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Research ArticleAdult Brain
Open Access

Radio-Pathomic Maps of Cell Density Identify Brain Tumor Invasion beyond Traditional MRI-Defined Margins

S.A. Bobholz, A.K. Lowman, M. Brehler, F. Kyereme, S.R. Duenweg, J. Sherman, S.D. McGarry, E.J. Cochran, J. Connelly, W.M. Mueller, M. Agarwal, A. Banerjee and P.S. LaViolette
American Journal of Neuroradiology May 2022, 43 (5) 682-688; DOI: https://doi.org/10.3174/ajnr.A7477
S.A. Bobholz
aFrom the Departments of Biophysics (S.A.B., S.R.D., J.S., S.D.M.)
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A.K. Lowman
bRadiology (A.L., M.B., M.A., P.S.L.)
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M. Brehler
bRadiology (A.L., M.B., M.A., P.S.L.)
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F. Kyereme
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S.R. Duenweg
aFrom the Departments of Biophysics (S.A.B., S.R.D., J.S., S.D.M.)
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J. Sherman
aFrom the Departments of Biophysics (S.A.B., S.R.D., J.S., S.D.M.)
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S.D. McGarry
aFrom the Departments of Biophysics (S.A.B., S.R.D., J.S., S.D.M.)
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E.J. Cochran
cPathology (E.J.C.)
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J. Connelly
dNeurology (J.C.)
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W.M. Mueller
eNeurosurgery (W.M.M.)
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M. Agarwal
bRadiology (A.L., M.B., M.A., P.S.L.)
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A. Banerjee
fBiostatistics (A.B.)
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P.S. LaViolette
bRadiology (A.L., M.B., M.A., P.S.L.)
gBiomedical Engineering (P.S.L.), Medical College of Wisconsin, Milwaukee, Wisconsin
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  • FIG 1.
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    FIG 1.

    Overview of the data-collection process. A, MR imaging data are collected from the patient’s final imaging session before death and coregistered, and T1, T1C, and FLAIR images are intensity-normalized. Tissue fixation and sampling involve the use of 3D printed brain cages and slicing jigs to preserve structural integrity relative to the MR imaging. Following staining, tissue samples are digitized for cellularity calculation using an automated nuclei segmentation algorithm. B, In-house software is used to align each tissue sample to the FLAIR image using manually defined control points and ROIs. C, Single-image cellularity associations are computed using mixed-effects models, and a bagging regression ensemble is trained to predict cellularity using 5 × 5 voxel tiles from each image using a two-thirds to one-third train-test split.

  • FIG 2.
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    FIG 2.

    Single-image results depicting the relationship between image intensity and cellularity for each contrast. β values for the left-handed plots indicate the change in cellularity per SD increase in image intensity and indicate positive associations for T1, T1C, and FLAIR, with the expected negative association between ADC and cellularity present. β values for the right-handed plots indicate the difference in slope among patients with GBM and NGG and Other patients, indicating that patients with GBM show less pronounced cellularity associations than patients with NGG across all image types, with the exception of T1 intensity.

  • FIG 3.
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    FIG 3.

    A, Subject-level RMSE values for the training and test data sets. Despite some degree of overfitting, the test set RMSE indicates that the radio-pathomic model is able to accurately predict cellularity across most subjects. B, Sample predictions for test set imaging values presented in terms of their T1SUB, FLAIR, and ADC intensity values. Patterns suggest the presence of traditional imaging signatures but also indicate the lack of specificity for these signatures with regard to hypercellularity. TISUB indicates T1C–T1.

  • FIG 4.
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    FIG 4.

    Sample predictions for 3 representative subjects, including a 43-year-old man diagnosed with a grade III anaplastic astrocytoma (A), a 48-year-old man diagnosed with a GBM (B), and a 31-year-old woman diagnosed with a grade III anaplastic astrocytoma (C). These predictions indicate that the radio-pathomic model is able to predict regions of hypercellularity beyond the contrast-enhancing region as well as in the absence of restricted diffusion on the ADC image.

  • FIG 5.
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    FIG 5.

    IHC staining for a nonenhancing region of predicted hypercellularity outside of contrast enhancement (a 64-year-old man diagnosed with GBM). The ROI corresponds to an actual region of hypercellularity seen on H&E staining as well as portions of high MIB-1 index and CD31 positivity. These molecular features indicate that this CPM-identified region contains active, proliferating tumor beyond the contrast-enhancing region. CPM indicates cellularity prediction map.

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    Table 1:

    Clinical and demographic summary for study samplea

    OverallGBMNGGOther
    No. of subjects4432102
    Age (yr)60.2 (13.7)62.4 (11.6)50.3 (15.3)75.5 (13.4)
    Overall survival (mo)40.4 (61.5)35.3 (64.9)64.3 (46.1)2.0 (0)
    Radiation treatment (y/n)39/529/310/00/2
    Chemotherapy (y/n)40/430/210/00/2
    Tumor-treating fields (y/n)28/1616/160/100/2
    Other treatment (y/n)7/375/272/80/2
    Time between last MR imaging and death (days)63.0 (62.1)49.6 (42.3)111.8 (93.1)33.0 (13.4)
    • Note:—Y/n indicates yes/no.

    • ↵a Quantitative values are presented as mean (SD).

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    Table 2:

    Clinical and demographic summary for training and test set groupsa

    TrainingTest
    Diagnosis (GBM/NGG/Other)24/4/18/6/1
    Age (yr)62.5 (12.9)55.8 (14.5)
    Overall survival (mo)39.9 (69.5)41.3 (44.9)
    Radiation treatment (y/n)25/414/1
    Chemotherapy (y/n)26/314/1
    Tumor-treating fields (y/n)12/174/11
    Other treatment (y/n)3/264/11
    Time between last MR imaging and death (days)46.2 (39.2)95.5 (83.9)
    • Note:—Y/n indicates yes/no.

    • ↵a Quantitative values are presented as mean (SD).

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American Journal of Neuroradiology: 43 (5)
American Journal of Neuroradiology
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1 May 2022
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Cite this article
S.A. Bobholz, A.K. Lowman, M. Brehler, F. Kyereme, S.R. Duenweg, J. Sherman, S.D. McGarry, E.J. Cochran, J. Connelly, W.M. Mueller, M. Agarwal, A. Banerjee, P.S. LaViolette
Radio-Pathomic Maps of Cell Density Identify Brain Tumor Invasion beyond Traditional MRI-Defined Margins
American Journal of Neuroradiology May 2022, 43 (5) 682-688; DOI: 10.3174/ajnr.A7477

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Radio-Pathomic Maps of Cell Density Identify Brain Tumor Invasion beyond Traditional MRI-Defined Margins
S.A. Bobholz, A.K. Lowman, M. Brehler, F. Kyereme, S.R. Duenweg, J. Sherman, S.D. McGarry, E.J. Cochran, J. Connelly, W.M. Mueller, M. Agarwal, A. Banerjee, P.S. LaViolette
American Journal of Neuroradiology May 2022, 43 (5) 682-688; DOI: 10.3174/ajnr.A7477
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