Comparative Analysis of Subventricular Zone Glioblastoma Contact and Ventricular Entry During Resection in Predicting Dissemination, Hydrocephalus, and Survival.
ABSTRACT: BACKGROUND:Ventricular entry during glioblastoma resection and tumor contact with the subventricular zone (SVZ) have both been shown to associate with development of hydrocephalus, leptomeningeal dissemination, distant parenchymal recurrence, and decreased survival. However, prior studies did not analyze these variables together in a single-patient population; therefore, it is unknown which is an independent predictor of these outcomes. OBJECTIVE:To conduct a comparative outcome analysis of surgical ventricular entry and SVZ contact by glioblastoma in a retrospective cohort of 232 patients. METHODS:Outcomes studied included hydrocephalus, leptomeningeal dissemination, distant tumor recurrences, and progression-free (PFS) and overall (OS) survival. The Cox proportional regression analyses were adjusted for age at diagnosis, preoperative Karnofsky performance status score, extent of resection, temozolomide and radiation treatments, and tumor molecular status (specifically, IDH1/2 mutation and MGMT promoter methylation). RESULTS:Surgical ventricular entry, SVZ-contacting glioblastoma, hydrocephalus, leptomeningeal dissemination, and distant recurrences were observed in 85 (36.6%), 114 (49.1%), 19 (8.2%), 78 (33.6%), and 59 (25.4%) patients, respectively. Multivariate, adjusted analysis revealed SVZ tumor contact-but not ventricular entry-associated with hydrocephalus (hazard ratio, HR, 4.20 [1.13-15.7], P = .03), leptomeningeal dissemination (HR 1.93 [1.14-3.28], P = .01), PFS (HR 2.10 [1.53-2.88], P < .001), and OS (HR 1.90 [1.35-2.67], P < .001). Distant recurrences were not associated with either. No interaction between the 2 variables was statistically noted. CONCLUSION:SVZ contact by glioblastoma was independently associated with the development of hydrocephalus, leptomeningeal dissemination, and decreased survival. SVZ tumor contact was associated with ventricular entry during surgical resections, which did not independently correlate with these outcomes.
Project description:Glioblastoma multiforme (GBM), the most malignant of all gliomas is characterized by a high degree of heterogeneity and poor response to treatment. The sub-ventricular zone (SVZ) is the major site of neurogenesis in the brain and is rich in neural stem cells. Based on the proximity of the GBM tumors to the SVZ, the tumors can be further classified into SVZ+ and SVZ-. The tumors located in close contact with the SVZ are classified as SVZ+, while the tumors located distantly from the SVZ are classified as SVZ-. To gain an insight into the increased aggressiveness of SVZ+ over SVZ- tumors, we have used proteomics techniques like 2D-DIGE and LC-MS/MS to investigate any possible proteomic differences between the two subtypes. Serum proteomic analysis revealed significant alterations of various acute phase proteins and lipid carrying proteins, while tissue proteomic analysis revealed significant alterations in cytoskeletal, lipid binding, chaperone and cell cycle regulating proteins, which are already known to be associated with disease pathobiology. These findings provide cues to molecular basis behind increased aggressiveness of SVZ+ GBM tumors over SVZ- GBM tumors and plausible therapeutic targets to improve treatment modalities for these highly invasive tumors.
Project description:Heparin binding epidermal growth factor-like growth factor (HB-EGF) is an angiogenic factor mediating radial migration of the developing forebrain, while vascular endothelial growth factor (VEGF) is known to influence rostral migratory stream in rodents. Cell migratory defects have been identified in animal models of hydrocephalus; however, the relationship between HB-EGF and hydrocephalus is unclear. We show that mice overexpressing human HB-EGF with β-galactosidase reporter exhibit an elevated VEGF, localization of β-galactosidase outside the subventricular zone (SVZ), subarachnoid hemorrhage, and ventriculomegaly. In Wistar polycystic kidney rats with hydrocephalus, alteration of migratory trajectory is detected. Furthermore, VEGF infusions into the rats result in ventriculomegaly with an increase of SVZ neuroblast in rostral migratory stream, whereas VEGF ligand inhibition prevents it. Our results support the idea that excess HB-EGF leads to a significant elevation of VEGF and ventricular dilatation. These data suggest a potential pathophysiological mechanism that elevated HB-EGF can elicit VEGF induction and hydrocephalus.
Project description:INTRODUCTION:The subventricular zone (SVZ) in the brain is associated with gliomagenesis and resistance to treatment in glioblastoma. In this study, we investigate the prognostic role and biological characteristics of subventricular zone (SVZ) involvement in glioblastoma. METHODS:We analyzed T1-weighted, gadolinium-enhanced MR images of a retrospective cohort of 647 primary glioblastoma patients diagnosed between 2005-2013, and performed a multivariable Cox regression analysis to adjust the prognostic effect of SVZ involvement for clinical patient- and tumor-related factors. Protein expression patterns of a.o. markers of neural stem cellness (CD133 and GFAP-?) and (epithelial-) mesenchymal transition (NF-?B, C/EBP-? and STAT3) were determined with immunohistochemistry on tissue microarrays containing 220 of the tumors. Molecular classification and mRNA expression-based gene set enrichment analyses, miRNA expression and SNP copy number analyses were performed on fresh frozen tissue obtained from 76 tumors. Confirmatory analyses were performed on glioblastoma TCGA/TCIA data. RESULTS:Involvement of the SVZ was a significant adverse prognostic factor in glioblastoma, independent of age, KPS, surgery type and postoperative treatment. Tumor volume and postoperative complications did not explain this prognostic effect. SVZ contact was associated with increased nuclear expression of the (epithelial-) mesenchymal transition markers C/EBP-? and phospho-STAT3. SVZ contact was not associated with molecular subtype, distinct gene expression patterns, or markers of stem cellness. Our main findings were confirmed in a cohort of 229 TCGA/TCIA glioblastomas. CONCLUSION:In conclusion, involvement of the SVZ is an independent prognostic factor in glioblastoma, and associates with increased expression of key markers of (epithelial-) mesenchymal transformation, but does not correlate with stem cellness, molecular subtype, or specific (mi)RNA expression patterns.
Project description:Human brain development proceeds via a sequentially transforming stem cell population in the ventricular-subventricular zone (V-SVZ). An essential, but understudied, contributor to V-SVZ stem cell niche health is the multi-ciliated ependymal epithelium, which replaces stem cells at the ventricular surface during development. However, reorganization of the V-SVZ stem cell niche and its relationship to ependymogenesis has not been characterized in the human brain. Based on comprehensive comparative spatiotemporal analyses of cytoarchitectural changes along the mouse and human ventricle surface, we uncovered a distinctive stem cell retention pattern in humans as ependymal cells populate the surface of the ventricle in an occipital-to-frontal wave. During perinatal development, ventricle-contacting stem cells are reduced. By 7 months few stem cells are detected, paralleling the decline in neurogenesis. In adolescence and adulthood, stem cells and neurogenesis are not observed along the lateral wall. Volume, surface area and curvature of the lateral ventricles all significantly change during fetal development but stabilize after 1 year, corresponding with the wave of ependymogenesis and stem cell reduction. These findings reveal normal human V-SVZ development, highlighting the consequences of disease pathologies such as congenital hydrocephalus.
Project description:To determine if ventricular zone (VZ) and subventricular zone (SVZ) alterations are associated with intraventricular hemorrhage (IVH) and posthemorrhagic hydrocephalus, we compared postmortem frontal and subcortical brain samples from 12 infants with IVH and 3 nonneurological disease controls without hemorrhages or ventriculomegaly. Birth and expiration estimated gestational ages were 23.0-39.1 and 23.7-44.1 weeks, respectively; survival ranges were 0-42 days (median, 2.0 days). Routine histology and immunohistochemistry for neural stem cells (NSCs), neural progenitors (NPs), multiciliated ependymal cells (ECs), astrocytes (AS), and cell adhesion molecules were performed. Controls exhibited monociliated NSCs and multiciliated ECs lining the ventricles, abundant NPs in the SVZ, and medial vs. lateral wall differences with a complex mosaic organization in the latter. In IVH cases, normal VZ/SVZ areas were mixed with foci of NSC and EC loss, eruption of cells into the ventricle, cytoplasmic transposition of N-cadherin, subependymal rosettes, and periventricular heterotopia. Mature AS populated areas believed to be sites of VZ disruption. The cytopathology and extension of the VZ disruption correlated with developmental age but not with brain hemorrhage grade or location. These results corroborate similar findings in congenital hydrocephalus in animals and humans and indicate that VZ disruption occurs consistently in premature neonates with IVH.
Project description:The apical domain of embryonic (radial glia) and adult (B1 cells) neural stem cells (NSCs) contains a primary cilium. This organelle has been suggested to function as an antenna for the detection of morphogens or growth factors. In particular, primary cilia are essential for Hedgehog (Hh) signaling, which plays key roles in brain development. Their unique location facing the ventricular lumen suggests that primary cilia in NSCs could play an important role in reception of signals within the cerebrospinal fluid. Surprisingly, ablation of primary cilia using conditional alleles for genes essential for intraflagellar transport [kinesin family member 3A (Kif3a) and intraflagellar transport 88 (Ift88)] and Cre drivers that are activated at early [Nestin; embryonic day 10.5 (E10.5)] and late [human glial fibrillary acidic protein (hGFAP); E13.5] stages of mouse neural development resulted in no apparent developmental defects. Neurogenesis in the ventricular-subventricular zone (V-SVZ) shortly after birth was also largely unaffected, except for a restricted ventral domain previously known to be regulated by Hh signaling. However, Kif3a and Ift88 genetic ablation also disrupts ependymal cilia, resulting in hydrocephalus by postnatal day 4. To directly study the role of B1 cells' primary cilia without the confounding effects of hydrocephalus, we stereotaxically targeted elimination of Kif3a from a subpopulation of radial glia, which resulted in ablation of primary cilia in a subset of B1 cells. Again, this experiment resulted in decreased neurogenesis only in the ventral V-SVZ. Primary cilia ablation led to disruption of Hh signaling in this subdomain. We conclude that primary cilia are required in a specific Hh-regulated subregion of the postnatal V-SVZ.
Project description:Radiotherapy (RT) is commonly applied for the treatment of glioblastoma multiforme (GBM). Following the planning target volume (PTV) definition procedure standardized in guidelines, a 20% risk of missing non-local recurrences is present. Purpose of this study was to evaluate whether diffusion tensor imaging (DTI)-based fiber tracking may be beneficial for PTV definition taking into account the prediction of distant recurrences. 56 GBM patients were examined with magnetic resonance imaging (MRI) including DTI performed before RT after resection of the primary tumor. Follow-up MRIs were acquired in three month intervals. For the seven patients with a distant recurrence, fiber tracking was performed with three algorithms and it was evaluated whether connections existed from the primary tumor region to the distant recurrence. It depended strongly on the used tracking algorithm and the used tracking parameters whether a connection was observed. Most of the connections were weak and thus not usable for PTV definition. Only in one of the seven patients with a recurring tumor, a clear connection was present. It seems unlikely that DTI-based fiber tracking can be beneficial for predicting distant recurrences in the planning of PTVs for glioblastoma multiforme.
Project description:We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma.Forty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS).Median age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p?=?0.014) and TTP (4.6 vs 12.9 months, p?=?0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p?=?0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR?=?3.07, p?=?0.012 and HR?=?2.67, p?=?0.047, respectively).Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.
Project description:BACKGROUND:Glioblastoma carries a poor prognosis primarily because of its high rate of recurrence. The ability to predict the recurrence pattern and timing would be highly useful for determining effective treatment strategies. We examined the correlation between prognostic factors and the pattern of recurrence in patients with primary glioblastoma. In particular, we examined whether there was a correlation between the expression of CD133 and glioblastoma recurrence. METHODS:We retrospectively analyzed 112 patients with primary glioblastoma. The timing and pattern (local or distant) of the initial recurrence were obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by Western blots and immunohistochemistry, clinical (age, sex, KPS, Ki67 labeling index, surgery, ventricular entry) and genetic (IDH1, 7p, 9p, 10q, MGMT) factors. RESULTS:Of the 112 patients, 99 suffered recurrence. The first recurrence was local in 77 patients and distant in 22 patients. Among the factors to predict the pattern of recurrence, CD133 expression was significantly higher in distant than in local recurrence. Of the factors to predict the timing of recurrence, high CD133 expression was associated with shorter time to distant recurrence in both univariate and multivariate analyses (P = .0011 and P = .038, respectively). CONCLUSIONS:The expression of CD133 may be a predictor of the pattern and timing of recurrence of primary glioblastoma.
Project description:Recent studies suggest that glioblastomas (GBMs) contacting the subventricular zone (SVZ) as the main adult neurogenic niche confer a dismal prognosis but disregard the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase 1 (IDH1) mutations. We therefore examined location-dependent prognostic factors, growth, and recurrence patterns in a consecutive cohort of 285 IDH1-wildtype GBMs. Based on pre-operative contrast-enhanced MRI, patients were allotted to four location-dependent groups with (SVZ+; groups I, II) and without (SVZ-; groups III, IV) SVZ involvement or with (cortex+; groups I, III) and without (cortex-; groups II, IV) cortical involvement and compared for demographic, treatment, imaging, and survival data at first diagnosis and recurrence. SVZ involvement was associated with lower Karnofsky performance score (p < 0.001), lower frequency of complete resections at first diagnosis (p < 0.0001), and lower non-surgical treatment intensity at recurrence (p < 0.001). Multivariate survival analysis employing a Cox proportional hazards model identified SVZ involvement as an independent prognosticator of inferior overall survival (p < 0.001) and survival after relapse (p = 0.041). In contrast, multifocal growth at first diagnosis (p = 0.031) and recurrence (p < 0.001), as well as distant recurrences (p < 0.0001), was more frequent in cortex+ GBMs. These findings offer the prospect for location-tailored prognostication and treatment based on factors assessable on pre-operative MRI.