Subtraction
American Journal of Neuroradiology Feb 2024, 45 (2) 188-197; DOI: 10.3174/ajnr.A8094

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Quantifying T2-FLAIR Mismatch in Diffuse Gliomas
Nicholas S. Cho, Francesco Sanvito, Viên Lam Le, Sonoko Oshima, Ashley Teraishi, Jingwen Yao, Donatello Telesca, Catalina Raymond, Whitney B. Pope, Phioanh L. Nghiemphu, Albert Lai, Timothy F. Cloughesy, Noriko Salamon, Benjamin M. Ellingson
American Journal of Neuroradiology Feb 2024, 45 (2) 188-197; DOI: 10.3174/ajnr.A8094
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