Magnetic resonance and computed tomographic imaging characteristics and potential molecular mechanisms of feline meningioma associated calvarial hyperostosis.

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.

Characterizing the Ablative Effects of Histotripsy for Osteosarcoma: In Vivo Study in Dogs.

Osteosarcoma (OS) is a malignant bone tumor treated by limb amputation or limb salvage surgeries and chemotherapy. Histotripsy is a non-thermal, non-invasive focused ultrasound therapy using controlled acoustic cavitation to mechanically disintegrate tissue. Recent ex vivo and in vivo pilot studies have demonstrated the ability of histotripsy for ablating OS but were limited in scope. This study expands on these initial findings to more fully characterize the effects of histotripsy for bone tumors, particularly in tumors with different compositions. A prototype 500 kHz histotripsy system was used to treat ten dogs with suspected OS at an intermediate treatment dose of 1000 pulses per location. One day after histotripsy, treated tumors were resected via limb amputation, and radiologic and histopathologic analyses were conducted to determine the effects of histotripsy for each patient. The results of this study demonstrated that histotripsy ablation is safe and feasible in canine patients with spontaneous OS, while offering new insights into the characteristics of the achieved ablation zone. More extensive tissue destruction was observed after histotripsy compared to that in previous reports, and radiographic changes in tumor size and contrast uptake following histotripsy were reported for the first time. Overall, this study significantly expands our understanding of histotripsy bone tumor ablation and informs future studies for this application.

Mechanical High-Intensity Focused Ultrasound (Histotripsy) in Dogs With Spontaneously Occurring Soft Tissue Sarcomas.

INTRODUCTION: Histotripsy is a non-invasive focused ultrasound therapy that uses controlled acoustic cavitation to mechanically disintegrate tissue. To date, there are no reports investigating histotripsy for the treatment of soft tissue sarcoma (STS). OBJECTIVE: This study aimed to investigate the in vivo feasibility of ablating STS with histotripsy and to characterize the impact of partial histotripsy ablation on the acute immunologic response in canine patients with spontaneous STS. METHODS: A custom 500 kHz histotripsy system was used to treat ten dogs with naturally occurring STS. Four to six days after histotripsy, tumors were surgically resected. Safety was determined by monitoring vital signs during treatment and post-treatment physical examinations, routine lab work, and owners' reports. Ablation was characterized using radiologic and histopathologic analyses. Systemic immunological impact was evaluated by measuring changes in cytokine concentrations, and tumor microenvironment changes were evaluated by characterizing changes in infiltration with tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) using multiplex immunohistochemistry and differential gene expression. RESULTS: Results showed histotripsy ablation was achievable and well-tolerated in all ten dogs. Immunological results showed histotripsy induced pro-inflammatory changes in the tumor microenvironment. Conclusion & Significance: Overall, this study demonstrates histotripsy's potential as a precise, non-invasive treatment for STS.

Non-coagulopathic hemothorax in a dog: A case report.

An 8-year-old, female-spayed, Blue Heeler presented with suspected non-coagulopathic spontaneous, hemothorax with neoplasia as the most likely differential as coagulation parameters were normal and no obvious history of trauma was reported. Computed tomography scan was crucial for diagnosis of a traumatic partial vascular avulsion injury that was successfully managed supportively.

Histotripsy Ablation of Spontaneously Occurring Canine Bone Tumors In Vivo.

OBJECTIVE: Osteosarcoma (OS) is a devastating primary bone tumor in dogs and humans with limited non-surgical treatment options. As the first completely non-invasive and non-thermal ablation technique, histotripsy has the potential to significantly improve the standard of care for patients with primary bone tumors. INTRODUCTION: Standard of care treatment for primary appendicular OS involves surgical resection via either limb amputation or limb-salvage surgery for suitable candidates. Biological similarities between canine and human OS make the dog an informative comparative oncology research model to advance treatment options for primary OS. Evaluating histotripsy for ablating spontaneous canine primary OS will build a foundation upon which histotripsy can be translated clinically into a standard of care therapy for canine and human OS. METHODS: Five dogs with suspected spontaneous OS were treated with a 500 kHz histotripsy system guided by real-time ultrasound image guidance. Spherical ablation volumes within each tumor (1.25-3 cm in diameter) were treated with single cycle histotripsy pulses applied at a pulse repetition frequency of 500 Hz and a dose of 500 pulses/point. RESULTS: Tumor ablation was successfully identified grossly and histologically within the targeted treatment regions of all subjects. Histotripsy treatments were well-tolerated amongst all patients with no significant clinical adverse effects. Conclusion & Significance: Histotripsy safely and effectively ablated the targeted treatment volumes in all subjects, demonstrating its potential to serve as a non-invasive treatment modality for primary bone tumors.

Evaluation of a procaspase-3 activator with hydroxyurea or temozolomide against high-grade meningioma in cell culture and canine cancer patients.

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.

Feasibility of targeting canine soft tissue sarcoma with MR-guided high-intensity focused ultrasound.

PURPOSE: Magnetic resonance imaging-guided high-intensity-focused ultrasound (MR-HIFU) is a non-invasive treatment modality that precisely focuses ultrasound energy within a tumour and can be customised to result in a wide range of local bioeffects. The purpose of this study was to determine the feasibility of using MR-HIFU to treat soft tissue sarcoma (STS) in dogs. MATERIALS AND METHODS: Medical records of dogs admitted to the Virginia-Maryland College of Veterinary Medicine from 1 January 2012 to 31 December 2016 were searched for a diagnosis of sarcoma with available cross-sectional imaging of the tumour (MRI or CT). Fifty-three (53) dogs were eligible for inclusion. Tumor tissue (in bone as well as in soft tissue) was considered targetable unless: (1) the ultrasound path was completely obstructed by bone or gas and (2) the MR-HIFU target was within the spinal cord or less than 1 cm from the margin of the spinal cord. Tumors were categorised as <50% targetable, ≥50% targetable or non-targetable. RESULTS: Eighty-one percent of STS (81.1%, 43/53) were targetable. The head/spine tumour sites had the highest proportion of non-targetable tumours (36%, 9/25). The majority of truncal and axillary tumours were ≥50% targetable (88.9%, 16/18) ,and all extremity tumours were considered ≥50% targetable (100%, 5/5). CONCLUSIONS: The majority of STS were targetable. This is the first study to evaluate MR-HIFU targetability of canine STS. HIFU has potential as a therapeutic modality for treating STS in dogs, and this veterinary application is a possible model for treatment of naturally occurring STS in humans.

Investigation of a novel variable dosing protocol for radioiodine treatment of feline hyperthyroidism.

BACKGROUND: Radioiodine is the treatment of choice for hyperthyroidism in cats. The ideal method of dose determination of radioiodine remains controversial. OBJECTIVE: To compare a method of radioiodine dose determination that utilized thyroid scintigraphy with a standard fixed dose for treatment of hyperthyroidism. ANIMALS: Fifty-seven and 23 client-owned hyperthyroid cats in the variable and fixed dose groups, respectively. METHODS: Cats with a percent dose uptake using 99m Tc-pertechnetate uptake on thyroid scintigraphy <5%, 5%-10%, and >10% were to receive 3, 3.5, or 4.5 millicuries (mCi) of radioiodine, respectively, administered SC. Radioiodine dose was adjusted according to thyroid gland size as determined by the thyroid:salivary size ratio and categorized as <5:1, 5-10:1, and >10:1. If the thyroid size fell into a higher dosing category than the percent dose uptake, the dose was increased accordingly. Cats in the fixed dose group received 4.5 mCi. Six months after treatment, cats were determined to be euthyroid, hypothyroid, or hyperthyroid based on serum thyroxine and thyroid stimulating hormone concentrations. RESULTS: No difference in outcome was found between the variable and fixed dose treatment groups. Euthyroidism, hypothyroidism, and persistent hyperthyroidism developed in 61, 30, and 9% of cats in the fixed dose group compared to 58, 26, and 16%, respectively, in the variable dose group. CONCLUSIONS: A variable dosing method of radioiodine based on percent dose uptake primarily and thyroid gland size secondarily did not improve outcome compared to a standard fixed dose method.

Thyrotoxicosis induced by excessive 3,5,3'-triiodothyronine in a dog.

CASE DESCRIPTION A 7-year-old castrated male Havanese was evaluated at a veterinary teaching hospital because of a 12-week history of hyperactivity, aggression, and progressive weight loss despite a healthy appetite. CLINICAL FINDINGS Tachycardia was the only remarkable finding during physical examination. Serum 3,5,3'-triiodothyronine (T3) and free T3 concentrations were markedly increased, and thyroxine (T4), free T4, and thyroid-stimulating hormone concentrations were at or decreased from the respective reference ranges. Thyroid scintigraphy revealed suppressed uptake of sodium pertechnetate Tc 99m by the thyroid gland but no ectopic thyroid tissue, which was indicative of thyrotoxicosis induced by an exogenous source of T3. TREATMENT AND OUTCOME The dog was hospitalized for 24 hours, and its diet was changed, after which the clinical signs rapidly resolved and serum T3 and free T3 concentrations returned to within the respective reference ranges. This raised suspicion of an exogenous source of T3 in the dog's home environment. Analysis of the commercial beef-based canned food the dog was being fed revealed a high concentration of T3 (1.39 µg/g) and an iodine (82.44 µg/g) concentration that exceeded industry recommendations. No other source of T3 was identified in the dog's environment. CLINICAL RELEVANCE To our knowledge, this is the first report of clinical thyrotoxicosis in a dog induced by exogenous T3, although the source of exogenous T3 was not identified. This case highlights the importance of measuring serum T3 and thyroid-stimulating hormone concentrations in addition to T4 and free T4 concentrations when there is incongruity between clinical findings and thyroid function test results.

EVALUATION OF THYROID TO BACKGROUND RATIOS AND COMPARISON OF VARIOUS SCINTIGRAPHIC MEASUREMENTS AND THEIR CORRELATION TO SERUM T4 IN HYPERTHYROID CATS.

Thyroid-to-salivary ratio and percent dose uptake are the most widely recognized scintigraphic measurements. Recently, the thyroid-to-background ratio has been proposed as an alternate method. However, this method has not been validated. The purpose of this observational, cross-sectional, prospective study was to determine the location of a background region of interest (ROI) that is most reflective of blood pool activity. We also hypothesized that the thyroid-to-background ratio using this background ROI would be a better predictor of thyroid function. Fifty-six cats presented to the Virginia-Maryland College of Veterinary Medicine seeking radioiodine therapy for hyperthyroidism were enrolled in this cross-sectional study to evaluating thyroid-to-background ratio. A blood sample for measuring plasma radioactivity was collected at the time of scintigraphy. The plasma radioactivity was compared to the background ROIs in eight anatomic regions. Scintigraphic measures of thyroid-to-background and thyroid-to-salivary ratios, and percent dose were then compared to serum T4 . The heart ROI was most closely correlated with plasma pertechnetate activity (r = 0.70). Percent dose uptake was most closely correlated with serum T4 (r = 0.74), followed by thyroid-to-salivary ratio (r = 0.66) and thyroid-to-background ratio using the heart ROI (r = 0.59). Thyroid-to-background ratio using the heart background ROI is a good predictor T4 but percent dose uptake and thyroid-to-salivary ratio proved to be better predictors of T4 than any of the thyroid-to-background ratios.

Invited review--neuroimaging response assessment criteria for brain tumors in veterinary patients.

The evaluation of therapeutic response using cross-sectional imaging techniques, particularly gadolinium-enhanced MRI, is an integral part of the clinical management of brain tumors in veterinary patients. Spontaneous canine brain tumors are increasingly recognized and utilized as a translational model for the study of human brain tumors. However, no standardized neuroimaging response assessment criteria have been formulated for use in veterinary clinical trials. Previous studies have found that the pathophysiologic features inherent to brain tumors and the surrounding brain complicate the use of the response evaluation criteria in solid tumors (RECIST) assessment system. Objectives of this review are to describe strengths and limitations of published imaging-based brain tumor response criteria and propose a system for use in veterinary patients. The widely used human Macdonald and response assessment in neuro-oncology (RANO) criteria are reviewed and described as to how they can be applied to veterinary brain tumors. Discussion points will include current challenges associated with the interpretation of brain tumor therapeutic responses such as imaging pseudophenomena and treatment-induced necrosis, and how advancements in perfusion imaging, positron emission tomography, and magnetic resonance spectroscopy have shown promise in differentiating tumor progression from therapy-induced changes. Finally, although objective endpoints such as MR imaging and survival estimates will likely continue to comprise the foundations for outcome measures in veterinary brain tumor clinical trials, we propose that in order to provide a more relevant therapeutic response metric for veterinary patients, composite response systems should be formulated and validated that combine imaging and clinical assessment criteria.

Thyroid scintigraphy in veterinary medicine.

Thyroid scintigraphy is performed in cats and dogs and has been used to a limited degree in other species such as the horse. Thyroid scintigraphy is most commonly used to aid in the diagnosis and treatment management of feline hyperthyroidism but is also used in the evaluation of canine hypothyroidism and canine thyroid carcinoma. This article reviews the normal scintigraphic appearance of the thyroid in the cat, the dog, and the horse and the principles of interpretation of abnormal scan results in the cat and the dog. Radioiodine is the treatment of choice for feline hyperthyroidism, and the principles of its use in the cat are reviewed.

Renal scintigraphy in veterinary medicine.

Renal scintigraphy is performed commonly in dogs and cats and has been used in a variety of other species. In a 2012 survey of the members of the Society of Veterinary Nuclear Medicine, 95% of the respondents indicated they perform renal scintigraphy in their practice. Renal scintigraphy is primarily used to assess renal function and to evaluate postrenal obstruction. This article reviews how renal scintigraphy is used in veterinary medicine and describes the methods of analysis. Species variation is also discussed.

Estimation of feline renal volume using computed tomography and ultrasound.

Renal volume estimation is an important parameter for clinical evaluation of kidneys and research applications. A time efficient, repeatable, and accurate method for volume estimation is required. The purpose of this study was to describe the accuracy of ultrasound and computed tomography (CT) for estimating feline renal volume. Standardized ultrasound and CT scans were acquired for kidneys of 12 cadaver cats, in situ. Ultrasound and CT multiplanar reconstructions were used to record renal length measurements that were then used to calculate volume using the prolate ellipsoid formula for volume estimation. In addition, CT studies were reconstructed at 1 mm, 5 mm, and 1 cm, and transferred to a workstation where the renal volume was calculated using the voxel count method (hand drawn regions of interest). The reference standard kidney volume was then determined ex vivo using water displacement with the Archimedes' principle. Ultrasound measurement of renal length accounted for approximately 87% of the variability in renal volume for the study population. The prolate ellipsoid formula exhibited proportional bias and underestimated renal volume by a median of 18.9%. Computed tomography volume estimates using the voxel count method with hand-traced regions of interest provided the most accurate results, with increasing accuracy for smaller voxel sizes in grossly normal kidneys (-10.1 to 0.6%). Findings from this study supported the use of CT and the voxel count method for estimating feline renal volume in future clinical and research studies.

Comparison of four ventilatory protocols for computed tomography of the thorax in healthy cats.

OBJECTIVE: To identify ventilatory protocols that yielded good image quality for thoracic CT and hemodynamic stability in cats. Animals-7 healthy cats. PROCEDURES: Cats were anesthetized and ventilated via 4 randomized protocols (hyperventilation, 20 seconds [protocol 1]; single deep inspiration, positive inspiratory pressure of 15 cm H(2)O [protocol 2]; recruitment maneuver [protocol 3]; and hyperventilation, 20 seconds with a positive end-expiratory pressure of 5 cm H(2)O [protocol 4]). Thoracic CT was performed for each protocol; images were acquired during apnea for protocols 1 and 3 and during positive airway pressure for protocols 2 and 4. Heart rate; systolic, mean, and diastolic arterial blood pressures; blood gas values; end-tidal isoflurane concentration; rectal temperature; and measures of atelectasis, total lung volume (TLV), and lung density were determined before and after each protocol. RESULTS: None of the protocols eliminated atelectasis; the number of lung lobes with atelectasis was significantly greater during protocol 1 than during the other protocols. Lung density and TLV differed significantly among protocols, except between protocols 1 and 3. Protocol 2 TLV exceeded reference values. Arterial blood pressure after each protocol was lower than before the protocols. Mean and diastolic arterial blood pressure were higher after protocol 3 and diastolic arterial blood pressure was higher after protocol 4 than after protocol 2. CONCLUSIONS AND CLINICAL RELEVANCE: Standardization of ventilatory protocols may minimize effects on thoracic CT images and hemodynamic variables. Although atelectasis was still present, ventilatory protocols 3 and 4 provided the best compromise between image quality and hemodynamic stability.

Static and dynamic (18) FDG-PET in normal hispaniolan Amazon parrots (Amazona ventralis).

Positron emission tomography (PET) is often used to stage and monitor human cancer and has recently been used in a similar fashion in veterinary medicine. The most commonly used radiopharmaceutical is 2-Deoxy-2-[(18) F]-Fluoro-d-glucose ((18) F-FDG), which is concentrated and trapped within cells that use glucose as their energy substrate. We characterized the normal distribution of (18) F-FDG in 10 healthy Hispaniolan Amazon parrots (Amazona ventralis) by performing whole body PET scans at steady state, 60min after injection. Significant variability was found in the intestinal activity. Avian species are known to reflux fluid and electrolytes from their cloaca into their colon. To evaluate reflux as the cause of variability in intestinal distribution of (18) F-FDG, dynamic PET scans were performed on the coelomic cavity of six Hispaniolan Amazon parrots from time 0 to 60min postinjection of radiotracer. Reflux of radioactive material from the cloaca into the colon occurred in all birds to varying degrees and occurred before 60min. To evaluate the intestinal tract of clinical avian patients, dynamic scans must be performed starting immediately after injection so that increased radioactivity due to metabolism or hypermetabolic lesions such as cancer can be differentiated from increased radioactivity due to reflux of fluid from the cloaca.

Sensitivity of low-field T2 images for detecting the presence and severity of histopathologic meniscal lesions in dogs.

The sensitivity of low-field magnetic resonance (MR) T2 images for predicting the presence of meniscal lesions was determined in 12 dogs with naturally-occurring cranial cruciate ligament rupture and three control dogs, using histopathology as the reference standard. Previously published grading systems were used to grade the severity of meniscal lesions on MR images, gross inspection and histopathology. Focal areas of increased signal intensity were detected in 11/12 symptomatic dogs and 3/3 control dogs. Lesions mimicking meniscal tears (pseudotears) were identified at junctions between meniscal margins and adjacent connective tissue in control dogs and dogs with naturally occurring disease. Histopathologic lesions were present in all menisci of both symptomatic and control dogs, including the menisci from two affected dogs that appeared grossly normal but were removed and submitted based on MR imaging findings. Histopathologic lesions identified included hyaline cartilage metaplasia and changes in the amount of ground substance and cellularity. The sensitivity of MR imaging for detecting the presence of meniscal histopathologic lesions was 90% in symptomatic dogs and 91% in control dogs. However, agreement between severity scores for the different tests was poor. Low-field MR imaging is a sensitive test for predicting the presence but not severity of meniscal histopathologic lesions in dogs with naturally-occurring cranial cruciate ligament rupture. Findings also supported previous studies indicating that histopathologic lesions can be present in dogs with grossly normal menisci. An improved grading system for comparing MR images and histopathologic severity of meniscal lesions in dogs is needed.

Estimated operator exposure for hand holding portable X-ray units during imaging of the equine distal extremity.

Hand holding of portable X-ray units is common in large animal ambulatory veterinary practice. Portable X-ray equipment manuals, veterinary teaching institutions, and state regulations discourage, or prohibit, hand holding of portable X-ray units. Our goal was to quantify surface radiation leakage of a typical portable X-ray unit and to measure operator exposure at simulated hand and collar positions during imaging of the equine distal extremity. Each exposure for the study was performed at 80 kVp and 7.5 mAs and repeated 10 times. Measurement of tube radiation leakage was performed along each surface of the portable X-ray unit. To determine the operator exposure more accurately, an equine cadaver limb was used to generate scatter radiation for the following views: lateral carpus, lateral foot, palmaroproximal-palmarodistal, and dorsal 60° proximal-palmarodistal obliques of the navicular region. A Pancake Ion Chamber was placed at the handle and at simulated collar position to record estimated occupational exposure. To estimate the effect of lead shielding, exposure measurements were performed within the primary beam and behind a 0.5 mm lead equivalent apron and within an >0.5 mm lead equivalent glove. The average hand and collar dose was 0.471 and 0.327 mR/exposure, respectively. The lead apron and glove attenuated the primary beam 96.9 and 99.2%, respectively. This reduced average hand and collar exposures to 0.0038 and 0.0101 mR/exposure, respectively. Theoretical occupational limits are reached for the collar (whole body) before the hand (extremity).

Determination of an oral aflatoxin dose that acutely impairs hepatic function in domestic pigeons (Columba livia).

Aflatoxin B1 is a common hepatotoxin in birds. The goal of this study was to establish an acute model for hepatotoxicosis and decreased hepatic function in the white Carneaux pigeon (Columba livia) via oral administration of this mycotoxin. Aflatoxin B1 was orally administered at a dose of 3 mg/kg dissolved in dimethyl sulfoxide to 3 groups of pigeons every 24 hours for 2, 4, and 6 consecutive days, respectively. Diagnostic modalities used to evaluate hepatic damage and impaired hepatic function pre- and postaflatoxin administration included liver enzyme activity, bile acid levels, scintigraphy, and histopathologic evaluation of liver biopsy specimens. Deaths occurred in all groups, increasing with the number of consecutive days the aflatoxin B1 was dosed. Significant histopathologic lesions were seen on evaluation of hepatic tissue from each group after accumulated aflatoxin exposure (P < .05); therefore, an oral aflatoxin B1 dose of 3 mg/kg given for 2 consecutive days was selected for the purpose of inducing acute hepatic damage while minimizing mortality. However, although increased liver enzyme activity indicated hepatocellular damage at this dosage, bile acids testing and hepatobiliary scintigraphy did not show significantly decreased hepatic function.