Article Figures & Data
Figures
- FIG 1.
Flow chart for patient selection in the retrospective data. Ambiguous imaging time means the imaging and operation were on the same day. A complete study includes at least one of each of the following: T1-weighted precontrast, T1-weighted postcontrast, T2-weighted, and FLAIR images.
- FIG 2.
Maps of estimated CD for gliomas of known WHO grades. T2-weighted images are shown in the upper row for reference. Note the graphic nature of CD estimates and how CD maps can be used for image-guided therapy.
- FIG 3.
The best CD (in nuclei/square millimeters) measure for dichotomizing survival in adult gliomas is a max CD (stabilized with 0.01-cm3 volume constraint) of 7681 nuclei/mm2. Upper left: Patients with WHO grade IV gliomas have much worse overall survival (median, 497 days) than patients with WHO II or III gliomas (median unreached, 75% survival at 2131 days). Upper right: An optimal cutoff (maximizing hazard ratio) of 7681 nuclei/mm2 divides the glioma population into groups with median survivals of 630 and 5120 days, respectively (log-rank, P < .001). Lower row: A histogram of all cases (bin size = 123 nuclei/mm2) demonstrates stabilized max CD values ranging from 6089 to 12,260 with an interquartile range of 7632–10,717 and a mean of 9175. WHO grade II, III, and IV cases are color-coded, and the optimized cutoff value used in the upper right panel (7681 nuclei/mm2) is shown with a solid red line. The lower histogram has all bins scaled to height 1 to show the relative proportion of each WHO grade in each bin.
- FIG 4.
Upper left: Survival curves stratified by WHO grade. Median survival for WHO grades II, III, and IV: unreached, 3486 days, 497 days, respectively. Upper right: CD thresholds at 7443 and 8358 nuclei separate patients into 3 survival groups that are similar to the WHO II, III, and IV groups (median survival unreached, 3738 days, and 603 days, respectively). There is a significant difference in the red and blue survival curves (log-rank, P = .004). Lower right: P-spline fit (3 degrees of freedom) for nonlinear estimation of the hazard ratio with respect to CD for constant age and KPS. The reference point, hazard ratio 1, is arbitrary. The shaded background corresponds to the three groupings based on CD shown in the upper right panel. Dashed lines are 95% confidence intervals. Relative risk increases with increasing CD up to a max CD of about 9000 nuclei/mm2, after which it plateaus. Max CD allows a continuous estimate of risk, unlike the categoric WHO grade.
Tables
WHO Grade No. Age (yr) Sex (Male/Female) Median KPS Score Median Tumor Volume (mL) Max CD (Nuclei/mm2) Median OS (Days) II 207 40 (SD, 12) 121/86 90 37.16 8059 (SD, 1048) NAb III 246 43 (SD, 14) 135/111 90 47.25 8401 (SD, 1198) 5066 IV 728 59 (SD, 13) 446/282 90 72.64 10,218 (SD, 1167) 495 Univariate Multivariate HR 95% CI P HR 95% CI P Model A: C = 0.761 Age older than 55 yr 3.69 (3.16–4.31) <.001 2.05 (1.74–2 .42) <.001 KPS <90 3.05 (2.61–3.57) <.001 1.68 (1.43–1.98) <.001 WHO grade IV 7.57 (6.18–9.27) <.001 5.25 (4.23–6.53) <.001 Model B: C = 0.734 Age older than 55 yr 3.69 (3.16–4.31) <.001 2.74 (2.33–3.22) <.001 KPS <90 3.05 (2.61–3.57) <.001 2.02 (1.72–2.38) <.001 Max CD >7681 4.21 (3.05–4.42) <.001 2.91 (2.28–3.71) <.001 Model C: C = 0.764 Age >older than 55 yr 3.69 (3.16–4.31) <.001 2.02 (1.72–2.39) <.001 KPS <90 3.05 (2.61–3.57) <.001 1.67 (1.42–1.96) <.001 WHO grade IV 7.57 (6.18–9.27) <.001 4.60 (3.60–5.87) <.001 Max CD >7681 4.21 (3.05–4.42) <.001 1.36 (1.03–1.80) .03 Note:—HR indicates hazard ratio; C, C-index.
↵a The univariate P values for max CD are corrected for multiple comparisons. The multivariate HRs are for models using only the factors listed in the specific panel. A) HRs for clinical factors and high WHO grade. B) HR for clinical factors and max CD (nuclei/square millimeter). C) HR for clinical factors, high WHO grade, and max CD. HRs for WHO grading are higher than those for max CD, but max CD retains a predictive value even when WHO grading is included in model C.
Cellular Density Cutoff Ranges WHO IIMedian OS: NA95% CI, 4040 to NA WHO IIIMedian OS: 5066 95% CI, 3486 to NA WHO IVMedian OS: 49595% CI, 463–538 CD, <7443Median OS: NA95% CI, 4444 to NA 65 69 13 7443 < CD < 8358Median OS: 373895% CI, 2452 to NA 84 80 35 8358 < CDMedian OS: 60395% CI, 535–658 57 97 679 Note:—NA indicates not achieved; OS, overall survival.
↵a The cutoff values for CD were calibrated to separate WHO IV cases from WHO II and III cases and WHO II and III cases from each other using ROC analysis. The off-diagonal values in this matrix speak to the nonredundancy of information captured by CD and WHO grading, respectively.
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