## 4 Discussion
### Clinical Prognosis Based on Tractography-Derived Metrics  
In the historical cohort from MDACC, we individually observed and documented the regional overlap of observed tumor-specific tractograms with known white matter bundles of anatomic significance (Table 2). From an analysis of patient outcomes, tumors which occupied the corpus callosum had significantly worse outcomes than those who did not (\(p<0.001\)), while those who had tumors located elsewhere but with tractography crossing over to the opposite hemisphere also demonstrated a trend towards worse outcomes (\(p=0.09\)). This is consistent with the prior literature noting corpus callosum involvement as a poor prognostic indicator in glioblastoma [58; 59; 60]. Similarly, patients whose tractography overlapped with the inferior longitudinal fasciculus and/or inferior frontal-occipital fasciculus had a worse prognosis (\(p=0.008\)). These results lend support to the idea that the specific tract impacted by the tumor, depending on its location of origin, may matter for patient outcomes, as has been reported previously [39]. This may be due to location-related functional impairments, or perhaps because cell invasiveness is more efficient in or along prominent axon bundles due to interactivity with resident normal cells [19; 20]. Furthermore, metrics including a longer mean tract length and longer projecting tract length were also associated with shorter overall survival. More extensive tumor cell invasion, or greater opportunity for wide-spread invasion through the presence of more (or longer) white matter bundles intersecting the tumor, may be associated with earlier progression of disease. While progression free survival was not separately tracked as an outcome in this study, earlier progression may itself lead to shorter overall survival, explaining the observed results. Future investigation of disease progression and recurrence patterns relative to pre-operative diffusion tractography would provide additional information useful for understanding this relationship. Other investigations of post-processed tractograms generated from dwMRI sequences have recently been published, lending support to the notion that tumor-associated tractography may be associated with tumor cell migration [39; 40; 42]. In particular, [PERSON] et al. presented an FA-derived composite white-matter score which showed prognostic significance in MGMT-unmethylated glioblastoma [39] and [PERSON] et al. examined the core-shell ratio (length of tracts within the \"necrotic core\" of the tumor compared to the length of the tracts which circumscribe the mass at its visible margin) [40]. Of note, [PERSON] et al. carried out their study using the same MDACC cohort combined with a small number of cases available through the Cancer Genome Atlas, and found that a higher core-shell ratio was correlated with poorer overall survival. Motivated by the hypothesis that more extensive tumor-associated tractograms may be associated with the long-distance migration of glioblastoma cells, the present study focused on the quantification of features which account for tracts reaching beyond the tumor margin inferred from routine neuroimaging in addition to conventional intra-tumoral dwMRI metrics (e.g., MD, FA) [37; 61; 62]. While mean (total) tract length captures all core, shell, and projecting tracts generated through the tracking algorithm, the mean projecting tract length captures only tracts manually selected as projecting away from the \"shell\" of the tumor upon the analysis of processed tractograms. Longer tract length, in terms of both metrics, was significantly associated with poorer overall survival (Figure 3). Additional meaningful prognostic metrics could also perhaps be uncovered if diffusion parameters were systematically varied to optimize ability to distinguish between tissue structures expressed at varying spatial scales [63; 64; 65; 66].