The "Claw Sign" may aid in axial localization in cases of peripherally located canine glioma on MRI.

The "claw sign" is a radiographic sign studied in human imaging to determine if a mass arises from a solid structure or organ versus a close adjacent location, resulting in distortion of the outline of an organ. We investigated its utility in characterizing MRI axial localization of peripherally located intracranial glioma versus meningioma, due to their overlap in MRI appearance. This retrospective, secondary analysis, cross-sectional study aimed to report the sensitivity, specificity, and inter- and intraobserver variabilities using kappa statistics, hypothesizing that the claw sign will have strong inter- and intraobserver agreement (κ > 0.8). Dogs with a histologically confirmed diagnosis of peripherally located glioma or meningioma and available 3T MRI data were retrieved from medical record archives from 2009 to 2021. A total of 27 cases, 11 glioma and 16 meningioma, were included. The postcontrast T1-weighted images were provided to five blinded image evaluators in two separate randomized sessions separated by a 6-week wash out period. Prior to the first evaluation, evaluators were provided with a training video and set of training cases for the "claw sign," which were excluded from the study. Evaluators were asked to rate cases as "positive," "negative," or "indeterminate" for the "claw sign." The sensitivity and specificity for the "claw sign" for the first session were 85.5% and 80%, respectively. The interobserver agreement for identifying the "claw sign" was moderate (κ = 0.48), and the intraobserver agreement across the two sessions was substantial (κ = 0.72). These findings indicate the claw sign is supportive but not pathognomonic for intra-axial localization in cases of canine glioma on MRI.

Circulating neutrophil activation in dogs with naturally occurring spinal cord injury secondary to intervertebral disk herniation.

OBJECTIVE: To investigate the time course of circulating neutrophil priming and activity in dogs with spinal cord injury secondary to intervertebral disk herniation that undergo decompressive surgery. ANIMALS: 9 dogs with spinal cord injury and 9 healthy dogs (controls). PROCEDURES: For dogs with spinal cord injury, blood samples were collected on the day of hospital admission and 3, 7, 30, and 90 days after injury and decompressive surgery. A single blood sample was collected from the control dogs. Flow cytometry analysis was performed on isolated neutrophils incubated with antibody against CD11b and nonfluorescent dihydrorhodamine 123, which was converted to fluorescent rhodamine 123 to measure oxidative burst activity. RESULTS: Expression of CD11b was increased in dogs with spinal cord injury 3 days after injury and decompressive surgery, relative to day 7 expression. Neutrophils expressed high oxidative burst activity both 3 and 7 days after injury and decompressive surgery, compared with activity in healthy dogs. CLINICAL RELEVANCE: For dogs with spinal cord injury, high CD11b expression 3 days after injury and decompressive surgery was consistent with findings for rodents with experimentally induced spinal cord injury. However, the high oxidative burst activity 3 and 7 days after injury and decompressive surgery was not consistent with data from other species, and additional studies on inflammatory events in dogs with naturally occurring spinal cord injury are needed.

Intratumoral Delivery of STING Agonist Results in Clinical Responses in Canine Glioblastoma.

PURPOSE: Activation of STING (stimulator of interferon genes) can trigger a robust, innate antitumor immune response in immunologically "cold" tumors such as glioblastoma. PATIENTS AND METHODS: A small-molecule STING agonist, IACS-8779, was stereotactically administered using intraoperative navigation intratumorally in dogs with spontaneously arising glioblastoma. The phase I trial used an escalating dose design, ascending through four dose levels (5-20 µg). Treatment was repeated every 4-6 weeks for a minimum of two cycles. Radiographic response to treatment was determined by response assessment in neuro-oncology (RANO) criteria applied to isovoxel postcontrast T1-weighted MR images obtained on a single 3T magnet. RESULTS: Six dogs were enrolled and completed ≥1 cycle of treatment. One dog was determined to have an abscess and was removed from further analysis. One procedure-related fatality was observed. Radiographic responses were dose dependent after the first cycle. The first subject had progressive disease, whereas there was 25% volumetric reduction in one subject and greater than 50% in the remaining surviving subjects. The median progression-free survival time was 14 weeks (range: 0-22 weeks), and the median overall survival time was 32 weeks (range: 11-39 weeks). CONCLUSIONS: Intratumoral STING agonist (IACS-8779) administration was well tolerated in dogs with glioblastoma to a dose of 15 µg. Higher doses of IACS-8779 were associated with radiographic responses.

Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats.

The updated VCOG-CTCAE v2 guidelines contain several important updates and additions since the last update (v1.1) was released in 2011 and published within Veterinary and Comparative Oncology in 2016. As the Veterinary Cooperative Oncology Group (VCOG) is no longer an active entity, the original authors and contributors to the VCOG-CTCAE v1.0 and v1.1 were consulted for input, and additional co-authors sought for expansion and refinement of the adverse event (AE) categories. VCOG-CTCAE v2 includes expanded neurology, cardiac and immunologic AE sections, and the addition of procedural-specific AEs. It is our intent that, through inclusion of additional authors from ACVIM subspecialties and the American College of Veterinary Surgery, that we can more comprehensively capture AEs that are observed during clinical studies conducted across a variety of disease states, clinical scenarios, and body systems. It is also our intent that these updated veterinary CTCAE guidelines will offer improved application and ease of use within veterinary practice in general, as well as within clinical trials that assess new therapeutic strategies for animals with a variety of diseases. Throughout the revision process, we strived to ensure the grading structure for each AE category was reflective of the decision-making process applied to determination of dose-limiting events. As phase I trial decisions are based on these criteria and ultimately determine the maximally tolerated dose, there is impact on standard dosing recommendations for any new drug registration or application. This document should be updated regularly to reflect ongoing application to clinical studies carried out in veterinary patients.

Extended durotomy to treat severe spinal cord injury after acute thoracolumbar disc herniation in dogs.

OBJECTIVE: To report recovery of ambulation of dogs treated with extended thoracolumbar durotomy for severe spinal cord injury caused by intervertebral disc herniation. STUDY DESIGN: Descriptive cohort. ANIMALS: Twenty-six consecutive paraplegic dogs presented with loss of deep pain sensation after acute thoracolumbar intervertebral disc herniation. METHODS: Each dog underwent routine diagnostic assessment and surgery for removal of extradural herniated intervertebral disc, followed by a four-vertebral body length durotomy centered on the herniated disc. Each dog was followed up until it was able to walk 10 steps without assistance or until 6 months after surgery. RESULTS: Sixteen of 26 dogs recovered to walk unaided (all but one also recovered fecal and urinary continence), and six dogs did not; four dogs were lost to follow-up. One dog was euthanized because of signs consistent with progressive myelomalacia. There was no evidence of detrimental effects of durotomy within the period of study. Using Bayesian analysis, we found a point estimate of successful outcome of 71% with 95% credible interval from 52% to 87%. CONCLUSION: Extended durotomy seemed to improve the outcome of dogs in our case series without increase in morbidity. CLINICAL SIGNIFICANCE: Extended durotomy appears safe and may improve the outcome of dogs with severe thoracolumbar mixed contusion and compressive injuries associated with acute intervertebral disc extrusion.

Comparative Molecular Life History of Spontaneous Canine and Human Gliomas.

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole-genome, exome, transcriptome, and methylation sequencing of 83 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, TP53 and cell-cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA-methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.

Reliability of interpretation of neurologic examination findings for the localization of vestibular dysfunction in dogs.

OBJECTIVE To estimate reliability of interpretation of neurologic examination findings for localization of vestibular dysfunction in dogs. DESIGN Cross-sectional study. ANIMALS 496 dogs that underwent MRI of the head for diagnosis of a neurologic problem between September 2011 and September 2015. PROCEDURES Medical records were reviewed and data collected regarding signalment and neurologic examination, MRI, and CSF findings. Independent observers interpreted the findings, and agreement was assessed for a subset of dogs. Distributions of variables were compared between dogs with and without a neurologic findings-based interpretation of vestibular disease. RESULTS 37% (185/496) of dogs had signs of vestibular dysfunction, of which 82% (151/185) had MRI abnormalities. In 73% (110/151) of dogs with MRI abnormalities, lesions involved central vestibular structures, and in 19% (29/151), lesions involved peripheral vestibular structures. On the basis of neurologic findings interpretation, 86% (160/185) of dogs were classified as having central vestibular dysfunction, and 61% (98/160) of these had an MRI-identified central vestibular lesion. Agreement among 3 independent observers was good (κ = 0.72) regarding use of neurologic examination findings to diagnose central versus peripheral vestibular dysfunction and very good (κ = 0.85) regarding use of MRI to diagnose peripheral vestibular lesions. Despite this agreement, only 29% (7/24) of dogs with a consensus clinical interpretation of peripheral vestibular dysfunction had MRI-identified peripheral lesions. CONCLUSIONS AND CLINICAL RELEVANCE Although interobserver agreement was good for distinguishing central from peripheral vestibular dysfunction in dogs through interpretation of neurologic examination findings, this interpretation did not agree with the MRI-based diagnosis.

Pharmacokinetics and safety of oral glyburide in dogs with acute spinal cord injury.

BACKGROUND: Glyburide (also known as glibenclamide) is effective in reducing the severity of tissue destruction and improving functional outcome after experimental spinal cord injury in rodents and so has promise as a therapy in humans. There are many important differences between spinal cord injury in experimental animals and in human clinical cases, making it difficult to introduce new therapies into clinical practice. Spinal cord injury is also common in pet dogs and requires new effective therapies, meaning that they can act as a translational model for the human condition while also deriving direct benefits from such research. In this study we investigated the pharmacokinetics and safety of glyburide in dogs with clinical spinal cord injury. METHODS: We recruited dogs that had incurred an acute thoracolumbar spinal cord injury within the previous 72 h. These had become acutely non-ambulatory on the pelvic limbs and were admitted to our veterinary hospitals to undergo anesthesia, cross sectional diagnostic imaging, and surgical decompression. Oral glyburide was given to each dog at a dose of 75 mcg/kg. In five dogs, we measured blood glucose concentrations for 10 h after a single oral dose. In six dogs, we measured serum glyburide and glucose concentrations for 24 h and estimated pharmacokinetic parameters to estimate a suitable dose for use in a subsequent clinical trial in similarly affected dogs. RESULTS: No detrimental effects of glyburide administration were detected in any participating dog. Peak serum concentrations of glyburide were attained at a mean of 13 h after dosing, and mean apparent elimination half-life was approximately 7 h. Observed mean maximum plasma concentration was 31 ng/mL. At the glyburide dose administered there was no observable association between glyburide and glucose concentrations in blood. DISCUSSION: Our data suggest that glyburide can be safely administered to dogs that are undergoing anesthesia, imaging and surgery for treatment of their acute spinal cord injury and can attain clinically-relevant serum concentrations without developing hazardous hypoglycemia. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25-50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury.

Early Blockade of Matrix Metalloproteinases in Spinal-Cord-Injured Dogs Results in a Long-Term Increase in Bladder Compliance.

Spinal cord injury (SCI) is often accompanied by reduced bladder compliance, which contributes to adverse conditions including urinary tract infections and vesicoureteral reflux. Reduced compliance is, in part, attributed to extensive remodeling of the bladder wall, including the extracellular matrix (ECM). Here, we tested the hypothesis that blockade of matrix metalloproteinases (MMPs), known for their ability to remodel the ECM, improves bladder compliance in dogs with SCI. We first evaluated dogs with naturally occurring SCIs resulting from intervertebral disc herniation (IVDH). After characterizing the natural history of urological recovery by cystometry in healthy dogs (n = 10) and dogs with SCIs (n = 20), we conducted a randomized, double-blinded, placebo-controlled clinical trial in dogs with IVDH-associated SCIs to assess the efficacy of the broad-spectrum MMP inhibitor, GM6001, given within 48 h post-injury. The primary outcomes were bladder compliance, as measured by cystometry, and an ordinal gait score (Texas Spinal Cord Injury Score; TSCIS) at day 42 post-SCI. Dogs (n = 93) were randomized to receive either dimethyl sulfoxide (DMSO) or GM6001+DMSO. There were transient, but significantly (p = 0.023) greater, adverse events (31 of 42; 74%) in the GM6001-treated group relative to vehicle controls (22 of 46; 48%). Whereas there were no differences in TSCIS between treatment groups at day 42 (p = 0.9679), bladder compliance was significantly higher in dogs treated with GM6001+DMSO compared to controls (p = 0.0272). Further studies are needed to determine whether this inhibition results from a direct interaction with the bladder wall or indirectly through neural-based mechanisms.

Multi-Center Retrospective Evaluation of Screw and Polymethylmethacrylate Constructs for Atlantoaxial Fixation in Dogs.

OBJECTIVE: To evaluate outcome and adverse events following ventral stabilization of the atlantoaxial (AA) joint in dogs with clinical AA subluxation using screw/polymethymethacrylate (PMMA) constructs in a retrospective, multi-center cohort study. STUDY DESIGN: Historical cohort study. ANIMALS: 35 client-owned dogs. METHODS: Medical records from 3 institutions were reviewed to identify dogs with AA subluxation treated with ventral screw and PMMA constructs. Data on signalment, pre- and postoperative neurologic status, imaging performed, and adverse events were retrieved. Neurologic examination data were abstracted to generate a modified Frankel score at admission, discharge, and re-examination. Telephone interview of owners >180 days postoperative was conducted. RESULTS: Thirty-five dogs with AA subluxation treated with ventral screw/PMMA constructs were included. Most dogs were young (median age 1 year), small breed dogs with acute onset of neurologic signs (median duration 22.5 hours). Most dogs were non-ambulatory at the time of admission (median modified Frankel score 3). Adverse events were identified in 15/35 dogs including 9 dogs with major adverse events. Four dogs required a second surgery due to vertebral canal violation (n = 2) or implant failure (n = 2). Re-examination at 4-6 weeks postoperative reported 15/28 dogs with improved neurologic status and 19/28 dogs were ambulatory. Telephone follow-up was available for 23/35 dogs with 23/23 reported as ambulatory (median follow-up 390 days). CONCLUSIONS: Ventral application of screw and PMMA constructs for AA subluxation, as described here, is associated with clinical improvement in the majority of dog. Major adverse events are infrequent and the technique is considered relatively safe.

Arachidonic acid pathway alterations in cerebrospinal fluid of dogs with naturally occurring spinal cord injury.

BACKGROUND: Canine intervertebral disc πherniation causes a naturally-occurring spinal cord injury (SCI) that bears critical similarities to human SCI with respect to both injury pathomechanisms and treatment. As such, it has tremendous potential to enhance our understanding of injury biology and the preclinical evaluation of novel therapies. Currently, there is limited understanding of the role of arachidonic acid metabolites in canine SCI. RESULTS: The CSF concentrations of PLA2 and PGE2 were higher in SCI dogs compared to control dogs (p = 0.0370 and 0.0273, respectively), but CSF LCT4 concentration in SCI dogs was significantly lower than that in control dogs (p < 0.0001). Prostaglandin E2 concentration in the CSF was significantly and positively associated with increased severity of SCI at the time of sampling (p = 0.041) and recovery 42 days post-injury (p = 0.006), as measured by ordinal behavioral scores. CONCLUSION: Arachidonic acid metabolism is altered in dogs with SCI, and these data suggest that these AA metabolites reflect injury severity and recovery, paralleling data from other model systems.

Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients.

On September 14-15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed.

Acute Phase Proteins in Cerebrospinal Fluid from Dogs with Naturally-Occurring Spinal Cord Injury.

Spinal cord injury (SCI) affects thousands of people each year and there are no treatments that dramatically improve clinical outcome. Canine intervertebral disc herniation is a naturally-occurring SCI that has similarities to human injury and can be used as a translational model for evaluating therapeutic interventions. Here, we characterized cerebrospinal fluid (CSF) acute phase proteins (APPs) that have altered expression across a spectrum of neurological disorders, using this canine model system. The concentrations of C-reactive protein (CRP), haptoglobin (Hp), alpha-1-glycoprotein, and serum amyloid A were determined in the CSF of 42 acutely injured dogs, compared with 21 healthy control dogs. Concentrations of APPs also were examined with respect to initial injury severity and motor outcome 42 d post-injury. Hp concentration was significantly higher (p<0.0001) in the CSF of affected dogs, compared with healthy control dogs. Additionally, the concentrations of CRP and Hp were significantly (p=0.0001 and p=0.0079, respectively) and positively associated with CSF total protein concentration. The concentrations of CRP and Hp were significantly higher (p=0.0071 and p=0.0197, respectively) in dogs with severe injury, compared with those with mild-to-moderate SCI, but there was no significant correlation between assessed CSF APP concentrations and 42 d motor outcome. This study demonstrated that CSF APPs were dysregulated in dogs with naturally-occurring SCI and could be used as markers for SCI severity. As Hp was increased following severe SCI and is neuroprotective across a number of model systems, it may represent a viable therapeutic target.

Effects of task difficulty and target likelihood in area V4 of macaque monkeys.

Spatial attention improves performance at attended locations and correspondingly modulates firing rates of cortical neurons. The size of these behavioral and neuronal effects depends on the difficulty of the task performed at the attended location. Psychological theorists have attributed this to a tighter focus of a fixed amount of processing resource at the attended location, but the effects of task difficulty on the distribution of neuronal effects of attention across the visual field have not been fully explored. We trained rhesus monkeys to do a detection task in which difficulty and spatial attention were manipulated independently. Probe stimuli were used to measure behavioral performance in different conditions of attention and difficulty. Animals performed better at attended locations and this advantage increased with difficulty, consistent with data from human psychophysics. Neuronal modulation by spatial attention was larger with greater difficulty. In two animals, increasing difficulty caused a modest increase in neuronal responses to visual stimuli regardless of the locus of spatial attention. In a third animal, which was previously trained to ignore multiple distracting stimuli, increasing task difficulty increased responses at the focus of attention and suppressed responses away from the focus of attention. The results show that difficulty can modulate effects of spatial attention in V4; it can alter the distribution of sensory responses across the visual scene in ways that may depend on the subject's behavioral strategy.

Short-term depression in thalamocortical synapses of cat primary visual cortex.

Neurons in primary visual cortex exhibit several nonlinearities in their responses to visual stimuli, including response decrements to repeated stimuli, contrast-dependent phase advance, contrast saturation, and cross-orientation suppression. Thalamocortical synaptic depression has been implicated in these phenomena but has not been examined directly in visual cortex in vivo. We assessed depression of visual thalamocortical synapses in vivo using 20-100 Hz trains of electrical stimuli delivered to the LGN. Cortical cells receiving direct input from the LGN, identified by short latency and low jitter of LGN-evoked PSPs, showed moderate reductions in PSP amplitude during the fastest trains. Cells receiving indirect input from the thalamus via other cortical excitatory neurons show a marked reduction in PSP amplitude during a train, which could be explained either by synaptic depression in corticocortical synapses or by an inhibition-mediated suppression of the firing of their afferents. Reducing spontaneous activity in the LGN (by retinal blockade) unmasked additional depression at the thalamocortical synapse but only for the first stimulus in the train. That is, the first PSP was increased in amplitude relative to the unblocked condition, but subsequent responses were essentially unchanged. Thus, the synapses are maintained at significant levels of depression by spontaneous activity. These findings constrain the role that thalamocortical depression can play in shaping cortical responses to visual stimuli.