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Abstract The National Cancer Institute-led multidisciplinary Comparative Brain Tumor Consortium (CBTC) convened a glioma pathology board, comprising both veterinarian and physician neuropathologists, and conducted a comprehensive review of 193 cases of canine glioma. The immediate goal was to improve existing glioma classification methods through creation of a histologic atlas of features, thus yielding greater harmonization of phenotypic characterization. The long-term goal was to support future incorporation of clinical outcomes and genomic data into proposed simplified diagnostic schema, so as to further bridge the worlds of veterinary and physician neuropathology and strengthen validity of the dog as a naturally occurring, translationally relevant animal model of human glioma. All cases were morphologically reclassified according to a new schema devised by the entire board, yielding a majority opinion diagnosis of astrocytoma (43, 22.3%), 19 of which were low-grade and 24 high-grade, and oligodendroglioma (134, 69.4%), 35 of which were low-grade and 99 were high-grade. Sixteen cases (8.3%) could not be classified as oligodendroglioma or astrocytoma based on morphology alone and were designated as undefined gliomas. The simplified classification scheme proposed herein provides a tractable means for future addition of molecular data, and also serves to highlight histologic similarities and differences between human and canine glioma.

Abstract Background Gliomas in dogs remain poorly understood. Objectives To characterize the clinicopathologic findings, diagnostic imaging features and survival of a large sample of dogs with glioma using the Comparative Brain Tumor Consortium diagnostic classification. Animals Ninety-one dogs with histopathological diagnosis of glioma. Methods Multicentric retrospective case series. Signalment, clinicopathologic findings, diagnostic imaging characteristics, treatment, and outcome were used. Tumors were reclassified according to the new canine glioma diagnostic scheme. Results No associations were found between clinicopathologic findings or survival and tumor type or grade. However, definitive treatments provided significantly (P = .03) improved median survival time (84 days; 95% confidence interval [CI], 45-190) compared to palliative treatment (26 days; 95% CI, 11-54). On magnetic resonance imaging (MRI), oligodendrogliomas were associated with smooth margins and T1-weighted hypointensity compared to astrocytomas (odds ratio [OR], 42.5; 95% CI, 2.42-744.97; P = .04; OR, 45.5; 95% CI, 5.78-333.33; P < .001, respectively) and undefined gliomas (OR, 84; 95% CI, 3.43-999.99; P = .02; OR, 32.3; 95% CI, 2.51-500.00; P = .008, respectively) and were more commonly in contact with the ventricles than astrocytomas (OR, 7.47; 95% CI, 1.03-53.95; P = .049). Tumor spread to neighboring brain structures was associated with high-grade glioma (OR, 6.02; 95% CI, 1.06-34.48; P = .04). Conclusions and Clinical Importance Dogs with gliomas have poor outcomes, but risk factors identified in survival analysis inform prognosis and the newly identified MRI characteristics could refine diagnosis of tumor type and grade.

Abstract Background Corticosteroids (CS) are a common treatment prescribed for dogs with brain tumors, but little data characterizing the clinical and neuroradiologic effects of CS treatment exist. Hypotheses Decreases in peritumoral brain edema (PBE) would be observed in dogs with brain tumors treated with CS and anticonvulsants, and decreases in edema would be accompanied by clinical improvement. Animals Fifty dogs with gliomas and 22 with meningiomas. Materials and Methods Retrospective case series. Dogs with brain tumors receiving treatments with CS and anticonvulsants underwent pre- and posttreatment clinical and brain magnetic resonance imaging (MRI) examinations within a 3-week follow-up period, and peritumoral edema and tumor volumes were calculated from each MRI study. Dogs were characterized as clinical responders or nonresponders independent of imaging results based on longitudinal changes in clinical findings and owner-reported quality of life (QOL). Clinicopathologic and MRI variables were compared pre- and posttreatment by clinical response. Results At follow-up, 23/50 (46%) of dogs with glioma and 15/22 (68%) with meningioma were classified as clinical responders, and 23/50 (46%) of gliomas and 14/22 (64%) of meningiomas had decreases in edema volume. Responders had significantly larger decreases in edema and mass effect than nonresponders. Decreases in tumor volumes occurred in approximately 25% of gliomas. Conclusions and Clinical Importance Peritumoral brain edema was decreased in 50%–60% of gliomas and meningiomas in dogs at follow-up, and amelioration of edema often was accompanied by improved neurological signs and QOL. Corticosteroids may also clinically benefit dogs without PBE and can influence MRI surrogates used to determine glioma therapeutic responses.

Abstract Background Blood-brain barrier (BBB) permeability can be assessed quantitatively using advanced imaging analysis. Hypothesis/Objectives Quantification and characterization of blood-brain barrier dysfunction (BBBD) patterns in dogs with brain tumors can provide useful information about tumor biology and assist in distinguishing between gliomas and meningiomas. Animals Seventy-eight hospitalized dogs with brain tumors and 12 control dogs without brain tumors. Methods In a 2-arm study, images from a prospective dynamic contrast-enhanced (DCE; n = 15) and a retrospective archived magnetic resonance imaging study (n = 63) were analyzed by DCE and subtraction enhancement analysis (SEA) to quantify BBB permeability in affected dogs relative to control dogs (n = 6 in each arm). For the SEA method, 2 ranges of postcontrast intensity differences, that is, high (HR) and low (LR), were evaluated as possible representations of 2 classes of BBB leakage. BBB score was calculated for each dog and was associated with clinical characteristics and tumor location and class. Permeability maps were generated, using the slope values (DCE) or intensity difference (SEA) of each voxel, and analyzed. Results Distinctive patterns and distributions of BBBD were identified for intra- and extra-axial tumors. At a cutoff of 0.1, LR/HR BBB score ratio yielded a sensitivity of 80% and specificity of 100% in differentiating gliomas from meningiomas. Conclusions and Clinical Importance Blood-brain barrier dysfunction quantification using advanced imaging analyses has the potential to be used for assessment of brain tumor characteristics and behavior and, particularly, to help differentiating gliomas from meningiomas.

Abstract 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.

Background Radiotherapy (RT) is currently considered the treatment of choice for presumed canine intracranial gliomas. However, variable therapeutic responses are described, due to heterogeneous populations and different radiation methods or protocols. Only one study dedicated to intracranial suspected glioma highlighted prognostic criteria. Determination or confirmation of specific clinical and imaging prognostic factors may guide the therapeutic management of these tumours. The objectives were to provide data on long-term clinical outcome (including quality of life, QoL) and to determine specific prognostic factors associated with survival time. We report a single-institution retrospective study, including all dogs with suspected symptomatic primary solitary intracranial glioma, treated with a complete uniform fractionated megavoltage radiation protocol of 15x3Gy over 5 weeks, between January 2013 and February 2019. Thirty-eight client-owned dogs were included. Medical records were retrospectively evaluated for median overall survival time (MST), clinical and imaging responses. Prognostic factors on survival were researched in terms of signalment, clinical presentation, tumour imaging characteristics and response following RT. Finally, the RT’s impact on the dogs’ clinical signs and Qol were evaluated by the owners. Results The disease-specific MST was 698 days (95% CI: 598–1135). Survival at 1 and 2 years were respectively 74.2 ± 7.4% and 49.0 ± 9.8%. Initial clinical signs were related to survival, as well as tumour characteristics such as cystic-pattern, mass effect and Tumour/Brain volume ratio. No significant adverse effect or radiotoxicity was observed. Conclusions RT appears as a safe and effective treatment for canine intracranial gliomas, allowing long-term tumour control, improvement of life’s quality and management of associated clinical signs. The initial clinical signs and MRI characteristics (Tumour/Brain volume ratio, cyst-like lesion and mass effect) may help predict the prognosis.

Abstract 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.

Abstract 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 cm3, 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.

Abstract Background Intracranial neoplasia is relatively common in dogs and stereotactic radiotherapy, surgical debulking, or both, are the most successful treatment approaches. A key component of treatment planning involves delineating tumor margin on magnetic resonance imaging (MRI) examinations. How MRI signal intensity alterations relate to histological tumor margins is unknown. Objectives Directly compare histological brain sections to MRI sequence images and determine which sequence alteration best correlates with tumor margins. Animals Five dogs with glioma, 4 dogs with histiocytic sarcoma, and 3 dogs with meningioma. Methods Retrospective cohort study. Histological brain sections were registered to in vivo MRI scan images obtained within 7 days of necropsy. Margins of signal intensity alterations (T2-weighted, fluid-attenuating inversion recovery [FLAIR], T1-weighted and contrast enhancement) were compared directly to solid tumor and surgical margins identified on histology. Jacquard similarity metrics (JSM) and cross-sectional areas were calculated. Results In glioma cases, margins drawn around T2-weighted hyperintensity were most similar to surgical margins (JSM, 0.66 ± 0.17) when compared to other sequences. In both meningioma (JSM, 0.57 ± 0.21) and histiocytic sarcoma (JSM, 0.75 ± 0.11) margins of contrast enhancement were most similar to surgical margins. Conclusions and Clinical Importance Signal intensities correspond to tumor margins for different tumor types and facilitate surgical and radiation therapy planning using MRI images.

Abstract 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.