Download - GMB and Imaging
-
8/19/2019 GMB and Imaging
1/13
Page 1 of 13
Glioblastoma multiforme: perfusion and its relation to thesubventricular zone
Poster No.: C-0757
Congress: ECR 2013
Type: Scientific Exhibit
Authors: M. C. G. Kimura, Y. Lee, M. Castillo; Chapel Hill, NC/US
Keywords: Neuroradiology brain, Oncology, MR-Diffusion/Perfusion, MR,
Experimental, Diagnostic procedure, Imaging sequences,Technology assessment, Neoplasia, Gene therapy, Tissuecharacterisation
DOI: 10.1594/ecr2013/C-0757
Any information contained in this pdf file is automatically generated from digital material
submitted to EPOS by third parties in the form of scientific presentations. References
to any names, marks, products, or services of third parties or hypertext links to third-
party sites or information are provided solely as a convenience to you and do not inany way constitute or imply ECR's endorsement, sponsorship or recommendation of the
third party, information, product or service. ECR is not responsible for the content of
these pages and does not make any representations regarding the content or accuracy
of material in this file.
As per copyright regulations, any unauthorised use of the material or parts thereof as
well as commercial reproduction or multiple distribution by any traditional or electronically
based reproduction/publication method ist strictly prohibited.
You agree to defend, indemnify, and hold ECR harmless from and against any and all
claims, damages, costs, and expenses, including attorneys' fees, arising from or related
to your use of these pages.Please note: Links to movies, ppt slideshows and any other multimedia files are not
available in the pdf version of presentations.
www.myESR.org
-
8/19/2019 GMB and Imaging
2/13
Page 2 of 13
Purpose
To determine if the initial location of glioblastoma (GB) and its relationship to the
subventricular zone (SVZ) can predict the pattern of recurrence and to access if relative
cerebral blood volume (rCBV) maps are able to show increased perfusion on the borders
of GB corresponding to SVZ.
Rationale
The statement made by Ramon y' Cajal that the mature brain was incapable of producing
new neurons was a common belief during most of the 20th
century. The central dogma
of neurobiology vanished with the discovery of adult neurogenesis made by Altman's in
1962 (1) when he observed new born cells in well-defined areas of the adult rodent brain.
It is important to mention the development technology using bromodeoxyuridine (BrdU),
which made the labeling of proliferating cells in the brain possible and enabled Eriksson
et al in 1998 (2) to prove the existence of adult neurogenesis in humans.
The consensus is that adult neurogenesis is active in two main areas: the Subgranular
Zone in Dentate Gyrus of the hippocampus and SVZ.
However, a large number of reports describe adult neurogenesis in a variety of adult
brain regions as neocortex, striatum, amygdala, substantia nigra, olfactory bulb, spinal
cord (3-8).
A Neural stem cell (NSC) is a cell with the capacity to self-renew and generates multiple
neural lineages. Cancer stem cells (CSCs) are adult NSCs dysregulated in vivo. Themicroenvironment that supports and regulates stem cell maintenance, self-renewal, fate
specification and development is called Niche. It involves physiological humoral factors,
anatomical organization and neuronal activity. CSCs have been isolated from major
malignant brain tumors and many authors believe that these cells arise from endogenous
stem cells that suffered genetical or epigenetical alterations (9).
In order to detect neurogenesis in live human brain, new technologies have been
developed for the detection of NSC.
Perfusion Weighted Imaging (PWI) allows CBV studies for neurogenesis. The basis
for the use of CBV to detect neurogenesis relies on the correlation between CBV-angiogenesis and angiogenesis-neurogenesis (10-12).
According to Pereira et al 2007 (13), CBV might provide an indirect measure of
neurogenesis in the adult human hippocampus.
-
8/19/2019 GMB and Imaging
3/13
Page 3 of 13
We applied rCBV technique to search for higher blood volume in GBs borders related
to SVZ neurogenesis. In an attempt to verify whether those borders would demonstrate
higher rCBV values and consequently higher angiogenesis/neurogenesis.
Methods and Materials
MR of 48 subjects with pathologically proved GB prior to any treatment and their
post contrast images were divided into 3 groups according to the relationship of their
enhancing margins to the SVZ.
Group I: enhancing margins of GB in continuity with the SVZ,
Group II: enhancing margins of GB distant of SVZ, in SC region,
Group III: enhancing margins of GB abutting SVZ and SC region.
Follow-up studies were performed after surgical treatment and recurrences or continuous
growth seen as enhancing areas were characterized as local when they occurred within
the surgical bed, as spread when they happened within 1 cm of the surgical bed and as
distant when they did not have any contact with it.
The averages and p -values were calculated using Microsoft Excel 2007. A Fisher Exact
Test was performed as you can see in the table bellow.
Fig. 1: The table shows the Fisher Exact Test of the GBs patients and their types ofrecurrences in relation to the SVZ.References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
-
8/19/2019 GMB and Imaging
4/13
Page 4 of 13
A group of 38 subjects that had PWI studies was selected from the total of 48 with GB to
have their postcontrast images and rCVB maps analysed.
GBs were divided by orthogonal lines in rCBV maps and four parts were created: MA, MP,
LA and LP. Regions of interest (ROIs) were manually drawn for any fourth-part of GBs.
Fig. 2: GB T1 contrast-enhanced axial image and corresponding rCBV map withorthogonal lines dividing the tumor in 4 parts and ROIs drawn circumscribing increased
perfusion in lesion borders. ROI in the contralateral white matter is delineated and itsintensity value was used to normalize.References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
The values for which fourth-part were acquired, registered separately and normalized.
Data Analysis:
The data analysis was performed in two parts. Out of the 48 subjects that were studied,
16 were female and 32 were male.
The mean ages at presentation were lower and more varied for group III or I than group
II. A total of 48% of GBs were in contact with the SC and SVZ (Group III). Group II where
GB had contact with SC region was the second most common with 42% and Group I
where the GBs were in contact just with SVZ was the least frequent.
-
8/19/2019 GMB and Imaging
5/13
Page 5 of 13
In order to verify PWI data it was used Microsoft Excel 2007 to calculate mean and
standard deviation values of rCBV for the subtype regions and the statistical comparisons
were made between the regions using a Tukey´s multiple comparisons test.
Results
Overall, spread and local patterns of recurrence or continuous growth were present in
45% and 43% of subjects respectively and distant pattern in 12%.
In group I, 80% showed spread pattern of recurrence, 20% a local pattern and none were
a distant pattern.
Fig. 9: Group I type of GB and the spread type of recurrence.References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
-
8/19/2019 GMB and Imaging
6/13
Page 6 of 13
Fig. 3: Group I type of GB and on local type of recurrenceReferences: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
In group II, 48% demonstrated a spread pattern, 33% a local pattern and 19% a distant
pattern of recurrence.
Fig. 4: Group II type of GB (in relation to SC area) and local type of recurrence.
-
8/19/2019 GMB and Imaging
7/13
Page 7 of 13
References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
Fig. 5: Group II type of GB and distant type of recurrence.References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
In group III, 56% had a local pattern, 35% a spread pattern and 9% a distant pattern.
-
8/19/2019 GMB and Imaging
8/13
Page 8 of 13
Fig. 6: Group III type of GB (in relation to the SVZ and SC region) and local type ofrecurrence.References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
Fig. 10: Group III type of GB and spread type of recurrence.
-
8/19/2019 GMB and Imaging
9/13
Page 9 of 13
References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
Fig. 7: Group III type of GB and distant type of recurrence.References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
Perfusion demonstrated random values for ROI analysis of rCVB maps.
There was no statistically significant evidence of higher rCBV on borders, either at SVZor SC zones.
-
8/19/2019 GMB and Imaging
10/13
Page 10 of 13
Fig. 8: Graphic: Statistical analysis of rCBV values for GBs and Tukey's multiplecomparisons test. P>0.05References: Department of Radiology, UNIVERSITY OF NORTH CAROLINA - ChapelHill/US
Conclusion
The type and location of recurrences had no specific relationship to the location of
the initial tumors and GBs in relationship to SVZ did not predict the pattern of tumor
recurrence.
Our observation disagrees with the literature (14,15) that suggests that types of
recurrences can be predicted according to initial location of GBs.
What we found was similar to Kappadakunnel et al 2010 (16) and we agree with this
author when affirming that there is no evidence that tumors contacting the SVZ are more
likely to be 'stem-cell-derived'.
It is not established yet whether cancer cells initiate in NSCs, progenitors or differetiated
cells eventhough NSCs being attractive candidates (17).
-
8/19/2019 GMB and Imaging
11/13
Page 11 of 13
On the other hand, if ones considers dormant NSCs are present in multiple regions of
the adult brain, and that these cells can be activated by physiological or pathological
conditions to start the neurogenesis process. Theoretically, GBs or their recurrences
started in CSCs from those multiple regions would not have contact or relation to the SVZ.
In resume, GB does not have a typical and consistent pattern of recurrence and it is not
possible to establish a connection between neurogenesis activity that exists in SVZ and
GB recurrence based on the GBs locations in relation to the SVZ.
Regarding, the perfusion analysis of GBs, it could be noted that it demonstrated random
values for ROI analysis of our rCVB maps.
There was no statistically significant evidence of higher rCBV on borders, either at SVZ
or SC zones.
Herein it is accepted angiogenesis-neurogenesis coupling occurs in exercise condition
according to (13).
Although, validation is required to demonstrate whether angiogenesis is specific for
neurogenesis. In other words, it is necessary to determine if data correlate with NSCs
proliferating or other cells types that proliferate.
Our results did not show evidence of higher CBV values on the GB borders abutting
SVZ. They varied randomly demonstrating angiogenesis was more likely to be related to
putative proliferation than any other phenomena.
Additionally, the putative proliferation was not higher close to SVZ. This fact makes we
believe that Cancer Stem Cells are not migrating from SVZ to GB. Otherwise, CBV values
would be higher on the GB borders abutting SVZ.
A possible explanation for our negative results may be related to the fact that Steady-
state T1 method renders absolute estimations of the CBV and has high spatial resolution
however rCBV maps derived from gradient echo PWI do not.
References
1. Altman J. Are new neurons formed in the brains of adult mammals? 1962.Science 135(3509):1127-1128.
2. Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A. M., Nordborg,C., Peterson, D. A., and Gage, F. H. Neurogenesis in the adult humanhippocampus. 1998. Nat. Med. 4, 1313-1317.
-
8/19/2019 GMB and Imaging
12/13
Page 12 of 13
3. Arsenijevic Y, Villemure JG, Brunet JF, Bloch JJ, Déglon N, Kostic C, ZurnA, Aebischer P. Isolation of multipotent neural precursors residing in thecortex of the adult human brain. 2001.Exp Neurol 170(1):48-62
4. Pagano, S. F., Impagnatiello, F., Girelli, M., Cova, L., Grioni, E., Onofri, M.,Cavallaro, M., Etteri, S., Vitello, F., Giombini, S., Solero, C. L., and Parati, E.A. Isolation and characterization of neural stem cells from the adult humanolfactory bulb. 2000. Stem Cells 18, 295-300.
5. Jin, K., Wang, X., Xie, L., Mao, X. O., Zhu, W., Wang, Y., Shen, J.,
Mao, Y., Banwait, S., and Greenberg, D. A. Evidence for stroke-inducedneurogenesis in the human brain. 2006. Proc. Natl. Acad. Sci. U.S.A. 103,13198-13202.
6. Macas J, Nern C, Plate KH, Momma S. Increased generation of neuronalprogenitors after ischemic injury in the aged adult human forebrain. 2006.JNeurosci 26(50):13114-13119
7. Shen, J., Xie, L., Mao, X., Zhou, Y., Zhan, R., Greenberg, D. A., and Jin, K.Intracerebral hemorrhage in adult human brain. 2008. J. Cereb. Blood FlowMetab. 28, 1460-1468.
8. Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC, Reynolds
BA. Multipotent CNS stem cells are present in the adult mammalian spinalcord and ventricular neuroaxis. 1996. J Neurosci 16(23):7599-76099. Dirks PB. Brain tumor stem cells: bringing order to the chaos of brain
cancer. 2008. J Clin Oncol 26(17):2916-292410. Palmer, T. D., Willhoite, A. R., and Gage, F. H. Vascular niche for adult
hippocampal neurogenesis. 2000. J. Comp. Neurol. 425, 479-494.11. Van Praag, H., Shubert, T., Zhao, C., and Gage, F. H. Exercise enhances
learning and hippocampal neurogenesis in aged mice. 2005. J. Neurosci.25, 8680-8685.
12. Van der Borght, K., Kobor-Nyakas, D. E.,Klauke, K., Eggen, B. J., Nyakas,C., Van der Zee, E. A., and Meerlo, P. Physical exercise leads to rapid
adaptations in hippocampal vasculature: temporal dynamics and relationshipto cell proliferation and neurogenesis. 2009. Hippocampus 19, 928-936.
13. Pereira, A. C., Huddleston, D. E., Brickman, A. M., Sosunov, A. A., Hen,R., McKhann, G. M., Sloan, R., Gage, F. H., Brown, T. R., and Small,S. A.2007. An in vivo correlate of exercise-induced neurogenesis in the adultdentate gyrus. Proc. Natl. Acad.Sci. U.S.A. 104, 5638-5643.
14. Lim DA, Cha S, Mayo MC, Chen M-H, Keles E, VandenBerg S, BergerMS. Relationship of glioblastoma multiforme to neural stem cell regionspredicts invasive and multifocal tumor phenotype. 2007. Neuro-oncology9(4):424-429.
15. Barami K, Sloan AE, Rojiani A, Schell MJ, Staller A, Brem S. Relationship ofgliomas to the ventricular walls. 2009. J Clin Neurosci 16(2):195-201
16. Kappadakunnel M, Eskin A, Dong J, et al. Stem cell associated geneexpression in glioblastoma multiforme: relationship to survival and thesubventricular zone. 2010. J Neurooncol 96(3):359-367
17. Ma DK, Bonaguidi MA, Ming G-L, Song H. Adult neural stem cells in themammalian central nervous system. 2009.Cell Res 19(6):672-682.
-
8/19/2019 GMB and Imaging
13/13
Page 13 of 13
Personal Information
Margareth Cristina G. Kimura MD, Research Fellow at the Radiology Department of
Medical University of North Carolina, Chapel Hill, North Carolina, USA in 2011 and
currently Neuroradiologist at CDPI, Rio de Janeiro, Brazil; [email protected].
Yueh Lee MD, PhD, Assistant Professor of Radiology, Physics and Astronomy at
University of North Carolina, Chapel Hill, North Carolina, USA.
Mauricio Castillo MD, FACR, Professor of Radiology and Division Chief of Neuroradiology
at University of North Carolina, Chapel Hill, North Carolina, USA.