Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum

Abstract

Background The clinical effect of radiographic contact of glioblastoma (GBM) with neurogenic zones (NZ)—the ventricular-subventricular (VSVZ) and subgranular (SGZ) zones—and the corpus callosum (CC) remains unclear and, in the case of the SGZ, unexplored. We investigated 1) if GBM contact with a NZ correlates with decreased survival; 2) if so, whether this effect is associated with a specific NZ; and 3) if radiographic contact or invasion by GBM of the CC, the largest identifiable white matter tract, is associated with decreased survival. Methods We retrospectively identified 207 adult patients who underwent cytoreductive surgery for GBM followed by chemotherapy and/or radiation. Age, preoperative Karnofsky performance status score (KPS), and extent of resection were recorded. Preoperative MRIs were blindly analyzed to calculate tumor volume and contact with VSVZ, SGZ, CC, and cortex. Overall (OS) and progression free (PFS) survivals were calculated and analyzed with multivariate Cox analyses. Results Among 207 patients, 111 had GBM contacting VSVZ (VSVZ+GBMs), 23 SGZ+GBMs, 52 CC+GBMs, and 164 cortex+GBMs. VSVZ+, SGZ+, and CC+ GBMs had significantly larger volume relative to non-contacting controls. In addition to age, KPS, gross total resection, chemotherapy, and radiation, multivariate Cox survival analyses revealed contact with VSVZ as an independent predictor of lower OS and the only predictor of lower PFS and early recurrence. Conclusions GBM contact with the VSVZ, but not SGZ, CC, or cortex, is associated with early recurrence and decreased survival. We hypothesize that the VSVZ niche has unique properties that contribute to GBM pathobiology in adults.

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

“…The SVZ is a site of frequent spread in HGG, and glioma spread to the SVZ is associated with decreased survival (Chaichana et al, 2008; Jafri et al, 2013; Mistry et al, 2017a, 2017b) and increased tumor recurrence (Adeberg et al, 2014; Chen et al, 2015). Notably, decreased survival and increased early recurrence in adult GBM are associated specifically with glioma contact of the lateral ventricle SVZ (Mistry et al, 2017b), for reasons that have yet to be fully elucidated.…”

“…Notably, decreased survival and increased early recurrence in adult GBM are associated specifically with glioma contact of the lateral ventricle SVZ (Mistry et al, 2017b), for reasons that have yet to be fully elucidated. Clinical studies have sought to improve outcomes by increasing the radiation dose to the SVZ in GBM patients, which in some cases has increased progression-free survival (Chen et al, 2013; Evers et al, 2010; Lee et al, 2013).…”

“…The lateral ventricle subventricular zone (SVZ) stem cell niche is thought to be a tumor reservoir for a range of HGGs including adult glioblastoma (GBM). Glioma contact of neural stem cell niches, particularly the SVZ, has been closely associated with decreased survival (Chaichana et al, 2008; Jafri et al, 2013; Mistry et al, 2017a, 2017b) and increased tumor recurrence (Adeberg et al, 2014; Chen et al, 2015). Diffuse intrinsic pontine glioma (DIPG; recently re-classified as diffuse midline glioma, H3K27M mutant (Louis et al, 2016)) is the most common HGG of childhood and the leading cause of pediatric brain tumor-related death, with a median survival of only 9 months and a 5-year survival of less than 1% (Donaldson et al, 2006).…”

Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth

“…Clinically, the precise cause of lethality due to brain tumors appears to be highly nuanced and is still unclear . Multiple retrospective studies assign higher importance to tumor location, rather than volume, as a reliable prognostic factor . We implanted genetically identical tumor cells in the same location across multiple animals and saw no difference in survival whether the tumors were larger or smaller.…”

High risk glioblastoma cells revealed by machine learning and single cell signaling profiles

“…Although much has been made of loss or gain of genetic aberrations post-temozolomide and radiation therapies, little is known about signaling in recurrent tumor cells and thus it is unclear if clonal evolution and/or a shift in activated phosphoproteins is necessary for tumor cell survival and repopulation. Other factors have recently been shown to correlate with patient outcomes including the location of the tumor with respect to the largest neural stem cell niche in the adult brain, the ventricular-subventricular zone (V-SVZ) 65 .…”