R. Timothy Bentley

Vaccination for Invasive Canine Meningioma Induces in Situ Production of Antibodies Capable of Antibody-Dependent Cell-Mediated Cytotoxicity

Malignant and atypical meningiomas are resistant to standard therapies and associated with poor prognosis. Despite progress in the treatment of other tumors with therapeutic vaccines, this approach has not been tested preclinically or clinically in these tumors. Spontaneous canine meningioma is a clinically meaningful but underutilized model for preclinical testing of novel strategies for aggressive human meningioma. We treated 11 meningioma-bearing dogs with surgery and vaccine immunotherapy consisting of autologous tumor cell lysate combined with toll-like receptor ligands. Therapy was well tolerated, and only one dog had tumor growth that required intervention, with a mean follow up of 585 days. IFN-γ-elaborating T cells were detected in the peripheral blood of 2 cases, but vaccine-induced tumor-reactive antibody responses developed in all dogs. Antibody responses were polyclonal, recognizing both intracellular and cell surface antigens, and HSP60 was identified as one common antigen. Tumor-reactive antibodies bound allogeneic canine and human meningiomas, showing common antigens across breed and species. Histologic analysis revealed robust infiltration of antibody-secreting plasma cells into the brain around the tumor in posttreatment compared with pretreatment samples. Tumor-reactive antibodies were capable of inducing antibody-dependent cell-mediated cytotoxicity to autologous and allogeneic tumor cells. These data show the feasibility and immunologic efficacy of vaccine immunotherapy for a large animal model of human meningioma and warrant further development toward human trials.

Magnetic resonance imaging diagnosis of brain tumors in dogs.

A great deal of information is now available regarding the range of magnetic resonance imaging (MRI) features of many primary and secondary brain tumors from dogs. In this review, these canine neoplasms are grouped into meningeal masses, ventricular masses, intra-axial enhancing lesions, intra-axial mildly to non-enhancing lesions, and multifocal lesions. For each of these patterns, the major and sporadic neoplastic differential diagnoses are provided, and guidance on how to rank differential diagnoses for each individual patient is presented. The implication of MRI features such as contrast-enhancement, signal intensities and location is discussed. However, the information garnered from MRI must be correlated with all available clinical information and with epidemiological data before creating a differential diagnosis.

Successful management of an intracranial phaeohyphomycotic fungal granuloma in a dog.

CASE DESCRIPTION A 12-month-old castrated male Boxer was examined because of signs of acute, progressive intracranial disease. CLINICAL FINDINGS Cytologic and histologic findings were consistent with an intracranial fungal granuloma in the right cerebral hemisphere. Fungal culture yielded a Cladophialophora sp. TREATMENT AND OUTCOME The granuloma was surgically debulked to remove infected brain tissue and the avascular purulent core. Postoperatively, the patient was treated with fluconazole (2.3 mg/kg [1 mg/lb], PO, q 12 h) for 4 months, followed by voriconazole (3.4 mg/kg [1.5 mg/lb], PO, q 12 h) for a further 10 months. The outcome was considered excellent on the basis of resolution of neurologic signs and a lack of evidence of recurrence of the granuloma during magnetic resonance imaging and CSF analysis 8 months after surgery. Magnetic resonance imaging and CSF analysis 9 weeks after administration of antifungal medications was discontinued (16 months after surgery) confirmed resolution. CLINICAL RELEVANCE Intracranial phaeohyphomycosis in small animals is rare and is most commonly associated with Cladophialophora infection. Phaeohyphomycosis frequently causes a focal granuloma, whereas other fungal infections typically cause diffuse meningoencephalitis. In all previous reports of phaeohyphomycosis of the CNS in dogs, treatment has been limited to medical management with conventional antifungal drugs and had failed to prevent death. The present report suggested that combined management of granulomas with surgery and newer triazole medications such as voriconazole may represent a novel strategy that improves the prognosis for this disease.

Dogs are man's best friend: in sickness and in health

With the median survival of 14.6 months following best available standard of care, malignant gliomas (MGs) remain one of the biggest therapeutic challenges of the modern time. Although the last several decades have witnessed tremendous advancement in our understanding of MG and evolution of many successful preclinical therapeutic strategies, even the most successful preclinical therapeutic strategies often fail to cross the phase I/II clinical trial threshold. One of the significant, but less commonly discussed, barriers in developing effective glioma therapy is the lack of a robust preclinical model. For the last 30 years, rodent orthotopic xenograft models have been extensively used in the preclinical setting. Although they provide a good basic model for understanding tumor biology, their value in successfully translating preclinical therapeutic triumph into clinical success is extremely poor. Companion dogs, which share the same environmental stress as their human counterparts, also spontaneously develop MGs. Dog gliomas that develop spontaneously in an immunocompetent host are very similar to human gliomas and potentially provide a stronger platform for validating the efficacy of therapeutic strategies proven successful in preclinical mouse models. Integrating this model can accelerate development of effective therapeutic options that will benefit both human subjects and pet dogs.

MAGNETIC RESONANCE IMAGING FEATURES OF INTRACRANIAL GRANULAR CELL TUMORS IN SIX DOGS

Magnetic resonance (MR) imaging characteristics of intracranial granular cell tumors (GCTs) have been previously reported in three dogs. The goal of this retrospective study was to examine a larger number of dogs and determine whether distinctive MR characteristics of intracranial GCTs could be identified. Six dogs with histologically confirmed intracranial GCTs and MR imaging were included. Tumor location, size, mass effect, T1- and T2-weighted signal intensity, and peritumoral edema MR characteristics were recorded. In all dogs, GCTs appeared as well-defined, extra-axial masses with a plaque-form, sessile distribution involving the meninges. All tumors were located along the convexity of the cerebrum, the falx cerebri, or the ventral floor of the cranial vault. All tumors were mildly hyperintense on T1-weighted images, and iso- to hyperintense on T2-weighted images. A moderate-to-severe degree of peritumoral edema and mass effect were evident in all dogs. Findings indicated that, while several MR imaging characteristics were consistently identified in canine cerebral GCTs, none of these characteristics were unique or distinctive for this tumor type alone.

MAGNETIC RESONANCE IMAGING FEATURES AND OUTCOME FOR SOLITARY CENTRAL NERVOUS SYSTEM COCCIDIOIDES GRANULOMAS IN 11 DOGS AND CATS.

Little published information is available to guide therapy for canine and feline patients with Coccidioides infections involving the central nervous system (CNS). The purpose of this cross-sectional retrospective study was to describe magnetic resonance imaging (MRI) features and outcome for a group of dogs and cats with solitary CNS Coccidiodes granulomas. Nine canine and two feline cases met inclusion criteria; four diagnosed and treated with surgery and fluconazole and seven diagnosed by serology or cytology and treated medically. Three cases had left Coccidioides endemic areas long before developing neurological disease. The MRI lesions shared many features with neoplastic masses. The extra-axial granulomas often had a lack of a distinct border between the mass and neural parenchyma. Four cases were extra-axial and seven were intra-axial, but distinguishing between extra-axial and intra-axial locations was sometimes challenging. The surgical cases had good outcomes and histology allowed definitive diagnosis. Medically managed patients also had generally good outcomes, with resolution of clinical signs in most cases. Findings indicated that distinction between neoplasia and focal Coccidioides granulomas based on MRI features is likely to be imprecise. Demonstration of the organism by cytology or histology is required for definitive diagnosis. The role of surgery for improving the outcome of brain or spinal coccidioidomycosis granulomas warrants further study.

A preliminary evaluation of the reliability of a modified functional scoring system for assessing neurologic function in ambulatory thoracolumbar myelopathy dogs

BackgroundThe objective of this study was to develop and assess the reliability of a modified scoring system for evaluating the function of the two pelvic limbs separately, in ambulatory thoracolumbar myelopathy dogs. A previously established neurologic score scale for dogs with T3-L3 lesions was modified in order to provide a separate score for each pelvic limb.ResultsSeventeen ambulatory dogs with thoracolumbar myelopathies were evaluated. Using the new scale, two observers independently performed 22 observational gait analyses (OGAs) in ten dogs without videotape. Another 18 OGAs were performed in seven dogs by watching videotapes of them ambulating. There was poor agreement (concordance correlation coefficient, 0.87) between the two observers for all 40 OGAs. When stratified, the agreement was moderate (concordance correlation coefficient, 0.90) in the OGAs without videotaping and poor (concordance correlation coefficient, 0.80) for the OGAs based on videotapes. For the decision regarding which pelvic limb was more severely affected, a fair agreement (kappa value, 0.30) between the two observers was noted. Without videotape there was only slight agreement (kappa value, 0.05), but with videotape there was moderate agreement (kappa value, 0.56).ConclusionsThe modified scoring system in this study provides moderate reliability in assessing the functional neurologic status of each pelvic limb, by OGA without videotape, in canine T3-L3 patients. Further development of this scoring system is required. However, imperfect agreement when visually quantifying neurological deficits is not unexpected.

Ependymal and periventricular magnetic resonance imaging changes in four dogs with central nervous system blastomycosis.

Rapid detection of central nervous system (CNS) involvement is important for dogs with blastomycosis, as this can affect antifungal drug selection and has been associated with an increased risk of death. Previous reports describing magnetic resonance imaging (MRI) characteristics of canine CNS blastomycosis primarily identified mass lesions. The purpose of this retrospective study was to determine whether other MRI characteristics of CNS blastomycosis may also occur. Medical records of the Purdue University Veterinary Teaching Hospital were searched and four dogs met inclusion criteria. Magnetic resonance imaging characteristics included periventricular edema, periventricular and meningeal contrast enhancement, and ventriculomegaly. Periventricular lesions most commonly involved the rostral horn of the lateral ventricles and the third ventricle. Increased meningeal contrast enhancement involved the cerebrum, thalamus, sella turcica, and brainstem. Findings indicated that, in addition to mass lesions, MRI characteristics of periventricular hyperintensity, contrast enhancement, and ventriculomegaly may also occur in dogs with CNS blastomycosis.

Recurrent vestibular paroxysms associated with systemic hypertension in a dog

CASE DESCRIPTION A 9-year-old 19.7-kg (43.3-lb) spayed female Australian Shepherd was examined for an increase in frequency of episodic neurologic signs, often occurring upon exercise. CLINICAL FINDINGS Between episodes of neurologic signs, the dog was considered clinically normal on the basis of findings on physical and neurologic examinations. An episode of ataxia with central vestibular signs was induced by exercising the patient in the hospital. All clinicopathologic values were within reference ranges, as were findings on magnetic resonance imaging of the brain and peripheral vestibular system. Systolic blood pressures of 180 to 200 mm Hg were recorded, and systemic hypertension was diagnosed. TREATMENT AND OUTCOME While the dog received amlodipine and enalapril, blood pressure returned to within reference range, and episodes of neurologic signs no longer occurred. When clinical signs later recurred, systolic blood pressure was again found to be high. Following an increase in medication dosage, blood pressure normalized, and only 4 further episodes of neurologic signs were observed during a follow-up period totaling 30 months. CLINICAL RELEVANCE Transient ischemic attack is a common diagnosis in humans but has not been described for dogs. In humans, it is defined as focal brain dysfunction caused by vascular disease that resolves completely in less than 24 hours and is often recurrent. Systemic hypertension is one of the most common preexisting conditions. We propose that the dog in the present report had clinical signs and diagnostic test results supportive of a diagnosis of transient ischemic attack.

Peripheral blood biomarkers of solid tumor angiogenesis in dogs: a polychromatic flow cytometry pilot study.

A subset of peripheral blood hematopoietic stem and progenitor cells of bone marrow origin is elevated in humans with solid cancers before treatment and declines with therapy. This biomarker of angiogenesis is not specific to tumor type and has great potential in the objective assessment of treatment response in clinical trials. This pilot study was designed to develop a biomarker of neoangiogenesis in dogs for the diagnosis of cancer, the measurement of treatment response, and the provision of objective data in clinical trials. Polychromatic flow cytometry was used to quantify two subsets of circulating hematopoietic stem and progenitor cells in dogs with spontaneous solid tumors before (n = 8) and after (n = 3) treatment, and normal controls (n = 6). Pro-angiogenic peripheral blood cells of bone marrow origin were detected in all eight cases and the six normal controls; however, there was no statistically significant difference between the two groups. Interestingly, an apparent decline in pro-angiogenic cells was observed after treatment. Bone marrow derived hematopoietic cells appear to contribute to tumor angiogenesis in dogs, as has been previously reported in humans. While the methodology for pro-angiogenic cell quantification in a small number of dogs in the current study did not result in a significant difference from normal controls, an optimized canine polychromatic flow cytometry protocol holds great promise in the development of a canine cancer model and for the objective measurements of treatment response in clinical trials.