Invited Review

J Vet Intern Med 2014;28:1165–1185

Invited Reviews provide the veterinary community with an overview of the state of the art in a special-
ized area of veterinary internal medicine. Reviews are written by individuals actively working in the
area of the review and who are experts in the field. The JVIM Editorial Board oversees selection of
relevant topics and authors. Invited Reviews are peer reviewed.

Advances in Diagnostic and Treatment Modalities for Intracranial

Tumors
P.J. Dickinson
Intracranial neoplasia is a common clinical condition in domestic companion animals, particularly in dogs. Application
of advances in standard diagnostic and therapeutic modalities together with a broad interest in the development of novel
translational therapeutic strategies in dogs has resulted in clinically relevant improvements in outcome for many canine
patients. This review highlights the status of current diagnostic and therapeutic approaches to intracranial neoplasia and
areas of novel treatment currently in development.
Key words: Brain tumor; CNS disorders; Neuroimaging; Neurology; Neurosurgery; Oncology; Oncology treatment.

ntracranial neoplasia represents a major cause of incidence of brain tumors in dogs has been underesti-
I morbidity and mortality in companion animals, pre-
dominantly in dogs. Recent advances in diagnosis and
mated. Although individual studies vary, meningiomas
compromise approximately 50% of primary tumors in
treatment of intracranial neoplasia in veterinary medi- dogs with gliomas representing 40–70% and choroid
cine have been driven by a combination of improved plexus tumors being the next most common
access to advanced imaging and neurosurgical equip- tumor.7,9,11,12 Secondary neoplasia accounts for
ment together with the recognition of brain tumors in approximately 50% of all intracranial tumors in dogs,
dogs as a viable and potentially valuable model for with the most common tumor types being hemangio-
translational and basic research.1–3 Collaborative ther- sarcoma, pituitary tumors, lymphoma, metastatic car-
apeutic research embracing the “one medicine” cinoma, extension of nasal neoplasms, and histiocytic
approach has demanded both basic molecular genetic sarcoma.13 The majority of primary and secondary
characterization of these tumors in dogs to validate intracranial tumors occur in older adult dogs with the
the next generation of targeted therapies, and advances majority over 5 years of age.11–16 Median age for dogs
in the diagnostic and surgical techniques necessary to with meningiomas, gliomas, and choroid plexus tumors
apply these approaches in a clinical setting. Accurate is reported as 10–11 years, 8 years, and 5–6 years,
data for true incidence of brain tumors in dogs are respectively.9,12,15,16 Primary tumors (particularly glio-
limited to a study in the 1960s and 1970s in Northern mas) occasionally may be seen in younger dogs.9,17 No
California4,5; however, the reported 14.5 cases per sex predisposition has been reported; however it has
100,000 dogs included all nervous system tumors, and been suggested that brain tumors generally are over-
numbers were small. These results are similar to data represented in larger breeds and meningiomas are
in humans where an incidence of 20.59 primary CNS overrepresented in Golden Retrievers, Boxers, and
tumors per 100,000 human patients in the United Miniature Schnauzers. Astrocytiomas and oligoden-
States has been reported.6 A more accurate compari- drogliomas are highly overrepresented in specific
son may be based on necropsy data where intracra- brachycephalic breeds (Boxers, Boston Terriers, and
nial/nervous system neoplasia has been reported in Bulldogs), and choroid plexus tumors are overrepre-
approximately 2–4.5% of dogs7–9 compared to approx- sented in Golden Retrievers.7,9,12,15,16,18 Intracranial
imately 2% of human patients.10 Given the practical neoplasia generally is accepted to be less common in
limitations of veterinary care, it is likely that true cats, although a necropsy study of approximately
4,000 cats suggested a frequency of just under 2%.19
The majority of intracranial tumors in cats are pri-
From the Department of Surgical and Radiological Sciences, mary, with meningiomas being the predominant type.
School of Veterinary Medicine, University of California Davis,
Lymphoma and pituitary tumors are the most com-
Davis, CA (Dickinson).
Corresponding author: P.J. Dickinson, Department of Surgical mon secondary tumors with other primary and second-
and Radiological Sciences, School of Veterinary Medicine, Univer- ary tumors, such as gliomas, occurring at relatively
sity of California Davis, Davis, CA 95616; e-mail: pjdickin- low frequencies compared to dogs.19–21
son@ucdavis.edu. Advances in the treatment of intracranial tumors in
Submitted January 27, 2014; Revised February 24, 2014; dogs to date have largely been because of improve-
Accepted March 25, 2014. ments in diagnosis, and optimization of standard ther-
Copyright © 2014 by the American College of Veterinary Internal
apeutic modalities such as surgical cytoreduction,
Medicine
DOI: 10.1111/jvim.12370 radiation therapy and, to a lesser extent, chemother-
1166 Dickinson

apy. The marked breed association of specific tumors their tumor counterparts in humans. The only veteri-
such as gliomas with brachycephalic breeds7,9,12,18 may nary WHO classification was published in 1999,28
provide an opportunity to decrease incidence by selec- based on the 1993 WHO classification for humans.
tive breeding once provisionally defined genetic associ- Since that time the system in humans has been revised
ations22,23 are further characterized. Most of the recent 3 times and, although there are limitations, it generally
major advances in human oncology have been made is accepted that intracranial tumors in dogs should be
by elimination of environmental factors such as classified using the current WHO classification system
smoking, improved screening, and use of targeted ther- used in humans29 until specific data relating to biologic
apies in cancers such as chronic myelogenous leukemia behavior are available in dogs. Molecular genetic
and breast cancer.24,25 For neurooncology specifically, analysis of tumors has become commonplace in human
only 2 new drugs have been approved by the FDA for neurooncology and grading and prognostication is
treatment of high-grade gliomas in humans in the last becoming a composite of both histopathologic and
30 years, the chemotherapeutic temozolamide,a which molecular criteria (discussed below).29,30
increases overall median survival in humans with grade
IV astrocytomas/glioblastoma multiforme by approxi- CSF and Blood Biomarkers
mately 12 weeks,26 and bevacizumab,b which was given
fast track approval, but has recently been shown to As a generalization, CSF usually is not diagnostic
have limited if any survival benefit in a large prospec- for a specific neoplastic condition. Neoplastic cells
tive phase III clinical trial.27 It is hoped that transla- anecdotally may be seen in CSF with almost any
tional studies in dogs with intracranial tumors may tumor type, but presence of neoplastic cells may occur
improve this situation for both species. more commonly with specific tumors such as choroid
plexus tumors,16,31 lymphoma,12,32,33 glioma,33 and his-
Diagnosis of Intracranial Tumors tiocytic sarcoma.34,35 Based on larger case series, mod-
erate increases in total nucleated cell counts (TNCC;
Diagnosis of intracranial disease involves practical 5–50 cells/lL, predominantly mononuclear cells) and
and economic considerations that are somewhat total protein (TP) are typical with most intracranial
unique to the anatomic location. Advanced imaging neoplasia, although some tumors may have normal
such as magnetic resonance imaging (MRI) or com- CSF findings, and some may result in marked
puted tomography (CT) often is required for tentative increases in TNCC and TP.12,16,33,36–40 Common find-
diagnosis, and acquisition of diseased tissue for defini- ings have been reported in some tumor types. For
tive histopathologic diagnosis requires either special- example, increased TP is seen in most choroid plexus
ized biopsy equipment or invasive surgical procedures. tumors,16,37,40 and this may be more pronounced in
Cerebrospinal fluid (CSF) analysis is rarely diagnostic, choroid plexus carcinomas compared to papillomas.16
but its value often is overlooked. Monitoring lesions Most meningiomas have TNCC < 5 cells/lL, but
to determine biological behavior (with or without med- increased cell counts, often with a neutrophilic compo-
ical treatment) may provide valuable information, par- nent may be associated with meningiomas arising in
ticularly when invasive or expensive therapeutic the caudal cranial fossa.39
options are contemplated. This approach, however, Defining biomarkers (in CSF or blood) for assess-
may be practically limited by the expense of repeated ment of tumor burden and therapeutic response is a
advanced imaging techniques. The 2 major conse- priority in human neurooncology.41 Classes of tumor
quences of these issues are (1) much effort has been markers include circulating tumor DNA or microRNA
expended trying to define biomarkers of disease to aid (miRNA) and circulating proteins such as glial fibril-
in diagnosis, often involving advanced imaging and lary acidic protein, vascular endothelial growth factor
CSF analysis; and (2) a large amount of published (VEGF), matrix metalloproteinase-9 (MMP-9), and
information relating to treatment has been based on miRNA-21, but ideal markers have yet to be
presumptive diagnoses, and is of limited value because defined.41,42 A limited number of biomarkers (beyond
many nonneoplastic lesions may have been included in tumor cells specifically) have been evaluated in CSF
therapeutic outcome data. from dogs with intracranial tumors, including MMP-2
and -9,43,44 uric acid,45 and fibrinolytic activity (D-
Histopathologic Diagnosis dimers),46 as well as VEGF in plasma, but findings to
date are similar to those in humans with regard to lim-
Definitive diagnosis of intracranial tumors is based itations of sensitivity and specificity.
on histopathologic assessment using the World Health
Organization (WHO) classification system. This is a Imaging
continuously evolving system in human medicine with
amendment of classification and tumor grade based on Although many investigators have attempted to uti-
analysis of clinical outcomes and survival relative to lize a variety of imaging techniques to diagnose, and
specific pathologic criteria. Because there is little infor- even grade, intracranial lesions in dogs, specificity, sen-
mation relating to the natural biology of intracranial sitivity, or both have been shown to be consistently
tumors in dogs, or their response to treatment, veteri- suboptimal in numerous studies,12,15,16,36,47–56 particu-
nary classification systems largely have been based on larly when applied to clinically relevant prospective
 Brain Tumors 1167

random populations of patients. A majority of intra- terns on postcontrast T1-weighted images has been
cranial tumors in both dogs and cats are hypo- to iso- associated with meningiomas and gliomas, respectively,
intense on T1-weighted imaging, and hyperintense on but studies suggest that these patterns may be seen in
T2-weighted imaging. The majority are also contrast a wide variety of intracranial diseases.53,56,59 Realisti-
enhancing after administration of gadolinium-based cally, many therapeutic decisions are made based on
contrast agents.12,15,16,21,54,55 A variety of tumor “spe- presumptive imaging-based data, but the limitations of
cific” findings relating to MRI have been reported these data and the consequences in individual animals
variably in several studies, some of which are listed should not be overlooked.
below. Peritumoral hyperintensity (edema) on T2- Future advances in the use of imaging in brain tumors
weighted images is a relatively common finding and of dogs likely will be based on treatment planning and
has been suggested to be more common in astrocyto- assessment of therapeutic response, as definitive biopsy-
mas as compared to oligodendrogliomas and in rostro- based diagnoses become more commonplace. The use
tentorial as compared to infratentorial of metabolic and physiologic imaging techniques has
meningiomas.15,52 Edema also has been reported to be become routine in human neurooncology to define
particularly severe in relatively rare intracranial granu- parameters such as tumor cellularity, hypoxia, vascular
lar cell tumors.57 Contrast enhancement is generally density, and permeability.60
more common in high-grade gliomas compared to Diffusion-weighted imaging (DWI), which evaluates
lower grade tumors, consistent with the microvascular decreased movement of water molecules, allows for
proliferation inherent to high grade tumors.49,52 The assessment of changes in tissue characteristics resulting
imaging characteristics of the most commonly occur- from a variety of diseases. Although definitive diagno-
ring extra-axial tumor, meningioma, can be indistin- ses are not possible in humans61 or dogs,62 DWI may
guishable from those of other tumors such as aid in the differentiation of neoplasia from conditions
histiocytic sarcoma, lymphoma, and granular cell such as bacterial abscessation or infarction, in which
tumors.15,57,58 Granular cell tumors are reported to diffusion is typically severely restricted (Fig 1).63 DWI
commonly have hyperintensity on precontrast T1- has been shown to be a sensitive technique to define
weighted images, but these findings also may be pres- injury to normal canine brain following irradiation,64
ent in approximately 20% of meningiomas. Large cys- and may help to differentiate tumor recurrence from
tic structures may be associated with many tumor the effects of treatment. In addition, diffusion tensor
types, but they occur most commonly with meningio- imaging (which measures diffusion in specific direc-
mas where their frequency is approximately 25%.15 tions) may be used to define white matter tracts critical
Presence of “dural tails” and ring enhancement pat- for surgical and radiation treatment planning.65

A B C D

E F G H

Fig 1. Diffusion-weighted imaging (DWI) may aid in better defining mass lesions. (A, E) T1-weighted postcontrast images of 2 ring-
enhancing cerebral lesions. Marked restricted diffusion, typical of abscess (E–H), but not glioblastoma multiforme (A–D) is seen as
bright signal on DWI images (C, G). Apparent diffusion coefficient maps (D, H) allow background hyperintense signal because of T2
relaxation (“T2 shine through” B, F) to be differentiated from true restricted diffusion. Restricted diffusion appears hypointense on
apparent diffusion coefficient (ADC) maps (D, H).
1168 Dickinson

Assessment of the vascular properties of tumors tomic definition of vascular structures associated with
may be valuable for surgical planning and also for intracranial tumors either by magnetic resonance angi-
determining response to treatment, particularly with ography (MRA) or contrast-enhanced CT provides
the recent availability of antiangiogenic therapies such information to improve both surgical planning and to
as bevacizumab and the multitargeted tyrosine kinase allow interventional techniques such as tumor emboli-
inhibitor toceranib.c,60 Both MRI- and CT-based zation, local delivery of therapeutic agents, or both
dynamic contrast-enhanced techniques have been (Fig 2).69 Chemoembolization of an intracranially
described in canine tumors to assess blood volume, extended nasal tumor has been reported in a cat,70 and
perfusion, and permeability (Fig 2).66,67 As with other treatment of nasal tumors is in progress in dogs, but
imaging techniques, assessment of vascular parameters the more challenging goal of brain tumor embolization
in veterinary patients has limitations for diagnosis66,67; has not been reported in dogs. Normal canine intracra-
however, utility in monitoring vascular response to nial vasculature has been defined using both contrast-
therapies including radiation has been reported.68 Ana- enhanced and time-of-flight (TOF) MRA71–73 and

Fig 2. A variety of vascular imaging techniques may aid in the definition of vascular supply to, and management of, intracranial
tumors. (A, B) Transverse T1-weighted pre- (A) and post- (B) contrast magnetic resonance (MR) images of a dog with 2 tumors; a meta-
static melanoma (hyperintence precontrast administration/image A) and a highly vascular choroid plexus tumor (contrast enhancing/
image B). Dynamic contrast computed tomography (CT) imaging allows definition of higher blood volume (C) and perfusion (D) in the
choroid plexus tumor (arrows). (E) Sagittal T1-weighted postcontrast MRI of a cerebello-medullary meningioma. Surgical access
involves transection of the transverse sinus. Time-of-flight (F) and phase contrast (G) MR angiography techniques show that the tumor
(arrow) has already caused substantial ablation of the transverse sinus on the side of the tumor, compared to the opposite side (*),
allowing for informed surgical planning. (H–J) Contrast-enhanced CT imaging with reconstruction of intracranial vessels. Major vessels
that may be associated with intracranial tumors and interventional procedures such as tumor embolization are identified along the floor
of the cranial vault (I, J) (basilar artery-red, arterial circle-yellow, internal carotid artery-gray, middle cerebral artery-green, caudal cere-
bral artery-magenta, rostral cerebellar artery-blue) (C, D, H–J courtesy of R. Pollard, M. Steffey UC Davis).
 Brain Tumors 1169

feasibility of imaging tumor vascularity has been dem- will provide the optimal information for therapeutic
onstrated.73 planning, tumor stratification, and assessment of thera-
Magnetic resonance metabolic imaging of brain peutic response, particularly when used in a linear
tumors by using proton magnetic resonance spectros- manner.60,82,83
copy (1H MRS) allows determination of the chemical
composition of tumor tissue, and it is a commonly Brain Biopsy
used complementary technique in human neurooncolo-
gy.60 MRS techniques have been described in normal Definitive diagnosis of intracranial lesions is based
canine brain,72,74 and experimentally in canine models on histopathologic examination, culture, and occasion-
of nonneoplastic brain disease.75–77 ally additional analysis of tissue obtained from the
Positron emission tomography (PET) and single lesion. In cases where surgical resection is not consid-
photon emission computed tomography are functional ered the optimal approach to treatment and diagnosis,
imaging techniques that allow for qualitative and minimally invasive biopsy techniques are considered
quantitative measurement of tissue metabolism the most appropriate way to obtain diagnostic data
together with anatomic localization after image fusion permitting a maximally informed approach to treat-
with CT or MR images. The most commonly used tra- ment. Free-hand, image-guided, and endoscope-
cer is 2-deoxy-2[18F]fluoro-D-glucose (FDG), which assisted brain biopsy has been described for dogs84–86;
reflects increased glucose metabolism in brain tissue or however, stereotactic-guided procedures have many
tumors. High background activity in metabolically advantages. Both CT- and MRI-based stereotactic sys-
active brain can be a major confounding issue, and tems were developed for dogs in the 1980s in the
alternative tracers such as 18F-fluoroethythyrosine also experimental setting,87,88 and a variety of stereotactic
are used in humans. Major uses for the technique approaches to clinical brain biopsy have been
include defining metabolically active areas for biopsy described in dogs and cats, the majority of which have
and definition of tumor recurrence or increasing malig- involved CT-based systems.89–95 Only 1 commercially
nancy. PET imaging has been evaluated in dogs,78,79 available MRI-based system has been reported,96 that
and specifically in those with intracranial disease, is likely to become a mainstay of stereotactic biopsy in
although as with spectroscopy, clinical use is not yet the future. Both CT- and MRI-based systems have
routine.80,81 inherent advantages and disadvantages. MR-based sys-
Development and utilization of these metabolic and tems allow for better resolution of parenchymal
physiologic imaging techniques is very much in the lesions, whereas CT allows for better spatial resolution
developmental stage in veterinary neurooncology. and more rapid imaging (eg, for real-time imaging of
Similar to human medicine, it is likely that combined biopsy needle placement, and postbiopsy hemorrhage
use of these techniques together with standard imaging assessment). Combining MR and CT images by using

Fig 3. Stereotactic computed tomography (CT)-guided brain biopsy: (A) Dog head fixed in stereotactic frame. A center of arc system
allows for numerous possible biopsy trajectories. (B, C) Fusion of CT and magnetic resonance images maximizes both resolution of the
lesion and spatial resolution. (D, E) Rapid CT imaging allows for real-time imaging of biopsy needle position before biopsy. The biopsy
port (approximately 8 mm length) can be seen within and at the edge of the tumor (E). (F) Insertion of biopsy needle; needle depth is
determined and fixed by an adjustable collar. (G) Intraoperative rapid biopsy smears are ideally done to confirm collection of pathologic
material, in this case an oligodendroglioma, before postbiopsy hemorrhage evaluation imaging and recovery.
1170 Dickinson

image fusion software (Fig 3) may maximize the ben- 2) Defining specific molecular pathways for which
efits of both modalities. Repeated imaging is often targeted therapeutics may be indicated to either
necessary if initial diagnostic procedures are com- restore or inhibit aberrant pathways, and
pleted more than a few days before biopsy, to allow 3) Defining tumor cell-specific markers allowing
appropriate targeting of evolving lesions or to iden- tumor-specific targeting, typically of suicide gene,
tify resolving lesions where biopsy may not be indi- or toxic therapies.
cated. Diagnostic yield is generally >90% for
neoplastic lesions, but may be considerably lower There are many examples for which molecular classifi-
with inflammatory or infectious diseases. Morbidity cation has redefined or extended previous histopatho-
and mortality associated with brain biopsy vary with logic grading systems. Meningiomas in humans have
the equipment used, experience of the clinician, loca- been shown to have a molecular phenotype that pre-
tion of the lesion, and neurologic status of the dicts proliferative behavior more specifically than clas-
patient. Early published data described morbidity and sical histologic subtyping,97 and extensive genomic
mortality rates of 12–27% and 7–9%, respec- analysis of human high-grade astrocytomas has
tively.89,91 At the author’s institution, complications defined key commonly disrupted signaling pathways
generally occur currently in less than 5% of cases related to receptor tyrosine kinase (RTK)/Ras/PI3K,
with experienced operators, and mortality associated p53, and Rb signaling.98,99 Similarly, the cancer gen-
with the procedure is rare. Although there is substan- ome atlas and other studies have used genome-wide
tial expense associated with the procedure, increased expression, copy number, epigenetic, and proteomic
utilization hopefully will result in more informed profiling to define 3 major molecular subclasses (pro-
therapeutic planning based on accurate diagnoses, as neural, mesenchymal, classical) that may form the
well as providing the potential to monitor therapeutic basis for future therapeutic and prognostic stratifica-
response and biomarkers after specific therapeutic tion.98,100–102 Despite these classifications, optimal tar-
interventions. geted treatment still may require individualized
characterization of specific markers in individual
Molecular Diagnostics tumors (Fig 4).103–106
Advances in sequencing technology and availability
Molecular genetic characterization of neoplasia is of canine-specific platforms have opened the door for
becoming a mainstay of human neuropathology parallel characterization of canine and human brain
and neurooncology for both tumor classification tumors. An ever-expanding repertoire of targeted ther-
and prognostic evaluation as well as for the appropri- apies is becoming available for cancer treatment,104
ate application of molecular-targeted therapies. Charac- but appropriate characterization of canine tumors is
terization allows for: critical, because although many similarities are likely,
regardless of species or tumor type,107 specific differ-
1) Defining specific subgroups of tumors that are ences have already been documented. Similar to
either within histologic subtypes, or across histo- human brain tumors, overexpression of cellular prolif-
logic grades, relative to therapeutic outcome and eration and apoptosis-associated markers such as
prognosis. EGFR, PDGFRa, VEGFR1,2, c-Met, IGFBP2,108–111

Fig 4. Molecular genetic characterization. Common oncogenic pathways in human glioma are shown on the left. The potential for indi-
vidualized treatment targeted at specific molecular abnormalities is demonstrated in a single canine glioblastoma multiforme tumor. Wes-
tern blot defines increased (green) or decreased (red) expression of key pathway proteins relative to normal brain. Chromosomal copy
number alterations and transcriptionally upregulated genes for the same tumor are shown in the table on the right. Defined pathway
abnormalities for this tumor are indicated by an *. Potential surface markers for targeting are underlined.
 Brain Tumors 1171

c-erbB2, pERK, pAkt, Bcl-2, Bcl-xL,111 and the novel therapeutic strategies. Prognostic value and
angiogenic factor VEGF112–116 has been reported in therefore relevance to tumor grading in canine tumors
both canine gliomas and meningiomas. Decreased pro- is limited by a lack of information relating to long-
gesterone receptor expression has been reported in term outcome for untreated and treated tumors
canine meningiomas associated with higher prolifera- matched to archived tumor tissue, and establishment
tive indices and poorer prognosis,117,118 and these fea- of these databases should be a priority for the field.
tures also are associated with increased VEGF
expression.114 Treatment
The cellular immortality-related gene telomerase
reverse transcriptase has been shown to be expressed Conclusions from most veterinary neurooncology
in a variety of canine and feline brain tumors, and therapeutic studies are generally limited by small case
similar to human tumors has been associated with numbers, retrospective study design, and most criti-
tumor grade.119–121 Similarly, overexpression of MMP- cally, a lack of specific histologic evaluation including
2 and -9, E-cadherin, claudin-1, IL-6, and cyclooxy- tumor typing and grading. The latter issues become
genase-2 has been documented in canine and feline especially critical when small case numbers are
meningiomas,121–126 and MMP-2/9 has been identified involved. Lack of easily monitored objective criteria
in canine gliomas and choroid plexus tumors.125 Over- for therapeutic response is an additional problem
expression of surface markers previously defined in because repeated advanced imaging is often cost pro-
human tumors, suitable for tumor targeting strategies, hibitive, and many animals present with clinical signs
has been demonstrated for IL-13RA2, EphA2, and such as seizures and clinical response may be more
alpha3-beta1 integrin in a variety of canine brain reflective of adjunctive antiepileptic treatment than
tumors (Fig 4).127–130 To date, global expression specific tumor response. This is confounded by highly
studies have utilized relatively limited microarray variable criteria for time of presentation and time of
platforms and have shown some similarities to differ- euthanasia. Large-scale, multicenter therapeutic trials
entially expressed genes found in human tumors.131 At will be difficult to complete, and it is likely that a large
the epigenetic level, preliminary studies profiling gen- amount of data addressing more focused questions in
ome-wide methylation status of canine glioma suggest the future will be obtained from translational clinical
that hypermethylation patterns in developmentally trials that are becoming more common as the use of
regulated genes may be similar to those in human canine intracranial tumor models becomes more wide-
gliomas.132 spread. Continued collection of data relating to the
At the chromosomal level, there are limited data natural biology and clinical course of specific tumor
defining copy number variations in canine brain types and grades is critical for assessment of therapies,
tumors, and reported resolution to date has been as is insistence on a minimum of histologic diagnosis
approximately 1–3 Mb. As might be expected based for publication. Advances in diagnostic classification
on data in humans, there is decreased genomic insta- described above are likely to become more critical as
bility in canine meningiomas compared to generally molecular based therapies are developed.106
more aggressive gliomas. Potential similarities to
human tumors have been documented including loss Palliative Care
of canine chromosome (CFA) 17 and 27 (CFA 17, 27),
syntenic to human chromosome (HSA) 1p and 12p; Corticosteroids targeting peritumoral edema together
HSA 1, 12 in meningiomas.133,134 with antiepileptic drugs to control seizures (one of the
Key hallmarks of human gliomas and meningiomas most common presenting sign for intracranial
such as loss of HSA 22 (NF2 gene) in meningiomas tumors)11–13,138 form the mainstay of palliative care for
and HSA 1p/19q in gliomas, however, have not yet intracranial neoplasia. Response to corticosteroids often
been found, nor have classical glioma gene mutations can be predicted based on the degree of suspected perit-
such as those involving IDH1 and TP53.133–137 More umoral vasogenic edema as defined by white matter
detailed analysis of canine tumors using whole genome associated hyperintensity on T2-weighted or fluid atten-
sequencing and single nucleotide polymorphism arrays uated inversion recovery (FLAIR) MR images (Fig 5).
is likely to identify additional similarities and likely When secondary obstruction of CSF drainage occurs,
novel findings, and it is probable that common key intraventricular shunting may provide resolution of clin-
pathways in human and canine tumors will be affected ical signs temporarily as a palliative measure, or as with
by different modifications.107 Preliminary data suggest corticosteroids, to provide time and decreased morbidity
that some classical deletions in human gliomas includ- for biopsy or more definitive treatment (Fig 6). Mean-
ing the INK4a/b locus and the NF-1 gene may be ingful statements regarding the natural biology of
present in smaller deletions,132 but, documented differ- canine intracranial tumors and survival after palliative
ences to date highlight the necessity for preclinical care are difficult to make based on available data for the
characterization of canine tumors before use of specific reasons described above. There are no meaningful data
targeted approaches. relating to specific tumor types or grades. Published
Overall, ongoing identification of aberrant gene data suggest that for all masses combined, median sur-
expression as described above is likely to become vival is between approximately 1 and 10 weeks,139–142
increasingly important for appropriate targeting of with supratentorial tumors having a better prognosis
1172 Dickinson

Fig 5. Palliative treatment with corticosteroids. T2-weighted transverse images documenting the therapeutic potential of corticosteroids
in a biopsy and necropsy-confirmed anaplastic oligodendroglioma (grade III): Upper row = pretreatment, bottom row, 4 weeks after
0.5 mg/kg prednisone q24h. Even with 4 weeks of potential tumor growth, there is an overall decrease in tumor mass, with decreased
presumed peritumoral vasogenic edema in surrounding white matter (arrow heads), and decreased mass effect, initially visualized as devi-
ation of the falx cerebri (arrow).

Fig 6. Intraventricular shunt placement provides palliative treatment of hydrocephalus secondary to obstruction of drainage from the
lateral ventricles in a dog with a choroid plexus papilloma. (A) Dorsal plane reconstructed computed tomography (CT) image showing
the contrast-enhanced mass and enlarged lateral ventricle. (B) 3D-reconstructed CT image showing the shunt tip passing intracranially
through a small burr hole in the skull. (C) Postoperatively, the hyperattenuating catheter tip is seen in the now nondistended ventricle.
Ventricular shunting was done to alleviate clinical signs while stereotactic radiosurgery of the tumor was undertaken.

(median survival approximately 25 weeks).143 However, mately 4.5–7 months,144–146 with an improvement in
anecdotally many clinicians recognize that survival median survival to 16.5–30 months with adjunctive
times for some individual patients, even those with in- radiation therapy.118,145 However, use of cortical resec-
traaxial tumors, can be considerably longer. tion, ultrasonic aspiration, or endoscope-assisted tech-
niques has been reported to result in median survival
Surgical Treatment times of 16, 41, and 70 months, respectively, for ro-
strotentorial meningiomas.146–148 Given the large varia-
More than most other therapeutic modalities, effi- tion in outcome for different surgical techniques in
cacy of surgical cytoreduction of intracranial tumors is individual studies, it is difficult to make general recom-
highly operator and equipment dependent. Most pub- mendations for surgical treatment other than the
lished information with meaningful case numbers is observations that cytoreduction (particularly for ro-
related to more easily accessible canine and feline men- strotentorial tumors) may be “curative” for many
ingiomas, with only anecdotal data for other tumor older animals with some surgeons and techniques and
types such as gliomas and choroid plexus tumors. Cur- that adjunctive radiation therapy has an apparent ben-
rently available studies highlight the large variation in eficial effect (Fig 7).
outcome, and the potential impact of applied technol- Meningiomas are the most common primary intra-
ogy. In dogs with confirmed meningiomas, standard cranial tumor in cats. Median survival time for cats
surgical cytoreduction alone generally has been with surgical cytoreduction of meningiomas is
reported to result in median survival times of approxi- reported to be between 23 and 28 months.149–151
 Brain Tumors 1173

Fig 7. Advances in imaging and availability of neurosurgical equipment such as intraoperative stereotaxy, endoscopy, and ultrasonic
aspiration has made extensive surgical resection of both extra-axial and intraaxial tumors more commonplace. Presurgery transverse T1-
weighted postcontrast images of an intraaxial glioblastoma multiforme (A–C), sagittal (D). Postsurgery transverse (E–G), sagittal (H)
TI-weighted postcontrast images. Presurgery T1-weighted postcontrast images of a caudal fossa extra-axial grade II meningioma pre- (I)
and post- (J) surgical resection. Gross total resection of tumor has been achieved in both cases. (K) Ultrasonic aspirators utilizing a vari-
ety of soft tissue and bone tips (inset) allow for safer and more complete resection of tumors (images courtesy of B Sturges UC Davis).

Feline meningiomas are generally less aggressive and cols.156,157 Application of stereotactic radiotherapy
locally invasive biologically than their canine counter- protocols, potentially using 1–3 applied doses may
parts, making gross total resection more likely. Infor- provide similar outcomes to hypophysectomy and are
mation for other treatment modalities is anecdotal for currently under investigation.
both meningiomas and other sporadic tumor types in Intraoperative neuronavigation techniques using ste-
cats. reotactic coordinates based on either CT or MR
No meaningful conclusions can be made from pub- images are standard practice in human neurooncology.
lished data relating to surgery for intraaxial tumors in Availability of veterinary MR-based stereotactic equip-
dogs other than that anecdotally it can be beneficial mentd and custom-made devices is likely to advance
with some animals surviving many months to over surgical treatment, particularly of intraaxial tumors,
a year with surgery with or without adjunctive substantially in the near future (Fig 8). Several experi-
treatments.140,152–154 Microsurgical transsphenoidal mental and translational surgical procedures have been
hypophysectomy has become a successful neurosurgi- described in both experimental and clinical canine
cal technique for the management of intracranial pitui- patients, including use of lasers,158–160 automated tis-
tary tumors with survival times similar to those sue excision systems,93 irreversible electroporation
obtained with medical management, although tumor (Fig 9),161,162 ultrasound hyperthermia,163 and robotic
size is a limiting factor,155 and survival times are likely neurosurgery.164 Some of these techniques have shown
to improve with application of neuronavigational promise and may progress to mainstream treatment.
devices and operator experience. Most pituitary ma- Combined with recent advances in imaging of both
crotumors are best managed by radiation-based proto- tumors and their vascular supply (above), as well as
1174 Dickinson

the potential use of fluorescent markers to aid in intra-

operative tumor identification,165 continued advances
in outcome are likely with surgical cytoreduction of
canine and feline intracranial tumors.

Chemotherapy
There is little meaningful information available relat-
ing to the efficacy of chemotherapeutic agents for canine
intracranial neoplasia. Most data relate to the use of ni-
trosurea-based alkylating agents such as lomustine and
carmustine, or the ribunucleotide reductase inhibitor
hydroxyurea. Almost all studies lack histologic diagno-
ses for most cases, and thus have limited value. A large
retrospective study suggested no benefit for CT-defined
brain masses from lomustine (CCNU) chemotherapy
compared to palliative care (93 days versus 60 days),
but none of the 71 animals had a histologic diagnosis.142
Anecdotal histologically confirmed cases from published
data show apparent survival benefits and occasional
responses with survival of many months in some cases,
but overall, chemotherapy alone appears to have limited
value for intracranial tumors.147,154,166–169 Temozola-
mide, a novel oral alkylating agent, has become the stan-
dard-of-care for adjuvant and monotherapy of high-
grade gliomas and other tumors in humans, although its
use not been reported in dogs with clinical brain tumors.
Canine glioma cell lines appear to have responses similar
to human glioma cell lines with commonly used chemo-
therapeutic agents such as CCNU, CPT-11, and temozo-
lamide,170 and it is likely that the moderate advantages
of adjuvant chemotherapy seen in human patients26,171
are likely to be present for their canine tumor counter-
parts. Tumor resistance against alkylating agents is well
documented in human brain tumors, and has been
attributed to a variety of factors including DNA repair
mechanisms, prevention of drug uptake, and inactiva-
tion and elimination of agents. Multidrug resistance
proteins have been described in human brain tumors
and preliminary data suggest they may play a role in
drug resistance in dogs, particularly in meningiomas.172
Epigenetic silencing of the DNA repair enzyme O6-
methylguanine-DNA-methyltransferase by promoter
hypermethylation has been associated with better
responses to alkylating agents and better prognosis in
human patients with gliomas,173 and is becoming a stan-
dard biomarker for therapeutic planning. Epigenetic
alterations in canine brain tumors have been docu-
mented in a small number of cases,174 but their value has
Fig 8. Stereotactic neuronavigation allows the surgeon to iden- yet to be determined in clinical canine patients. The
tify tumor boundaries in real-time based on magnetic resonance value of additional novel chemotherapeutic agents,
(MR) or computed tomography (CT) images. This approach is either alone or in combination, combined with other
particularly valuable for intraaxial tumors such as gliomas that therapeutic modalities or delivered in a more targeted
must be approached through normal brain parenchyma. (A) 3D- manner remains to be evaluated. Local delivery of drug-
CT image showing position of titanium screws (red) used as fidu-
impregnated wafers (eg, carmustine wafers) into resec-
cials for stereotactic referencing. (B) BrainLab VectorVision sys-
tion cavities has shown some small benefits in human
tem.j Fiducial screws are referenced on the MR images, and then
in the surgery suite to the surgical pointer (arrow/green dots) and patients with gliomas,175 but has not been evaluated in
markers on the head frame (arrowhead/red dots). (C) In real- canine patients. Intratumoral delivery of a liposomal
time, the pointer is placed at the ventral edge of the craniectomy formulation of CPT-11 has been shown to have efficacy
and the green line (representing the pointer) shows that the expo- in selected canine glioma cases, with some survival times
sure is adequate to reach the ventral tumor margin. approaching 2 years for monotherapy (Fig 10).176
 Brain Tumors 1175

A B C D

E F G H

I J K L

Fig 9. Stereotactic ablation of an anaplastic oligodendroglioma in a Boston Terrier with irreversible electroporation (IRE). (A) A
threaded nylon 6-6 probe guide pedestal (PGP- arrows in A–C) is implanted into the skull using titanium, self-tapping screws, and dental
acrylic to facilitate tumor biopsy (A, inset and E) and IRE electrode insertion. Pretreatment MR (B and F) and CT (C and G) images
are used to plan the electrode approach trajectories and pulse delivery parameters using imaging-based tissue segmentation (D), volumet-
ric meshing with thermal and electrical field (H; in V/cm) threshold distributions, and finite element modeling. Posttreatment tumor
biopsy and diagnostic imaging demonstrating target ablation as indicated by the necrotic tumor phenotype (I) and decrease in the con-
trast-enhancing tumor burden (J, K). L-Fused pretreatment MRI and intraoperative CT of electrode insertion into the target, with the
PGP highlighted in blue (images courtesy of J Rossmeisl University of Virginia).

Fig 10. Convection-enhanced delivery of liposomal CPT-11 (a topoisomerase inhibitor) intratumorally by using real-time MR imaging
to optimize delivery. (A, B) Schematic representation of fused silica cannulae being guided into the tumor based on stereotactically
placed guide pedestals. (C, D) Transverse T1-weighted images at different levels showing infusate (white) of liposomal CPT-11 and gad-
oteridol contrast agent within the tumor. Different cannulae can be seen highlighted against the infusate after passing down the guide
pedestal (arrow). (E, F) Tumor volume (hypointense) pre- and posttreatment is decreased by 90% (arrowhead) after CPT-11 infusion.
(G–N) Time-lapse imaging over approximately 2 hours infusion. Three initial cannulae result in partial tumor coverage. Real-time imag-
ing allows monitoring of infusion, and placement of additional cannulae (*) resulting in optimal volume of coverage.
1176 Dickinson

Radiation Therapy extensive “inverse planning” defining tumor and nor-

mal tissues on the basis of individual CT slices is nec-
Radiation therapy has become a mainstay of treat- essary. Local delivery of radiation therapy (ie,
ment for intracranial neoplasia in both human and brachytherapy) has been investigated as a potential
veterinary patients, either as a primary or adjunctive modality in experimental dogs,93,181,182 but overall suc-
treatment. Interpretation of published data can be cess in humans with a variety of intracranial tumors
problematic when considering specific tumor types has been limited.183,184
because of a lack of histologic diagnoses for many More recent advances in veterinary radiation oncol-
masses treated, and variability in radiation type and ogy for brain tumors have been driven by the avail-
dosing schedule. Radiation therapy has been reported ability of stereotactic radiotherapy (SRT) equipment
specifically to be beneficial when compared to surgical and procedures, in which radiation is delivered to
resection alone for treatment of meningiomas.145 In sterotactically defined tumor volumes. Radiation may
general, reported median survival times for radiation be delivered by multiple cobalt sources,e or linear
treatment alone for all masses, inraaxial masses, and accelerators delivering extremely precise, high dose/
extra-axial masses are approximately 33–99 weeks, gradient plans. These may involve multiple static
approximately 40 weeks, approximately 40–49 weeks, beams using a 6 MV linear accelerator on a robotic
respectively.140,141,145,152,153,177–180 Although specific arm with 6 degrees of freedom,f or standard linear
data are limited in most studies, surgery combined accelerators fitted with stereotactic cones or micromul-
with radiation is reported to have improved outcomes tileaf collimators using multiple arcs planned around
compared to radiation alone.145,152 Extra-axial masses isocenters. SRT uses image-guided (MRI or CT), for-
(presumptive meningioma) tend to have a better prog- ward-based planning, and requires stringent quality
nosis than intraaxial masses.140,152 Standard megavolt- assurance (Fig 11). SRT has become widely used for
age external beam radiation therapy has been extended the treatment of nonresectable intracranial masses,
by use of intensity-modulated radiation therapy in either intraaxial or involving the skull base. Experience
which use of multileaf collimators that move during with skull base meningiomas and gliomas in humans
treatment allow for more precise, conformal delivery suggests responses may approach those seen with sur-
of radiation. Dose to tumor is increased with minimi- gically resected tumors.185,186 One of the major advan-
zation of dose to adjacent normal structures, although tages of SRT techniques is the ability to deliver the

Fig 11. (A, B) T1-weighted postcontrast and T2-weighted transverse images of a 4th ventricle choroid plexus tumor. (C) Dog posi-
tioned in stereotactic thermoplastic head restraint. The VARIAN trueBEAM linear acceleratork is equipped with a 2.5-mm leaf multileaf
collimator, a couch with 0.1-mm incremental movement, and on-board Kv, MV and cone beam CT to allow precise stereotactic delivery
of radiation. (D) BrainLab planning systemj showing the planned treatment trajectories to the tumor (magenta) sparing defined vital
structures (eyes-red/green, inner ears-yellow/blue). (E) Transverse CT image with isodose planning superimposed (images courtesy of M.
Kent, UC Davis).
 Brain Tumors 1177

therapeutic dose of radiation in 2–5 fractions (single 2) therapies targeting aberrant molecular pathways;
dose treatments are referred to as stereotactic radiosur- 3) toxin or suicide gene therapies targeted to tumor
gery [SRS]) compared to 16–20 fractions for standard cell-specific markers; and
radiation protocols. This is particularly relevant in vet- 4) immunotherapies.
erinary patients, where general anesthesia is required
for each treatment. There are limitations to the size of Targeting of brain tumors at the gross level has been
masses that can be treated with SRT (several cms), advanced by techniques such as convection-enhanced
and it is generally not suitable for treating microscopic delivery (CED), in which infusion of therapeutic
residual disease (eg, after surgical resection). Availabil- agents directly into tumor tissue results in the potential
ity of treatment centers is limited, and only linear for extremely high intratumoral drug concentrations
accelerator-based systems have been used in dogs and with minimal to no systemic toxicity. The technique
cats, but preliminary data suggest that efficacy is com- involves delivery of macromolecules by bulk flow using
parable to standard radiation protocols with poten- low pressures and specifically designed catheters, and
tially fewer short-term adverse effects.187–191 Final allows clinically relevant volumes of therapeutic agents
evaluation of SRT will be dependent on long-term to be delivered, usually over several hours to days.195
assessment of histologically confirmed cases. Boron Recent advances in the technique have allowed for
neutron capture treatment is a localized radiation ther- real-time imaging of infusions allowing for both accu-
apy depending on preferential local delivery of 10B to rate planning and meaningful assessment of therapeu-
tumor tissue followed by delivery of thermal neutrons. tic outcome (Fig 10). A variety of imaging agents have
Resultant 7Li nuclei and 4He (a-particles) produce been used including gadolinium, iron oxide nanoparti-
high-dose radiotherapy with potential for selective kill- cles, and PET tracers.176,196–198 Specifically in canine
ing of 10B-loaded cells. Preliminary translational stud- brain tumors, CED of liposomal CPT-11, and EG-
ies in dogs with a variety of intracranial tumors FRvIII-antibody bioconjugated magnetic iron oxide
demonstrated the feasibility of the approach and anec- nanoparticles have been shown to have efficacy in
dotal therapeutic successes with and without surgical canine gliomas, even as monotherapies, with minimal
cytoreduction.192,193 Although availability of equip- adverse effects (Figs 10, 12).176,199 CED approaches
ment is limiting, recent advances in more tumor-selec- are often limited by an inability to distribute therapeu-
tive boron delivery drugs may improve the limited tic agents to the entire tumor volume. Advances in
clinical efficacy and toxicity (eg, radiation necrosis) in catheter designs, predictive imaging software, and ther-
the future.194 apeutic agent strategies are helping to improve vol-
umes of distribution throughout heterogenous tumors,
Novel Therapies and include the use of arborizing fiberoptic catheters
and local hyperthermia.175,200 CED infusion of replica-
Recognition of small animal diseases as clinically tion competent retroviral vectors capable of tumor
relevant translational models for human disease has spread beyond the borders of the CED distribution is
opened up numerous collaborative opportunities for an alternative strategy to maximize tumor coverage,
veterinarians, most notably in the field of oncology. and has been utilized in both human and canine clini-
Canine brain tumor patients are increasingly being cal trials to deliver suicide gene therapy vectors,
enrolled in a variety of clinical trials. Ongoing areas of although efficacy has not yet been shown.201,202
research involving veterinary centers can be broadly Many experimental gene therapies have been devel-
divided into: oped for trials in humans utilizing a variety of viral vec-
tors (often nonreplicating or conditionally replicative),
1) Novel delivery approaches to circumvent drug most commonly adenovirus, adeno-associated virus,
delivery limitations because of the blood–brain herpes simplex virus, and retrovirus. Common therapeu-
barrier; tic strategies include suicide gene therapy, oncolytic

Fig 12. Intratumoral delivery of iron oxide nanoparticles. (A) Pretreatment T2-weighted transverse image showing a large intraaxial oli-
godendroglioma. (B) Seven days after surgical resection, cetuximabl-conjugated iron oxide nanoparticles targeting to EGFR were infused
into the residual tumor. Susceptibility artifact generated by the iron particles allows the infusion to be determined as an area of hypoin-
tensity within the residual tumor mass. (C) Nanoparticles are still apparent 4 weeks postinfusion and tumor mass effect is substantially
decreased. The dog is alive 2 years posttreatment (images courtesy of S. Platt University of Georgia).
1178 Dickinson

treatment, immunomodultion, gene replacement, proa- tumors. Ideal markers are expressed in all tumor cells,
poptotic treatment, and antiangiogenesis.175,203 Success- ideally in all tumors, and have minimal to no expres-
ful delivery or efficacy of gene therapy approaches using sion in either local (eg, brain) or systemic tissues, if
viral vectors and plasmid DNA has been shown experi- systemic delivery strategies are to be used. Several
mentally in canine brain tumor cells and brain using markers such as IL-13 receptor alpha 2, EGFR, and
adenoviral,204–209 retroviral201,202,210 herpes,211 and transferring receptor, either alone or in combination,
adeno-associated viral212–214 delivery. Few viral thera- have been targeted in human neurooncology to deliver
pies have progressed to phase III clinical trials, and none toxin based or suicide gene therapies.175 Similar to
have been shown to have significant efficacy in high- human gliomas, most canine gliomas overexpress both
grade brain tumors in phase III trials to date.175 IL-13 alpha 2 receptor and EphA2 receptor.128,129 Tri-
Targeting of defined aberrant pathways in oncology als in humans using Pseudomonas-derived IL-13 toxin
has resulted in some of the most dramatic improve- conjugates have shown some efficacy, and trials in
ments in survival times for several human cancers, dogs utilizing similar canine optimized toxins127–129 are
most notably trastuzumabg antibody targeting of planned. Similarly, targeting of canine tumors overex-
Her2/Neu overexpressing breast cancers24 and small pressing EGFR using antibodies conjugated to iron
molecule inhibitor imatinibh targeting of BCR-ABL nanoparticles is in progress.199
positive chronic myelogenous leukemia.25 A majority Small peptides have major advantages over antibod-
of targeted therapies involve either antibodies or small ies for tumor targeting in that they are less immuno-
molecule inhibitors, and many have been investigated genic, have longer tissue half-lives, and have the
in human brain tumors with minimal activity demon- potential to be readily modified and conjugated for a
strated to date.104 This may be a reflection of many variety of therapeutic or imaging options. Random
factors including insufficient characterization of both screening of peptide libraries is an efficient method to
tumors and patients, as well as the potential need for define tumor-specific peptides,224 and has been done
multiple target strategies. Two small molecule inhibi- for several canine cancers including lymphoma, mela-
tors have been approved for use in veterinary medi- noma, and glioma.130,225,226 Tumor-specific targeting
cine, toceranib phosphatec which blocks a variety of of glioma using peptides recognizing alpha 3 beta 1 in-
RTKs including VEGFR2, PDGFRalpha/beta, KIT, tegrin has been demonstrated in human cancers.227
and FLt3, and masitinibi which inhibits PDGFRalpha/ Similar findings in canine glioma as well as in vivo
beta and KIT. Veterinary trials with toceranib and demonstration of the feasibility of peptide targeting in
masitinib have shown benefit in several cancers but dogs228,229 opens the possibility of future peptide-con-
have not been reported for brain tumors. Documented jugated therapies for canine glioma (Fig 13).
overexpression of VEGF, VEGF receptors, and
PDGFR alpha in some canine brain tumors108–116 may Immunotherapy
justify trials with these or similar small molecules in
defined patients. Augmentation of the patient’s T cell-mediated
A growing body of evidence has implicated tumor immune response against neoplastic cells, normally
cells with stem cell-like properties as a potential source limited by the brain’s immuno-privileged niche, is a
of both tumor initiation and tumor recurrence or resis- developing field in humans for both gliomas and on a
tance to treatment.215–217 Although this is still a con- smaller scale meningiomas.203,230–232 Several
troversial area of research, many investigators have approaches are being explored including gene therapy
defined populations of tumor cells that have genetic delivery of immunostimulatory genes such as IL-2, 4,
and epigenetic phenotypes similar to primitive precur- 12, TNF alpha, interferon alpha, beta, and gamma
sor cells with molecular profiles more typical of cells and dendritic cell growth factors such as Flt3L. Sev-
during brain neuro- and gliogenesis and develop- eral “vaccine”-based approaches have been developed
ment.218 Targeting either stem cell surface markers or including vaccination with patient dendritic cells
dysregulated “developmental” pathways in tumors is “primed” with tumor antigen, tumor peptides, heat
an attractive and ongoing area of research. Stem-like shock proteins, and autologous and allogenic tumor
cells expressing putative developmental markers such cell preparations.203,230–233 Limited information is
as CD133, Olig2, and nestin have been described by available defining immune cell activity in canine brain
several authors in canine gliomas (Fig 4), and preli- tumors, but preliminary studies defining immune cell
minary data suggest that epigenetic alterations in infiltration in canine meningiomas,234 and the ability
canine glioma may parallel the developmental profile of Flt3L to stimulate canine dendritic cells,235 suggest
seen in human tumors.219–223 An alternative utilization that there will be many similarities to human tumors.
of stem cells in neurooncology is the exploitation of Translational studies in dogs with glioma using tumor
the inherent tumor-tropic properties of normal or cell lysate/CpG vaccines, combined with postsurgical
modified stem cells. The ability to target distant, inva- intracavitary delivery of IFNg via an adenoviral vec-
sive tumor cells and deliver a variety of therapeutic tor, have demonstrated the feasibility of immunother-
agents is a developing and promising field.203 apy in dogs, with tumor-reactive IgG and CD8+ T
Targeting of aberrantly expressed surface markers cells being documented in 1 reported case.206,236 Simi-
on tumor cells has been exploited as a strategy for lar studies using autologous tumor lysate vaccines
delivering imaging or therapeutic agents specifically to combined with toll-like receptor ligands (CpG, imiqui-
 Brain Tumors 1179

Fig 13. Isolation of canine glioma-targeting peptides for delivery of imaging and therapeutic agents. Tumor-specific peptides have many
advantages over more traditional antibody based targeting strategies. (A) Canine glioma cells bind to bead-specific peptide sequences in
random screening libraries. (B, C) Isolation of bead peptides and conjugation to fluorescent markers allows targeting to canine glioma
tumors grown in mouse subcutaneous models.

mod) after resection of meningiomas in dogs also have

been reported.237 Treatment resulted in the production Footnotes
of polyclonal antibody responses in all dogs, with infil-
a
tration of plasma cells into surrounding brain tissue. Temodar; Merk & Co, Inc, Whitehouse Station, NJ
b
Additional studies investigating combinations of local Avastin; Genentech Inc, South San Francisco, CA
c
adenoviral gene therapy delivery of HSV-tk suicide SU11654 Palladia; Pfizer Animal Health, New York, NY
d
genes and Flt3L dendritic growth factor postresection Brainsight Vet; Rogue Research Inc, Montreal, QC, Canada
e
Gamma Knife Elekta AB, Stockholm, Sweden
and tumor lysate vaccines derived under varying oxy- f
CyberKnife; Accuray, Sunnyvale, CA
gen tensions are in progress.236 Although efficacy of g
Herceptin; Genentech Inc
immune-based therapies has yet to be shown in phase h
Gleevec; Novartis Pharmaceuticals Corporation, East Hanover,
III trials in humans or veterinary patients, preliminary NJ
results are encouraging and show the feasibility of i
Kinavet, Masivet; AB Science, Short Hills, NJ
j
these approaches. VectorVision, BRAINLAB; Feldkirschen, Germany
k
trueBEAM; Varian Medical Systems, Inc, Palo Alto, CA
l
Erbitux; ImClone Systems Inc, Somerville, NJ
Future
Veterinary neurooncology still has a large amount
of benefit to be obtained from application of currently
available techniques and advancements in standard Acknowledgment
surgical, chemotherapeutic, and radiation-based thera-
Conflict of Interest Declaration: The authors disclose
pies, but expense, species-specific factors, and availabil-
no conflict of interest.
ity may be limiting in some areas.
Rapid advances in global analysis of cancer molecu-
lar phenotypes together with industrial scale develop- References
ment of targeted small molecule therapeutics are likely 1. Kimmelman J, Nalbantoglu J. Faithful companions: A pro-
to provide the greatest opportunity for advances in posal for neurooncology trials in pet dogs. Cancer Res
outcome in both human and veterinary neurooncolo- 2007;67:4541–4544.
gy. Realistically, companion animal neurooncology 2. Paoloni M, Khanna C. Translation of new cancer treatments
will rely on use or modification of therapeutics devel- from pet dogs to humans. Nat Rev Cancer 2008;8:147–156.
oped for human patients, and although it appears that 3. Candolfi M, Curtin JF, Nichols WS, et al. Intracranial glio-
blastoma models in preclinical neuro-oncology: Neuropathologi-
most cancers follow similar developmental pathways,
cal characterization and tumor progression. J Neurooncol
subtle differences may be critical for appropriate appli- 2007;85:133–148.
cation. Continued in-depth evaluation of both the 4. Dorn CR, Taylor DO, Frye FL, et al. Survey of animal
molecular genetics and natural biology of companion neoplasms in Alameda and Contra Costa Counties, California. I.
animal intracranial tumors will be critical for optimal Methodology and description of cases. J Natl Cancer Inst
future outcomes for patients with these tumors. 1968;40:295–305.
1180 Dickinson

5. Schneider R. General considerations. In: Moulton JE, ed. radiotherapy alone on survival in glioblastoma in a randomised
Tumors in Domestic Animals, 2nd ed. Berkley: University of phase III study: 5-year analysis of the EORTC-NCIC trial. Lan-
California Press; 1978:1–15. cet Oncol 2009;10:459–466.
6. Dolecek TA, Propp JM, Stroup NE, et al. CBTRUS statis- 27. Gilbert MR, Dignam JJ, Armstrong TS, et al. A random-
tical report: Primary brain and central nervous system tumors ized trial of bevacizumab for newly diagnosed glioblastoma. N
diagnosed in the United States in 2005–2009. Neuro Oncol Engl J Med 2014;370:699–708.
2012;14(Suppl 5):v1–v49. 28. Koestner A, Bilzer T, Fatzer R, et al. Histological Classifi-
7. McGrath JT. Intracranial pathology of the dog. Acta Neu- cation of Tumors of the Nervous System of Domestic Animals,
ropathol (Berl) 1962;(Suppl I):3–4. 2nd ed. Washington, DC: The Armed Forces Institute of Pathol-
8. Priester WA, Mantel N. Occurrence of tumors in domestic ogy; 1999:71.
animals. Data from 12 United States and Canadian colleges of 29. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO
veterinary medicine. J Natl Cancer Inst 1971;47:1333–1344. classification of tumours of the central nervous system. Acta
9. Song RB, Vite CH, Bradley CW, et al. Postmortem evalua- Neuropathol (Berl) 2007;114:97–109.
tion of 435 cases of intracranial neoplasia in dogs and relation- 30. Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classifi-
ship of neoplasm with breed, age, and body weight. J Vet Intern cation of Tumors of the Central Nervous System, 4th ed. Gen-
Med 2013;27:1143–1152. eva: WHO Press; 2007.
10. Klotz M. Incidence of brain tumors in patients hospital- 31. Grevel V, Machus B. Diagnosing brain tumors with a
ized for chronic mental disorders. Psychiatr Q 1957;31:669–680. CSF sedimantation technique. Vet Med Rep 1990;2:403–408.
11. Bagley RS, Gavin PR, Moore MP, et al. Clinical signs 32. Palus V, Volk HA, Lamb CR, et al. MRI features of
associated with brain tumors in dogs: 97 cases (1992–1997). J CNS lymphoma in dogs and cats. Vet Radiol Ultrasound
Am Vet Med Assoc 1999;215:818–819. 2012;53:44–49.
12. Snyder JM, Shofer FS, Van Winkle TJ, et al. Canine 33. Vandevelde M, Richard A, Fankhauser R. Liquorunter-
intracranial primary neoplasia: 173 cases (1986–2003). J Vet suchungen bei neurologisch kranken hunden und katzen. Schweiz
Intern Med 2006;20:669–675. Arch Tierheilk 1987;129:443–456.
13. Snyder JM, Lipitz L, Skorupski KA, et al. Secondary 34. Tzipory L, Vernau KM, Sturges BK, et al. Antemortem
intracranial neoplasia in the dog: 177 cases (1986–2003). J Vet diagnosis of localized central nervous system histiocytic sarcoma
Intern Med 2008;22:172–177. in 2 dogs. J Vet Intern Med 2009;23:369–374.
14. Song YK, Liu F, Chu S, et al. Characterization of cat- 35. Zimmerman K, Almy F, Carter L, et al. Cerebrospinal
ionic liposome-mediated gene transfer in vivo by intravenous fluid from a 10-year-old dog with a single seizure episode. Vet
administration. Hum Gene Ther 1997;8:1585–1594. Clin Pathol 2006;35:127–131.
15. Sturges BK, Dickinson PJ, Bollen AW, et al. Magnetic 36. Bohn AA, Wills TB, West CL, et al. Cerebrospinal fluid
resonance imaging and histological classification of intracranial analysis and magnetic resonance imaging in the diagnosis of neu-
meningiomas in 112 dogs. J Vet Intern Med 2008;22:586–595. rologic disease in dogs: A retrospective study. Vet Clin Pathol
16. Westworth DR, Dickinson PJ, Vernau W, et al. Choroid 2006;35:315–320.
plexus tumors in 56 dogs (1985–2007). J Vet Intern Med 37. Bailey CS, Higgins RJ. Characteristics of cisternal cerebro-
2008;22:1157–1165. spinal fluid associated with primary brain tumors in the dog: A
17. Kube SA, Bruyette DS, Hanson SM. Astrocytomas in retrospective study. J Am Vet Med Assoc 1986;188:414–417.
young dogs. J Am Anim Hosp Assoc 2003;39:288–293. 38. Rand JS, Parent J, Percy D, et al. Clinical, cerebrospinal
18. Hayes HM, Priester WA Jr, Pendergrass TW. Occurrence fluid, and histological data from thirty-four cats with primary
of nervous-tissue tumors in cattle, horses, cats and dogs. Int J noninflammatory disease of the central nervous system. Can Vet
Cancer 1975;15:39–47. J 1994;35:174–181.
19. Zaki FA, Hurvitz AI. Spontaneous neoplasms of the cen- 39. Dickinson PJ, Sturges BK, Kass PH, et al. Characteristics
tral nervous system of the cat. J Small Anim Pract 1976;17:773– of cisternal cerebrospinal fluid associated with intracranial menin-
782. giomas in dogs: 56 cases (1985–2004). J Am Vet Med Assoc
20. Tomek A, Cizinauskas S, Doherr M, et al. Intracranial 2006;228:564–567.
neoplasia in 61 cats: Localisation, tumour types and seizure pat- 40. Moore MP, Gavin PR, Bagley RS, et al. Cerebrospinal
terns. J Feline Med Surg 2006;8:243–253. fluid analysis in dogs with intracranial tumors. In: Proceedings of
21. Troxel MT, Vite CH, Massicotte C, et al. Magnetic reso- the American College of Veterinary Internal Medicine Forum,
nance imaging features of feline intracranial neoplasia: Retro- San Franscisco, CA, June 2, 1994:917–921.
spective analysis of 46 cats. J Vet Intern Med 2004;18:176–189. 41. Holdhoff M, Yovino SG, Boadu O, et al. Blood-based bio-
22. Bannasch D, Young A, Myers J, et al. Localization of markers for malignant gliomas. J Neurooncol 2013;113:345–352.
canine brachycephaly using an across breed mapping approach. 42. Ilhan-Mutlu A, Wagner L, Preusser M. Circulating bio-
PLoS One 2010;5:e9632. markers of CNS tumors: An update. Biomark Med 2013;7:267–
23. Truve K, Dickinson P, York D, et al. Evaluation of selec- 285.
tive sweeps for brachycephaly in dogs and associated susceptibil- 43. Mariani CL, Boozer LB, Braxton AM, et al. Evaluation
ity loci for glioma. In: Proceedings of the 6th International of matrix metalloproteinase-2 and -9 in the cerebrospinal fluid of
Conference on Advances in Canine and Feline Genomics and dogs with intracranial tumors. Am J Vet Res 2013;74:122–129.
Inherited Diseases, Visby, Sweden, May 28-June 1, 2012. 44. Turba ME, Forni M, Gandini G, et al. Recruited leuko-
24. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of che- cytes and local synthesis account for increased matrix metallo-
motherapy plus a monoclonal antibody against HER2 for meta- proteinase-9 activity in cerebrospinal fluid of dogs with central
static breast cancer that overexpresses HER2. N Engl J Med nervous system neoplasm. J Neurooncol 2007;81:123–129.
2001;344:783–792. 45. Platt SR, Marlin D, Smith N, et al. Increased cerebrospi-
25. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety nal fluid uric acid concentrations in dogs with intracranial menin-
of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic gioma. Vet Rec 2006;158:830.
myeloid leukemia. N Engl J Med 2001;344:1031–1037. 46. de la Fuente C, Monreal L, Ceron J, et al. Fibrinolytic
26. Stupp R, Hegi ME, Mason WP, et al. Effects of radiother- activity in cerebrospinal fluid of dogs with different neurological
apy with concomitant and adjuvant temozolomide versus disorders. J Vet Intern Med 2012;26:1365–1373.
 Brain Tumors 1181

47. Cervera V, Mai W, Vite CH, et al. Comparative magnetic mass lesions using dynamic contrast-enhanced computed tomog-
resonance imaging findings between gliomas and presumed cere- raphy in the dog. Acad Radiol 2009;16:1187–1195.
brovascular accidents in dogs. Vet Radiol Ultrasound 67. Zhao Q, Lee S, Kent M, et al. Dynamic contrast-
2011;52:33–40. enhanced magnetic resonance imaging of canine brain tumors.
48. Leclerc MK, d’Anjou MA, Blond L, et al. Interobserver Vet Radiol Ultrasound 2010;51:122–129.
agreement and diagnostic accuracy of brain magnetic resonance 68. Zwingenberger AL, Pollard RE, Kent MS. Measuring
imaging in dogs. J Am Vet Med Assoc 2013;242:1688–1695. response of brain tumors to stereotactic radiosurgery:Interim
49. Young BD, Levine JM, Porter BF, et al. Magnetic results. Vet Radiol Ultrasound 2010;51:577.
resonance imaging features of intracranial astrocytomas and oli- 69. Duffis EJ, Gandhi CD, Prestigiacomo CJ, et al. Head,
godendrogliomas in dogs. Vet Radiol Ultrasound 2011;52: neck, and brain tumor embolization guidelines. J Neurointerv
132–141. Surg 2012;4:251–255.
50. Keenihan EK, Summers BA, David FH, et al. Canine 70. Marioni-Henry K, Schwarz T, Weisse C, et al. Cystic
meningeal disease: Associations between magnetic resonance nasal adenocarcinoma in a cat treated with piroxicam and
imaging signs and histologic findings. Vet Radiol Ultrasound chemoembolization. J Am Anim Hosp Assoc 2007;43:347–351.
2013;54:504–515. 71. Jacqmot OD, Snaps FR, Maquet NM, et al. Arterial head
51. Lamb CR, Croson PJ, Cappello R, et al. Magnetic reso- vascularization cartographies of normal metencephalic dogs using
nance imaging findings in 25 dogs with inflammatory cerebrospi- magnetic resonance angiography. Anat Rec (Hoboken) 2011;
nal fluid. Vet Radiol Ultrasound 2005;46:17–22. 294:1834–1841.
52. Bentley RT, Ober CP, Anderson KL, et al. Canine intra- 72. Martin-Vaquero P, da Costa RC, Echandi RL, et al.
cranial gliomas: Relationship between magnetic resonance imag- Magnetic resonance spectroscopy of the canine brain at 3.0 T
ing criteria and tumor type and grade. Vet J 2013;198:463–471. and 7.0 T. Res Vet Sci 2012;93:427–429.
53. Cherubini GB, Mantis P, Martinez TA, et al. Utility of 73. Sager M, Assheuer J, Trummler H, et al. Contrast-
magnetic resonance imaging for distinguishing neoplastic from enhanced magnetic resonance angiography (CE-MRA) of intra-
non-neoplastic brain lesions in dogs and cats. Vet Radiol Ultra- and extra-cranial vessels in dogs. Vet J 2009;179:92–100.
sound 2005;46:384–387. 74. Shores A, Warber-Matich S, Cooper TG. The role of
54. Kraft SL, Gavin PR, DeHaan C, et al. Retrospective magnetic resonance spectroscopy in neuro-oncology. Semin Vet
review of 50 canine intracranial tumors evaluated by magnetic Med Surg (Small Anim) 1990;5:237–240.
resonance imaging. J Vet Intern Med 1997;11:218–225. 75. Barreiro CJ, Williams JA, Fitton TP, et al. Noninvasive
55. Rodenas S, Pumarola M, Gaitero L, et al. Magnetic reso- assessment of brain injury in a canine model of hypothermic cir-
nance imaging findings in 40 dogs with histologically confirmed culatory arrest using magnetic resonance spectroscopy. Ann Tho-
intracranial tumours. Vet J 2011;187:85–91. rac Surg 2006;81:1593–1598.
56. Singh JB, Oevermann A, Lang J, et al. Contrast media 76. Kang BT, Jang DP, Lee JH, et al. Detection of cerebral
enhancement of intracranial lesions in magnetic resonance imag- metabolites in a canine model of ischemic stroke using 1H mag-
ing does not reflect histopathologic findings consistently. Vet netic resonance spectroscopy. Res Vet Sci 2009;87:300–306.
Radiol Ultrasound 2011;52:619–626. 77. Lee SH, Kim SY, Woo DC, et al. Differential neurochem-
57. Anwer CC, Vernau KM, Higgins RJ, et al. Magnetic reso- ical responses of the canine striatum with pentobarbital or keta-
nance imaging features of intracranial granular cell tumors in six mine anesthesia: A 3T proton MRS study. J Vet Med Sci 2010;
dogs. Vet Radiol Ultrasound 2013;54:271–277. 72:583–587.
58. Tamura S, Tamura Y, Nakamoto Y, et al. MR imaging 78. Hansen AE, McEvoy F, Engelholm SA, et al. FDG PET/
of histiocytic sarcoma of the canine brain. Vet Radiol Ultrasound CT imaging in canine cancer patients. Vet Radiol Ultrasound
2009;50:178–181. 2011;52:201–206.
59. Graham JP, Newell SM, Voges AK, et al. The dural tail 79. Kang BT, Son YD, Lee SR, et al. FDG uptake of normal
sign in the diagnosis of meningiomas. Vet Radiol Ultrasound canine brain assessed by high-resolution research tomography-
1998;39:297–302. positron emission tomography and 7 T-magnetic resonance imag-
60. Nelson SJ. Assessment of therapeutic response and treat- ing. J Vet Med Sci 2012;74:1261–1267.
ment planning for brain tumors using metabolic and physiologi- 80. Kang BT, Kim SG, Lim CY, et al. Correlation between
cal MRI. NMR Biomed 2011;24:734–749. fluorodeoxyglucose positron emission tomography and magnetic
61. Stadnik TW, Chaskis C, Michotte A, et al. Diffusion- resonance imaging findings of non-suppurative meningoencepha-
weighted MR imaging of intracerebral masses: Comparison with litis in 5 dogs. Can Vet J 2010;51:986–992.
conventional MR imaging and histologic findings. AJNR Am J 81. Kang BT, Park C, Yoo JH, et al. 18F-fluorodeoxyglucose
Neuroradiol 2001;22:969–976. positron emission tomography and magnetic resonance imaging
62. Sutherland-Smith J, King R, Faissler D, et al. Magnetic findings of primary intracranial histiocytic sarcoma in a dog. J
resonance imaging apparent diffusion coefficients for histologi- Vet Med Sci 2009;71:1397–1401.
cally confirmed intracranial lesions in dogs. Vet Radiol Ultra- 82. Horska A, Barker PB. Imaging of brain tumors: MR spec-
sound 2011;52:142–148. troscopy and metabolic imaging. Neuroimaging Clin N Am
63. Desprechins B, Stadnik T, Koerts G, et al. Use of diffu- 2010;20:293–310.
sion-weighted MR imaging in differential diagnosis between 83. Li Y, Lupo JM, Polley MY, et al. Serial analysis of imag-
intracerebral necrotic tumors and cerebral abscesses. AJNR Am ing parameters in patients with newly diagnosed glioblastoma
J Neuroradiol 1999;20:1252–1257. multiforme. Neuro Oncol 2011;13:546–557.
64. Wang Y, Lv X, Gong H, et al. Acute irradiation injury of 84. Flegel T, Oevermann A, Oechtering G, et al. Diagnostic
canine brain with pathology control is detected by diffusion- yield and adverse effects of MRI-guided free-hand brain biopsies
weighted imaging of MRI. Clin Imaging 2013;37:440–445. through a mini-burr hole in dogs with encephalitis. J Vet Intern
65. Gerstner ER, Sorensen AG. Diffusion and diffusion tensor Med 2012;26:969–976.
imaging in brain cancer. Semin Radiat Oncol 2011;21:141–146. 85. Harari J, Moore MM, Leathers CW, et al. Computed
66. MacLeod AG, Dickinson PJ, LeCouteur RA, et al. Quan- tomographic-guided free-hand needle biopsy of brain tumors in
titative assessment of blood volume and permeability in cerebral dogs. Prog Vet Neurol 1993;4:41–44.
1182 Dickinson

86. Klopp LS, Ridgway M. Use of an endoscope in minimally 106. Betensky RA, Louis DN, Cairncross JG. Influence of
invasive lesion biopsy and removal within the skull and cranial unrecognized molecular heterogeneity on randomized clinical tri-
vault in two dogs and one cat. J Am Vet Med Assoc als. J Clin Oncol 2002;20:2495–2499.
2009;234:1573–1577. 107. Vogelstein B, Papadopoulos N, Velculescu VE, et al.
87. Coffey RJ, Lunsford LD. Animal research stereotactic Cancer genome landscapes. Science 2013;339:1546–1558.
instrument modified for computed tomographic guidance. Appl 108. Dickinson PJ, Roberts BN, Higgins RJ, et al. Expression
Neurophysiol 1987;50:81–86. of receptor tyrosine kinases VEGFR-1 (FLT-1), VEGFR-2
88. Maciunas RJ, Galloway RL. Magnetic resonance and (KDR), EGFR-1, PDGFRalpha and c-Met in canine primary
computed tomographic image-directed stereotaxy for animal brain tumours. Vet Comp Oncol 2006;4:132–140.
research. Stereotact Funct Neurosurg 1989;53:197–201. 109. Higgins RJ, Dickinson PJ, Lecouteur RA, et al. Sponta-
89. Koblik PD, LeCouteur RA, Higgins RJ, et al. CT-guided neous canine gliomas: Overexpression of EGFR, PDGFRalpha
brain biopsy using a modified Pelorus Mark III stereotactic sys- and IGFBP2 demonstrated by tissue microarray immunopheno-
tem: Experience with 50 dogs. Vet Radiol Ultrasound typing. J Neurooncol 2009;98:49–55.
1999;40:434–440. 110. Stoica G, Kim HT, Hall DG, et al. Morphology, immu-
90. Koblik PD, LeCouteur RA, Higgins RJ, et al. Modifica- nohistochemistry, and genetic alterations in dog astrocytomas.
tion and application of a Pelorus Mark III stereotactic system Vet Pathol 2004;41:10–19.
for CT-guided brain biopsy in 50 dogs. Vet Radiol Ultrasound 111. Ide T, Uchida K, Kikuta F, et al. Immunohistochemical
1999;40:424–433. characterization of canine neuroepithelial tumors. Vet Pathol
91. Moissonnier P, Blot S, Devauchelle P, et al. Stereotactic 2010;47:741–750.
CT-guided brain biopsy in the dog. J Small Anim Pract 112. Lipsitz D, Higgins RJ, Kortz GD, et al. Glioblastoma
2002;43:115–123. multiforme: Clinical findings, magnetic resonance imaging, and
92. Troxel MT, Vite CH. CT-guided stereotactic brain biopsy pathology in five dogs. Vet Pathol 2003;40:659–669.
using the Kopf stereotactic system. Vet Radiol Ultrasound 113. Dickinson PJ, Sturges BK, Higgins RJ, et al. Vascular
2008;49:438–443. endothelial growth factor mRNA expression and peritumoral
93. Packer RA, Freeman LJ, Miller MA, et al. Evaluation of edema in canine primary central nervous system tumors. Vet
minimally invasive excisional brain biopsy and intracranial Pathol 2008;45:131–139.
brachytherapy catheter placement in dogs. Am J Vet Res 114. Platt SR, Scase TJ, Adams V, et al. Vascular endothelial
2011;72:109–121. growth factor expression in canine intracranial meningiomas and
94. Flegel T, Podell M, March PA, et al. Use of a disposable association with patient survival. J Vet Intern Med 2006;20:663–668.
real-time CT stereotactic navigator device for minimally invasive 115. Matiasek LA, Platt SR, Adams V, et al. Ki-67 and vas-
dog brain biopsy through a mini-burr hole. AJNR Am J Neuro- cular endothelial growth factor expression in intracranial menin-
radiol 2002;23:1160–1163. giomas in dogs. J Vet Intern Med 2009;23:146–151.
95. Taylor AR, Cohen ND, Fletcher S, et al. Application and 116. Rossmeisl JH, Duncan RB, Huckle WR, et al. Expres-
machine accuracy of a new frameless computed tomography- sion of vascular endothelial growth factor in tumors and plasma
guided stereotactic brain biopsy system in dogs. Vet Radiol from dogs with primary intracranial neoplasms. Am J Vet Res
Ultrasound 2013;54:332–342. 2007;68:1239–1245.
96. Chen AV, Wininger FA, Frey S, et al. Description and vali- 117. Mandara MT, Ricci G, Rinaldi L, et al. Immunohisto-
dation of a magnetic resonance imaging-guided stereotactic brain chemical identification and image analysis quantification of oes-
biopsy device in the dog. Vet Radiol Ultrasound 2012;53:150–156. trogen and progesterone receptors in canine and feline
97. Carvalho LH, Smirnov I, Baia GS, et al. Molecular signatures meningioma. J Comp Pathol 2002;127:214–218.
define two main classes of meningiomas. Mol Cancer 2007;6:64. 118. Theon AP, Lecouteur RA, Carr EA, et al. Influence of
98. Cancer Genome Atlas Research N. Comprehensive geno- tumor cell proliferation and sex-hormone receptors on effective-
mic characterization defines human glioblastoma genes and core ness of radiation therapy for dogs with incompletely resected
pathways. Nature 2008;455:1061–1068. meningiomas. J Am Vet Med Assoc 2000;216:701–707.
99. Verhaak RG, Hoadley KA, Purdom E, et al. Integrated 119. Long S, Argyle DJ, Nixon C, et al. Telomerase reverse
genomic analysis identifies clinically relevant subtypes of glioblas- transcriptase (TERT) expression and proliferation in canine brain
toma characterized by abnormalities in PDGFRA, IDH1, tumours. Neuropathol Appl Neurobiol 2006;32:662–673.
EGFR, and NF1. Cancer Cell 2010;17:98–110. 120. Mandrioli L, Panarese S, Cesari A, et al. Immunohisto-
100. Phillips HS, Kharbanda S, Chen R, et al. Molecular sub- chemical expression of h-telomerase reverse transcriptase in
classes of high-grade glioma predict prognosis, delineate a pat- canine and feline meningiomas. J Vet Sci 2007;8:111–115.
tern of disease progression, and resemble stages in neurogenesis. 121. Mandara MT, Pavone S, Mandrioli L, et al. Matrix me-
Cancer Cell 2006;9:157–173. talloproteinase-2 and matrix metalloproteinase-9 expression in
101. Shen R, Mo Q, Schultz N, et al. Integrative subtype dis- canine and feline meningioma. Vet Pathol 2009;46:836–845.
covery in glioblastoma using iCluster. PLoS One 2012;7:e35236. 122. Beltran E, Matiasek K, Risio LD, et al. Expression of
102. Brennan C, Momota H, Hambardzumyan D, et al. Glio- MMP-2 and MMP-9 in benign canine rostrotentorial meningio-
blastoma subclasses can be defined by activity among signal mas is not correlated to the extent of peritumoral edema. Vet
transduction pathways and associated genomic alterations. PLoS Pathol 2013;50:1091–1098.
One 2009;4:e7752. 123. Platt S, Kent M, Northrup N, et al. Immunohistochemi-
103. Huse JT, Holland E, DeAngelis LM. Glioblastoma: cal quantification of interleukin-6 and interleukin-8 expression in
Molecular analysis and clinical implications. Annu Rev Med canine intracranial meningiomas. J Vet Intern Med 2012;26:807.
2013;64:59–70. (abstract)
104. Tanaka S, Louis DN, Curry WT, et al. Diagnostic and 124. Ramos-Vara JA, Miller MA, Gilbreath E, et al. Immu-
therapeutic avenues for glioblastoma: No longer a dead end? Nat nohistochemical detection of CD34, E-cadherin, claudin-1, glu-
Rev Clin Oncol 2013;10:14–26. cose transporter 1, laminin, and protein gene product 9.5 in 28
105. Weller M, Stupp R, Hegi M, et al. Individualized tar- canine and 8 feline meningiomas. Vet Pathol 2010;47:725–737.
geted therapy for glioblastoma: Fact or fiction? Cancer J 125. Mariani CJ. Matrix metalloproteinase-2 and -9 in canine
2012;18:40–44. central nervous system tumors. In: Proceedings of the American
 Brain Tumors 1183

College of Veterinary Internal Medicine Forum, New Orleans, 147. Greco JJ, Aiken SA, Berg JM, et al. Evaluation of intra-
LA, May 30-June 2, 2012:421. cranial meningioma resection with a surgical aspirator in dogs:
126. Rossmeisl JH Jr, Robertson JL, Zimmerman KL, et al. 17 cases (1996–2004). J Am Vet Med Assoc 2006;229:394–400.
Cyclooxygenase-2 (COX-2) expression in canine intracranial men- 148. Klopp LS, Rao S. Endoscopic-assisted intracranial tumor
ingiomas. Vet Comp Oncol 2009;7:173–180. removal in dogs and cats: Long-term outcome of 39 cases. J Vet
127. Gibo DM, Dickinson P, Robertson J, et al. Highly Intern Med 2009;23:108–115.
potent toxin targeting IL-13Ra2 in canine and human glioblas- 149. Gordon LE, Thacher C, Matthiesen DT, et al. Results of
toma. Neuro Oncol 2012;14:vi31–vi32. craniotomy for the treatment of cerebral meningioma in 42 cats.
128. Gibo DM, Dickinson P, Robertson J, et al. Interleukin Vet Surg 1994;23:94–100.
13 receptor alpha-2 is widely over-expressed in human and canine 150. Gallagher JG, Berg J, Knowles KE, et al. Prognosis after
primary brain tumors as detected by novel bispecies-specific surgical excision of cerebral meningiomas in cats: 17 cases (1986–
monoclonal antibodies. Neuro Oncol 2012;14:vi47. 1992). J Am Vet Med Assoc 1993;203:1437–1440.
129. Debinski W, Dickinson P, Rossmeisl JH, et al. New 151. Troxel MT, Vite CH, Van Winkle TJ, et al. Feline intra-
agents for targeting of IL-13RA2 expressed in primary human cranial neoplasia: Retrospective review of 160 cases (1985–2001).
and canine brain tumors. PLoS One 2013;8:e77719. J Vet Intern Med 2003;17:850–859.
130. Sturges BK, Dickinson PJ, Aina OH, et al. Identification 152. Brearley MJ, Jeffery ND, Phillips SM, et al. Hypofrac-
of novel targeting peptides for canine glioma. J Vet Intern Med tionated radiation therapy of brain masses in dogs: A retrospec-
2008;22:771. tive analysis of survival of 83 cases (1991–1996). J Vet Intern
131. Thomson SA, Kennerly E, Olby N, et al. Microarray Med 1999;13:408–412.
analysis of differentially expressed genes of primary tumors in the 153. Niebauer GW, Dayrell-Hart BL, Speciale J. Evaluation
canine central nervous system. Vet Pathol 2005;42:550–558. of craniotomy in dogs and cats. J Am Vet Med Assoc
132. Dickinson PJ, Nagarajan RP, Lin D, et al. Genome wide 1991;198:89–95.
methylation sequencing to profile epigenetic modifications in 154. Fulton LM, Steinberg HS. Preliminary study of lomus-
canine glioma. In: Proceedings of the American College of Veter- tine in the treatment of intracranial masses in dogs following
inary Internal Medicine, Seattle, WA, June 12-15, 2013:343. localization by imaging techniques. Semin Vet Med Surg (Small
133. Courtay-Cahen C, Platt SR, De Risio L, et al. Prelimin- Anim) 1990;5:241–245.
ary analysis of genomic abnormalities in canine meningiomas. 155. Meij B, Voorhout G, Rijnberk A. Progress in transsphe-
Vet Comp Oncol 2008;6:182–192. noidal hypophysectomy for treatment of pituitary-dependent hy-
134. Thomas R, Duke SE, Wang HJ, et al. ‘Putting our heads peradrenocorticism in dogs and cats. Mol Cell Endocrinol
together’: Insights into genomic conservation between human 2002;197:89–96.
and canine intracranial tumors. J Neurooncol 2009;94:333–349. 156. Kent MS, Bommarito D, Feldman E, et al. Survival,
135. Dickinson PJ, Surace EI, Cambell M, et al. Expression neurologic response, and prognostic factors in dogs with pituitary
of the tumor suppressor genes NF2, 4.1B, and TSLC1 in canine masses treated with radiation therapy and untreated dogs. J Vet
meningiomas. Vet Pathol 2009;46:884–892. Intern Med 2007;21:1027–1033.
136. Reitman ZJ, Olby NJ, Mariani CL, et al. IDH1 and 157. Theon AP, Feldman EC. Megavoltage irradiation of
IDH2 hotspot mutations are not found in canine glioma. Int J pituitary macrotumors in dogs with neurologic signs. J Am Vet
Cancer 2010;127:245–246. Med Assoc 1998;213:225–231.
137. York D, Higgins RJ, LeCouteur RA, et al. TP53 muta- 158. Hirano T, Nakagawa A, Uenohara H, et al. Pulsed
tions in canine brain tumors. Vet Pathol 2012;49:796–801. liquid jet dissector using holmium:YAG laser—A novel neurosur-
138. Schwartz M, Lamb CR, Brodbelt DC, et al. Canine gical device for brain incision without impairing vessels. Acta
intracranial neoplasia: Clinical risk factors for development of Neurochir (Wien) 2003;145:401–406; discussion 406.
epileptic seizures. J Small Anim Pract 2011;52:632–637. 159. Feder BM, Fry TR, Kostolich M, et al. Nd:YAG laser
139. Foster ES, Carrillo JM, Patnaik AK. Clinical signs of cytoreduction of an invasive intracranial meningioma in a dog.
tumors affecting the rostral cerebrum in 43 dogs. J Vet Intern Prog Vet Neurol 1993;4:3–9.
Med 1988;2:71–74. 160. Schwartz JA, Shetty AM, Price RE, et al. Feasibility
140. Heidner GL, Kornegay JN, Page RL, et al. Analysis of study of particle-assisted laser ablation of brain tumors in ortho-
survival in a retrospective study of 86 dogs with brain tumors. J topic canine model. Cancer Res 2009;69:1659–1667.
Vet Intern Med 1991;5:219–226. 161. Ellis TL, Garcia PA, Rossmeisl JH Jr, et al. Nonthermal
141. Turrel JM, Fike JR, LeCouteur RA, et al. Radiotherapy irreversible electroporation for intracranial surgical applications.
of brain tumors in dogs. J Am Vet Med Assoc 1984;184:82–86. Laboratory investigation. J Neurosurg 2011;114:681–688.
142. Van Meervenne S, Verhoeven PS, de Vos J, et al. Com- 162. Garcia PA, Pancotto T, Rossmeisl JH Jr, et al. Non-
parison between symptomatic treatment and lomustine supple- thermal irreversible electroporation (N-TIRE) and adjuvant frac-
mentation in 71 dogs with intracranial, space-occupying lesions. tionated radiotherapeutic multimodal therapy for intracranial
Vet Comp Oncol 2012;12:67–77. malignant glioma in a canine patient. Technol Cancer Res Treat
143. Rossmeisl JH Jr, Jones JC, Zimmerman KL, et al. Survival 2011;10:73–83.
time following hospital discharge in dogs with palliatively treated 163. Herickhoff CD, Light ED, Bing KF, et al. Dual-mode
primary brain tumors. J Am Vet Med Assoc 2013;242:193–198. intracranial catheter integrating 3D ultrasound imaging and
144. Kostolich M, Dulisch ML. A surgical approach to the hyperthermia for neuro-oncology: Feasibility study. Ultrason
canine olfactory bulb for meningioma removal. Vet Surg Imaging 2009;31:81–100.
1987;16:273–277. 164. Chan F, Kassim I, Lo C, et al. Image-guided robotic neu-
145. Axlund TW, McGlasson ML, Smith AN. Surgery alone rosurgery—An in vitro and in vivo point accuracy evaluation exper-
or in combination with radiation therapy for treatment of intra- imental study. Surg Neurol 2009;71:640–647; discussion 647–648.
cranial meningiomas in dogs: 31 cases (1989–2002). J Am Vet 165. Li Y, Rey-Dios R, Roberts DW, et al. Intraoperative flu-
Med Assoc 2002;221:1597–1600. orescence-guided resection of high-grade gliomas: A comparison
146. Rossmeisl J. Craniectomy for the treatment of canine of the present techniques and evolution of future strategies.
meningiomas. In: Proceedings of the American College of Veteri- World Neurosurg 2013 Jul 9. pii: S1878-8750(13):00760–2. doi:
nary Surgery Symposium, Washington, DC, October 9-12, 2003. 10.1016/j.wneu.2013.06.014. [Epub ahead of print]
1184 Dickinson

166. Jeffery N, Brearley MJ. Brain tumors in the dog: Treat- 187. Lester NV, Hopkins AL, Bova FJ, et al. Radiosurgery
ment of 10 cases and review of recent literature. J Small Anim using a stereotactic headframe system for irradiation of brain
Pract 1993;34:367–372. tumors in dogs. J Am Vet Med Assoc 2001;219:1562–1567, 1550.
167. Dimski DS, Cook JR. Carmustine-induced partial remis- 188. Mariani CL, Schubert TA, House RA, et al. Frameless
sion of an astrocytoma in a dog. J Am Anim Hosp Assoc stereotactic radiosurgery for the treatment of primary intracranial
1990;26:179–182. tumours in dogs. Vet Comp Oncol 2013 Sep 6. doi: 10.1111/vco.
168. Jung DI, Kim HJ, Park C, et al. Long-term chemother- 12056. [Epub ahead of print]
apy with lomustine of intracranial meningioma occurring in a 189. Charney S, Witten M, Ettinger S, et al. CyberKnife ra-
miniature schnauzer. J Vet Med Sci 2006;68:383–386. diosurgery for irradiation of tumors in dogs and cats. Vet Comp
169. Tamura S, Tamura Y, Ohoka A, et al. A canine case of Oncol 2011;9:e42.
skull base meningioma treated with hydroxyurea. J Vet Med Sci 190. Kent MS. Stereotactic radiosurgery for brain tumors:
2007;69:1313–1315. Clinical trial update. In: Proceedings of the American College of
170. Boudreau CE, York D, Higgins RJ, et al. Investigation Veterinary Medicine Specialty Symposium (Pre-Forum Neurol-
of molecular signaling pathways in canine primary gliomas. J Vet ogy), New Orleans, LA, May 30-June 2, 2012:25–26.
Intern Med 2013;27:675. 191. Larue SM. Advances in radiotherapy of neurological
171. Kim L, Glantz M. Chemotherapeutic options for primary tumors. In: Proceedings of the American College of Veterinary
brain tumors. Curr Treat Options Oncol 2006;7:467–478. Internal Medicine Forum, Seattle, WA, June 12-15, 2013:426–427.
172. Matiasek K. Drug resistance—Does it matter in human 192. Kraft SL, Gavin PR, Leathers CW, et al. Biodistribution of
and canine brain tumors? In: Proceedings of the American Col- boron in dogs with spontaneous intracranial tumors following boro-
lege of Veterinary Internal Medicine Forum, Denver, CO, June captate sodium administration. Cancer Res 1994;54:1259–1263.
15-18, 2011:389–390. 193. Bagley RS, Gavin PR, Moore MP, et al. Survival after
173. Wick W, Meisner C, Hentschel B, et al. Prognostic or BNCT in combination with surgery for dogs with spontaneous
predictive value of MGMT promoter methylation in gliomas brain tumors. In: Hawthorn MF, Shelly K, Wiersema RJ, eds.
depends on IDH1 mutation. Neurology 2013;81(17):1515–1522. Frontiers in Neutron Capture Therapy, Vols 1 and 2. New York,
174. Matiasek LA, Schlegel J, Starkey MP, et al. Testing epi- NY: Kluwer Academic/Plenum Publ; 2001:1257–1261.
genetic concepts in canine neurooncology I: Methylation of 194. Nakamura H. Boron lipid-based liposomal boron deliv-
DNA-repair enzyme o6-methylguanin-DNA-methyltransferase. ery system for neutron capture therapy: Recent development and
In: Proceedings of the European Society of Veterinary Neurol- future perspective. Future Med Chem 2013;5:715–730.
ogy/European College of Veterinary Neurology Neurooncology 195. Bobo RH, Laske DW, Akbasak A, et al. Convection-
Symposium, Bologna, Italy, September 24-26, 2009:39–40. enhanced delivery of macromolecules in the brain. Proc Natl
175. Juratli TA, Schackert G, Krex D. Current status of local Acad Sci USA 1994;91:2076–2080.
therapy in malignant gliomas—A clinical review of three selected 196. Sampson JH, Brady ML, Petry NA, et al. Intracerebral
approaches. Pharmacol Ther 2013;139:341–358. infusate distribution by convection-enhanced delivery in humans
176. Dickinson PJ, LeCouteur RA, Higgins RJ, et al. Canine with malignant gliomas: Descriptive effects of target anatomy
spontaneous glioma: A translational model system for convec- and catheter positioning. Neurosurgery 2007;60:ONS89-98; dis-
tion-enhanced delivery. Neuro Oncol 2010;12:928–940. cussion ONS98-89.
177. Bley CR, Sumova A, Roos M, et al. Irradiation of brain 197. Dickinson PJ, LeCouteur RA, Higgins RJ, et al. Canine
tumors in dogs with neurologic disease. J Vet Intern Med model of convection-enhanced delivery of liposomes containing
2005;19:849–854. CPT-11 monitored with real-time magnetic resonance imaging:
178. Evans SM, Dayrell-Hart B, Powlis W, et al. Radiation Laboratory investigation. J Neurosurg 2008;108:989–998.
therapy of canine brain masses. J Vet Intern Med 1993;7:216– 198. Platt S, Nduom E, Kent M, et al. Canine model of con-
219. vection-enhanced delivery of cetuximab-conjugated iron-oxide
179. Spugnini EP, Thrall DE, Price GS, et al. Primary irradia- nanoparticles monitored with magnetic resonance imaging. Clin
tion of canine intracranial masses. Vet Radiol Ultrasound Neurosurg 2012;59:107–113.
2000;41:377–380. 199. Kaluzova M, Platt SR, Kent M, et al. Targeted therapy
180. Norman A, Ingram M, Skillen RG, et al. X-ray photother- of glioma stem cells using cetuximab-conjugated IONPs. J Clin
apy for canine brain masses. Radiat Oncol Investig 1997;5:8–14. Invest 2014. In press.
181. Ostertag CB, Warnke P, Kleihues P, et al. Iodine-125 200. Hood RL, Andriani RT Jr, Emch S, et al. Fiberoptic mi-
interstitial irradiation of virally induced dog brain tumours. Neu- croneedle device facilitates volumetric infusate dispersion during
rol Res 1984;6:176–180. convection-enhanced delivery in the brain. Lasers Surg Med
182. Stubbs JB, Frankel RH, Schultz K, et al. Preclinical eval- 2013;45:418–426.
uation of a novel device for delivering brachytherapy to the mar- 201. Robbins J, Dickinson PJ, York D, et al. Evaluation of
gins of resected brain tumor cavities. J Neurosurg 2002;96:335– delivery of retroviral replicating vector TOCA 511 in spontane-
343. ous canine brain tumor. Neuro Oncol 2012;14:vi48.
183. Liu BL, Cheng JX, Zhang X, et al. Controversies con- 202. Dickinson PJ. TOCA-511 gene therapy clinical trial
cerning the application of brachytherapy in central nervous sys- update. In: Proceedings of the American College of Veterinary
tem tumors. J Cancer Res Clin Oncol 2010;136:173–185. Internal Medicine Specialty Symposium (Pre-Forum Neurology),
184. Schwarz SB, Thon N, Nikolajek K, et al. Iodine-125 New Orleans, LA, May 30-June 2, 2012:29–31.
brachytherapy for brain tumours—a review. Radiat Oncol 203. Tobias A, Ahmed A, Moon KS, et al. The art of gene
2012;7:30. therapy for glioma: A review of the challenging road to the bed-
185. Minniti G, Amichetti M, Enrici RM. Radiotherapy and side. J Neurol Neurosurg Psychiatry 2013;84:213–222.
radiosurgery for benign skull base meningiomas. Radiat Oncol 204. Garcia-Escudero V, Gargini R, Izquierdo M. Glioma
2009;4:42. regression in vitro and in vivo by a suicide combined treatment.
186. Villavicencio AT, Burneikiene S, Romanelli P, et al. Sur- Mol Cancer Res 2008;6:407–417.
vival following stereotactic radiosurgery for newly diagnosed and 205. Chauvet AE, Kesava PP, Goh CS, et al. Selective intra-
recurrent glioblastoma multiforme: A multicenter experience. arterial gene delivery into a canine meningioma. J Neurosurg
Neurosurg Rev 2009;32:417–424. 1998;88:870–873.
 Brain Tumors 1185

206. Pluhar GE, Grogan PT, Seiler C, et al. Anti-tumor 222. York D, Higgins RJ, LeCouteur RA, et al. A novel anti-
immune response correlates with neurological symptoms in a dog canine CD133 antibody colocalizes with GFAP in normal and
with spontaneous astrocytoma treated by gene and vaccine ther- neoplastic brain tissue. J Vet Intern Med 2012;26:807.
apy. Vaccine 2010;28:3371–3378. 223. Lynch S, Pang L, Argyle D. Identification of cancer stem
207. Candolfi M, Kroeger KM, Pluhar GE, et al. Adenoviral- cells in canine glioma and resistance to therapeutic modalities.
mediated gene transfer into the canine brain in vivo. Neurosur- Vet Comp Oncol 2011;9:e1.
gery 2007;60:167–177; discussion 178. 224. Pennington ME, Lam KS, Cress AE. The use of a com-
208. Candolfi M, Pluhar GE, Kroeger K, et al. Optimization binatorial library method to isolate human tumor cell adhesion
of adenoviral vector-mediated transgene expression in the canine peptides. Mol Divers 1996;2:19–28.
brain in vivo, and in canine glioma cells in vitro. Neuro Oncol 225. Zwingenberger AL, Kent MS, Shi C, et al. Affinity of
2007;9:245–258. the alpha4-beta1 integrin-targeting peptide LLP2A to canine lym-
209. Oh S, Pluhar GE, McNeil EA, et al. Efficacy of nonviral phoma. Vet Immunol Immunopathol 2012;145:298–304.
gene transfer in the canine brain. J Neurosurg 2007;107:136–144. 226. Aina OH, Maeda Y, Harrison M, et al. Canine malig-
210. Traas AM, Wang P, Ma X, et al. Correction of clinical nant melanoma alpha-3 integrin binding peptides. Vet Immunol
manifestations of canine mucopolysaccharidosis I with neonatal Immunopathol 2011;143:11–19.
retroviral vector gene therapy. Mol Ther 2007;15:1423–1431. 227. Xiao W, Yao N, Peng L, et al. Near-infrared optical
211. Springer SL, Vite CH, Polesky AC, et al. Infection and imaging in glioblastoma xenograft with ligand-targeting alpha 3
establishment of latency in the dog brain after direct inoculation integrin. Eur J Nucl Med Mol Imaging 2009;36:94–103.
of a nonpathogenic strain of herpes simplex virus-1. J Neurovirol 228. Zwingenberger AL, Kent MS, Liu R, et al. In-vivo bio-
2001;7:149–154. distribution and safety of 99mTc-LLP2A-HYNIC in canine non-
212. Haurigot V, Marco S, Ribera A, et al. Whole body cor- Hodgkin lymphoma. PLoS One 2012;7:e34404.
rection of mucopolysaccharidosis IIIA by intracerebrospinal fluid 229. Zwingenberger AL, Kent MS, Liu R, et al. Targeted
gene therapy. J Clin Invest 2013;123:3254–3271. imaging of the alpha4-beta1 integrin in canine lymphoma. Vet
213. Ciron C, Desmaris N, Colle MA, et al. Gene therapy of Radiol Ultrasound 2010;51:577.
the brain in the dog model of Hurler’s syndrome. Ann Neurol 230. Assi H, Candolfi M, Baker G, et al. Gene therapy for
2006;60:204–213. brain tumors: Basic developments and clinical implementation.
214. Jimenez D, Higgins R, LeCouteur R, et al. Bystander Neurosci Lett 2012;527:71–77.
killing in canine meningioma cells with a recombinant adeno- 231. Jackson C, Ruzevick J, Brem H, et al. Vaccine strategies
associated virus vector containing herpes simplex viral thymidine for glioblastoma: Progress and future directions. Immunotherapy
kinase [rAAV HSV-tk]. Vet Pathol 1998;35:443. 2013;5:155–167.
215. Ignatova TN, Kukekov VG, Laywell ED, et al. Human 232. Sioka C, Kyritsis AP. Chemotherapy, hormonal therapy,
cortical glial tumors contain neural stem-like cells expressing as- and immunotherapy for recurrent meningiomas. J Neurooncol
troglial and neuronal markers in vitro. Glia 2002;39:193–206. 2009;92:1–6.
216. Liu G, Yuan X, Zeng Z, et al. Analysis of gene expres- 233. Marsh JC, Goldfarb J, Shafman TD, et al. Current sta-
sion and chemoresistance of CD133+ cancer stem cells in glio- tus of immunotherapy and gene therapy for high-grade gliomas.
blastoma. Mol Cancer 2006;5:67. Cancer Control 2013;20:43–48.
217. Singh SK, Hawkins C, Clarke ID, et al. Identification of 234. Boozer LB, Davis TW, Borst LB, et al. Characterization
human brain tumour initiating cells. Nature 2004;432:396–401. of immune cell infiltration into canine intracranial meningiomas.
218. Wu X, Rauch TA, Zhong X, et al. CpG island hyperme- Vet Pathol 2012;49:784–795.
thylation in human astrocytomas. Cancer Res 2010;70:2718– 235. Xiong W, Candolfi M, Liu C, et al. Human Flt3L gener-
2727. ates dendritic cells from canine peripheral blood precursors:
219. Blacking TM, Waterfall M, Argyle DJ. CD44 is associ- Implications for a dog glioma clinical trial. PLoS ONE 2010;5:
ated with proliferation, rather than a specific cancer stem cell e11074.
population, in cultured canine cancer cells. Vet Immunol Immu- 236. Pluhar GE. Canine brain tumor clinical trials at the Uni-
nopathol 2011;141:46–57. versity of Minnesota. In: Proceedings of the American College of
220. Stoica G, Lungu G, Martini-Stoica H, et al. Identifica- Veterinary Internal Medicine Specialty Symposium (Pre-Forum
tion of cancer stem cells in dog glioblastoma. Vet Pathol Neurology), Denver, CO, June 15-18, 2011:29–31.
2009;46:391–406. 237. Andersen BM, Pluhar GE, Seiler C, et al. Vaccination
221. York D, Higgins RJ, LeCouteur RA, et al. Characteriza- for invasive canine meningioma induces in situ production of
tion of a novel canine GBM-derived cell line (G06A) and ortho- antibodies capable of antibody-dependent cell-mediated cytotox-
topic tumors in mice. J Vet Intern Med 2012;26:808. icity. Cancer Res 2013;73:2987–2997.

Peter J. Dickinson BVSc, PhD, Diplomate ACVIM (Neurology) Peter Dickinson graduated from
Liverpool University Veterinary School in 1989. Following 1 year in mixed general practice he
completed a 2 year surgery/anesthesia internship at Glasgow University Veterinary School. He
received his PhD in developmental neuroscience in 1995, also at Glasgow University, before com-
pleting a Neurology/Neurosurgery residency at the University of California, Davis. He is cur-
rently Professor of Neurology/Neurosurgery at UC Davis Veterinary School and is a diplomate
of the American College of Veterinary Medicine (Neurology). His clinical and research interest
has been in the field of neurooncology and he is director of the Petersen Foundation Brain
Tumor Laboratory.