Results of iterative Kaplan-Meier Analysis in each invasiveness cohort.

<p>Number of cells remaining was calculated for each patient, based on their ρ/D and measured residual enhancing disease. Each possible threshold was iterated through to separate the patients into large and small residual tumor cell population cohorts. White boxes correspond to thresholds separating patients into groups with significantly different (p<0.05) survival. White stars indicate tests with no p-value, as the threshold did not separate the patients in the given invasiveness cohort into two groups. Black asterisks indicate tests with p<0.05. Black bins with white x's indicate no the threshold did not separate the patients in the given invasiveness cohort into two groups. For example, for the diffuse case (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099057#pone-0099057-g003" target="_blank">Figure 3</a>, top row), the black bins with white x's represent the fact that even GTR was unable to achieve a remaining cell burden less than the cutoff (up to approximately 10⁹). Further, amongst the most diffuse gliomas, no threshold for a residual cells following resection was found to be significant of outcome represented visually as the lack of a white bar in the top row. Although less dramatic, the moderate cohort was unable to equate a GTR with <10^8.5 cells remaining represented by the black bars with white x's to the left on middle row of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099057#pone-0099057-g003" target="_blank">Figure 3</a>. While resection of tumors in the nodular cohort were able to attain residual disease burdens at all levels down to <10⁷ cells.</p

ρ/D Assessment.

<p>This figure presents an overview of how the “relative invasiveness,” or ρ/D, is obtained. Tumor volumes are segmented from T1Gd and T2 MRI. The measured volume is approximated with a sphere in order to obtain a radius. The T1Gd and T2 radii are associated with different levels of detection, with T2 at low tumor cell density and T1Gd abnormality associated with high tumor cell density. The relationship between these two radii describes the steepness of the tumor cell profile, or “relative invasiveness.”</p

Patient-Specific Simulations of Tumor Cell Distribution and Density for both a Relatively Diffuse and a Relatively Nodular Glioblastoma.

<p>T1Gd and T2 MRIs for two newly diagnosed glioblastoma patients, one relatively diffuse with a low ρ/D (a,c) and one more nodular with a high ρ/D (b,d). A simulation of the diffuse glioma extent predicted by the patient-specific simulation for the diffuse (low ρ/D) patient (e) and the more nodular (high ρ/D) patient (f) is overlayed on the T1Gd MRI with red and blue indicating high and low (but nonzero) glioma cell density, respectively. The effect of GTR is shown as a black region with a white outline and highlights the significant diffuse extent of glioma cells remaining post-GTR. In the more nodular (high ρ/D) case, GTR removes 75% of the pre-treatment glioma cells leaving 8.4e8 cells while in the diffusely invasive (low ρ/D) case, GTR removes only 27% of the pre-treatment glioma cells leaving 4.2e9 cells, an order of magnitude higher than the nodular case. The large number of tumor cells remaining after resection of a diffuse tumor drives recurrence.</p

Clinical Data Table.

<p>Median age and range, distribution of males and females, race (unknown, Caucasian, Asian, Hispanic, Black), median KPS and range, median XRT Dose and range, number of patients diagnosed in the 90's, number of patients diagnosed in 2000 or later, number receiving preoperative steroids, and number of patients who received concurrent Temozolomide with XRT are shown. Proportion chi-square tests were performed to compare steroid administration, concurrent TMZ, and proportion of patients who received GTR vs. STR/Bx between the three invasiveness cohorts. No statistical difference at the P = 0.05 significance level was found in any of these variables between cohorts. ANOVA tests were performed to compare KPS scores, age, and XRT doses between invasiveness cohorts. No difference at the P = 0.05 significance level was found in any of these variables between cohorts.</p><p>* - Indicates no significant difference (p≤0.05) between cohorts in this variable, per Proportion Chi-square test.</p><p>** - Indicates no significant difference (p≤0.05) between cohorts in this variable, per ANOVA test.</p><p>Clinical Data Table.</p