DOSIMETRIC IMPACT OF DAILY SETUP VARIATIONS DURING TREATMENT OF CANINE NASAL TUMORS USING INTENSITY-MODULATED RADIATION THERAPY

Intensity-modulated radiation therapy (IMRT) can be employed to yield precise dose distributions that tightly conform to targets and reduce high doses to normal structures by generating steep dose gradients. Because of these sharp gradients, daily setup variations may have an adverse effect on clinical outcome such that an adjacent normal structure may be overdosed and/or the target may be underdosed. This study provides a detailed analysis of the impact of daily setup variations on optimized IMRT canine nasal tumor treatment plans when variations are not accounted for due to the lack of image guidance. Setup histories of ten patients with nasal tumors previously treated using helical tomotherapy were replanned retrospectively to study the impact of daily setup variations on IMRT dose distributions. Daily setup shifts were applied to IMRT plans on a fraction-by-fraction basis. Using mattress immobilization and laser alignment, mean setup error magnitude in any single dimension was at least 2.5 mm (0–10.0 mm). With inclusions of all three translational coordinates, mean composite offset vector was 5.9±3.3 mm. Due to variations, a loss of equivalent uniform dose for target volumes of up to 5.6% was noted which corresponded to a potential loss in tumor control probability of 39.5%. Overdosing of eyes and brain was noted by increases in mean normalized total dose and highest normalized dose given to 2% of the volume. Findings suggest that successful implementation of canine nasal IMRT requires daily image guidance to ensure accurate delivery of precise IMRT distributions when non-rigid immobilization techniques are utilized. Unrecognized geographical misses may result in tumor recurrence and/or radiation toxicities to the eyes and brain.     

ASSESSMENT OF A RADIOTHERAPY PATIENT CRANIAL IMMOBILIZATION DEVICE USING DAILY ON-BOARD KILOVOLTAGE IMAGING

The purpose of this study was to utilize state-of-the-art on-board digital kilovoltage (kV) imaging to determine the systematic and random set-up errors of an immobilization device designed for canine and feline cranial radiotherapy treatments. The immobilization device is comprised of a custom made support bridge, bite block, vacuum-based foam mold and a modified thermoplastic mask attached to a commercially available head rest designed for human radiotherapy treatments. The immobilization device was indexed to a Varian exact couch-top designed for image guided radiation therapy (IGRT). Daily orthogonal kV images were compared to Eclipse treatment planning digitally reconstructed radiographs (DRRs). The orthogonal kV images and DRRs were directly compared online utilizing the Varian on-board imaging (OBI) system with set-up corrections immediately and remotely transferred to the treatment couch prior to treatment delivery. Off-line review of 124 patient treatments indicates systematic errors consisting of +0.18 mm vertical, +0.39 mm longitudinal and −0.08 mm lateral. The random errors corresponding to 2 standard deviations (95% CI) consist of 4.02 mm vertical, 2.97 mm longitudinal and 2.53 mm lateral and represent conservative CTV to PTV margins if kV OBI is not available. Use of daily kV OBI along with the cranial immobilization device permits reduction of the CTV to PTV margins to approximately 2.0 mm.     

ASSESSMENT OF A RADIOTHERAPY PATIENT IMMOBILIZATION DEVICE USING SINGLE PLANE PORT RADIOGRAPHS AND A REMOTE COMPUTED TOMOGRAPHY SCANNER

Radiation treatment requires a precise procedure for interfraction repositioning of the patient. The purpose of this study was to determine the accuracy of our fixation device in treatment position and to evaluate the setup accuracy with two different methods. The positioning data of 19 canine patients with tumors in the head region (oral, nasal, cerebral) treated with photon or proton irradiation were included in this study. The patients were immobilized by means of an individualized fixation device. Focus was set upon interfraction displacement with systematic and random components. In one method, treatment position was evaluated using single plane port radiographs and megavoltage x-rays. In the other method, two orthogonal CT-topograms were acquired to evaluate the precision of positioning of the patient in the immobilization device. Systematic and random displacements were calculated and presented as mean values with corresponding 95% confidence intervals. In spite of a difference between both methods, the positioning seemed to be accurate within the expected range. It seems that a safety margin of 3.7 mm would be enough for both methods to take into account systematic and random position variability in the fixation device, thereby preventing geometric inaccuracies of treatment delivery. The reported immobilization protocol provides accurate patient immobilization for photon and conformal proton radiation therapy.     

VALIDATION OF NEW BITE BLOCK‐TYPE HEAD‐IMMOBILIZATION DEVICES FOR RADIOTHERAPY IN DOGS

An ideal head‐immobilization method provides a high level of accuracy and reproducibility in the immobilization. Various head‐immobilization methods for radiotherapy have been published and are excellent in terms of accuracy; however, these methods are complicated to use, and labor intensive. The present study describes two new bite block‐type head‐immobilization devices designed for higher stability and lower vertical variation. The device designed in our previous study (the bite block‐type head‐immobilization device; Device A) was modified by making a groove on the top the horizontal plate (Device B) for a stable ventral‐dorsal position, or beneath the horizontal plate (Device C) for a stable dorsal‐ventral position. The three devices were objectively compared with respect to setup time, and accuracy of the computed tomography scan images by two authors independently. Five male healthy beagles were used in this study. For each device, the setup time and the variation in the coordinates were measured five times for each dog. The mean setup times for Devices A, B, and C were 3.3, 1.5, and 2.4 min, respectively, showing the groove modifications were able to reduce the setup time (in device B, by at least 50%). Moreover, three‐dimensional analysis of the computed tomography images revealed that the measurement variability of Device A (1.6 ± 1.0 mm) was significantly higher than that of Device C (0.7 ± 0.4 mm; P < 0.001). Collectively, our results show that use of a bite block‐type head‐immobilization device with a groove improves the setup time and head‐immobilization accuracy.     

Residual setup error in the canine intracranial region after megavoltage,kilovoltage, or cone‐beam computed tomographic image guidance for radiation therapy

Sources of residual setup error after image guidance include image localization accuracy, errors associated with image registration, and inability of some treatment couches to correct submillimeter translational errors and/or pitch and roll errors. The purpose of this experimental study was to measure setup error after image‐guided correction of the canine intracranial region, using a four degrees‐of‐freedom couch capable of 1 mm translational moves. Six cadaver dogs were positioned 45 times as for clinical treatment using a vacuum deformable body cushion, a customizable head cushion, a thermoplastic mask and an indexed maxillary plate with a dental mould. The location of five fiducial markers in the skull bones was compared between the reference position and after megavoltage (MV), kilovoltage (kV) and cone‐beam computed tomography (CBCT)‐guided correction using orthogonal kV images. The mean three‐dimensional distance vectors (3DDV) after MV, kV and CBCT‐guided correction were 1.7, 1.5 and 2.2 mm, respectively. All values were significantly different (P < .01). The 95th percentiles of the 3DDV after online MV, kV and CBCT‐guided correction were 2.8, 2.6 and 3.6 mm, respectively. Residual setup error in the clinical scenario examined was on the order of millimetres and should be considered when choosing PTV margins for image‐guided radiation therapy of the canine intracranial region.     

Bias—Is it a problem,and what should we do?

Observational studies are prone to two types of errors: random and systematic. Random error arises as a result of variation between samples that might be drawn in a study and can be reduced by increasing the sample size. Systematic error arises from problems with the study design or the methods used to obtain the study data and is not influenced by sample size. Over the last 20 years, veterinary epidemiologists have made great progress in dealing more effectively with random error (particularly through the use of multilevel models) but paid relatively little attention to systematic error. Systematic errors can arise from unmeasured confounders, selection bias and information bias. Unmeasured confounders include both factors which are known to be confounders but which were not measured in a study and factors which are not known to be confounders. Confounders can bias results toward or away from the null. The impact of selection bias can also be difficult to predict and can be negligible or large. Although the direction of information bias is generally toward the null, this cannot be guaranteed and its impact might be very large. Methods of dealing with systematic errors include: qualitative assessment, quantitative bias analysis and incorporation of bias parameters into the statistical analyses.     

OUTCOMES AND PROGNOSTIC FACTORS ASSOCIATED WITH CANINE SINONASAL TUMORS TREATED WITH CURATIVE INTENT CONE‐BASED STEREOTACTIC RADIOSURGERY (1999–2013)

Stereotactic radiosurgery (SRS) is a relatively new therapeutic option in veterinary oncology. The role of this modality has not been extensively evaluated for the use in canine nasal tumors. The objective of this retrospective, observational study was to describe the clinical outcome and prognostic factors associated with survival times in a sample of canine patients treated with SRS for sinonasal tumors. Fifty‐seven dogs with sinonasal tumors met inclusion criteria. Histologic diagnoses included sarcoma (SA) (n = 9), carcinoma (CA) (n = 40), osteosarcoma (OSA) (n = 7), and round cell (n = 1). Four of 57 cases were treated twice with SRS. For these, the median and mean doses delivered were 30Gy and 33Gy, respectively (range 18.75Gy–56Gy). Late effects occurred in 23 cases and ranged from grades I–III. The median overall survival time was 8.5 months. The median overall survival times in dogs with tumor type of CA, SA, and OSA were 10.4, 10.7, and 3.1 months, respectively. Dogs with the tumor type of OSA had shorter overall survival time than that in dogs with tumor type of CA and SA. Findings from this retrospective study indicated that SRS may be beneficial for canine patients with sinonasal tumors, however a controlled clinical trial would be needed to confirm this. Prospective studies are also needed to better define the role of SRS as palliative or curative, and to further investigate the risk of clinically significant toxicity.     

Volumetric tumor response assessment is inefficient without overt clinical benefit compared to conventional,manual veterinary response assessment in canine nasal tumors

Accurate assessment of tumor response to therapy is critical in guiding management of veterinary oncology patients and is most commonly performed using response evaluation criteria in solid tumors criteria. This process can be time consuming and have high intra‐ and interobserver variability. The primary aim of this serial measurements, secondary analysis study was to compare manual linear tumor response assessment to semi‐automated, contoured response assessment in canine nasal tumors. The secondary objective was to determine if tumor measurements or clinical characteristics, such as stage, would correlate to progression‐free interval. Three investigators evaluated paired CT scans of skulls of 22 dogs with nasal tumors obtained prior to and following radiation therapy. The automatically generated tumor volumes were not useful for canine nasal tumors in this study, characterized by poor intraobserver agreement between automatically generated contours and hand‐adjusted contours. The radiologist's manual linear method of determining response evaluation criteria in solid tumors categorization and tumor volume is significantly faster (P < .0001) but significantly underestimates nasal tumor volume (P < .05) when compared to a contour‐based method. Interobserver agreement was greater for volume determination using the contour‐based method when compared to response evaluation criteria in solid tumors categorization utilizing the same method. However, response evaluation criteria in solid tumors categorization and percentage volume change were strongly correlated, providing validity to response evaluation criteria in solid tumors as a rapid method of tumor response assessment for canine nasal tumors. No clinical characteristics or tumor measurements were significantly associated with progression‐free interval.     

INVITED REVIEW—IMAGE REGISTRATION IN VETERINARY RADIATION ONCOLOGY: INDICATIONS,IMPLICATIONS, AND FUTURE ADVANCES

The field of veterinary radiation therapy (RT) has gained substantial momentum in recent decades with significant advances in conformal treatment planning, image‐guided radiation therapy (IGRT), and intensity‐modulated (IMRT) techniques. At the root of these advancements lie improvements in tumor imaging, image alignment (registration), target volume delineation, and identification of critical structures. Image registration has been widely used to combine information from multimodality images such as computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) to improve the accuracy of radiation delivery and reliably identify tumor‐bearing areas. Many different techniques have been applied in image registration. This review provides an overview of medical image registration in RT and its applications in veterinary oncology. A summary of the most commonly used approaches in human and veterinary medicine is presented along with their current use in IGRT and adaptive radiation therapy (ART). It is important to realize that registration does not guarantee that target volumes, such as the gross tumor volume (GTV), are correctly identified on the image being registered, as limitations unique to registration algorithms exist. Research involving novel registration frameworks for automatic segmentation of tumor volumes is ongoing and comparative oncology programs offer a unique opportunity to test the efficacy of proposed algorithms.     

Computerized morphometry of mean nuclear diameter and nuclear roundness in canine mammary gland tumors on cytologic smears

BACKGROUND: The use of computer-based image analysis systems in veterinary oncology has increased. Computerized morphometry is a part of image analysis that describes geometric figures of cellular structures in any dimension. Most investigators have performed morphometric analysis on histologic specimens. Computer-assisted nuclear cytomorphometry can provide important preoperative information on neoplastic lesions in animals. OBJECTIVES: The aim of this study was to define whether the morphometric parameters of mean nuclear diameter and nuclear roundness could be used to differentiate benign from malignant canine mammary gland tumors on cytologic specimens. METHODS: Mean nuclear diameter and nuclear roundness were determined by computer-assisted morphometry of epithelial cells in Hemacolor-stained cytologic smears from normal canine mammary gland (n = 7) and from canine mammary adenomas (n = 8), tubulopapillary carcinomas (n = 9), and solid carcinomas (n = 6). Data were analyzed by the Mann-Whitney U test. RESULTS: Significant differences (P <.001) were found in mean nuclear diameter and nuclear roundness among all tumor types and in comparison with normal canine mammary gland epithelial cells (except for nuclear roundness between tubulopapillary carcinomas and solid carcinomas). CONCLUSIONS: The morphometric parameters of mean nuclear diameter and nuclear roundness can be used in the preoperative differentiation of benign from malignant canine mammary gland tumors.     

A VACUUM-FORMABLE MATTRESS FOR VETERINARY RADIOTHERAPY POSITIONING: COMPARISON WITH CONVENTIONAL METHODS

This prospective study was undertaken to compare the positioning repeatability and setup time of a rigid immobilization device (Vac-Lok mattress) to conventional positioning methods (sandbags, tape, foam wedges) in the clinical veterinary radiotherapy setting. Positioning repeatability was determined by using port films to verify appropriate patient positioning. Setup time was determined by recording the time required to set up each patient using each positioning method. Sixty-seven patients receiving radiotherapy were positioned using both the Vac-Lok mattresses and conventional positioning methods during their treatments. Seventy-eight total sites were treated. Forty-eight were treated daily (Monday through Friday, 2 to 4 weeks) and 30 were treated once weekly (4 weeks). Patients were grouped according to the site treated: head (29), neck/body (24), and limb (25). Vac-Lok mattresses were similar to conventional means in positioning repeatability and setup time. Vac-Lok mattresses are potentially advantageous in specific situations, including use during pre-radiotherapy tumor imaging. These mattresses are not recommended for distal limb positioning.     

VALIDATION OF AN INDEXED RADIOTHERAPY HEAD POSITIONING DEVICE FOR USE IN DOGS AND CATS

Setup variability affects the appropriate delivery of radiation and informs the setup margin required to treat radiation patients. Twenty‐four veterinary patients with head and neck cancers were enrolled in this prospective, cross‐sectional study to determine the accuracy of an indexed board immobilization device for positioning. Couch position values were defined at the first treatment based on setup films. At subsequent treatments, patients were moved to the previously defined couch location, orthogonal films were acquired, table position was modified, and displacement was recorded. The mean systematic displacement, random displacement, overall displacement, and mean displacement values of the three‐dimensional (3D) vector were calculated. Three hundred thirty‐two pairs of orthogonal setup films were analyzed for displacement in cranial–caudal, lateral, and dorsal–ventral directions. The mean systematic displacements were 0.5, 0.8, and 0.5 mm, respectively. The mean random displacements were 1.0, 1.1, and 0.7 mm, respectively. The overall displacements were 1.1, 1.4, and 0.9 mm, respectively. The mean 3D vector value was 1.6 mm with a standard deviation of 1.2 mm. Ninety‐five percent of the vectors were <3.6 mm. These values were compared to data obtained with a previously used immobilization device. A t‐test was used to compare the two devices. The 3D vector, random displacement in all directions, and overall displacement in the cranial–caudal and dorsal–ventral directions were significantly smaller than displacements with the previous device. The precision and accuracy of the indexed board device was superior to the historical head and neck device.     

Pullout strength for three suture patterns used for canine tracheal anastomosis

OBJECTIVE: To compare pullout strength of 3 suture patterns used for canine tracheal anastomosis. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Cadaveric canine tracheae (n = 20). METHOD: Tracheal segments were anastomosed with 1 of 3 suture patterns: simple continuous, simple interrupted, and simple interrupted reinforced with horizontal mattress, each encircling annular cartilage rings adjacent to the transection site. Horizontal mattress sutures encircled the annular rings proximal and distal to the rings closest to the anastomosis. Each construct was distracted (0.5 mm/s) in a materials testing machine to failure. Load-displacement curves were generated and failure load (pullout strength) determined and mode of failure recorded. RESULTS: Tracheal anastomosis with a simple interrupted pattern was significantly weaker (mean+/-SD pullout strength, 102.55+/-30.14 N) than simple continuous (135.53+/-15.47 N) or simple interrupted plus horizontal mattress (132.39+/-21.46 N), which were not different from each other. Mode of failure was consistently by suture tear out. CONCLUSIONS: Both simple continuous and simple interrupted reinforced with horizontal mattress suture patterns have significant biomechanical advantage over a simple interrupted pattern alone in canine cadaveric tracheal anastomosis. The simple continuous pattern had the least variability in pullout strength. CLINICAL RELEVANCE: A simple continuous technique should be considered when selecting a tension-relieving pattern for canine tracheal anastomosis. It offers the same biomechanical advantage as a simple interrupted pattern reinforced with a horizontal mattress pattern and its strength appears to be reliably maintained when tested in canine cadaver tracheae.     

Canine sacroiliac luxation: anatomic study of the craniocaudal articular surface angulation of the sacrum to define a safe corridor in the dorsal plane for placement of screws used for fixation in lag fashion

Objective: To define a safe corridor in the dorsal plane relative to the articular surface for placement of a single screw in lag fashion to achieve stabilization of sacroiliac luxation in the dog. Study Design: Cadaveric study. Methods: Dorsoventral radiographs of denuded canine sacra (n=49) were taken to determine the safe corridor in the craniocaudal plane, and the maximum, optimum and minimum angles were calculated that would allow a screw inserted in lag fashion to engage at least 60% of the width of the sacral body without cranial or caudal penetration through the bone. Results: The mean safe corridor in the dorsal plane is ～24° wide. Mean craniocaudal minimum, optimum and maximum drill angles from the drill start point were 88°, 100°, and 111° from the articular surface, respectively. No single angle will completely avoid risk of screw penetration beyond the safe corridor cranially and caudally. Conclusions: There is sufficient anatomic variation between different canine sacra that a single angle cannot be recommended for screw placement in the dorsal plane. Clinical Relevance: A standard angle cannot be recommended for screw placement in lag fashion within the canine sacrum in the dorsal plane. Because of the narrow width of the safe corridor, preoperative measurements on radiographs are recommended and a range of angled drill guides may be useful to decrease surgeon margin of error.     

The Elekta Fraxion™ system is not suitable for maxillary fixation in canine conformal radiation therapy techniques

In this prospective, exploratory study, we evaluated the positioning accuracy in a group of 15 dogs undergoing fractionated stereotactic radiotherapy for tumors affecting the head, using a modified human maxillary fixation device (Elekta Fraxion? system). Positioning was assessed using on‐board volumetric imaging, with a six‐degrees‐of‐freedom image registration technique. Prior to treatment delivery, CBCT images were obtained and patient alignment was corrected, in both translational and rotational planes, using a six‐degrees‐of‐freedom robotic patient positioning system (HexaPOD Evo RT System). The maximum angular inter‐fraction motions observed were 6.1° (yaw), 10.9° (pitch), and 4.5° (roll). The mean systematic translational errors were 4.7, 2.6, and 2.3 mm, mean random translational errors were 3.0, 2.2, and 2.5 mm, and mean overall translational errors were 2.4, 0.7, and 2.3 mm in the cranial‐caudal, lateral, and dorsal‐ventral directions, respectively. The mean systematic rotational errors were 1.17°, 0.77°, and 1.43°, the mean rotational random errors were 1.65°, 1.46°, and 1.34° and the mean overall rotational errors were 0.56°, 0.22°, and 0.29° in the yaw, pitch, and roll directions, respectively. The mean error of the three‐dimensional vector was 6.9 mm with a standard deviation of 3.8 mm. Ninety‐five percent of the three‐dimensional vectors were <14.8 mm. This study demonstrates that this maxillary fixation device relies on six‐degrees‐of‐freedom registration and an ability to apply corrections using a six‐degrees‐of‐freedom couch for accurate patient positioning and tumor targeting. Its use in conformal radiation therapy in dogs is not recommended.     

Influence of surgical margin completeness on risk of local tumour recurrence in canine cutaneous and subcutaneous soft tissue sarcoma: A systematic review and meta‐analysis

The present peer‐reviewed veterinary literature contains conflicting information regarding the impact of surgical margin completeness on risk of local tumour recurrence in canine soft tissue sarcoma (STS). This systematic review and meta‐analysis was designed to answer the clinical question: “Does obtaining microscopically tumour‐free surgical margins reduce risk for local tumour recurrence in canine cutaneous and subcutaneous STS?” A total of 486 citations were screened, 66 of which underwent full‐text evaluation, with 10 studies representing 278 STS excisions ultimately included. Cumulatively, 16/164 (9.8%) of completely excised and 38/114 (33.3%) of incompletely excised STS recurred. Overall relative risk of 0.396 (95% confidence interval = 0.248‐0.632) was calculated for local recurrence in STS excised with complete margins as compared to STS excised with incomplete margins. Risk of bias was judged to be low for all studies in terms of selection bias and detection bias but high for all studies in terms of performance bias and exclusion bias. The results of the present meta‐analysis, coupled with the results of individual previous studies, strongly suggest that microscopically complete surgical margins confer a significantly reduced risk for local tumour recurrence in canine STS. Future studies ideally should adhere to standardized conducting and reporting guidelines to reduce systematic bias.     

Description and validation of a magnetic resonance imaging-guided stereotactic brain biopsy device in the dog

A stereotactic brain biopsy system that is magnetic resonance (MR) imaging-guided has not been validated in dogs. Our purpose was to determine the mean needle placement error in the caudate nucleus, thalamus, and midbrain of a canine cadaver brain using the modified Brainsight stereotactic system. Relocatable reference markers (fiducial markers) were attached to the cadaver head using a dental bite block. A T1-weighted gradient echo three-dimensional (3D) sequence was acquired using set parameters. Fiducial markers were used to register the head to the acquired MR images in reference to a 3D position sensor. This allowed the planning of trajectory path to brain targets in real time. Coordinates (X, Y, Z) were established for each target and 0.5 microl of diluted gadolinium was injected at each target using a 26-gauge needle to create a lesion. The center of the gadolinium deposition was identified on the postoperative MR images and coordinates (X', Y', Z') were established. The precision of this system in bringing the needle to target (needle placement error) was calculated. Seventeen sites were targeted in the brain. The mean needle placement error for all target sites was 1.79 +/- 0.87 mm. The upper bound of error for this stereotactic system was 3.31 mm. There was no statistically significant relationship between needle placement error and target depth (P = 0.23). The ease of use and precision of this stereotactic system support its development for clinical use in dogs with brain lesions > 3.31 mm.     

Variation among pathologists in histologic grading of canine cutaneous mast cell tumors.

Ten veterinary pathologists at 1 veterinary institution independently assigned histologic grades to the same 60 canine cutaneous mast cell tumors (MCTs). There was significant variation among pathologists in grading the MCTs (P < 0.001). The probability of assigning a low grade was significantly higher for the pathologists in this study who use a published reference for histologic grading of canine cutaneous MCTs that allows subcutaneous MCTs or MCTs with mitotic figures to be included in the low-grade category (P < 0.0001 and P < 0.0001, respectively).     

The oncolytic effects of reovirus in canine solid tumor cell lines

Oncolytic virotherapy is a new strategy for cancer treatment for humans and dogs. Reovirus has been proven to be a potent oncolytic virus in human medicine. Our laboratory has previously reported that canine mast cell tumor and canine lymphoma were susceptible to reovirus. In this study, canine solid tumor cell lines (mammary gland tumor, osteosarcoma and malignant melanoma) were tested to determine their susceptibility towards reovirus. We demonstrated that reovirus induces more than 50% cell death in three canine mammary gland tumors and one canine malignant melanoma cell line. The reovirus-induced cell death occurred via the activation of caspase 3. Ras activation has been shown to be one of the important mechanisms of reovirus-susceptibility in human cancers. However, Ras activation was not related to the reovirus-susceptibility in canine solid tumor cell lines, which was similar to reports in canine mast cell tumor and canine lymphoma. The results of this study highly suggest that canine mammary gland tumor and canine malignant melanoma are also potential candidates for reovirus therapy in veterinary oncology.