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The blood-brain barrier and knowledge gaps in tumor biology remain significant obstacles to the development of effective treatments for brain tumors. The identification of shared molecular and genetic pathways that contribute to tumorigenesis in both dogs and people has been key to the discovery and translation of targeted pharmacologic and biologic therapies. Treatment approaches often utilize targeted or multifunctional antitumor agents, such as nanocarriers, molecularly targeted agents, immunotherapeutics, and oncolytic viruses in combination with alternative therapeutic delivery strategies. The article discusses about various treatments albeit none of the treatments discussed here are widely available or approved for clinical use., Competing Interests: Disclosure J.H. Rossmeisl holds patents and has patents pending on QUAD compound targeted and oncolytic viral therapeutics for cancer and is an advisory board member with Zoetis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Histotripsy is a non-thermal focused ultrasound therapy in development for the non-invasive ablation of cancerous tumors. Intracranial histotripsy has been limited by significant pressure attenuation through the skull, requiring large, complex array transducers to overcome this effect., Objective: Recently, a biocompatible, polyolefin-based cranioplasty device was developed to allow ultrasound (US) transmission into the intracranial space with minimal distortion. In this study, we investigated the in vitro feasibility of applying US-guided histotripsy procedures across the prosthesis., Methods: Pressure waveforms and beam profiles were collected for single- and multi-element histotripsy transducers. Then, high-speed optical images of the bubble cloud with and without the prosthesis were collected in water and tissue-mimicking agarose gel phantoms. Finally, red blood cell (RBC) tissue phantom and excised brain tissue experiments were completed to test the ablative efficacy across the prosthesis., Results: Single element tests revealed increased pressure loss with increasing transducer frequency and increasing transducer-to-prosthesis angle. Array transducer measurements at 1 MHz showed average pressure losses of >50% across the prosthesis. Aberration correction recovered up to 18% of the pressure lost, and high-speed optical imaging in water, agarose gels, and RBC phantoms demonstrated that histotripsy bubble clouds could be generated across the prosthesis at pulse repetition frequencies of 50-500 Hz. Histologic analysis revealed a complete breakdown of brain tissue treated across the prosthesis. Conclusion & Significance: Overall, the results of this study demonstrate that the cranial prosthesis may be used as an acoustic window through which intracranial histotripsy can be applied under US guidance without the need for large transcranial array transducers.

Background: To ameliorate anticipated or ongoing neurological deficits, dogs undergoing brain tumor irradiation often are prescribed lengthy courses of prednisone PO during and after radiotherapy (RT). This practice can contribute to unwanted corticosteroid-associated morbidity and may be unnecessary., Objective: Determine whether long-term corticosteroid dependency can be minimized by use of succinct prednisone tapering., Animals: Fifty-five pet dogs undergoing brain tumor irradiation., Methods: Nineteen dogs were treated using a "rapid-taper" protocol wherein corticosteroid dose reduction began 0 to 20 days after completing RT. Outcomes were compared with a retrospectively studied control group ("slow-taper"; N = 36 dogs) in which corticosteroids were tapered more slowly according to individual clinician recommendations., Results: Patient demographics were similar between groups. Mean time to lowest prednisone dose was 41 days postirradiation in the rapid-taper group and 117 days in the slow-taper group (P = .003). In the rapid-taper group, 15 of 19 dogs (84%) were completely tapered off prednisone, vs 18 of 36 (50%) in the slow-taper group (P = .04). Rates at which corticosteroids had to be reinstituted later were similar for the 2 groups (approximately 1 in 3 dogs). Adverse effect rates were similar for the 2 groups. Although no comparable questionnaire-derived data were available for the "slow-taper" group, overall and neurologic quality of life remained stable after RT in the rapid-taper group., Conclusions and Clinical Importance: For many dogs, lengthy courses of PO prednisone are avoidable after intracranial RT. Future efforts should aim to identify which dogs benefit most from accelerated prednisone tapering., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

The objective of this research was to compare two previously described stereotactic brain biopsy (SBB) techniques, three-dimensional skull contoured guides (3D-SCGs) and neuronavigation with Brainsight, to a novel SBB technique using Brainsight combined with a 3D-printed headframe (BS3D-HF) to improve the workflow of SBB in dogs. This was a prospective methods comparison with five canine cadavers of different breeds and size. Initial helical CT was performed on cadavers with fiducial markers in place. Ten different target points were randomly selected for each method. The headframe for the BS3D-HF was designed and printed. Trajectories were planned for each method. Steinmann pins (SPs) were placed into the target points using the planned trajectories for each method, and CT was repeated (post CT). Accuracy was assessed by overlaying the initial CT onto the post CT and measuring the difference of the planned target point to the SP placement. For 3D-SCG, the median deviation was 2.48 mm (0.64-4.04). With neuronavigation, the median deviation was 3.28 mm (1.04-4.64). For BS3D-HF, the median deviation was 14.8 mm (8.87-22.1). There was no significant difference between 3D-SCG and neuronavigation for the median deviation ( p  = 0.42). When comparing BS3D-HF to 3D-SCG, there was a significant difference in the median deviation ( p  < 0.0001). Additionally, when comparing BS3D-HF to neuronavigation, there was a significant difference for the median deviation ( p  < 0.0001). Our findings concluded that both 3D-SCGs and neuronavigation were accurate for SBB, however BS3D-HF was not. Although feasible, the current BS3D-HF technique requires further refinement before it can be recommended for use for SBB in dogs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Shinn, Hollingsworth, Parker, Rossmeisl and Werre.)

Meningiomas are the most common feline primary brain tumours, and calvarial hyperostosis (CH) is frequently documented in association with this neoplastic entity. The clinical significance of and mechanisms driving the formation of CH in cats with meningiomas are poorly understood, although tumour invasion into the skull and tumour production of cytokines and enzymes have been implicated as causes of CH in humans. This retrospective study investigated relationships between signalment, MRI or CT imaging features, histopathologic tumour characteristics, alkaline phosphatase (ALP) isoenzyme concentrations, tumour expression of matrix metalloproteinases (MMP)-2, MMP-9, and interleukin-6 (IL-6), and progression free survival times (PFS) following surgical treatment in 27 cats with meningiomas with (n = 15) or without (n = 12) evidence of CH. No significant differences in breed, age, sex, body weight, tumour grade, tumour volume, peritumoral edema burden, ALP isoenzyme concentrations, tumour Ki-67 labelling indices or MMP-2 or MMP-9 expression and activity, or PFS were noted between cats with or without CH. There was a trend towards higher serum (p = .06) and intratumoral (p = .07) concentrations of IL-6 in cats with CH, but these comparisons were not statistically significant. Histologic evidence of tumour invasion into bone was observed in 5/12 (42%) with CH and in no (0/6) cats without CH, although this was not statistically significant (p = .07). Tumour invasion into bone and tumour production of IL-6 may contribute to the formation of meningioma associated CH in cats, although larger studies are required to further substantiate these findings and determine their clinical relevance., (© 2024 The Authors. Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.)

The blood-brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE's transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond., Competing Interests: R.D. and J.R. have issued patents and/or patents pending in the area of irreversible electroporation and may receive royalties. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Author(s).)

Background: Neurofilament light chain (NfL) is a frequently used biomarker in humans for both diagnostic and therapeutic monitoring purposes in various neurologic diseases., Hypothesis/objectives: It was hypothesized that dogs with diagnosed structural epilepsy (SE) would have a significantly higher serum NfL concentrations compared to dogs with idiopathic epilepsy (IE). The secondary hypothesis was that dogs would have a significantly higher serum NfL concentrations when measured within 7 days after a seizure compared to being seizure-free for at least 30 days., Animals: Fifty client-owned dogs presented to the neurology service for evaluation of seizures were enrolled. Fourteen dogs had SE and 36 dogs had IE., Methods: Prospective cohort study performed on 52 serum samples obtained for NfL concentration measurement using single molecule array technology., Results: The median serum concentration of NfL in dogs with SE was significantly higher (109 pg/mL; range, 11.4-741.3 pg/mL) than in dogs with IE (17.7 pg/mL; range, 5.8-188 pg/mL; Wilcoxon rank sum test, P = .001). No significant relationship was found between serum NfL concentration and time of sampling in relation to the most recent seizure in dogs with IE., Conclusions and Clinical Importance: Serum NfL may serve as an adjunctive biomarker for the differentiation of SE and IE., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Magnetic resonance imaging (MRI) is used pervasively in veterinary practice for the antemortem diagnosis of intracranial tumors. Here, we provide an illustrated summary of the published MRI features of primary and secondary intracranial tumors of dogs and cats, following PRISMA scoping review guidelines. The PubMed and Web of Science databases were searched for relevant records, and input from stakeholders was solicited to select data for extraction. Sixty-seven studies of moderate to low-level evidence quality describing the MRI features of pathologically confirmed canine and feline brain tumors met inclusion criteria. Considerable variability in data inclusion and reporting, as well as low case numbers, prohibited comparative data analyses. Available data support a holistic MRI approach incorporating lesion number, location within the brain, shape, intrinsic signal appearances on multiparametric sequences, patterns of contrast enhancement, and associated secondary changes in the brain to prioritize differential imaging diagnoses, and often allows for accurate presumptive diagnosis of common intracranial tumors. Quantitative MRI techniques show promise for improving discrimination of neoplastic from non-neoplastic brain lesions, as well as differentiating brain tumor types and grades, but sample size limitations will likely remain a significant practical obstacle to the design of robustly powered radiomic studies. For many brain tumor variants, particularly in cats, there remains a need for standardized studies that correlate clinicopathologic and neuroimaging data.

Although many interventions for acute spinal cord injury (SCI) appear promising in experimental models, translation directly from experimental animals to human patients is a large step that can be problematic. Acute SCI occurs frequently in companion dogs and may provide a model to ease translation. Recently, incision of the dura has been highlighted in both research animals and human patients as a means of reducing intraspinal pressure, with a view to improving perfusion of the injured tissue and enhancing functional recovery. Observational clinical data in humans and dogs support the notion that it may also improve functional outcome. Here, we report the results of a multi-center randomized controlled trial of durotomy as an adjunct to traditional decompressive surgery for treatment of severe thoracolumbar SCI caused by acute intervertebral disc herniation in dogs. Sample-size calculation was based on the proportion of dogs recovering ambulation improving from an expected 55% in the traditional surgery group to 70% in the durotomy group. Over a 3.5-year period, we enrolled 140 dogs, of which 128 had appropriate duration of follow-up. Overall, 65 (51%) dogs recovered ambulation. Recovery in the traditional decompression group was 35 of 62 (56%) dogs, and in the durotomy group 30 of 66 (45%) dogs, associated with an odds ratio of 0.643 (95% confidence interval: 0.320-1.292) and z-score of -1.24. This z-score indicates trial futility to reach the target 15% improvement over traditional surgery, and the trial was terminated at this stage. We conclude that durotomy is ineffective in improving functional outcome for severe acute thoracolumbar SCI in dogs. In the future, these data can be compared with similar data from clinical trials on duraplasty in human patients and will aid in determining the predictive validity of the "companion dog model" of acute SCI., Competing Interests: No competing financial interests exist., (© Nick D. Jeffery et al., 2024; Published by Mary Ann Liebert, Inc.)

Neurotropic oncolytic viruses are appealing agents to treat brain tumors as they penetrate the blood-brain barrier and induce preferential cytolysis of neoplastic cells. The pathobiological similarities between human and canine brain tumors make immunocompetent dogs with naturally occurring tumors attractive models for the study of oncolytic virotherapies. In this dose-escalation/expansion study, an engineered Lasota NDV strain targeting the urokinase plasminogen activator system (rLAS-uPA) was administered by repetitive intravenous infusions to 20 dogs with intracranial tumors with the objectives of characterizing toxicities, immunologic responses, and neuroradiological anti-tumor effects of the virus for up to 6 months following treatment. Dose-limiting toxicities manifested as fever, hematologic, and neurological adverse events, and the maximum tolerated dose (MTD) of rLAS-uPA was 2 × 10 7 pfu/mL. Mild adverse events, including transient infusion reactions, diarrhea, and fever were observed in 16/18 of dogs treated at or below MTD. No infectious virus was recoverable from body fluids. Neutralizing antibodies to rLAS-uPA were present in all dogs by 2 weeks post-treatment, and viral genetic material was detected in post-treatment tumors from six dogs. Tumor volumetric reductions occurred in 2/11 dogs receiving the MTD. Systemically administered rLAS-uPA NDV was safe and induced anti-tumor effects in canine brain tumors, although modifications to evade host anti-viral immunity are needed to optimize this novel therapy.

Background: In humans, the T2-weighted (T2W)-fluid-attenuated inversion recovery (FLAIR) mismatch sign (T2FMM) is a specific imaging biomarker for the isocitrate dehydrogenase 1 (IDH1)-mutated, 1p/19q non-codeleted low-grade astrocytomas (LGA). The T2FMM is characterized by a homogeneous hyperintense T2W signal and a hypointense signal with a hyperintense peripheral rim on FLAIR sequences. In gliomas in dogs, the T2FMM has not been described., Hypotheses/objectives: In dogs with focal intra-axial brain lesions, T2FMM will discriminate gliomas from other lesions. The T2FMM will be associated with the LGA phenotype and presence of microcysts on histopathology. Interobserver agreement for T2FMM magnetic resonance imaging (MRI) features will be high., Animals: One hundred eighty-six dogs with histopathologically diagnosed focal intra-axial lesions on brain MRI including oligodendrogliomas (n = 90), astrocytomas (n = 47), undefined gliomas (n = 9), cerebrovascular accidents (n = 33), and inflammatory lesions (n = 7)., Methods: Two blinded raters evaluated the 186 MRI studies and identified cases with the T2FMM. Histopathologic and immunohistochemical slides of T2FMM cases were evaluated for morphologic features and IDH1-mutations and compared to cases without the T2FMM. Gene expression analyses were performed on a subset of oligodendrogliomas (n = 10) with and without T2FMM., Results: The T2FMM was identified in 14/186 (8%) of MRI studies, and all dogs with T2FMM had oligodendrogliomas (n = 12 low-grade [LGO], n = 2 high-grade [HGO]; P < .001). Microcystic change was significantly associated with the T2FMM (P < .00001). In oligodendrogliomas with T2FMM, IDH1-mutations or specific differentially expressed genes were not identified., Conclusion and Clinical Importance: The T2FMM can be readily identified on routinely obtained MRI sequences. It is a specific biomarker for oligodendroglioma in dogs, and was significantly associated with non-enhancing LGO., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

Background: Irreversible electroporation (IRE) has been previously investigated in preclinical trials as a treatment for intracranial malignancies. Here, we investigate next generation high-frequency irreversible electroporation (H-FIRE), as both a monotherapy and a combinatorial therapy, for the treatment of malignant gliomas., Methods: Hydrogel tissue scaffolds and numerical modeling were used to inform in-vivo H-FIRE pulsing parameters for our orthotopic tumor-bearing glioma model. Fischer rats were separated into five treatment cohorts including high-dose H-FIRE (1750V/cm), low-dose H-FIRE (600V/cm), combinatorial high-dose H-FIRE + liposomal doxorubicin, low-dose H-FIRE + liposomal doxorubicin, and standalone liposomal doxorubicin groups. Cohorts were compared against a standalone tumor-bearing sham group which received no therapeutic intervention. To further enhance the translational value of our work, we characterize the local and systemic immune responses to intracranial H-FIRE at the study timepoint., Results: The median survival for each cohort are as follows: 31 days (high-dose H-FIRE), 38 days (low-dose H-FIRE), 37.5 days (high-dose H-FIRE + liposomal doxorubicin), 27 days (low-dose H-FIRE + liposomal doxorubicin), 20 days (liposomal doxorubicin), and 26 days (sham). A statistically greater overall survival fraction was noted in the high-dose H-FIRE + liposomal doxorubicin (50%, p = 0.044), high-dose H-FIRE (28.6%, p = 0.034), and the low-dose H-FIRE (20%, p = 0.0214) compared to the sham control (0%). Compared to sham controls, brain sections of rats treated with H-FIRE demonstrated significant increases in IHC scores for CD3+ T-cells (p = 0.0014), CD79a+ B-cells (p = 0.01), IBA-1+ dendritic cells/microglia (p = 0.04), CD8+ cytotoxic T-cells (p = 0.0004), and CD86+ M1 macrophages (p = 0.01)., Conclusions: H-FIRE may be used as both a monotherapy and a combinatorial therapy to improve survival in the treatment of malignant gliomas while also promoting the presence of infiltrative immune cells., Competing Interests: RD, JR, SV, and ML have issued patents and/or patents pending in the area of irreversible electroporation and may receive royalties. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Campelo, Lorenzo, Partridge, Alinezhadbalalami, Kani, Garcia, Saunier, Thomas, Hinckley, Verbridge, Davalos and Rossmeisl.)

Convection-enhanced delivery (CED) is a drug delivery technique used to deliver therapeutics directly to the brain and is a continually evolving technique to treat glioblastoma. Early versions of CED have proven to result in inadequate drug volume dispersed (V d ), increasing the likelihood of tumor recurrence. Fiber optic microneedle devices (FMDs) with the ability to deliver fluid and thermal energy simultaneously have shown an ability to increase V d , but FMDs have historically had low light transmission efficiency. In this study, we present a new fabrication method, solid fiber inside capillary (SFIC) FMD, and a modified fusion splicing (FS) method with the goal of increasing light delivery efficiency. The modified FS FMD resulted in an increase in light transmission efficiency between 49% and 173% compared to previous prototypes. However, the FS FMD resulted in significantly lower transmission efficiencies compared to the SFIC FMD (p ≤ 0.04) and FS FMDs perform much worse when light-absorptive materials, like black dye, are placed in the bore. The light absorption of a candidate cytotoxic agent, QUAD-CTX, appear to be similar to water, and light delivery through FS FMDs filled with QUAD-CTX achieves a transmission efficiency of 85.6 ± 5.4%. The fabrication process of the SFIC FMDs results in extremely fragile FMDs. Therefore, the use of a modified FS FMD fabrication process appears to be better suited for balancing the desire to increase light transmission efficiency while retaining a sturdy FMD construction., (Copyright © 2022 by ASME.)

Convection-enhanced delivery (CED) has been extensively studied for drug delivery to the brain due to its inherent ability to bypass the blood-brain barrier. Unfortunately, CED has also been shown to inadequately distribute therapeutic agents over a large enough targeted tissue volume to be clinically beneficial. In this study, we explore the use of constant pressure infusions in addition to controlled catheter movement as a means to increase volume dispersed (Vd) in an agarose gel brain tissue phantom. Constant flow rate and constant pressure infusions were conducted with a stationary catheter, a catheter retracting at a rate of 0.25 mm/min, and a catheter retracting at a rate of 0.5 mm/min. The 0.25 mm/min and 0.5 mm/min retracting constant pressure catheters resulted in significantly larger Vd compared to any other group, with a 105% increase and a 155% increase compared to the stationary constant flow rate catheter, respectively. These same constant pressure retracting infusions resulted in a 42% and 45% increase in Vd compared to their constant flow rate counterparts. Using constant pressure infusions coupled with controlled catheter movement appears to have a beneficial effect on Vd in agarose gel. Furthermore, constant pressure infusions reveal the fundamental limitation of flow-driven infusions in both controlled catheter movement protocols as well as in stationary protocols where maximum infusion volume can never be reliably obtained., (Copyright © 2022 by ASME.)

The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the brain. These technologies have addressed many of the limitations imposed by the BBB by: (1) designing or modifying the physiochemical properties of therapeutic compounds to allow for transport across the BBB; (2) bypassing the BBB by administration of drugs via alternative routes; and (3) transiently disrupting the BBB (BBBD) using biophysical therapies. Here we specifically review colloidal drug carrier delivery systems, intranasal, intrathecal, and direct interstitial drug delivery methods, focused ultrasound BBBD, and pulsed electrical field induced BBBD, as well as the key features of BBB structure and function that are the mechanistic targets of these approaches. Each of these drug delivery technologies are illustrated in the context of their potential clinical applications and limitations in companion animals with naturally occurring intracranial diseases., Competing Interests: Authors ML, CA, RD, and JR have issued patents and/or patents pending in the area of irreversible electroporation induced blood-brain barrier disruption and may receive royalties. CR and JR have issued patents for convection enhanced delivery catheter systems and may receive royalties. AM has issued and pending patents in focused ultrasound blood-barrier disruption and may receive royalties. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Partridge, Eardley, Morales, Campelo, Lorenzo, Mehta, Kani, Mora, Campbell, Arena, Platt, Mintz, Shinn, Rylander, Debinski, Davalos and Rossmeisl.)

Glioblastoma is the deadliest malignant brain tumor. Its location behind the blood-brain barrier (BBB) presents a therapeutic challenge by preventing effective delivery of most chemotherapeutics. H-FIRE is a novel tumor ablation method that transiently disrupts the BBB through currently unknown mechanisms. We hypothesized that H-FIRE mediated BBB disruption (BBBD) occurs via cytoskeletal remodeling and alterations in tight junction (TJ) protein regulation. Intracranial H-FIRE was delivered to Fischer rats prior to sacrifice at 1-, 24-, 48-, 72-, and 96 h post-treatment. Cytoskeletal proteins and native and ubiquitinated TJ proteins (TJP) were evaluated using immunoprecipitation, Western blotting, and gene-expression arrays on treated and sham control brain lysates. Cytoskeletal and TJ protein expression were further evaluated with immunofluorescent microscopy. A decrease in the F/G-actin ratio, decreased TJP concentrations, and increased ubiquitination of TJP were observed 1-48 h post-H-FIRE compared to sham controls. By 72-96 h, cytoskeletal and TJP expression recovered to pretreatment levels, temporally corresponding with increased claudin-5 and zonula occludens-1 gene expression. Ingenuity pathway analysis revealed significant dysregulation of claudin genes, centered around claudin-6 in H-FIRE treated rats. In conclusion, H-FIRE is capable of permeating the BBB in a spatiotemporal manner via cytoskeletal-mediated TJP modulation. This minimally invasive technology presents with applications for localized and long-lived enhanced intracranial drug delivery.

Background: Brain tumor therapeutic responses can be quantified from magnetic resonance images (MRI) using 1- (1D) and 2-dimensional (2D) linear and volumetric methods, but few studies in dogs compare these techniques., Hypotheses: Linear methods will be obtained faster, but have less agreement than volumetric measurements. Therapeutic response agreement will be highest with the total T2W tumor volumetric (TTV) method. Therapeutic response at 6-weeks will correlate with overall survival (OS)., Animals: Forty-six dogs with intracranial gliomas., Methods: Prospective study. Three raters measured tumors using 1D and 2D linear, TTV, and contrast-enhancing volumetric (CEV) techniques on 143 brain MRI to determine agreement between methods, define therapeutic responses, and assess relations with OS., Results: Raters performed 1D the fastest (2.9 ± 0.57 minutes) and CEV slowest (17.8 ± 6.2 minutes). Inter- and intraobserver agreements were excellent (intraclass correlations ≥.91) across methods. Correlations between linear (1D vs 2D; ρ > .91) and volumetric (TTV vs CEV; ρ > .73) methods were stronger than linear to volumetric comparisons (ρ range, .26-.59). Incorporating clinical and imaging data resulted in fewer discordant therapeutic responses across methods. Dogs having partial tumor responses at 6 weeks had a lower death hazard than dogs with stable or progressive disease when assessed using 2D, CEV, and TTV (hazard ration 2.1; 95% confidence interval, 1.22-3.63; P = .008)., Conclusions and Clinical Importance: One-dimensional, 2D, CEV, and TTV are comparable for determining therapeutic response. Given the simplicity, universal applicability, and superior performance of the TTV, we recommend its use to standardize glioma therapeutic response criteria., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Improved therapeutics for malignant brain tumors are urgently needed. High-frequency irreversible electroporation (H-FIRE) is a minimally invasive, nonthermal tissue ablation technique, which utilizes high-frequency, bipolar electric pulses to precisely kill tumor cells. The mechanisms of H-FIRE-induced tumor cell death and potential for cellular recovery are incompletely characterized. We hypothesized that tumor cells treated with specific H-FIRE electric field doses can survive and retain proliferative capacity. F98 glioma and LL/2 Lewis lung carcinoma cell suspensions were treated with H-FIRE to model primary and metastatic brain cancer, respectively. Cell membrane permeability, apoptosis, metabolic viability, and proliferative capacity were temporally measured using exclusion dyes, condensed chromatin staining, WST-8 fluorescence, and clonogenic assays, respectively. Both tumor cell lines exhibited dose-dependent permeabilization, with 1,500 V/cm permitting and 3,000 V/cm inhibiting membrane recovery 24 h post-treatment. Cells treated with 1,500 V/cm demonstrated significant and progressive recovery of apoptosis and metabolic activity, in contrast to cells treated with higher H-FIRE doses. Cancer cells treated with recovery-permitting doses of H-FIRE maintained while those treated with recovery-inhibiting doses lost proliferative capacity. Taken together, our data suggest that H-FIRE induces reversible and irreversible cellular damage in a dose-dependent manner, and the presence of dose-dependent recovery mechanisms permits tumor cell proliferation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Davalos, Aycock, Dervisis, and Rossmeisl have pending and issued patents related to electroporation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The fiberoptic microneedle device (FMD) is a fused-silica microcatheter capable of co-delivery of fluids and light that has been developed for convection-enhanced delivery and photothermal treatments of glioblastoma. Here we investigate the biocompatibility of FMD fragments chronically implanted in the rat brain in the context of evaluating potential mechanical device failure. Fischer rats underwent craniectomy procedures for sham control (n = 16) or FMD implantation (n = 16) within the brain. Rats were examined daily after implantation, and at 14, 30, 90, and 180 days after implantation were evaluated via computed tomography of the head, hematologic and blood biochemical profiling, and necropsy examinations. Clinical signs of illness and distant implant migration were not observed, and blood analyses were not different between control and FMD implanted groups at any time. Mild inflammatory and astrogliotic reactions localized to the treatment sites within the brain were observed in all groups, more robust in FMD implanted groups compared to controls at days 30 and 90, and decreased in severity over days 90-180 of the study. One rat developed a chronic, superficial surgical site pyogranuloma attributed to the FMD silica implant. Chronically implanted FMD fragments were well tolerated clinically and resulted in anticipated mild, localized brain tissue responses that were comparable with other implanted biomaterials in the brain., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Seizures in the early postoperative period after intracranial surgery may affect outcome in dogs., Objectives: To determine the incidence of early postoperative seizures (EPS) in dogs with brain tumors, identify specific risk factors for EPS, and determine if EPS affects outcome., Animals: Eighty-eight dogs that underwent 125 intracranial surgeries for diagnosis and treatment of rostrotentorial brain tumors., Methods: Retrospective cohort study. All patients with a diagnosis of rostrotentorial brain tumor from 2006 to 2020 were included. Early postoperative seizures were diagnosed by observation of seizure activity within 14 days of neurosurgery. Previously diagnosed structural epilepsy, perioperative anticonvulsant drug (ACD) use, magnetic resonance imaging (MRI), and tumor characteristics were evaluated. Outcome measures included neurologic and nonneurologic complications, duration of hospitalization, and survival to discharge., Results: Dogs with rostrotentorial brain tumors had EPS after 16/125 (12.8%) neurosurgical procedures (95% confidence interval [CI], 7%-19%). Presence of previous structural epilepsy was not associated with EPS risk (P = 1). Perioperative ACD use also was not associated with EPS (P = .06). Dogs with EPS had longer hospitalization (P < .001), were more likely to have neurologic complications postsurgery (P = .01), and were less likely to survive to discharge (P = .01)., Conclusions and Clinical Importance: It is difficult to predict which dogs are at risk of EPS because the presence of previous structural epilepsy and the use of perioperative ACDs was not associated with EPS. However, seizures in the early postoperative period are clinically important because affected dogs had prolonged hospitalization, more neurologic complications, and decreased short-term survival., (© 2022 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

New therapeutic strategies are direly needed in the fight against cancer. Over the last decade, several tumor ablation strategies have emerged as stand-alone or combination therapies. Histotripsy is the first completely noninvasive, nonthermal, and nonionizing tumor ablation method. Histotripsy can produce consistent and rapid ablations, even near critical structures. Additional benefits include real-time image guidance, high precision, and the ability to treat tumors of any predetermined size and shape. Unfortunately, the lack of clinically and physiologically relevant preclinical cancer models is often a significant limitation with all focal tumor ablation strategies. The majority of studies testing histotripsy for cancer treatment have focused on small animal models, which have been critical in moving this field forward and will continue to be essential for providing mechanistic insight. While these small animal models have notable translational value, there are significant limitations in terms of scale and anatomical relevance. To address these limitations, a diverse range of large animal models and spontaneous tumor studies in veterinary patients have emerged to complement existing rodent models. These models and veterinary patients are excellent at providing realistic avenues for developing and testing histotripsy devices and techniques designed for future use in human patients. Here, we provide a review of animal models used in preclinical histotripsy studies and compare histotripsy ablation in these models using a series of original case reports across a broad spectrum of preclinical animal models and spontaneous tumors in veterinary patients.

Background: Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing., Objective: To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT., Animals: Sixty dogs diagnosed with OT based on conscious electromyography., Methods: Multicenter retrospective case series study. Dogs were included if they had a conscious electromyography consistent with muscle discharge frequency >12 Hz while standing., Results: Fifty-three cases were diagnosed with primary OT (POT). Giant breed dogs represented most cases (83%; 44/53). Most dogs (79%; 42/53) were younger than 2 years of age at onset of signs, except for Retrievers which were all older than 3.5 years of age. The most common presenting complaints were pelvic limb tremors while standing (85%; 45/53) and difficulty when rising or sitting down (45%; 24/53). Improvement of clinical signs occurred in most dogs (85%; 45/53) treated medically with phenobarbital, primidone, gabapentin, pregabalin or clonazepam, but it was mostly partial rather than complete. Orthostatic tremor-plus was seen in 7 dogs that had concurrent neurological diseases., Conclusions and Clinical Importance: Primary OT is a progressive disease of young, purebred, giant/large-breed dogs, which appears to begin later in life in Retrievers. Primary OT apparently responds partially to medications. Orthostatic tremor-plus exists in dogs and can be concomitant or associated with other neurological diseases., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

The treatment of CNS disorders suffers from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). Herein, we investigated high-frequency pulsed electric field (HF-PEF) therapy of various pulse widths and interphase delays for BBB disruption while selectively minimizing cell ablation. Eighteen male Fisher rats underwent craniectomy procedures and two blunt-tipped electrodes were advanced into the brain for pulsing. BBB disruption was verified with contrast T1W MRI and pathologically with Evans blue dye. High-frequency irreversible electroporation cell death of healthy rodent astrocytes was investigated in vitro using a collagen hydrogel tissue mimic. Numerical analysis was conducted to determine the electric fields in which BBB disruption and cell ablation occur. Differences between the BBB disruption and ablation thresholds for each waveform are as follows: 2-2-2 μs (1028 V/cm), 5-2-5 μs (721 V/cm), 10-1-10 μs (547 V/cm), 2-5-2 μs (1043 V/cm), and 5-5-5 μs (751 V/cm). These data suggest that HF-PEFs can be fine-tuned to modulate the extent of cell death while maximizing peri-ablative BBB disruption. Furthermore, numerical modeling elucidated the diffuse field gradients of a single-needle grounding pad configuration to favor large-volume BBB disruption, while the monopolar probe configuration is more amenable to ablation and reversible electroporation effects.

Background: High-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical models., Methods: To leverage the known overexpression of procaspase-3 in meningioma, PAC-1, a blood-brain barrier penetrant procaspase-3 activator, was evaluated for its ability to induce apoptosis in meningioma cells. To enhance the effects of PAC-1, combinations with either hydroxyurea or temozolomide were explored in cell culture. Both combinations were further investigated in small groups of canine meningioma patients and assessed by MRI, and the novel apoptosis tracer, [18F]C-SNAT4, was evaluated in patients treated with PAC-1 + HU., Results: In meningioma cell lines in culture, PAC-1 + HU are synergistic while PAC-1 + TMZ show additive-to-synergistic effects. In canine meningioma patients, PAC-1 + HU led to stabilization of disease and no change in apoptosis within the tumor, whereas PAC-1 + TMZ reduced tumor burden in all three canine patients treated., Conclusions: Our results suggest PAC-1 + TMZ as a potentially efficacious combination for the treatment of human meningioma, and also demonstrate the utility of including pet dogs with meningioma as a means to assess anticancer strategies for this common brain tumor., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2021 The Authors. Veterinary and Comparative Oncology published by John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Dissemination of glioma in humans can occur as leptomeningeal nodules, diffuse leptomeningeal lesions, or ependymal lesions. Cerebrospinal fluid (CSF) drop metastasis of glioma is not well-recognized in dogs. Ten dogs with at least two anatomically distinct and histologically confirmed foci of glioma were included in this study. The 10 dogs underwent 28 magnetic resonance imaging (MRI) examinations, with distant CSF drop metastasis revealed in 13 MRIs. The CSF drop metastases appeared as leptomeningeal nodules in four dogs, diffuse leptomeningeal lesions in six dogs, and ependymal lesions in seven dogs; six dogs had a combination of lesion types. Primary tumors were generally T2-heterogeneous and contrast-enhancing. Many metastases were T2-homogeneous and non-enhancing. Diffuse leptomeningeal lesions were seen as widespread extra-axial contrast-enhancement, again very dissimilar to the intra-axial primary mass. Primary masses were rostrotentorial, whereas metastases generally occurred in the direction of CSF flow, in ventricles, CSF cisterns, and the central canal or leptomeninges of the cervical or thoracolumbar spinal cord. Seven of the dogs had received therapy limited to the primary mass, such as surgery or stereotactic radiation, then developed metastasis in the following months. CSF drop metastasis of glioma may take a very different appearance on MRI to the primary mass, including periventricular lesions that are more homogeneous and less contrast-enhancing, rostral horn signal changes, or leptomeningeal enhancement ventral to the brainstem or encircling the spinal cord., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bentley, Yanke, Miller, Heng, Cohen-Gadol and Rossmeisl.)

Background: The interleukin-13 receptor alpha 2 (IL13RA2) and ephrin type A receptor 2 (EPHA2) are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection-enhanced delivery (CED) method. In this study, IL-13 mutant and ephrin A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy., Methods: In this phase I, 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI monitoring. The primary endpoint was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas., Results: Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40-94%). Cytotoxins were well tolerated over a dose range of 0.012-1.278 μg/mL delivered to the target volume (median, 0.099 μg/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 μg/mL., Conclusions: This study provides preclinical data fundamental to the translation of this multireceptor targeted therapeutic approach to the human clinic., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Quantitative magnetic resonance imaging (QMRI) techniques of magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) provide microstructural information about the spinal cord., Objective: Compare neurologic grades using the modified Frankel scale with MTR and DTI measurements in dogs with thoracolumbar intervertebral disk herniation (IVDH)., Animals: Fifty-one dogs with thoracolumbar IVDH., Methods: Prospective cohort study. Quantitative MRI measurements of the spinal cord were obtained at the region of compression. A linear regression generalized estimating equations model was used to compare QMRI measurements between different neurological grades after adjusting for age, weight, duration of clinical signs, and lesion location., Results: Grade 5 (.79  ×  10 -3 mm 2 /s [median], .43-.91 [range]) and axial (1.47 × 10 -3 mm 2 /s, .58-1.8) diffusivity were lower compared to grades 2 (1.003, .68-1.36; P = .02 and 1.81 × 10 -3 mm 2 /s, 1.36-2.12; P < .001, respectively) and 3 (1.07 × 10 -3 mm 2 /s, .77-1.5; P = .04 and 1.92 × 10 -3 mm 2 /s, 1.83-2.37;P < .001, respectively). Compared to dogs with acute myelopathy, chronic myelopathy was associated with higher mean (1.02 × 10 -3 mm 2 /s, .77-1.36 vs. .83 × 10 -3 mm 2 /s, .64-1.5; P = .03) and radial diffusivity (.75 × 10 -3 mm 2 /s, .38-1.04 vs. .44 × 10 -3 mm 2 /s, .22-1.01; P = .008) and lower MTR (46.76, 31.8-56.43 vs. 54.4, 45.2-62.27; P = .004) and fractional anisotropy (.58, .4-0.75 vs. .7, .46-.85; P = .02). Fractional anisotropy was lower in dogs with a T2-weighted intramedullary hyperintensity compared to those without (.7, .45-.85 vs. .54, .4-.8; P = .01)., Conclusion and Clinical Relevance: Mean diffusivity and AD could serve as surrogates of severity of spinal cord injury and are complementary to the clinical exam in dogs with thoracolumbar IVDH., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Stereotactic brain biopsy (SBB) allows for histopathologic diagnosis of brain tumors. Adverse events (AE) occur in 5 to 29% of dogs after SBB, but risk factors associated with developing AE are poorly described., Objective: Identify clinicopathologic, diagnostic imaging, or procedural variables that are associated with AE in dogs after SBB., Animals: Twenty-nine dogs with brain tumors., Methods: Retrospective, case-control study. Dogs had laboratory investigations performed before SBB, as well as clinical examinations and diagnostic imaging of the brain before and after SBB. Cases experienced AE after SBB including transient exacerbation of preexisting neurologic deficits, transient new deficits, or permanent neurologic deficits. Controls had SBB performed without AE. Fisher's exact and Student's t tests were used to examine associations between the postulated risk factors and AE., Results: Adverse events occurred in 8/29 (27%) dogs, and 7/8 AE (88%) were transient. Cases were significantly more likely to have T2W-heterogenous tumors (88 versus 38%; P = .04) and lower platelet counts (194.75 ± 108.32 versus 284.29 ± 68.54 ×10 3 /mm 3 , P = .006). Dogs with gradient echo signal voids present on baseline imaging were significantly more likely to have hemorrhage present after biopsy, and 7/8 (88%) of cases had hemorrhage on imaging after SBB., Conclusion and Clinical Importance: Twenty-seven percent of dogs undergoing SBB experience AE, with the majority of AE resolving with 1 week. Platelet counts should be ≥185 000/mm 3 to minimize risk of SBB-associated AE. Observation of intracranial hemorrhage after biopsy can have important clinical implications, as this was observed in 88% of dogs with AE., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

In veterinary medicine, quality of life (QOL) assessment instruments, which are important components of the holistic evaluation of treatment success, have largely not included organ-specific concerns that may be broadly relevant to caregivers of dogs with intracranial disease. The objective of this study was to identify core questionnaire items and domains that contribute to health-related QOL (HRQOL) in dogs with intracranial disease. A questionnaire was developed that contained 39 QOL-related items encompassing physical, social/companionship, and brain-specific domains associated with the treatment of dogs with intracranial disease, and administered to caregivers of 56 dogs diagnosed with genetic, inflammatory, neoplastic, traumatic, and vascular brain diseases, 52 healthy dogs, and 20 dogs with non-neurological illnesses. Clinician derived functional measures of each dog's health status including chronic pain, Karnofsky performance, and modified Glasgow coma scale scores were also recorded. Principal component analysis refined the final questionnaire, termed the CanBrainQOL-24, to 24-items within the three domains with a minimum Cronbach's alpha of 0.7, indicative of good internal consistency. The CanBrainQOL-24 discriminated between healthy and diseased dogs. Physical and brain-specific domains were significantly different between dogs with intracranial and non-neurological diseases. Significant correlations were observed between owner reported visual analog scores and CanBrainQOL-24 scores, as well between clinician derived functional status measures and owner reported QOL. The CanBrainQOL-24 contains core questions relevant to caregiver assessment of HRQOL in dogs with a variety of intracranial diseases, and provides information that is complementary to clinician derived functional outcome measures., (Copyright © 2020 Weiske, Sroufe, Quigley, Pancotto, Werre and Rossmeisl.)

Background: Intracranial hypertension (ICH) is often presumptively diagnosed based on clinical or imaging findings. Clinical or imaging surrogates of ICH are not usually validated with reference standard direct intracranial pressure (dICP) recordings., Hypotheses: Dogs with brain magnetic resonance imaging (MRI) or clinical features of presumed ICH would have higher dICP than dogs lacking those features., Animals: Twenty dogs with gliomas and 3 normal controls., Methods: Prospective, convenience study. Dogs were presumptively categorized with normal ICP or ICH from scores generated from described clinical and brain MRI indicators of ICH. dICP was recorded in anesthetized dogs using an intraparenchymal microsensor and compared between groups., Results: dICP was not different between control (10.4 ± 2.1 mm Hg) and dogs with glioma (15.6 ± 8.3 mm Hg), or between dogs in clinically predicted ICP groups. Compared with dogs with MRI-predicted normal ICP, MRI-predicted ICH dogs had higher dICP (10.3 ± 4.1 versus 19.2 ± 7.9 mm Hg, P = .004), larger tumors (1.45 ± 1.2 versus 5.71 ± 3.03 cm 3 , P = .0004), larger optic nerve sheath diameters, and 14/14 (100%) displayed structural anatomical shifts on MRI. At a dICP threshold of 15 mm Hg, the sensitivity of MRI for predicting ICH was 90% and the specificity 69%., Conclusions and Clinical Relevance: dICP measurements are feasible in dogs with brain tumors. MRI features including brain herniations, mass effect, and optic nerve size aid in the identification of dogs with ICH. Clinical estimation of ICP did not discriminate between dogs with and without ICH., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Primary brain tumors are among the deadliest cancers that remain highly incurable. A need exists for new approaches to tumor therapy that can circumvent the blood brain barrier (BBB), target highly resistant tumors and cancer stem-like cells (CSCs) as well create an anti-cancer immunomodulatory environment. Successful treatments may also require a combinatory approach utilizing surgery, chemotherapy, radiation and novel ablation strategies that can both eliminate the bulk tumor and prevent any potential residual CSCs from propagating in the resected tissue. A number of thermal and non-thermal ablation methods have been developed and tested, which have gained much enthusiasm for the treatment of brain tumors. Here we review the most common primary brain tumors and the candidate ablation methods for targeting the tumor and its microenvironment., Competing Interests: Declaration of Competing Interest The author(s) declare no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Seizures are a common presenting sign in dogs with brain tumors., Hypothesis/objectives: To investigate the effect of radiotherapy on freedom from brain tumor-associated seizures and survival time in dogs., Animals: Thirty-two client-owned dogs with brain tumor-associated seizures; 18 received medical treatment and radiotherapy, 14 received medical treatment alone., Methods: Multicenter retrospective study. Baseline characteristics (seizure semiology, magnetic resonance imaging [MRI] characteristics, and treatment) and duration of seizure freedom were recorded for the 2 treatment groups. Duration of seizure freedom between groups was compared (log-rank test) using Cox's proportional hazard analysis, with baseline characteristics entered as covariates., Results: The duration of seizure freedom and survival time were significantly longer in the radiotherapy group (P < .001), with a mean of 24 months (95% confidence interval [CI], 14.3-33.8) versus 1.7 months in the control group (95% CI, 0.5-2.9) and a mean of 34.6 months (95% CI: 25.2-44.1) versus 6.2 months in the control group (95% CI, 2.6-9.7) respectively. Baseline characteristics were not associated with duration of seizure freedom after the start of treatment. In the radiotherapy group, 5 dogs were euthanized during the study period because of causes other than seizures. In the control group, recurrence of seizures was observed before death in all dogs., Conclusions and Clinical Importance: A longer period of seizure freedom and longer survival time was observed in dogs with brain tumors after radiotherapy compared to medical treatment only. The pathophysiological mechanisms of epileptogenesis and the effect of radiation therapy on seizure control are unclear to date. Further prospective studies are needed., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

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., Competing Interests: Declaration of Interests R.G.W.V. declares equity in Boundless Bio, Inc. A.B.H. receives royalties and milestone payments for licensed intellectual property from Celldex Therapeutics, research grant support from Merck, and is a scientific board member for Caris Life Sciences. The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Clinical translation of novel therapeutics that improve the survival and quality of life of patients with neurological disease remains a challenge, with many investigational drug and device candidates failing in advanced stage clinical trials. Naturally occurring inherited and acquired neurological diseases, such as epilepsy, inborn errors of metabolism, brain tumors, spinal cord injury, and stroke occur frequently in companion animals, and many of these share epidemiologic, pathophysiologic and clinical features with their human counterparts. As companion animals have a relatively abbreviated lifespan and genetic background, are immunocompetent, share their environment with human caregivers, and can be clinically managed using techniques and tools similar to those used in humans, they have tremendous potential for increasing the predictive value of preclinical drug and device studies. Here, we review comparative features of spontaneous neurological diseases in companion animals with an emphasis on neuroimaging methods and features, illustrate their historical use in translational studies, and discuss inherent limitations associated with each disease model. Integration of companion animals with naturally occurring disease into preclinical studies can complement and expand the knowledge gained from studies in other animal models, accelerate or improve the manner in which research is translated to the human clinic, and ultimately generate discoveries that will benefit the health of humans and animals., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Vertebral osteosarcoma (OSA) is the most common primary vertebral tumor in dogs, however studies examining the survival time after surgical decompression of these tumors are limited. There is also limited information regarding the benefit of adjunctive treatments such as radiation therapy or chemotherapy in these patients. The goal of this study was to determine survival time of dogs with primary vertebral OSA after palliative decompressive surgery alone and combined with radiation therapy and/or chemotherapy. Records from 22 client-owned dogs diagnosed with primary vertebral OSA and treated with decompressive surgery were collected retrospectively from eight referral institutions. Survival time was assessed for dogs treated with surgery alone as well as dogs who received adjunctive radiation therapy and/or chemotherapy. Median survival time in the 12 dogs treated with surgery alone was 42 days (range: 3-1333 days). The three dogs treated with surgery and chemotherapy had a median survival time of 82 days (range: 56-305 days). Only one dog was treated with surgery and radiation therapy; this dog survived 101 days. Six dogs were treated with surgery, radiation therapy and chemotherapy; these dogs had a median survival time of 261 days (range: 223-653 days). Cause of death in all cases that survived the initial postoperative period was euthanasia secondary to confirmed or suspected tumor regrowth. The results of this study suggest that definitive radiation therapy, possibly combined with concurrent chemotherapy, significantly improves survival in dogs treated with palliative decompressive surgery for vertebral OSA and should be the treatment of choice in selected cases., (© 2019 John Wiley & Sons Ltd.)

Treatment of intracranial disorders suffers from the inability to accumulate therapeutic drug concentrations due to protection from the blood-brain barrier (BBB). Electroporation-based therapies have demonstrated the capability of permeating the BBB, but knowledge of the longevity of BBB disruption (BBBD) is limited. In this study, we quantify the temporal, high-frequency electroporation (HFE)-mediated BBBD in an in vivo healthy rat brain model. 40 male Fisher rats underwent HFE treatment; two blunt tipped monopolar electrodes were advanced into the brain and 200 bursts of HFE were delivered at a voltage-to-distance ratio of 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye) at time points of 1, 24, 48, 72, and 96 h after HFE. Contrast enhanced T1W scans demonstrated BBBD for 1 to 72 h after HFE but intact BBB at 96 h. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated that brief BBBD was induced with low magnitude electric fields, and BBBD duration increased with field strength. These data suggest the spatiotemporal characteristics of HFE-mediated BBBD may be modulated with the locally applied electric field.

In the dog, primary intracranial neoplasia represents ~2-5% of all cancers and is especially common in certain breeds including English and French bulldogs and Boxers. The most common types of primary intracranial cancer in the dog are meningioma, glioma, and choroid plexus tumors, generally occurring in middle aged to older dogs. Much work has recently been done to understand the characteristic imaging and clinicopathologic features of these tumors. The gross and histologic landscape of these tumors in the dog compare favorably to their human counterparts with many similarities noted in histologic patterns, subtype, and grades. Data informing the underlying molecular abnormalities in the canine tumors have only begun to be unraveled, but reveal similar pathways are mutated between canine and human primary intracranial neoplasia. This review will provide an overview of the clinicopathologic features of the three most common forms of primary intracranial cancer in the dog, delve into the comparative aspects between the dog and human neoplasms, and provide an introduction to current standard of care while also highlighting novel, experimental treatments that may help bridge the gap between canine and human cancer therapies., (Copyright © 2019 Miller, Miller and Rossmeisl.)

Background: The intranasal (IN) route for rapid drug administration in patients with brain disorders, including status epilepticus, has been investigated. Status epilepticus is an emergency, and the IN route offers a valuable alternative to other routes, especially when these fail., Objectives: To compare IN versus IV midazolam (MDZ) at the same dosage (0.2 mg/kg) for controlling status epilepticus in dogs., Animals: Client-owned dogs (n = 44) with idiopathic epilepsy, structural epilepsy, or epilepsy of unknown origin manifesting as status epilepticus., Methods: Randomized parallel group clinical trial. Patients were randomly allocated to the IN-MDZ (n = 21) or IV-MDZ (n = 23) group. Number of successfully treated cases (defined as seizure cessation within 5 minutes and lasting for ≥10 minutes), seizure cessation time, and adverse effects were recorded. Comparisons were performed using the Fisher's exact and Wilcoxon rank sum tests with statistical significance set at α < .05., Results: IN-MDZ and IV-MDZ successfully stopped status epilepticus in 76% and 61% of cases, respectively (P = .34). The median seizure cessation time was 33 and 64 seconds for IN-MDZ and IV-MDZ, respectively (P = .63). When the time to place an IV catheter was taken into account, IN-MDZ (100 seconds) was superior (P = .04) to IV-MDZ (270 seconds). Sedation and ataxia were seen in 88% and 79% of the dogs treated with IN-MDZ and IV-MDZ, respectively., Conclusions and Clinical Importance: Both routes are quick, safe, and effective for controlling status epilepticus. However, the IN route demonstrated superiority when the time needed to place an IV catheter was taken into account., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Granulomas can "mimic" gliomas on magnetic resonance imaging (MRI) in human patients. The goal of this retrospective study was to report canine brain granulomas that were consistent with glioma based upon MRI, report their histologic diagnosis, and identify MRI criteria that might be useful to distinguish granuloma from glioma. Ten granulomas, initially suspected to be glioma based on MRI, were ultimately diagnosed as granulomatous meningoencephalomyelitis ( n = 5), infectious granulomas ( n = 3) or other meningoencephalitis ( n = 2). Age was 1.6-15.0 years and two dogs were brachycephalic breeds. MRI characteristics overlapping with glioma included intra-axial, heterogeneous, T2-weighted hyperintense, T1-weighted hypointense to isointense mass lesions with contrast-enhancement. Signals on fluid attenuation inversion recovery, gradient echo and diffusion weighted imaging also matched glioma. Peri-lesional edema and mass effect were toward the high end of findings reported for glioma. MRI characteristics that would be considered unusual for glioma included dural contact ( n = 4), T2-hypointensity ( n = 2), concomitant meningeal-enhancement ( n = 9), and minor changes in the contralateral brain ( n = 2). Cerebrospinal fluid analysis revealed albuminocytological dissociation or mild pleocytosis. These cases show that granulomas can "mimic" glioma on canine brain MRI. In individual cases, certain MRI findings may help increase the index of suspicion for granuloma. Lack of pronounced cerebrospinal fluid pleocytosis does not exclude granuloma. Signalment is very useful in the suspicion of glioma, and many of these dogs with granuloma were of ages and breeds in which glioma is less commonly seen.

Background: Despite promising treatments for breast cancer, mortality rates remain high and treatments for metastatic disease are limited. High-frequency irreversible electroporation (H-FIRE) is a novel tumor ablation technique that utilizes high-frequency bipolar electric pulses to destabilize cancer cell membranes and induce cell death. However, there is currently a paucity of data pertaining to immune system activation following H-FIRE and other electroporation based tumor ablation techniques., Methods: Here, we utilized the mouse 4T1 mammary tumor model to evaluate H-FIRE treatment parameters on cancer progression and immune system activation in vitro and in vivo., Findings: H-FIRE effectively ablates the primary tumor and induces a pro-inflammatory shift in the tumor microenvironment. We further show that local treatment with H-FIRE significantly reduces 4T1 metastases. H-FIRE kills 4T1 cells through non-thermal mechanisms associated with necrosis and pyroptosis resulting in damage associated molecular pattern signaling in vitro and in vivo. Our data indicate that the level of tumor ablation correlates with increased activation of cellular immunity. Likewise, we show that the decrease in metastatic lesions is dependent on the intact immune system and H-FIRE generates 4T1 neoantigens that engage the adaptive immune system to significantly attenuate tumor progression., Interpretation: Cell death and tumor ablation following H-FIRE treatment activates the local innate immune system, which shifts the tumor microenvironment from an anti-inflammatory state to a pro-inflammatory state. The non-thermal damage to the cancer cells and increased innate immune system stimulation improves antigen presentation, resulting in the engagement of the adaptive immune system and improved systemic anti-tumor immunity., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Stereotactic brain biopsy (SBB) is a technique that allows for definitive diagnosis of brain lesions. Little information is available regarding the diagnostic utility of SBB in dogs with intracranial diseases., Objective: To investigate the diagnostic accuracy (DA) of SBB in dogs with brain tumors., Animals: Thirty-one client-owned dogs that underwent SBB followed by surgical resection or necropsy examinations., Methods: Retrospective observational study. Two pathologists blinded to SBB and reference standard diagnoses reviewed histologic specimens and typed and graded tumors according to World Health Organization and revised canine glioma classification criteria. Agreement between tumor type and grade from SBB were compared to reference standards and assessed using kappa statistics. Patient and technical factors associated with agreement also were examined., Results: Stereotactic brain biopsy specimens were obtained from 24 dogs with gliomas and 7 with meningiomas. Tumor type agreement between SBB and the reference standard was observed in 30/31 cases (κ = 0.95). Diagnostic concordance was perfect for meningiomas. Grade agreement among gliomas was observed in 18/23 cases (κ = 0.47). Stereotactic brain biopsy underrepresented the reference standard glioma grade in cases with disagreement. The DA of SBB was 81%, with agreement noted in 56/69 biopsy samples. Smaller tumors and fewer SBB specimens obtained were significantly associated with diagnostic discordance., Conclusions and Clinical Importance: The DA of SBB readily allows for the diagnosis of common brain tumors in dogs. Although glioma grade discordance was frequent, diagnoses obtained from SBB are sufficient to currently inform therapeutic decisions. Multiple SBB specimens should be collected to maximize DA., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

In dogs diagnosed with solid tumors, regional lymph node involvement or evidence of distant metastasis can predict worse prognoses and significantly decreased survival. Lymph node size alone has been shown to be insufficient as a predictor for the accurate clinical staging of some canine neoplasia. However, certain regional lymph nodes (including those of the oral cavity) are difficult to access for routine tissue sampling. Diffusion weighted magnetic resonance imaging (MRI) has demonstrated the ability to differentiate metastatic from inflammatory/benign lymph nodes in clinical studies with human cancer patients through the calculation of quantitative values of diffusion termed apparent diffusion coefficients (ADC). The objective of this prospective, exploratory study was to evaluate diffusion-weighted MRI and ADC as potential methods for detecting metastatic lymph nodes in dogs with naturally occurring disease. We hypothesized that diffusion-weighted MRI would identify significantly different ADC values between benign and metastatic lymph nodes in a group of canine patients with head or neck disease. Our study population consisted of eight client-owned canine patients, with a total of 20 lymph nodes evaluated (six metastatic, 14 benign). Our results demonstrated that two of four observers identified a significant difference between the mean ADC values of the benign and metastatic lymph nodes. When data from all four observers were pooled, the difference between the mean apparent diffusion coefficients values of the benign and metastatic lymph nodes did not reach significance (P-value = 0.0566). Findings indicated that diffusion-weighted MRI is a feasible method for further characterizing enlarged lymph nodes in dogs with head and neck disease, however measured ADC values did not differ for benign vs. metastatic lymph nodes in this small sample of dogs., (© 2018 American College of Veterinary Radiology.)

A variety of inflammatory conditions of unknown cause (meningoencephalomyelitis of unknown etiology-MUE) and neoplastic diseases can affect the central nervous system (CNS) of dogs. MUE can mimic intracranial neoplasia both clinically, radiologically and even in some cases, histologically. Serum immunosignature protein microarray assays have been used in humans to identify CNS diseases such as Alzheimer's and neoplasia, and in dogs, to detect lymphoma and its progression. This study evaluated the effectiveness of immunosignature profiles for distinguishing between three cohorts of dogs: healthy, intracranial neoplasia, and MUE. Using the learned peptide patterns for these three cohorts, classification prediction was evaluated for the same groups using a 10-fold cross validation methodology. Accuracy for classification was 100%, as well as 100% specific and 100% sensitive. This pilot study demonstrates that immunosignature profiles may help serve as a minimally invasive tool to distinguish between MUE and intracranial neoplasia in dogs.

The National Cancer Institute Comparative Brain Tumor Consortium, Patient Outcomes Working Group, propose a consensus document in support of standardized magnetic resonance imaging protocols for canine brain tumor clinical trials. The intent of this manuscript is to address the widely acknowledged need to ensure canine brain tumor imaging protocols are relevant and have sufficient equivalency to translate to human studies such that: (1) multi-institutional studies can be performed with minimal inter-institutional variation, and (2) imaging protocols are consistent with human consensus recommendations to permit reliable translation of imaging data to human clinical trials. Consensus recommendations include pre- and postcontrast three-dimensional T1-weighted images, T2-weighted turbo spin echo in all three planes, T2*-weighted gradient recalled echo, T2-weighted fluid attenuated inversion recovery, and diffusion weighted imaging/diffusion tensor imaging in transverse plane; field of view of ≤150 mm; slice thickness of ≤2 mm, matrix ≥ 256 for two-dimensional images, and 150 or 256 for three-dimensional images., (© 2018 American College of Veterinary Radiology.)

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.