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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

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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.


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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


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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.


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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


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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.


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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.


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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.


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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.


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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).


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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.


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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.


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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.

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