Cancer Investigation

ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20

Naturally Occurring Canine Glioma as a Model for

Novel Therapeutics

Molly E. Hubbard, Susan Arnold, Abdullah Bin Zahid, Matthew McPheeters,

M. Gerard O’Sullivan, Alexandru-Flaviu Tabaran, Matthew A. Hunt & G.
Elizabeth Pluhar

To cite this article: Molly E. Hubbard, Susan Arnold, Abdullah Bin Zahid, Matthew McPheeters,
M. Gerard O’Sullivan, Alexandru-Flaviu Tabaran, Matthew A. Hunt & G. Elizabeth Pluhar (2018):
Naturally Occurring Canine Glioma as a Model for Novel Therapeutics, Cancer Investigation, DOI:
10.1080/07357907.2018.1514622

To link to this article: https://doi.org/10.1080/07357907.2018.1514622

Published online: 20 Sep 2018.

Submit your article to this journal

Article views: 5

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=icnv20
CANCER INVESTIGATION
https://doi.org/10.1080/07357907.2018.1514622

REVIEW

Naturally Occurring Canine Glioma as a Model for Novel Therapeutics

Molly E. Hubbarda, Susan Arnoldb, Abdullah Bin Zahidc, Matthew McPheetersd, M. Gerard O’Sullivanb,e,
Alexandru-Flaviu Tabaranb,e, Matthew A. Hunta and G. Elizabeth Pluharb
a
Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA; bCollege of Veterinary Medicine, University of
Minnesota, Minneapolis, MN, USA; cDivision of Neurosurgery, Hennepin County Medical Center, Minneapolis, MN, USA; dCollege of
Medicine, University of Minnesota, Minneapolis, MN, USA; eComparitive Pathology Shared Resource at Masonic Cancer Center,
University of Minnesota, Minneapolis, MN, USA

ABSTRACT ARTICLE HISTORY

Background: Current animal models of glioma are limited to small animal models, which Received 12 March 2018
are less predictive of treatment of human disease. Canines often develop gliomas de novo, Revised 5 July 2018
but the natural history of the disease is not well described. Accepted 19 August 2018
Objective: We provide data for naturally occurring canine gliomas; evaluating medical and
KEYWORDS
surgical therapies. Canine glioma model;
Methods: We reviewed medical records of pet dogs with a presumptive diagnosis of glioma natural glioma
from MRI imaging that underwent surgery as part of the Canine Brain Tumor Clinical Trials
Program. Breed, age, sex, median progression-free, and overall survival times and cause of
death were recorded for multivariate analysis.
Results: Ninety five dogs (56 male; mean age ¼ 8.3 years) were included, but nine were
excluded as final pathology was non-neoplastic. Gross total resection was reported in 81
cases based on postoperative MRI. Seventy had high-grade tumors (grade III or IV). Eighty
three dogs presented with seizures, being the most common presenting clinical sign.
Median survival after surgery was 723 days (95% CI 343–1103) for grade II tumors, 301 days
(197–404) for grade III and 200 days (126–274) for grade IV (p ¼ .009 Kaplan–Meier survival
analysis; Log Rank test). Age (cox regression, p ¼ .14) or sex (Kaplan–Meier test, p ¼ .22) did
not predict survival.
Conclusions: This study establishes normative data for a model exploiting dogs with natur-
ally occurring glioma, which can be used to test novel therapies prior to translation to
human trials. Further work will focus on the effects of different therapies, including chemo-
therapy, radiation therapy, and immunotherapy.

Introduction The earliest reported surgical resection of

Primary intracranial neoplasms are a relatively com-
mon disorder in dogs, with many studies based on
necropsy reports having a prevalence range between
0.014–4.5%. While some breeds are reported to be
predisposed to developing brain tumors, most breeds
are represented (1). Meningiomas are the most fre-
quently encountered canine primary intracranial
neoplasm, accounting for 45–50% of tumors, with
treatment well described in the literature (1, 2).
Gliomas and choroid plexus tumors are estimated to
account for approximately 31–36% and 5–7% of
tumors, respectively.
intracranial tumors in dogs was published by
Oliver in the 1960s (3, 4). The surgical
approaches and techniques for gaining access to
intracranial tumors were adapted based on tech-
niques from human neurosurgical procedures.
From this, the feasibility and success of canine
neurosurgery was established (5). Procedures
continue to be adapted as technology advances.
Over the past 50 years, surgical resection com-
bined with radiation has become the standard of
care for canine intracranial meningiomas (6, 7).
Surgical resection improves outcomes when com-
pared to radiation alone, with low risk of

CONTACT Molly Hubbard hubba166@umn.edu University of Minnesota, Mayo Building, MMC 96 Room D-429 420 Delaware St SE, Minneapolis,
MN 55455, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/icnv.
Supplemental data for this article can be accessed on the publisher’s website
ß 2018 Taylor & Francis Group, LLC
2 M. HUBBARD ET AL.
perioperative morbidity or mortality (8–10). In
the early 1990s, Motta et al. reported a median
survival of 214 days after surgery (7), which was
substantially improved in a later study to 1254
days for transitional and meningothelial grade I
tumors after resection with an ultrasonic aspir-
ator (10). Potential perioperative complications of
surgical treatment include cerebral edema, seiz-
ures, bradycardia, hyperthermia, and altered level
of consciousness (8, 10).
Despite extensive evidence in favor of surgical
resection for treatment of intracranial meningio-
mas, there is limited data to support or refute a
similar treatment for canine gliomas. In 1991, a
small study by Niebauer et al. evaluating craniot-
omy in pet dogs and cats found a survival rate
for non-meningiomas to be greater than meningi-
omas with 40% and 30% one-year canine survival
rates, respectively (11). However, only two of the
11 non-meningioma lesions were astrocytoma/gli-
oma; and survival times for individual animals
were not given. Another retrospective study on
survival of dogs with brain tumors had a median
survival of 0.9 months for dogs treated by surgery
þ/ 125I implants (12). In addition, there have
been no studies published regarding the out-
comes of surgical resection of gliomas. A recent
systematic review of brain tumor treatment in
dogs gave a median survival time of 226 days for
all dogs with presumptive intra-axial, extra-axial,
and pituitary tumors (12). There were no specific
results for surgery of intra-axial tumors listed.
Given the paucity of published research, the pur-
pose of this study is to describe the techniques
and outcomes for a series of canine gli-
oma resections.
The Canine Brain Tumor Treatment Clinical
Trials program aims to offer state–of-the-art
treatment to the dogs suffering from intracranial
lesions, and also use the information gained from
treating dogs to design similar treatments for
human brain tumors. As part of the program,
animals are randomized to various treatments
after surgical debulking including vaccine-based
immunotherapy with or without a checkpoint
blockade inhibitor, chemotherapy with temozolo-
mide, or combination thymidine kinase/Flt3L or
IFN-c gene therapy. This study reports the base-
line features of the animals enrolled.
Methods
A database consisting of pet dogs treated in the
Canine Brain Tumor Treatment Clinical Trials
Program between August 2008 and December
2015 was used for subject selection. All dogs
underwent surgical treatment as a part of the
Canine Brain Tumor Treatment Clinical Trials
program. All dogs had a presumptive diagnosis
of glioma based on previous workup and MRI
(GE Signa HDxt3.0 T MRI, Wabasha, Wisconsin)
characteristics of an intracranial mass by the
referring veterinary neurologist prior to surgical
intervention (see the list of MRI sequences in
Supplementary material). All owners gave written
informed consent for the therapies. Data were
obtained by the operative veterinarian or trained
surgical resident. Surgery was performed at the
College of Veterinary Medicine Veterinary
Medical Center by a veterinary and a human
neurosurgeon. The surgical approaches used were
planned as based on the tumor location (3, 4).
The intent in all cases was to perform gross total
resection of the lesion when possible. Follow up
MRIs were performed at 2, 6, 12 months, or 4, 8,
and 12 months, pending on subject availability;
unless tumor recurrence was suspected prior to a
schedule recheck time. Initial tumor volume,
residual tumor volume and recurrent tumor vol-
ume was measured on all MRIs.
Samples of each mass were collected and
reviewed by veterinary pathologists with consult-
ation from a neuropathologist at the medical
school. After the confirmation of the diagnosis
on histopathology, adjuvant treatment with
chemotherapy, immunotherapy, gene therapy, or
a combination, was offered. Extent of resection
(EOR) was evaluated with a complete brain MRI
study that among other sequences includes T2W,
T2 FLAIR, T1W with and without contrast in 3
planes immediately after the craniotomy. EOR
was defined as: gross total resection (GTR) if no
residual contrast-enhancement was seen for
tumors that were gadolinium enhancing or no T2
fluid attenuating inversion recovery (FLAIR) sig-
nal abnormality was seen for non-contrast
enhancing tumors; near total resection (NTR) if
20% of the preoperative lesion remained; and
subtotal resection (STR) if >20% of the

Table 1. Demographics of all animals referred to the program with suspicion for glioma.
Parameter
N 86
Age
Sex Female
Male
Skull shape Brachycephalic
Dolichocephalic
Mesocephalic
Diagnosis
Tumor grade II
III
IV
preoperative lesion remained. Finally, the dogs
were followed in outpatient clinic until death.
The progression of disease or recurrence of the
tumor was determined either on repeat MRI,
subsequent surgical intervention or at necropsy.
Descriptive statistics were performed for the
demographics. The dogs with final pathology as
non-tumor were excluded from the analyses and
described separately. Survival analysis was per-
formed to calculate all-cause mortality and cancer
specific mortality rates. Kaplan–Meir and cox
regression was done to analyze the effect of age
and gender on survival. For the dogs which under-
went multiple resections, only first instance was
used in the analyses. p-Values were considered sig-
nificant at <0.05. All statistics were done using
SPSS statistics 24 (IBM crop, Armonk, NY, USA).
Results
A total of 99 surgeries were performed on 95 pet
dogs, 39 female and 56 male; four dogs under-
went two surgical interventions. Eight dogs were
excluded from analyses as the final pathology was
not glioma. The age ranged from 0.75 to 14.04
with a mean age of 8.3 years. There was an
increased incidence in certain brachycephalic
breeds, specifically Boxer, Boston, and
Staffordshire terriers and French and English
bulldogs. Demographic and histologic data are
described in Table 1. Seizure was the most com-
mon presenting symptom, being present in 83
(87%) dogs at the time of presentation for sur-
gery. Followup rate till death was 100%, however,
not all animals had necropsy.
CANCER INVESTIGATION 3
Canines with tumor Canine with non-tumor
9
8.0 (range: 9 months–14 years) 9.6 (range: 3–14 years)
35 4
51 5
63 2
4 3
19 4
Astrocytoma: 42 (48.8%) Infarct: 4
Ganglioglioma: 14 (16.3%) GME: 2
Meningioma: 2 (2.3%) Histiocytic Sarcoma/tumor: 2
Oligoastrocytoma: 1 (1.2%) Cavernoma: 1
Oligodendroglioma: 23 (26.7%)
PNET: 4 (4.7%)
7 n/a
51 n/a
28 n/a
Based on the postoperative MRI imaging, gross
or near total resection was reported in 80 out of
87 tumor cases. Three of the remaining dogs did
not have postoperative imaging, six dogs had sub-
total tumor resection as it was not deemed safe to
remove the entire lesion. Eighty were found to
have high-grade tumors (defined as grade III or
grade IV). These included anaplastic astrocytoma,
glioblastoma, anaplastic oligodendroglioma, and
primitive neuroectodermal tumor-like neoplasms
(called PNET in this report).
Few dogs required second resection of their
tumor after recurrence. In general, their surgeries
were slightly more complex due to scar tissue
from the previous surgery. All four animals who
underwent a second surgical resection had high-
grade tumors initially. Two were diagnosed ini-
tially with GBM, which recurred eight months
later in both cases. One was euthanized due to
symptom progression two months after the
second surgical intervention, however, no tumor
was found on pathologic examination. An MRI
documented recurrence of the cerebellar tumor
before the second surgery and the immediate
postoperative MRI after the second surgery
showed subtotal resection due to scar tissue
adhering to the brain stem. The postmortem
examination of the brain did show residual GBM;
the volume of tumor on PM was the same as
that measured on the postoperative MRI. The
other animal was euthanized one month after the
second surgical intervention due to progressive
symptoms and tumor recurrence was later con-
firmed on the necropsy. A third animal was
4 M. HUBBARD ET AL.

diagnosed with an anaplastic astrocytoma (grade

III); and on the second resection three months
later, pathology was unchanged. However, the
animal died 27 days after the second surgery
from medical complications of treatment. The
dog was receiving a series of autologous tumor
lysate vaccines with OX40L after subtotal resec-
tion of the recurrent temporal lobe GBM. Four
days after a vaccine, she suddenly became
obtunded and rapidly progressed to stupor/coma.
The owner declined medical intervention and
opted for humane euthanasia, given the poor
long-term prognosis. The postmortem examin-
ation of the brain showed recurrence of the GBM
and spread to the lateral, third, and fourth ven-
tricles. The last dog underwent gross total resec-
tion of a PNET, and a second resection was done
six months later with unchanged pathology. This Figure 1. MRI of the brain with and without contrast demon-
strating a typical low grade lesion seen in our study of
animal was euthanized six months after the
pet dogs
second resection due to tumor recurrence, which
was confirmed on necropsy. All recurrences were
within the tumor bed and not at remote sites.
MRI findings demonstrating a typical low- and
high-grade lesion are seen in Figures 1 and 2.
Recently, a study by Bentley et al. concluded that
tumor type and grade are difficult to diagnose
using radiological characteristics typified in
humans. They found that intra-axial tumors that
have mild or no contrast enhancement, no cystic
or necrotic center and are superficial to the
internal capsule are more likely to be low grade.
Astrocytomas tend to cause less ventricular dis-
tortion and tend to have a greater amount of
peri-tumoral edema compared to oligodendro-
gliomas (13).
Astrocytoma was the most common diagnosis,
including both low and high-grade tumors, which Figure 2. MRI of the brain with and without contrast demon-
strating a typical high grade lesion seen in our study of
was found in 59 canines. This was followed by pet dogs
grade II or anaplastic oligodendroglioma in 22
animals. High-grade neoplasms were more com-
mon than low grade, as only 7 dogs were diag- The median survival after surgery was 723
nosed with grade II tumors. The most common days (95% CI 343–1103 days) for grade II
location for tumors were the frontal (27.9%) or tumors, 301 days (197–404) for grade III, and
temporal (26.7%) lobes, which dictated surgical 200 days (126–274) for grade IV (p-value for
approach (3, 4). There was no predilection for decreasing survival with higher grade ¼ 0.009
specific lobes based on grade (Figure 3). Kaplan–Meier survival analysis; Log Rank test
Representative histological images of grade II, III, (Figure 5). Age (cox regression, p-value ¼ .14)
and IV tumors are shown in Figure 4 (A–C). and sex (Kaplan–Meier test, p-value .22) did not

predict survival. However, no dogs with grade II
tumors were alive at the time of the data analysis
(Figure 6). Overall survival was highest for grade
II tumors, at 986 days (95% CI 517–1454 days)
followed by grade III tumors at 453 days (95% CI
257–649 days), and grade IV tumors at 274 days
(95% CI 178–370 days). Younger age at diagnosis
was associated with decreased survival when eval-
uating tumor specific survival (odds ratio 0.82;
CI 0.735–0.922). Adjuvant treatments will be dis-
cussed in future manuscripts, however, there was
no difference seen in tumor response and overall
survival among the various adjuvant therapies. It
is unknown if this is a real finding or secondary
to type II error as patient numbers in the
Figure 3. Bar graph showing the location of tumors.
Figure 4. (A–C) Representative histological images of canine gliomas. Panel A. Grade II astrocytoma, arrow indicates a gemistocytic
astrocyte. Panel B. Grade III anaplastic oligodendroglioma, arrow indicates microvascular proliferation. Panel C. Grade IV glioblast-
oma, asterisk indicates serpentine necrosis with palisading of tumor cells (arrows). All bars are 100 mm.
CANCER INVESTIGATION 5
treatment groups are low at this time (n ¼ 4–10
dogs). There were significant differences in
response and OS between low-grade (II) and
high-grade (III–IV) tumors but none between
various types of high-grade tumors (i.e., anaplas-
tic astrocytoma, anaplastic oligodendroglioma,
GBM, PNET, etc.). Animals with higher grade
tumors were more likely to die from recurrence
than those with lower grade (Figure 7)
When evaluating at tumor specific mortality
as an endpoint, the median survival was
853 days (767–938) for grade II tumors, 274 days
(188–359) for grade III tumors, and 211 days
(12–409) for grade IV tumors (p-value for
decreased survival with higher grade ¼ 0.031
Kaplan–Meier survival analysis; Log-Rank test).
Four dogs were still alive at the time of analysis;
430, 531, 1147, and 2054 days after surgery.
No dogs were lost to follow up, and mortality
data was available for each subject. However, the
cause of death was unknown for six dogs. The
most common cause of death was tumor recur-
rence (50 canines, 58.1%); followed by elective
euthanasia (15 animals, 17.4%) for reasons unre-
lated to tumor recurrence (Table 2). Animals with
grade III and IV tumors were more likely to die
due to recurrence (62.7% of grade III and 53.6%
of grade IV) compared to GRADE II (42.8%).
Discussion
Herein, we present data in a canine population
with spontaneous glioma that is a relevant model
for the human disease. There have been many
6 M. HUBBARD ET AL.
Figure 5. Kaplan–Meier estimate showing overall survival in
grade II, III, and IV glioma.
Figure 6. Kaplan–Meier estimate when cause of death is from
the tumor.
studies outlining the surgical outcomes after
meningioma resection in dogs (8–10, 14), but
this is the first report to our knowledge describ-
ing outcomes after surgery followed by adjuvant
medical treatment of gliomas. Reports that have
been published include any intracranial neoplasia
in dogs, and rarely cats, and have very low num-
bers for glioma (1, 2, 11). The use of a naturally
occurring model for cancer research and therapy
provides an important approach for developing
Figure 7. Tumor specific cause of death.
Table 2. List of cause of death in dogs included in the study.
Natural death was concluded after necropsy found no signs of
recurrent tumor.
Cause of death Number (%)
Alive 4 (5.8)
Recurrence 55 (58.1)
Euthanized-non-tumor 16 (7.0)
Natural 6 (17.4)
Other 6 (11.6)
Total 87 (100)
novel treatments, which can later be used in
human trials (15–18). The National Cancer
Institute has recently endorsed the utility of
canine models in the Comparative Brain Tumor
Consortium as well (19).
Herranz et al have described cell culture and
immunohistochemical characteristics of de novo
gliomas in dogs that suggest they have similar
phenotypic features and are an adequate model with
similar genetic markings for human gliomas (20).
Other studies have also demonstrated the molecular
similarities between human and canine gliomas,
which adds support for using a canine model for
novel treatment of gliomas (21). We also found that
tumors occur in similar locations in the canine
model and in human glioma (22).Our current work
is in the early stages of accumulating genomic data
to continue to improve the understanding of the
similarities between human and canine disease.
Further efforts to classify tumors based on genetic
markers is out of the scope of this article, but is
underway in other studies.

Figure 8. Kaplan–Meier estimate evaluating survival based on
extent of resection (EOR).
Hu et al. (12) published a review of treatments
for any canine brain tumor, and reported several
limitations of their literature search; many of
which we have addressed here. This was a single
center study, all the animals were recruited by
the same veterinarian and final histologic diagno-
sis was done in every case. Furthermore, survival
times and adverse events were known for all can-
ines enrolled, and cause of death was available
for 96% of canines in our study. We were able to
identify a “cause specific” mortality for the ani-
mals based on the grade of their tumor.
Interestingly, in our cohort, there was a predom-
inance of male animals, similar to what is seen in
some subtypes of human glioblastomas (23).
While this has been partially explained by sexual
dimorphism in expression of tumor suppressor
genes, it is not clear if this is the case in the
canine model as well, however, the model lends
itself to further investigation in this area as well.
However, this has not been previously reported
in a canine model. Furthermore, any influence of
hormones is unlikely as the majority of dogs had
undergone castration. EOR was associated with
improved survival, whereas dogs with GTR had
improved survival when compared to NTR or
STR (p ¼ .026), Figure 8. Interestingly, in our
cohort, older dogs had an increased overall sur-
vival when compared to younger dogs. We were
not able to compare between grades as the num-
bers were not high enough in each group, but
CANCER INVESTIGATION 7
this will be examined further in future studies
evaluating genetic markers.
There are limitations to this report, most obvi-
ous being that the animals underwent treatment in
addition to surgical intervention, which may alter
the survival in dogs with gliomas. Not all dogs
underwent necropsy, thus some dogs may have
been misclassified as to their cause of death being
from tumor progression. Unfortunately, when
working with pet dogs, the outcome data are
skewed as few dogs die a natural death. Most dogs
undergo elective euthanasia due to clinical deterior-
ation, uncontrollable epilepsy, or progression of the
disease. Furthermore, with or without necropsy,
the cause of death may not be accurately defined,
thus altering the results of treatment. In addition,
while we understand that canine models may not
be a perfect model, a spontaneously occurring
tumor may be more relevant than induced models;
including patient-derived xenograft, multiple muta-
tion, or humanized mouse models.
There is virtually no information regarding
response to any therapy in dogs with high-grade
glioma, and there certainly is no accepted stand-
ard of care. The median survival time reported
for surgical resection alone in dogs with supra-
tentorial glioma (6 low-grade, 8 high-grade) was
66 days, similar to that of palliative care (69
days) (24). Therefore, in our study, no dog was
treated with surgical resection alone. When ana-
lyzing our cohort, we found no significant differ-
ences in the overall survival among the groups
(Mantel–Cox log-rank test (p ¼ .4054) and
Gehan–Breslow–Wilcoxon test (p ¼ .4484)).
In addition, molecular and genetic markers were
not assessed in this study, which represents a rapidly
emerging field in neuro-oncology. The diagnoses
were made on histopathologic and immunohisto-
chemical criteria from the surgical biopsies, and pro-
gression was determined either after a subsequent
surgical intervention or at necropsy. Nevertheless,
this report remains useful as a benchmark to meas-
ure further treatment improvements and survival
gains in the setting of canine glioma.
Conclusions
This is descriptive data of a naturally occurring gli-
oma in pet dogs, which can be used to test
8 M. HUBBARD ET AL.
different therapies prior to human trials, and is the
largest study of its type. By understanding the
course of disease in a canine model, even with
immunotherapy and chemotherapy treatments, we
can assess the efficacy of novel treatments. Using a
naturally occurring model of glioma may decrease
the complications of using genetic knock-out mod-
els (21), and further advancement of treatment reg-
imens for human tumors. This naturally occurring
model also allows to test multimodality treatment
regimes, otherwise not possible. Further work is
needed to understand the effects of different
therapies, (chemotherapy, radiotherapy, and/or
immunotherapy) alone and combined.
Disclosure statement
The authors have no conflict of interest with the data presented.
Funding
This work was supported by American Cancer Society, NIH
Clinical Center, and Humor to Fight the Tumor
Foundation This work was supported by American Cancer
Society, NIH Clinical Center, and Humor to Fight the
Tumor Foundation
References
1. Song RB, Vite CH, Bradley CW, Cross JR.
Postmortem evaluation of 435 cases of intracranial
neoplasia in dogs and relationship of neoplasm with
breed, age, and body weight. J Vet Intern Med/Am
College Vet Intern Med. 2013;27(5):1143–52.
2. Snyder JM, Shofer FS, Van Winkle TJ, Massicotte C.
Canine intracranial primary neoplasia: 173 cases
(1986–2003). J Vet Intern Med/Am College Vet
Intern Med. 2006;20(3):669–75.
3. Oliver J. Surgical approaches to the canine brain. Am
J Vet Res. 1968;29(2):353–78.
4. Oliver J. Principles of Canine Brain Surgery. J Am
Anim Hosp Assoc. 1966;2:73–88.
5. Hoerlein BF, Few AB, Petty MF. Brain surgery in the
dog–preliminary studies. J Am Vet Med Assoc. 1963;
143:21–9.
6. Kube SA, Bruyette DS, Hanson SM. Astrocytomas in
young dogs. J Am Anim Hosp Assoc. 2003;39(3):
288–93.
7. LeCouteur RA. Current concepts in the diagnosis and
treatment of brain tumours in dogs and cats. J Small
Anim Pract. 1999;40(9):411–6.
8. Ijiri A, Yoshiki K, Tsuboi S, Shimazaki H, Akiyoshi
H, Nakade T. Surgical resection of twenty-three cases
of brain meningioma. J Vet Med Sci/Jpn Soc Vet Sci.
2014;76(3):331–8.
9. Motta L, Mandara MT, Skerritt GC. Canine and feline
intracranial meningiomas: an updated review. Vet J
(London, England: 1997). 2012;192(2):153–65.
10. Greco JJ, Aiken SA, Berg JM, Monette S, Bergman PJ.
Evaluation of intracranial meningioma resection with
a surgical aspirator in dogs: 17 cases (1996–2004).
J Am Vet Med Assoc. 2006;229(3):394–400.
11. Niebauer GW, Dayrell-Hart BL, Speciale J. Evaluation
of craniotomy in dogs and cats. J Am Vet Med Assoc.
1991;198(1):89–95.
12. Hu H, Barker A, Harcourt-Brown T, Jeffery N.
Systematic review of brain tumor treatment in dogs.
J Vet Int Med. 2015;29(6):1456–63.
13. Bentley RT, Ober CP, Anderson KL, Feeney DA,
Naughton JF, Ohlfest JR, et al. Canine intracranial
gliomas: relationship between magnetic resonance
imaging criteria and tumor type and grade. Vet J
(London, England: 1997). 2013;198(2):463–71.
14. Heidner GL, Kornegay JN, Page RL, Dodge RK,
Thrall DE. Analysis of survival in a retrospective
study of 86 dogs with brain tumors. J Vet Int Med/
Am College Vet Int Med. 1991;5(4):219–26.
15. Schiffman JD, Breen M. Comparative oncology: what
dogs and other species can teach us about humans
with cancer. Philos Trans R Soc Lond B Biol Sci.
2015;370(1673): 20140231–20140233.
16. Grenier JK, Foureman PA, Sloma EA, Miller AD.
RNA-seq transcriptome analysis of formalin fixed,
paraffin-embedded canine meningioma. PloS one.
2017;12(10):e0187150.
17. Thomas R, Duke SE, Wang HJ, Breen TE, Higgins RJ,
Linder KE, et al. ’Putting our heads together’: insights
into genomic conservation between human and canine
intracranial tumors. J Neurooncol. 2009;94(3):333–49.
18. Hicks J, Platt S, Kent M, Haley A. Canine brain
tumours: a model for the human disease? Vet Comp
Oncol. 2017;15(1):252–72.
19. LeBlanc AK, Mazcko C, Brown DE, Koehler JW,
Miller AD, Miller CR, et al. Creation of an NCI com-
parative brain tumor consortium: informing the trans-
lation of new knowledge from canine to human brain
tumor patients. Neuro-oncology. 2016;18(9):1209–18.
20. Herranz C, Fernandez F, Martin-Ibanez R, Blasco E,
Crespo E, De la Fuente C, et al. Spontaneously arising
canine glioma as a potential model for human glioma.
J Comp Pathol. 2016;154(2–3):169–79.
21. Candolfi M, Curtin JF, Nichols WS, Muhammad AG,
King GD, Pluhar GE, et al. Intracranial glioblastoma
models in preclinical neuro-oncology: neuropatho-
logical characterization and tumor progression. J
Neurooncol. 2007;85(2):133–48.
22. Larjavaara S, M€antyl€a R, Salminen T, Haapasalo H,
Raitanen J, J€a€askel€ainen J, et al. Incidence of gliomas
by anatomic location. Neuro-oncology. 2007;9(3):
319–25.

23. Sun T, Warrington NM, Luo J, Brooks MD,
Dahiya S, Snyder SC, et al. Sexually dimorphic RB
inactivation underlies mesenchymal glioblastoma
prevalence in males. J Clin Invest. 2014;124(9):
4123–33.
CANCER INVESTIGATION 9
24. Sunol A, Mascort J, Font C, Bastante AR, Pumarola
M, Feliu-Pascual AL. Long-term follow-up of surgical
resection alone for primary intracranial rostrotentorial
tumors in dogs: 29 cases (2002–2013). Open Vet J.
2017;7(4):375–83.